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CompletedNCT01684215Updated Nov 23, 2020Results posted

A Study Of Oral Palbociclib (PD-0332991), A CDK4/6 Inhibitor, As Single Agent In Japanese Patients With Advanced Solid Tumors Or In Combination With Letrozole For The First-Line Treatment Of Postmenopausal Japanese Patients With ER (+) HER2 (-) Advanced Breast Cancer

A Phase 2 interventional study of PD-0332991 and PD-0332991 in Neoplasms and Breast Neoplasms, sponsored by Pfizer. Completed at 16 sites in Japan. Open to participants aged 20 Years and older. Per ClinicalTrials.gov, last updated 2020-11-23.

Sponsored by Pfizer · Phase 2, Interventional, and Treatment

Phase
Phase 2
Study type
Interventional
Enrollment
61
Allocation
Non-randomized
Ages
20 Years and older
Sex
All
01

Study summary

This study is comprised of two portions: a Phase 1 portion and a Phase 2 portion. The Phase 1 portion is a single-country, non-randomized, open label, clinical trial which will evaluate the safety, tolerability, preliminary efficacy, and PK profile of PD-0332991 as a single agent in Japanese patients with advanced solid tumors, and PD-0332991 in combination with letrozole in the first-line treatment of Japanese patients with ER(+) HER2(-) ABC. The Phase 2 portion is a single-country, non-randomized, open-label, single-cohort, multi-center clinical trial to evaluate the efficacy and safety of PD-0332991 in combination with letrozole for the first-line treatment of postmenopausal Japanese patients with ER(+) HER2(-) ABC.

02

Conditions studied

  • Neoplasms
  • Breast Neoplasms

Keywords

  • Phase 1/2
  • PD-0332991
  • palbociclib
  • Cyclin Dependent Kinase 4/6 inhibitor
  • Japanese
  • solid tumors
  • breast cancer
  • A5481010
03

In context

Breast Neoplasms

12,544 studies on the registry are indexed under Breast Neoplasms; 2,892 are open to participants now.

This study's enrollment of 61 is below the median of 72 across 9,303 interventional studies indexed under Breast Neoplasms.

Browse Breast Neoplasms studies →

Lead sponsor

Pfizer is the lead sponsor of 3,244 studies on the registry; 139 are open to participants now.

Of its 582 completed or terminated interventional studies of FDA-regulated products, 381 (65%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
20 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

Phase 1

  • In Part 1, advanced solid tumor (except SCLC or retinoblastoma) proven histologically or cytologically at original diagnosis, that is refractory to standard therapy or for whom no standard of care therapy is available.
  • In Part 2 and Phase 2, post menopausal women with proven diagnosis of ER-positive, HER2-negative adenocarcinoma of the breast with evidence of locoregionally recurrent or metastatic disease (including bone only disease) not amenable to resection or radiation therapy with curative intent and for whom chemotherapy is not clinically indicated.
  • Adequate blood cell counts, kidney function and liver function and and Eastern Cooperative Oncology Group [ECOG] score of 0 or 1.
  • Resolved acute effects of any prior therapy to baseline severity or Grade ≤1

Phase 2

  • Adult women (≥ 20 years of age) with proven diagnosis of adenocarcinoma of the breast with evidence of locoregionally recurrent or metastatic disease not amenable to resection or radiation therapy with curative intent and for whom chemotherapy is not clinically indicated.
  • Documentation of histologically or cytologically confirmed diagnosis of ER(+) breast cancer based on local laboratory results.
  • Adequate blood cell counts, kidney function and liver function and and Eastern Cooperative Oncology Group [ECOG] score of 0 to 2.

Exclusion criteria

Exclusion Criteria:

Phase 1

  • Active uncontrolled or symptomatic CNS metastases.
  • Uncontrolled infection, unstable or sever intercurrent medical condition, or current drug or alcohol abuse
  • Active or unstable cardiac disease or history of heart attack within 6 months

Phase 2

  • HER2 positive tumor based on local laboratory results utilizing one of the sponsor approved assays.
  • Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease.
  • Prior neoadjuvant or adjuvant treatment with a non steroidal aromatase inhibitor (ie, anastrozole or letrozole) with disease recurrence while on or within 12 months of completing treatment.
05

Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomized
Masking
None (open label)
Enrollment
61 participants (actual)

Study arms

  • Experimental
    Single-agent PD-0332991

    Phase 1 Part 1

    Drug: PD-0332991

  • Experimental
    PD-0332991 in combination with letrozole

    Phase 1 Part 2

    Drug: PD-0332991 · Drug: letrozole

  • Experimental
    PD-0332991 with letrozole

    Phase 2

    Drug: PD-0332991 · Drug: letrozole

Interventions

  • DrugPD-0332991

    PD-0332991 (100 mg or 125 mg) will be orally administered once a day for 3 weeks followed by 1 week off treatment, in the morning on an empty stomach. Dose reduction of PD-0332991 by one (100 mg) or two (75 mg) dose level is permitted depending on treatment related toxicity.

  • DrugPD-0332991

    PD-0332991, 125 mg, will be orally administered with food once a day for 3 weeks followed by 1 week off treatment. PD-0332991 will be administered once a day together with letrozole. Dose reduction of PD-0332991 by one (100 mg) or two (75 mg) dose level is permitted depending on treatment related toxicity.

  • Drugletrozole

    Letrozole, 2.5 mg, will be orally administered once a day in continuous daily dosing together with PD-0332991. Dose reduction of letrozole is not permitted, but dosing interruptions for letrozole-related toxicity are allowed as per investigator's medical judgement.

  • DrugPD-0332991

    PD-0332991, 125 mg, will be orally administered with food once a day for 3 weeks followed by 1 week off treatment. PD-0332991 will be administered once a day together with letrozole. Dose reduction of PD-0332991 by one (100 mg) or two (75 mg) dose level is permitted depending on treatment related toxicity.

  • Drugletrozole

    Letrozole, 2.5 mg, will be orally administered once a day in continuous daily dosing together with PD-0332991. Dose reduction of letrozole is not permitted, but dosing interruptions for letrozole-related toxicity are allowed as per investigator's medical judgement.

06

What researchers measure

Primary outcomes

  1. Number of Participants With Dose Limiting Toxicities (DLT): Part 1 Phase 1

    DLT was classified as per common terminology criteria for adverse events (CTCAE) version 4.0 as any of the events occurring during 28 days of Cycle 1,attributed to study drug:grade 4 neutropenia(for a duration of greater than \[\>\]7 days); febrile neutropenia (grade greater than or equal to \[\>=\]3 neutropenia,body temperature \>=38.5 degree Celsius);grade \>=3 thrombocytopenia with bleeding episode;grade 4 thrombocytopenia;grade \>=3 non-hematologic toxicity except grade 3 or more nausea, vomiting,electrolyte abnormality(if controllable by therapy);grade 3 QTc prolongation(\>500 millisecond \[msec\])persist after correction of reversible cause such as electrolyte abnormalities or hypoxia. Lack of hematologic recovery (platelets less than \[\<\]50,000/microliter \[mcL\],absolute neutrophil count \<1,000/mcL,hemoglobin \<8.0 gram/deciliter \[g/dL\]) or prolonged non hematologic toxicities that delays initiation of next dose by \>7 days;receipt of \<75 percent of planned dose in first cycle due to toxicity.

    Time frame: Lead-in period (Day -7) up to Day 28 (Cycle 1)

  2. Number of Participants With Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs): Part 2 Phase 1

    A treatment related AE is any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event had a causal relationship with the treatment or usage. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Relatedness was judged by investigator. AEs included both serious and non-serious adverse events.

    Time frame: Baseline (Day 1) up to 28 days after last dose of study drug (up to 1673 days)

  3. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) By Severity: Part 2 Phase 1

    AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An AE was considered treatment emergent if occurred for the first time after the start of study treatment or occurred prior to the start of treatment but increased in National Cancer Institute (NCI) CTCAE grade during study treatment period. AE severity was defined to be the maximum toxicity grade of the TEAEs experienced by the participants during the study. AE was assessed according to severity as: Grade 1 (mild AE), Grade 2 (moderate AE), Grade 3 (severe AE), Grade 4 (life-threatening consequences) and Grade 5 (death related to AE).

    Time frame: Baseline (Day 1) up to 28 days after last dose of study drug (up to 1673 days)

  4. Percentage of Participants With 1 Year Progression Free Survival (PFS): Phase 2

    PFS was defined as the time from first dose of study treatment to the date of the first documentation of objective progression of disease (PD) or death due to any cause in the absence of documented PD, whichever occurred first. PD was defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.1-year PFS was defined as the percentage of participants without PFS events (PD or death due to any cause) at 12 months based on the Kaplan-Meier estimate. Percentage of participants with 1-year PFS with 90% confidence interval (CI) were reported.

    Time frame: From initiation of treatment up to 12 months

Secondary outcomes

  1. Number of Participants With Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs): Phase 1 (Part 1) and Phase 2

    A treatment related AE is any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event had a causal relationship with the treatment or usage. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Relatedness was judged by investigator. AEs included both serious and non-serious adverse events.

    Time frame: Part 1 Phase 1: Lead-in period (Day -7) up to 28 days after last dose of study drug (up to 308 days), Phase 2: Baseline (Day 1) up to 28 days after last dose of study drug (up to 1526 days)

  2. Number of Participants With Treatment-Emergent Adverse Events (AEs) By Severity: Phase 1 (Part 1) and Phase 2

    AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An AE was considered treatment emergent if occurred for the first time after the start of study treatment or occurred prior to the start of treatment but increased in NCI CTCAE version 4.0 grade during study treatment period. AE severity was defined to be the maximum toxicity grade of the TEAEs experienced by the participants during the study. AE was assessed according to severity as: Grade 1 (mild AE), Grade 2 (moderate AE), Grade 3 (severe AE), Grade 4 (life-threatening consequences) and Grade 5 (death related to AE).

    Time frame: Part 1 Phase 1: Lead-in period (Day -7) up to 28 days after last dose of study drug (up to 308 days), Phase 2: Baseline (Day 1) up to 28 days after last dose of study drug (up to 1526 days)

  3. Number of Participants With Clinically Significant Laboratory Abnormalities

    Abnormality criteria: hemoglobin: \<0.8\*lower limit of normal \[LLN\], platelets: \<0.5\*LLN or \>1.75\*upper limit of normal \[ULN\], leukocytes: \<0.6\*LLN or \>1.5\*ULN, lymphocytes, total neutrophils: \<0.8\*LLN or \>1.2\*ULN, basophils, eosinophil,monocytes: \>1.2\*ULN); aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma glutamyl transferase (GT): \>0.3\*ULN, total protein, albumin: \<0.8\*LLN or \>1.2\*ULN, total bilirubin, direct bilirubin: \>1.5\*ULN; blood urea nitrogen, creatinine: \>1.3\*ULN, uric acid: \>1.2\*ULN; sodium: \<0.95\*LLN or \>1.05\*ULN, potassium, chloride, calcium, magnesium: \<0.9\*LLN or \>1.1\*ULN, phosphate: \<0.8\*LLN or \>1.2\*ULN; creatine kinase: \>2.0\*ULN, glucose fasting: \<0.6\*LLN or \>1.5\*ULN, glycosylated haemoglobin: \>1.3\*ULN;urinalysis dipstick (urine protein, urine blood \>=1); urine protein 24 hour: \>1.1\*ULN; coagulation Activated partial thromboplastin time \[APTT\], Prothrombin, prothrombin international ratio: \>1.1\*ULN.

    Time frame: Part 1 Phase 1: Lead-in period (Day -7) up to 308 days; Part 2 Phase 1: Baseline (Day 1) up to 1673 days; Phase 2: Baseline (Day 1) up to 1526 days

  4. Area Under the Plasma Concentration Time Curve Over Dosing Interval (AUCtau) of PD-0332991 Following Multiple Dose: Part 1 Phase 1

    AUCtau is area under the plasma concentration-time curve over dosing interval which is calculated by log-linear trapezoidal method.

    Time frame: Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8

  5. AUCtau Dose Normalized to 125 Milligram (mg) of PD-0332991 Following Multiple Dose: Part 1 Phase 1

    AUCtau Dose Normalized to 125 mg is area under the plasma concentration-time curve over dosing interval dose normalized to 125 mg which is calculated by log-linear trapezoidal method.

    Time frame: Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8

  6. Area Under the Plasma Concentration-Time Curve From 0 to Time 24 Hours (AUC24) of PD-0332991 Following Single Dose: Part 1 Phase 1

    AUC24 is area under the plasma concentration-time curve from 0 to time 24 hours which is calculated by log-linear trapezoidal method.

    Time frame: Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12 and 24 hours post-dose in Lead-in period (Day -7)

  7. AUC24 Dose Normalized to 125 mg of PD-0332991 Following Single Dose: Part 1 Phase 1

    AUC24 Dose Normalized to 125 mg is area under the plasma concentration-time curve from 0 to time 24 hours dose normalized to 125 mg which is calculated by log-linear trapezoidal method.

    Time frame: Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12 and 24 hours post-dose in Lead-in period (Day -7)

  8. Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUCinf) of PD-0332991 Following Single Dose: Part 1 Phase 1

    AUCinf is area under the plasma concentration-time curve from 0 to infinity which is calculated by log-linear trapezoidal method.

    Time frame: Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7)

  9. AUCinf Dose Normalized to 125 mg of PD-0332991 Following Single Dose: Part 1 Phase 1

    AUCinf Dose Normalized to 125 mg is area under the plasma concentration-time curve from 0 to infinity dose normalized to 125 mg which is calculated by log-linear trapezoidal method.

    Time frame: Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7)

  10. Area Under the Plasma Concentration-Time Curve From 0 to Time of Last Measurable Concentration (AUClast) of PD-0332991 Following Single Dose: Part 1 Phase 1

    AUClast is area under the plasma concentration-time curve from 0 to time of last measurable concentration which is calculated by log-linear trapezoidal method.

    Time frame: Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7)

  11. AUClast Dose Normalized to 125 mg of PD-0332991 Following Single Dose: Part 1 Phase 1

    AUClast Dose Normalized to 125 mg is area under the plasma concentration-time curve from 0 to time of last measurable concentration dose normalized to 125 mg which is calculated by log-linear trapezoidal method.

    Time frame: Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7)

  12. Apparent Oral Clearance of PD-0332991: Part 1 Phase 1

    Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. It was calculated by dividing the given oral dose by AUCinf. AUCinf is area under the plasma concentration-time curve from 0 to infinity which is calculated by log-linear trapezoidal method.

    Time frame: Single dose: 0 hour (pre-dose),1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7), Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8

  13. Maximum Observed Plasma Concentration (Cmax) Of PD-0332991: Part 1 Phase 1

    Cmax is maximum plasma concentration which is observed directly from the actual time-concentration data.

    Time frame: Single dose: 0 hour (pre-dose),1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7), Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8

  14. Cmax Dose Normalized to 125 mg of PD-0332991: Part 1 Phase 1

    Cmax Dose Normalized to 125 mg is maximum plasma concentration dose normalized to 125 mg which is observed directly from the actual time-concentration data.

    Time frame: Single dose: 0 hour (pre-dose),1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7), Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8

  15. Pre-dose Plasma Concentration (Ctrough) of PD-0332991 Following Multiple Dose: Part 1 Phase 1

    Ctrough is pre-dose concentration during multiple dosing which is observed directly from the actual time-concentration data.

    Time frame: Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8

  16. Accumulation Ratio (Rac) of PD-0332991 Following Multiple Dose: Part 1 Phase 1

    Rac is the ratio of AUCtau (after multiple doses) to AUCtau (after single dose). AUCtau is area under the plasma concentration-time curve over dosing interval which is calculated by log-linear trapezoidal method.

    Time frame: Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7), Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8

  17. Linearity (Rss) of PD-0332991 Following Multiple Dose: Part 1 Phase 1

    Rss is the ratio of AUCtau (after multiple doses) to AUCinf (after single dose). AUCtau is area under the plasma concentration-time curve over dosing interval which is calculated by log-linear trapezoidal method. AUCinf is area under the plasma concentration-time curve from 0 to infinity which is calculated by log-linear trapezoidal method.

    Time frame: Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7), Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8

  18. Time to Reach Maximum Observed Plasma Concentration (Tmax) of PD-0332991: Part 1 Phase 1

    Tmax is time at which maximum plasma concentration (Cmax) was observed. It was observed directly from data as time of first occurrence.

    Time frame: Single dose: 0 hour (pre-dose),1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7), Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8

  19. Terminal Half-Life (t1/2) of PD-0332991: Part 1 Phase 1

    t1/2 is terminal elimination half-life which is calculated by loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.

    Time frame: Single dose: 0 hour (pre-dose),1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7), Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8

  20. Volume of Distribution (Vz/F) of PD-0332991 Following Single Dose: Part 1 Phase 1

    Vz/F is apparent volume of distribution estimated from terminal phase, which is calculated as CL/F/kel. Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. It was calculated by dividing the given oral dose by area under the plasma concentration-time curve from 0 to infinity which is calculated by log-linear trapezoidal method (AUCinf). kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.

    Time frame: Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7)

  21. Area Under the Plasma Concentration Time Curve Over Dosing Interval (AUCtau) of PD-0332991: Phase 2

    AUCtau is area under the plasma concentration-time curve over dosing interval which is calculated by log-linear trapezoidal method.

    Time frame: 0 (pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post dose on Cycle 1 Day 15

  22. Apparent Oral Clearance of PD-0332991: Phase 2

    Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. It was calculated by dividing the given oral dose by AUCtau. AUCtau is the area under the plasma concentration-time curve over dosing interval which is calculated by log-linear trapezoidal method.

    Time frame: 0 (pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post dose on Cycle 1 Day 15

  23. Maximum Observed Plasma Concentration (Cmax) Of PD-0332991: Phase 2

    Cmax is maximum plasma concentration which is observed directly from the actual time-concentration data.

    Time frame: 0 (pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post dose on Cycle 1 Day 15

  24. Time to Reach Maximum Observed Plasma Concentration (Tmax) of PD-0332991: Phase 2

    Tmax is time at which maximum plasma concentration (Cmax) was observed. It was observed directly from data as time of first occurrence.

    Time frame: 0 (pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post dose on Cycle 1 Day 15

  25. Pre-dose Plasma Concentration (Ctrough) of PD-0332991: Phase 2

    Ctrough is pre-dose concentration during multiple dosing which is observed directly from the actual time-concentration data.

    Time frame: 0 (pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post dose on Cycle 1 Day 15

  26. Percentage of Participants With Objective Response: Phase 1

    Objective response (OR) was defined as a complete response (CR) or partial response (PR) according to the RECIST version 1.1 recorded from first dose of study treatment until disease progression or death due to any cause. CR was defined as disappearance of all target lesions with the exception of nodal disease. All target nodes reduced to normal size (short axis \<10 millimeter \[mm\]). PR was defined as a \>=30 percent decrease in sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. Percentage of participants with objective response (who achieved CR or PR) were reported.

    Time frame: From initiation of treatment up to disease progression (up to 30 months)

  27. Percentage of Participants With Objective Response: Phase 2

    Objective response was defined as a complete response (CR) or partial response (PR) according to the RECIST version 1.1 recorded from first dose of study treatment until disease progression or death due to any cause. PD was defined using RECIST v1.1, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. CR was defined as disappearance of all target lesions with the exception of nodal disease. All target nodes reduced to normal size (short axis \<10 mm). PR was defined as a \>=30% decrease in sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. Percentage of participants with objective response (who achieved CR or PR) were reported.

    Time frame: From initiation of treatment up to disease progression (up to 1526 days)

  28. Duration of Response (DOR): Part 2 Phase 1

    Duration of response was defined as the interval from the first documentation of objective tumor response in participants with CR (disappearance of all target lesions with the exception of nodal disease. All target nodes reduced to normal size (short axis \<10 millimeter \[mm\]) or PR (a \>=30 percent decrease in sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions) according to RECIST version 1.1 to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first.

    Time frame: baseline up to 1673 days

  29. Duration of Response (DOR): Phase 2

    Duration of response was defined as the interval from the first documentation of objective tumor response in participants with CR (disappearance of all target lesions with the exception of nodal disease, all target nodes reduced to normal size (short axis \<10 mm) or PR (a \>=30 % decrease in sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions) according to RECIST version 1.1 to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first. PD was defined using RECIST v1.1, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

    Time frame: From initiation of treatment up to disease progression (up to 1526 days)

  30. Progression Free Survival (PFS): Part 2 Phase 1

    PFS was defined as the time from first dose of study treatment to the date of the first documentation of objective progression of disease (PD) or death due to any cause in the absence of documented PD, whichever occurs first. PD was defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

    Time frame: baseline up to 1673 days

  31. Percentage of Participants With Disease Control (DC): Phase 2

    DC: CR, PR or stable disease (SD) for \>=24 weeks according to RECIST version (v)1.1 recorded in time period between first dose of study treatment and disease progression or death to any cause. CR: disappearance of all target lesions with exception of nodal disease. All target nodes reduced to normal size (short axis \<10 mm). PR: \>=30% decrease in sum of longest dimensions of target lesions taking as a reference baseline sum longest dimensions. SD was defined as not achieving an OR with confirmed CR or PR according to RECIST v1.1, as determined by investigators, relative to response evaluable population, but remained stable for at least 24 weeks after first dose, then best overall response for such a participant was considered as stable disease. PD was defined using RECIST v1.1 as a 20% increase in sum of longest diameter of target lesions, or a measurable increase in a non-target lesion, or appearance of new lesions.

    Time frame: From initiation of treatment up to disease progression (up to 1526 days)

  32. Overall Survival (OS): Phase 2

    Overall survival was defined as the time from first dose of study treatment to date of death due to any cause. In the absence of confirmation of death, survival time was censored to last date the participant was known to be alive. OS was estimated with Kaplan-Meier method.

    Time frame: From initiation of treatment up to follow-up period (up to 1526 days)

  33. Change From Baseline in Functional Assessment of Cancer Therapy-Breast Cancer (FACT-B): Phase 2 at Day 1 of Cycle 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49 and End of Treatment

    The functional assessment of cancer therapy (FACT) is a modular approach to assess participant's health-related quality of life. FACT-B total score was derived from the sum of these 5 sub-scale scores: physical well-being, social/family well-being and functional well-being (all 3 sub-scales consisting of 7 items ranging from 0 to 28, where higher scores indicating better quality of life), emotional well-being (consists of 6 items and ranging from 0 to 24, where higher scores indicating better quality of life, and a breast cancer subscale (consists of 9 items and ranging from 0 to 36, where higher scores indicating better quality of life). Each individual item was rated on a 5-point Likert scale, ranging from 0 (not at all good) to 4 (very well), where higher scores indicating better quality of life. FACT-B total score range was of 0 (not at all good) to 144 (very well), where higher scores indicating better quality of life.

    Time frame: Baseline (Day 1 of Cycle 1), Day 1 of Cycle 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, End of treatment (up to 1526 days)

  34. Change From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G): Phase 2 at Day 1 of Cycle 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49 and End of Treatment

    FACT is a modular approach to assess participant's health-related quality of life. FACT-G total score was derived from the sum of these 4 sub-scale scores: physical well-being, social/family well-being and functional well-being (all 3 sub-scales consisting of 7 items ranging from 0 to 28, where higher scores indicating better quality of life), emotional well-being (consists of 6 items and ranging from 0 to 24, where higher scores indicating better quality of life). Each individual item was rated on a 5-point Likert scale, ranging from 0 (not at all good) to 4 (very well), where higher scores indicating better quality of life. FACT-G total score range was of 0 (not at all good) to 108 (very well), where higher scores indicating better quality of life.

    Time frame: Baseline (Day 1 of Cycle 1), Day 1 of Cycle 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, End of treatment (up to 1526 days)

  35. Change From Baseline in Trial Outcome Index (TOI): Phase 2 at Day 1 of Cycle 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49 and End of Treatment

    FACT is a modular approach to assess participant's health-related quality of life. TOI total score was derived from the sum of the 3 sub-scale scores: physical well-being, functional well-being (both sub-scales consisting of 7 items ranging from 0 to 28, where higher scores indicating better quality of life) and breast cancer subscale (consists of 9 items and ranging from 0 to 36, where higher scores indicating better quality of life). Each individual item was rated on a 5-point Likert scale, ranging from 0 (not at all good) to 4 (very well), where higher scores indicating better quality of life. TOI total score range was of 0 (not at all good) to 92 (very well), where higher scores indicating better quality of life.

    Time frame: Baseline (Day 1 of Cycle 1), Day 1 of Cycle 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, End of treatment (up to 1526 days)

  36. Presence of Tumor Tissue Biomarker- Ki67: Phase 2

    Tumor tissue biomarker, Ki67 was analyzed to investigate possible associations with resistance or sensitivity to treatment with study drugs and was selected based on its known relevance to mechanisms involved in cell cycle regulation. Number of participants with less than or equal to and greater than 20 percent of Ki67 tumor tissue biomarker were reported.

    Time frame: Baseline (Day 1)

  37. Presence of Tumor Tissue Biomarkers- Estrogen Receptor (ER) H-Score, Retinoblastoma (Rb) H-Score, B-cell Lymphoma-1 (BCL-1) H-Score, P16 H-Score: Phase 2

    Tumor tissue biomarkers ER, Rb, BCL-1 and P16 were analyzed to investigate possible associations with resistance or sensitivity to treatment with study drugs and were selected based on their known relevance to mechanisms involved in cell cycle regulation. Number of participants with positive ER (H-Score), Rb (H-Score), BCL-1 (H-Score) and P16 (H-Score) tumor tissue biomarkers were reported. The H-score is a method of assessing the extent of nuclear immunoreactivity, applicable to steroid receptors.

    Time frame: Baseline (Day 1)

07

Results

Posted May 2, 2017

Participant flow

Phase 1, Part 1
Participant flow — Phase 1, Part 1
MilestonePD-0332991 100 mg: Dose Escalation CohortPD-0332991 125 mg: Dose Escalation CohortPD-0332991 125 mg+ Letrozole 2.5 mg: MTD CohortPD-0332991 125 mg+ Letrozole 2.5 mg: Expanded Cohort
Started6600
Treated6600
Completed0000
Not completed6600
Withdrew: Adverse event1000
Withdrew: Objective progression or relapse5600
Phase 1, Part 2
Participant flow — Phase 1, Part 2
MilestonePD-0332991 100 mg: Dose Escalation CohortPD-0332991 125 mg: Dose Escalation CohortPD-0332991 125 mg+ Letrozole 2.5 mg: MTD CohortPD-0332991 125 mg+ Letrozole 2.5 mg: Expanded Cohort
Started0060
Completed0000
Not completed0060
Withdrew: Adverse event0010
Withdrew: Commercial avaliabity of palbociclib0040
Withdrew: Withdrawal by subject0010
Phase 2
Participant flow — Phase 2
MilestonePD-0332991 100 mg: Dose Escalation CohortPD-0332991 125 mg: Dose Escalation CohortPD-0332991 125 mg+ Letrozole 2.5 mg: MTD CohortPD-0332991 125 mg+ Letrozole 2.5 mg: Expanded Cohort
Started00043
Treated00042
Completed0000
Not completed00043
Withdrew: Death0008
Withdrew: Study terminated by sponsor00030
Withdrew: Enrolled but not treated0001
Withdrew: Lost to follow-up0004

Outcome measures

PrimaryNumber of Participants With Dose Limiting Toxicities (DLT): Part 1 Phase 1

DLT was classified as per common terminology criteria for adverse events (CTCAE) version 4.0 as any of the events occurring during 28 days of Cycle 1,attributed to study drug:grade 4 neutropenia(for a duration of greater than \[\>\]7 days); febrile neutropenia (grade greater than or equal to \[\>=\]3 neutropenia,body temperature \>=38.5 degree Celsius);grade \>=3 thrombocytopenia with bleeding episode;grade 4 thrombocytopenia;grade \>=3 non-hematologic toxicity except grade 3 or more nausea, vomiting,electrolyte abnormality(if controllable by therapy);grade 3 QTc prolongation(\>500 millisecond \[msec\])persist after correction of reversible cause such as electrolyte abnormalities or hypoxia. Lack of hematologic recovery (platelets less than \[\<\]50,000/microliter \[mcL\],absolute neutrophil count \<1,000/mcL,hemoglobin \<8.0 gram/deciliter \[g/dL\]) or prolonged non hematologic toxicities that delays initiation of next dose by \>7 days;receipt of \<75 percent of planned dose in first cycle due to toxicity.

Time frame:
Lead-in period (Day -7) up to Day 28 (Cycle 1)
Reported as:
Count of participants · Participants
Number of Participants With Dose Limiting Toxicities (DLT): Part 1 Phase 1
ParticipantsPD-0332991 100 mg: Dose Escalation CohortPD-0332991 125 mg: Dose Escalation Cohort
Number of Participants With Dose Limiting Toxicities (DLT): Part 1 Phase 111
PrimaryNumber of Participants With Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs): Part 2 Phase 1

A treatment related AE is any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event had a causal relationship with the treatment or usage. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Relatedness was judged by investigator. AEs included both serious and non-serious adverse events.

Time frame:
Baseline (Day 1) up to 28 days after last dose of study drug (up to 1673 days)
Reported as:
Count of participants · Participants
Number of Participants With Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs): Part 2 Phase 1
ParticipantsPD-0332991 125 mg+ Letrozole 2.5 mg: MTD Cohort
AEs6
SAEs2
PrimaryNumber of Participants With Treatment-Emergent Adverse Events (TEAEs) By Severity: Part 2 Phase 1

AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An AE was considered treatment emergent if occurred for the first time after the start of study treatment or occurred prior to the start of treatment but increased in National Cancer Institute (NCI) CTCAE grade during study treatment period. AE severity was defined to be the maximum toxicity grade of the TEAEs experienced by the participants during the study. AE was assessed according to severity as: Grade 1 (mild AE), Grade 2 (moderate AE), Grade 3 (severe AE), Grade 4 (life-threatening consequences) and Grade 5 (death related to AE).

Time frame:
Baseline (Day 1) up to 28 days after last dose of study drug (up to 1673 days)
Reported as:
Count of participants · Participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) By Severity: Part 2 Phase 1
ParticipantsPD-0332991 125 mg+ Letrozole 2.5 mg: MTD Cohort
Grade 10
Grade 20
Grade 34
Grade 42
Grade 50
PrimaryPercentage of Participants With 1 Year Progression Free Survival (PFS): Phase 2

PFS was defined as the time from first dose of study treatment to the date of the first documentation of objective progression of disease (PD) or death due to any cause in the absence of documented PD, whichever occurred first. PD was defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.1-year PFS was defined as the percentage of participants without PFS events (PD or death due to any cause) at 12 months based on the Kaplan-Meier estimate. Percentage of participants with 1-year PFS with 90% confidence interval (CI) were reported.

Time frame:
From initiation of treatment up to 12 months
Reported as:
Number · percentage of participants
Percentage of Participants With 1 Year Progression Free Survival (PFS): Phase 2
percentage of participantsPD-0332991 125 mg+ Letrozole 2.5 mg: Expanded Cohort
Percentage of Participants With 1 Year Progression Free Survival (PFS): Phase 275.6 (62.4 to 84.7)
SecondaryNumber of Participants With Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs): Phase 1 (Part 1) and Phase 2

A treatment related AE is any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event had a causal relationship with the treatment or usage. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Relatedness was judged by investigator. AEs included both serious and non-serious adverse events.

Time frame:
Part 1 Phase 1: Lead-in period (Day -7) up to 28 days after last dose of study drug (up to 308 days), Phase 2: Baseline (Day 1) up to 28 days after last dose of study drug (up to 1526 days)
Reported as:
Count of participants · Participants
Number of Participants With Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs): Phase 1 (Part 1) and Phase 2
ParticipantsPD-0332991 100 mg: Dose Escalation CohortPD-0332991 125 mg: Dose Escalation CohortPD-0332991 125 mg+ Letrozole 2.5 mg: Expanded Cohort
AEs6542
SAEs002
SecondaryNumber of Participants With Treatment-Emergent Adverse Events (AEs) By Severity: Phase 1 (Part 1) and Phase 2

AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An AE was considered treatment emergent if occurred for the first time after the start of study treatment or occurred prior to the start of treatment but increased in NCI CTCAE version 4.0 grade during study treatment period. AE severity was defined to be the maximum toxicity grade of the TEAEs experienced by the participants during the study. AE was assessed according to severity as: Grade 1 (mild AE), Grade 2 (moderate AE), Grade 3 (severe AE), Grade 4 (life-threatening consequences) and Grade 5 (death related to AE).

Time frame:
Part 1 Phase 1: Lead-in period (Day -7) up to 28 days after last dose of study drug (up to 308 days), Phase 2: Baseline (Day 1) up to 28 days after last dose of study drug (up to 1526 days)
Reported as:
Count of participants · Participants
Number of Participants With Treatment-Emergent Adverse Events (AEs) By Severity: Phase 1 (Part 1) and Phase 2
ParticipantsPD-0332991 100 mg: Dose Escalation CohortPD-0332991 125 mg: Dose Escalation CohortPD-0332991 125 mg+ Letrozole 2.5 mg: Expanded Cohort
Grade 1010
Grade 2012
Grade 34329
Grade 42110
Grade 5001
SecondaryNumber of Participants With Clinically Significant Laboratory Abnormalities

Abnormality criteria: hemoglobin: \<0.8\*lower limit of normal \[LLN\], platelets: \<0.5\*LLN or \>1.75\*upper limit of normal \[ULN\], leukocytes: \<0.6\*LLN or \>1.5\*ULN, lymphocytes, total neutrophils: \<0.8\*LLN or \>1.2\*ULN, basophils, eosinophil,monocytes: \>1.2\*ULN); aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma glutamyl transferase (GT): \>0.3\*ULN, total protein, albumin: \<0.8\*LLN or \>1.2\*ULN, total bilirubin, direct bilirubin: \>1.5\*ULN; blood urea nitrogen, creatinine: \>1.3\*ULN, uric acid: \>1.2\*ULN; sodium: \<0.95\*LLN or \>1.05\*ULN, potassium, chloride, calcium, magnesium: \<0.9\*LLN or \>1.1\*ULN, phosphate: \<0.8\*LLN or \>1.2\*ULN; creatine kinase: \>2.0\*ULN, glucose fasting: \<0.6\*LLN or \>1.5\*ULN, glycosylated haemoglobin: \>1.3\*ULN;urinalysis dipstick (urine protein, urine blood \>=1); urine protein 24 hour: \>1.1\*ULN; coagulation Activated partial thromboplastin time \[APTT\], Prothrombin, prothrombin international ratio: \>1.1\*ULN.

Time frame:
Part 1 Phase 1: Lead-in period (Day -7) up to 308 days; Part 2 Phase 1: Baseline (Day 1) up to 1673 days; Phase 2: Baseline (Day 1) up to 1526 days
Reported as:
Count of participants · Participants
Number of Participants With Clinically Significant Laboratory Abnormalities
ParticipantsPD-0332991 100 mg: Dose Escalation CohortPD-0332991 125 mg: Dose Escalation CohortPD-0332991 125 mg+ Letrozole 2.5 mg: MTD CohortPD-0332991 125 mg+ Letrozole 2.5 mg: Expanded Cohort
Number of Participants With Clinically Significant Laboratory Abnormalities66640
SecondaryArea Under the Plasma Concentration Time Curve Over Dosing Interval (AUCtau) of PD-0332991 Following Multiple Dose: Part 1 Phase 1

AUCtau is area under the plasma concentration-time curve over dosing interval which is calculated by log-linear trapezoidal method.

Time frame:
Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8
Reported as:
Geometric mean · nanogram*hour per milliliter (ng*hr/mL)
Area Under the Plasma Concentration Time Curve Over Dosing Interval (AUCtau) of PD-0332991 Following Multiple Dose: Part 1 Phase 1
nanogram*hour per milliliter (ng*hr/mL)PD-0332991 100 mg: Dose Escalation CohortPD-0332991 125 mg: Dose Escalation Cohort
Area Under the Plasma Concentration Time Curve Over Dosing Interval (AUCtau) of PD-0332991 Following Multiple Dose: Part 1 Phase 11276 ± 452838 ± 43
SecondaryAUCtau Dose Normalized to 125 Milligram (mg) of PD-0332991 Following Multiple Dose: Part 1 Phase 1

AUCtau Dose Normalized to 125 mg is area under the plasma concentration-time curve over dosing interval dose normalized to 125 mg which is calculated by log-linear trapezoidal method.

Time frame:
Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8
Reported as:
Geometric mean · ng*hr/mL
AUCtau Dose Normalized to 125 Milligram (mg) of PD-0332991 Following Multiple Dose: Part 1 Phase 1
ng*hr/mLPD-0332991 100 mg: Dose Escalation CohortPD-0332991 125 mg: Dose Escalation Cohort
AUCtau Dose Normalized to 125 Milligram (mg) of PD-0332991 Following Multiple Dose: Part 1 Phase 11595 ± 452838 ± 43
SecondaryArea Under the Plasma Concentration-Time Curve From 0 to Time 24 Hours (AUC24) of PD-0332991 Following Single Dose: Part 1 Phase 1

AUC24 is area under the plasma concentration-time curve from 0 to time 24 hours which is calculated by log-linear trapezoidal method.

Time frame:
Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12 and 24 hours post-dose in Lead-in period (Day -7)
Reported as:
Geometric mean · ng*hr/mL
Area Under the Plasma Concentration-Time Curve From 0 to Time 24 Hours (AUC24) of PD-0332991 Following Single Dose: Part 1 Phase 1
ng*hr/mLPD-0332991 100 mg: Dose Escalation CohortPD-0332991 125 mg: Dose Escalation Cohort
Area Under the Plasma Concentration-Time Curve From 0 to Time 24 Hours (AUC24) of PD-0332991 Following Single Dose: Part 1 Phase 1547.5 ± 191322 ± 42
SecondaryAUC24 Dose Normalized to 125 mg of PD-0332991 Following Single Dose: Part 1 Phase 1

AUC24 Dose Normalized to 125 mg is area under the plasma concentration-time curve from 0 to time 24 hours dose normalized to 125 mg which is calculated by log-linear trapezoidal method.

Time frame:
Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12 and 24 hours post-dose in Lead-in period (Day -7)
Reported as:
Geometric mean · ng*hr/mL
AUC24 Dose Normalized to 125 mg of PD-0332991 Following Single Dose: Part 1 Phase 1
ng*hr/mLPD-0332991 100 mg: Dose Escalation CohortPD-0332991 125 mg: Dose Escalation Cohort
AUC24 Dose Normalized to 125 mg of PD-0332991 Following Single Dose: Part 1 Phase 1684.5 ± 191322 ± 42
SecondaryArea Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUCinf) of PD-0332991 Following Single Dose: Part 1 Phase 1

AUCinf is area under the plasma concentration-time curve from 0 to infinity which is calculated by log-linear trapezoidal method.

Time frame:
Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7)
Reported as:
Geometric mean · ng*hr/mL
Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUCinf) of PD-0332991 Following Single Dose: Part 1 Phase 1
ng*hr/mLPD-0332991 100 mg: Dose Escalation CohortPD-0332991 125 mg: Dose Escalation Cohort
Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUCinf) of PD-0332991 Following Single Dose: Part 1 Phase 11039 ± 322483 ± 49
SecondaryAUCinf Dose Normalized to 125 mg of PD-0332991 Following Single Dose: Part 1 Phase 1

AUCinf Dose Normalized to 125 mg is area under the plasma concentration-time curve from 0 to infinity dose normalized to 125 mg which is calculated by log-linear trapezoidal method.

Time frame:
Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7)
Reported as:
Geometric mean · ng*hr/mL
AUCinf Dose Normalized to 125 mg of PD-0332991 Following Single Dose: Part 1 Phase 1
ng*hr/mLPD-0332991 100 mg: Dose Escalation CohortPD-0332991 125 mg: Dose Escalation Cohort
AUCinf Dose Normalized to 125 mg of PD-0332991 Following Single Dose: Part 1 Phase 11296 ± 322483 ± 49
SecondaryArea Under the Plasma Concentration-Time Curve From 0 to Time of Last Measurable Concentration (AUClast) of PD-0332991 Following Single Dose: Part 1 Phase 1

AUClast is area under the plasma concentration-time curve from 0 to time of last measurable concentration which is calculated by log-linear trapezoidal method.

Time frame:
Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7)
Reported as:
Geometric mean · ng*hr/mL
Area Under the Plasma Concentration-Time Curve From 0 to Time of Last Measurable Concentration (AUClast) of PD-0332991 Following Single Dose: Part 1 Phase 1
ng*hr/mLPD-0332991 100 mg: Dose Escalation CohortPD-0332991 125 mg: Dose Escalation Cohort
Area Under the Plasma Concentration-Time Curve From 0 to Time of Last Measurable Concentration (AUClast) of PD-0332991 Following Single Dose: Part 1 Phase 1971.7 ± 312396 ± 48
SecondaryAUClast Dose Normalized to 125 mg of PD-0332991 Following Single Dose: Part 1 Phase 1

AUClast Dose Normalized to 125 mg is area under the plasma concentration-time curve from 0 to time of last measurable concentration dose normalized to 125 mg which is calculated by log-linear trapezoidal method.

Time frame:
Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7)
Reported as:
Geometric mean · ng*hr/mL
AUClast Dose Normalized to 125 mg of PD-0332991 Following Single Dose: Part 1 Phase 1
ng*hr/mLPD-0332991 100 mg: Dose Escalation CohortPD-0332991 125 mg: Dose Escalation Cohort
AUClast Dose Normalized to 125 mg of PD-0332991 Following Single Dose: Part 1 Phase 11215 ± 312396 ± 48
SecondaryApparent Oral Clearance of PD-0332991: Part 1 Phase 1

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. It was calculated by dividing the given oral dose by AUCinf. AUCinf is area under the plasma concentration-time curve from 0 to infinity which is calculated by log-linear trapezoidal method.

Time frame:
Single dose: 0 hour (pre-dose),1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7), Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8
Reported as:
Geometric mean · liter per hour (L/hr)
Apparent Oral Clearance of PD-0332991: Part 1 Phase 1
liter per hour (L/hr)PD-0332991 100 mg: Dose Escalation CohortPD-0332991 125 mg: Dose Escalation Cohort
Single dose96.43 ± 3250.29 ± 49
Multiple dose78.43 ± 4544.03 ± 43
SecondaryMaximum Observed Plasma Concentration (Cmax) Of PD-0332991: Part 1 Phase 1

Cmax is maximum plasma concentration which is observed directly from the actual time-concentration data.

Time frame:
Single dose: 0 hour (pre-dose),1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7), Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8
Reported as:
Geometric mean · nanogram per milliliter (ng/mL)
Maximum Observed Plasma Concentration (Cmax) Of PD-0332991: Part 1 Phase 1
nanogram per milliliter (ng/mL)PD-0332991 100 mg: Dose Escalation CohortPD-0332991 125 mg: Dose Escalation Cohort
Single dose41.37 ± 15104.1 ± 39
Multiple dose77.36 ± 33185.5 ± 27
SecondaryCmax Dose Normalized to 125 mg of PD-0332991: Part 1 Phase 1

Cmax Dose Normalized to 125 mg is maximum plasma concentration dose normalized to 125 mg which is observed directly from the actual time-concentration data.

Time frame:
Single dose: 0 hour (pre-dose),1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7), Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8
Reported as:
Geometric mean · ng/mL
Cmax Dose Normalized to 125 mg of PD-0332991: Part 1 Phase 1
ng/mLPD-0332991 100 mg: Dose Escalation CohortPD-0332991 125 mg: Dose Escalation Cohort
Single dose51.74 ± 15104.1 ± 39
Multiple dose96.72 ± 33185.5 ± 27
SecondaryPre-dose Plasma Concentration (Ctrough) of PD-0332991 Following Multiple Dose: Part 1 Phase 1

Ctrough is pre-dose concentration during multiple dosing which is observed directly from the actual time-concentration data.

Time frame:
Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8
Reported as:
Geometric mean · ng/mL
Pre-dose Plasma Concentration (Ctrough) of PD-0332991 Following Multiple Dose: Part 1 Phase 1
ng/mLPD-0332991 100 mg: Dose Escalation CohortPD-0332991 125 mg: Dose Escalation Cohort
Pre-dose Plasma Concentration (Ctrough) of PD-0332991 Following Multiple Dose: Part 1 Phase 135.51 ± 5972.76 ± 48
SecondaryAccumulation Ratio (Rac) of PD-0332991 Following Multiple Dose: Part 1 Phase 1

Rac is the ratio of AUCtau (after multiple doses) to AUCtau (after single dose). AUCtau is area under the plasma concentration-time curve over dosing interval which is calculated by log-linear trapezoidal method.

Time frame:
Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7), Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8
Reported as:
Median · ratio
Accumulation Ratio (Rac) of PD-0332991 Following Multiple Dose: Part 1 Phase 1
ratioPD-0332991 100 mg: Dose Escalation CohortPD-0332991 125 mg: Dose Escalation Cohort
Accumulation Ratio (Rac) of PD-0332991 Following Multiple Dose: Part 1 Phase 12.060 (1.81 to 3.54)1.855 (1.74 to 3.10)
SecondaryLinearity (Rss) of PD-0332991 Following Multiple Dose: Part 1 Phase 1

Rss is the ratio of AUCtau (after multiple doses) to AUCinf (after single dose). AUCtau is area under the plasma concentration-time curve over dosing interval which is calculated by log-linear trapezoidal method. AUCinf is area under the plasma concentration-time curve from 0 to infinity which is calculated by log-linear trapezoidal method.

Time frame:
Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7), Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8
Reported as:
Median · ratio
Linearity (Rss) of PD-0332991 Following Multiple Dose: Part 1 Phase 1
ratioPD-0332991 100 mg: Dose Escalation CohortPD-0332991 125 mg: Dose Escalation Cohort
Linearity (Rss) of PD-0332991 Following Multiple Dose: Part 1 Phase 11.130 (1.03 to 1.73)1.105 (0.851 to 1.51)
SecondaryTime to Reach Maximum Observed Plasma Concentration (Tmax) of PD-0332991: Part 1 Phase 1

Tmax is time at which maximum plasma concentration (Cmax) was observed. It was observed directly from data as time of first occurrence.

Time frame:
Single dose: 0 hour (pre-dose),1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7), Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8
Reported as:
Median · hour
Time to Reach Maximum Observed Plasma Concentration (Tmax) of PD-0332991: Part 1 Phase 1
hourPD-0332991 100 mg: Dose Escalation CohortPD-0332991 125 mg: Dose Escalation Cohort
Single dose5.02 (3.97 to 8.02)4.00 (3.90 to 8.00)
Multiple dose4.02 (3.97 to 6.00)4.02 (3.95 to 6.02)
SecondaryTerminal Half-Life (t1/2) of PD-0332991: Part 1 Phase 1

t1/2 is terminal elimination half-life which is calculated by loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.

Time frame:
Single dose: 0 hour (pre-dose),1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7), Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8
Reported as:
Mean · hour
Terminal Half-Life (t1/2) of PD-0332991: Part 1 Phase 1
hourPD-0332991 100 mg: Dose Escalation CohortPD-0332991 125 mg: Dose Escalation Cohort
Single dose25.72 ± 5.263223.93 ± 2.6882
Multiple dose23.75 ± 6.777823.15 ± 7.7045
SecondaryVolume of Distribution (Vz/F) of PD-0332991 Following Single Dose: Part 1 Phase 1

Vz/F is apparent volume of distribution estimated from terminal phase, which is calculated as CL/F/kel. Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. It was calculated by dividing the given oral dose by area under the plasma concentration-time curve from 0 to infinity which is calculated by log-linear trapezoidal method (AUCinf). kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.

Time frame:
Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7)
Reported as:
Geometric mean · liter
Volume of Distribution (Vz/F) of PD-0332991 Following Single Dose: Part 1 Phase 1
literPD-0332991 100 mg: Dose Escalation CohortPD-0332991 125 mg: Dose Escalation Cohort
Volume of Distribution (Vz/F) of PD-0332991 Following Single Dose: Part 1 Phase 13514 ± 251730 ± 41
SecondaryArea Under the Plasma Concentration Time Curve Over Dosing Interval (AUCtau) of PD-0332991: Phase 2

AUCtau is area under the plasma concentration-time curve over dosing interval which is calculated by log-linear trapezoidal method.

Time frame:
0 (pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post dose on Cycle 1 Day 15
Reported as:
Geometric mean · ng*hr/mL
Area Under the Plasma Concentration Time Curve Over Dosing Interval (AUCtau) of PD-0332991: Phase 2
ng*hr/mLPD-0332991 125 mg+ Letrozole 2.5 mg: Expanded Cohort
Area Under the Plasma Concentration Time Curve Over Dosing Interval (AUCtau) of PD-0332991: Phase 21979 ± 16
SecondaryApparent Oral Clearance of PD-0332991: Phase 2

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. It was calculated by dividing the given oral dose by AUCtau. AUCtau is the area under the plasma concentration-time curve over dosing interval which is calculated by log-linear trapezoidal method.

Time frame:
0 (pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post dose on Cycle 1 Day 15
Reported as:
Geometric mean · L/hr
Apparent Oral Clearance of PD-0332991: Phase 2
L/hrPD-0332991 125 mg+ Letrozole 2.5 mg: Expanded Cohort
Apparent Oral Clearance of PD-0332991: Phase 263.21 ± 16
SecondaryMaximum Observed Plasma Concentration (Cmax) Of PD-0332991: Phase 2

Cmax is maximum plasma concentration which is observed directly from the actual time-concentration data.

Time frame:
0 (pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post dose on Cycle 1 Day 15
Reported as:
Geometric mean · ng/mL
Maximum Observed Plasma Concentration (Cmax) Of PD-0332991: Phase 2
ng/mLPD-0332991 125 mg+ Letrozole 2.5 mg: Expanded Cohort
Maximum Observed Plasma Concentration (Cmax) Of PD-0332991: Phase 2124.7 ± 26
SecondaryTime to Reach Maximum Observed Plasma Concentration (Tmax) of PD-0332991: Phase 2

Tmax is time at which maximum plasma concentration (Cmax) was observed. It was observed directly from data as time of first occurrence.

Time frame:
0 (pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post dose on Cycle 1 Day 15
Reported as:
Median · hour
Time to Reach Maximum Observed Plasma Concentration (Tmax) of PD-0332991: Phase 2
hourPD-0332991 125 mg+ Letrozole 2.5 mg: Expanded Cohort
Time to Reach Maximum Observed Plasma Concentration (Tmax) of PD-0332991: Phase 24.90 (2.00 to 8.20)
SecondaryPre-dose Plasma Concentration (Ctrough) of PD-0332991: Phase 2

Ctrough is pre-dose concentration during multiple dosing which is observed directly from the actual time-concentration data.

Time frame:
0 (pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post dose on Cycle 1 Day 15
Reported as:
Geometric mean · ng/mL
Pre-dose Plasma Concentration (Ctrough) of PD-0332991: Phase 2
ng/mLPD-0332991 125 mg+ Letrozole 2.5 mg: Expanded Cohort
Pre-dose Plasma Concentration (Ctrough) of PD-0332991: Phase 259.75 ± 38
SecondaryPercentage of Participants With Objective Response: Phase 1

Objective response (OR) was defined as a complete response (CR) or partial response (PR) according to the RECIST version 1.1 recorded from first dose of study treatment until disease progression or death due to any cause. CR was defined as disappearance of all target lesions with the exception of nodal disease. All target nodes reduced to normal size (short axis \<10 millimeter \[mm\]). PR was defined as a \>=30 percent decrease in sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. Percentage of participants with objective response (who achieved CR or PR) were reported.

Time frame:
From initiation of treatment up to disease progression (up to 30 months)
Reported as:
Number · percentage of participants
Percentage of Participants With Objective Response: Phase 1
percentage of participantsPD-0332991 100 mg: Dose Escalation CohortPD-0332991 125 mg: Dose Escalation CohortPD-0332991 125 mg+ Letrozole 2.5 mg: MTD Cohort
With Complete Response000
With Partial Response0033.3
SecondaryPercentage of Participants With Objective Response: Phase 2

Objective response was defined as a complete response (CR) or partial response (PR) according to the RECIST version 1.1 recorded from first dose of study treatment until disease progression or death due to any cause. PD was defined using RECIST v1.1, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. CR was defined as disappearance of all target lesions with the exception of nodal disease. All target nodes reduced to normal size (short axis \<10 mm). PR was defined as a \>=30% decrease in sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. Percentage of participants with objective response (who achieved CR or PR) were reported.

Time frame:
From initiation of treatment up to disease progression (up to 1526 days)
Reported as:
Number · percentage of participants
Percentage of Participants With Objective Response: Phase 2
percentage of participantsPD-0332991 125 mg+ Letrozole 2.5 mg: Expanded Cohort
Percentage of Participants With Objective Response: Phase 247.6
SecondaryDuration of Response (DOR): Part 2 Phase 1

Duration of response was defined as the interval from the first documentation of objective tumor response in participants with CR (disappearance of all target lesions with the exception of nodal disease. All target nodes reduced to normal size (short axis \<10 millimeter \[mm\]) or PR (a \>=30 percent decrease in sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions) according to RECIST version 1.1 to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first.

Time frame:
baseline up to 1673 days
Reported as:
Number · days
Duration of Response (DOR): Part 2 Phase 1
daysPD-0332991 125 mg+ Letrozole 2.5 mg: MTD Cohort
Participant 11509
Participant 21428
SecondaryDuration of Response (DOR): Phase 2

Duration of response was defined as the interval from the first documentation of objective tumor response in participants with CR (disappearance of all target lesions with the exception of nodal disease, all target nodes reduced to normal size (short axis \<10 mm) or PR (a \>=30 % decrease in sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions) according to RECIST version 1.1 to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first. PD was defined using RECIST v1.1, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Time frame:
From initiation of treatment up to disease progression (up to 1526 days)
Reported as:
Median · months
Duration of Response (DOR): Phase 2
monthsPD-0332991 125 mg+ Letrozole 2.5 mg: Expanded Cohort
Duration of Response (DOR): Phase 241.4 (19.0 to NA)
SecondaryProgression Free Survival (PFS): Part 2 Phase 1

PFS was defined as the time from first dose of study treatment to the date of the first documentation of objective progression of disease (PD) or death due to any cause in the absence of documented PD, whichever occurs first. PD was defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Time frame:
baseline up to 1673 days
Reported as:
Number · days
Progression Free Survival (PFS): Part 2 Phase 1
daysPD-0332991 125 mg+ Letrozole 2.5 mg: MTD Cohort
Participant 11590
Participant 21593
Participant 31602
Participant 436
Participant 531
Participant 61512
SecondaryPercentage of Participants With Disease Control (DC): Phase 2

DC: CR, PR or stable disease (SD) for \>=24 weeks according to RECIST version (v)1.1 recorded in time period between first dose of study treatment and disease progression or death to any cause. CR: disappearance of all target lesions with exception of nodal disease. All target nodes reduced to normal size (short axis \<10 mm). PR: \>=30% decrease in sum of longest dimensions of target lesions taking as a reference baseline sum longest dimensions. SD was defined as not achieving an OR with confirmed CR or PR according to RECIST v1.1, as determined by investigators, relative to response evaluable population, but remained stable for at least 24 weeks after first dose, then best overall response for such a participant was considered as stable disease. PD was defined using RECIST v1.1 as a 20% increase in sum of longest diameter of target lesions, or a measurable increase in a non-target lesion, or appearance of new lesions.

Time frame:
From initiation of treatment up to disease progression (up to 1526 days)
Reported as:
Number · percentage of participants
Percentage of Participants With Disease Control (DC): Phase 2
percentage of participantsPD-0332991 125 mg+ Letrozole 2.5 mg: Expanded Cohort
Percentage of Participants With Disease Control (DC): Phase 285.7
SecondaryOverall Survival (OS): Phase 2

Overall survival was defined as the time from first dose of study treatment to date of death due to any cause. In the absence of confirmation of death, survival time was censored to last date the participant was known to be alive. OS was estimated with Kaplan-Meier method.

Time frame:
From initiation of treatment up to follow-up period (up to 1526 days)
Reported as:
Median · months
Overall Survival (OS): Phase 2
monthsPD-0332991 125 mg+ Letrozole 2.5 mg: Expanded Cohort
Overall Survival (OS): Phase 2NA (47.5 to NA)
SecondaryChange From Baseline in Functional Assessment of Cancer Therapy-Breast Cancer (FACT-B): Phase 2 at Day 1 of Cycle 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49 and End of Treatment

The functional assessment of cancer therapy (FACT) is a modular approach to assess participant's health-related quality of life. FACT-B total score was derived from the sum of these 5 sub-scale scores: physical well-being, social/family well-being and functional well-being (all 3 sub-scales consisting of 7 items ranging from 0 to 28, where higher scores indicating better quality of life), emotional well-being (consists of 6 items and ranging from 0 to 24, where higher scores indicating better quality of life, and a breast cancer subscale (consists of 9 items and ranging from 0 to 36, where higher scores indicating better quality of life). Each individual item was rated on a 5-point Likert scale, ranging from 0 (not at all good) to 4 (very well), where higher scores indicating better quality of life. FACT-B total score range was of 0 (not at all good) to 144 (very well), where higher scores indicating better quality of life.

Time frame:
Baseline (Day 1 of Cycle 1), Day 1 of Cycle 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, End of treatment (up to 1526 days)
Reported as:
Mean · units on a scale
Change From Baseline in Functional Assessment of Cancer Therapy-Breast Cancer (FACT-B): Phase 2 at Day 1 of Cycle 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49 and End of Treatment
units on a scalePD-0332991 125 mg+ Letrozole 2.5 mg: Expanded Cohort
Baseline106.46 (101.87 to 111.04)
Change at Cycle 2: Day 1-1.20 (-4.56 to 2.16)
Change at Cycle 3: Day 1-2.22 (-6.27 to 1.83)
Change at Cycle 5: Day 1-2.38 (-6.07 to 1.31)
Change at Cycle 7: Day 1-4.62 (-8.43 to -0.81)
Change at Cycle 9: Day 1-4.45 (-7.86 to -1.04)
Change at Cycle 11: Day 1-4.48 (-7.99 to -0.97)
Change at Cycle 13: Day 1-6.32 (-10.56 to -2.09)
Change at Cycle 15: Day 1-4.06 (-7.84 to -0.27)
Change at Cycle 17: Day 1-6.07 (-9.48 to -2.65)
Change at Cycle 19: Day 1-7.39 (-12.06 to -2.72)
Change at Cycle 21: Day 1-5.85 (-10.29 to -1.42)
Change at Cycle 23: Day 1-5.89 (-10.97 to -0.82)
Change at Cycle 25: Day 1-4.22 (-8.61 to 0.17)
Change at Cycle 27: Day 1-4.76 (-9.22 to -0.30)
Change at Cycle 29: Day 1-6.26 (-10.94 to -1.57)
Change at Cycle 31: Day 1-5.13 (-9.46 to -0.79)
Change at Cycle 33: Day 1-7.12 (-11.14 to -3.11)
Change at Cycle 35: Day 1-7.68 (-11.66 to -3.70)
Change at Cycle 37: Day 1-8.07 (-12.56 to -3.58)
Change at Cycle 39: Day 1-6.87 (-10.89 to -2.85)
Change at Cycle 41: Day 1-5.70 (-11.41 to 0.02)
Change at Cycle 43: Day 1-10.42 (-17.24 to -3.59)
Change at Cycle 45: Day 1-7.94 (-26.09 to 10.20)
Change at Cycle 47: Day 1-8.56 (-22.48 to 5.36)
Change at Cycle 49: Day 1-10.58 (-66.70 to 45.54)
End of Treatment-9.17 (-13.82 to -4.52)
SecondaryChange From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G): Phase 2 at Day 1 of Cycle 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49 and End of Treatment

FACT is a modular approach to assess participant's health-related quality of life. FACT-G total score was derived from the sum of these 4 sub-scale scores: physical well-being, social/family well-being and functional well-being (all 3 sub-scales consisting of 7 items ranging from 0 to 28, where higher scores indicating better quality of life), emotional well-being (consists of 6 items and ranging from 0 to 24, where higher scores indicating better quality of life). Each individual item was rated on a 5-point Likert scale, ranging from 0 (not at all good) to 4 (very well), where higher scores indicating better quality of life. FACT-G total score range was of 0 (not at all good) to 108 (very well), where higher scores indicating better quality of life.

Time frame:
Baseline (Day 1 of Cycle 1), Day 1 of Cycle 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, End of treatment (up to 1526 days)
Reported as:
Mean · units on a scale
Change From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G): Phase 2 at Day 1 of Cycle 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49 and End of Treatment
units on a scalePD-0332991 125 mg+ Letrozole 2.5 mg: Expanded Cohort
Baseline80.22 (76.21 to 84.23)
Change at Cycle 2: Day 1-1.15 (-4.10 to 1.80)
Change at Cycle 3: Day 1-1.34 (-4.72 to 2.04)
Change at Cycle 5: Day 1-0.36 (-3.21 to 2.48)
Change at Cycle 7: Day 1-3.56 (-6.52 to -0.60)
Change at Cycle 9: Day 1-2.39 (-4.94 to 0.16)
Change at Cycle 11: Day 1-3.94 (-6.79 to -1.09)
Change at Cycle 13: Day 1-4.74 (-8.11 to -1.37)
Change at Cycle 15: Day 1-2.98 (-6.23 to 0.26)
Change at Cycle 17: Day 1-4.64 (-7.37 to -1.91)
Change at Cycle 19: Day 1-5.48 (-8.94 to -2.01)
Change at Cycle 21: Day 1-4.34 (-7.94 to -0.74)
Change at Cycle 23: Day 1-4.39 (-8.42 to -0.37)
Change at Cycle 25: Day 1-3.22 (-6.94 to 0.50)
Change at Cycle 27: Day 1-3.80 (-7.34 to -0.26)
Change at Cycle 29: Day 1-4.52 (-8.58 to -0.45)
Change at Cycle 31: Day 1-4.55 (-8.27 to -0.84)
Change at Cycle 33: Day 1-6.67 (-10.26 to -3.08)
Change at Cycle 35: Day 1-6.63 (-10.38 to -2.88)
Change at Cycle 37: Day 1-6.49 (-10.52 to -2.46)
Change at Cycle 39: Day 1-5.07 (-8.37 to -1.76)
Change at Cycle 41: Day 1-5.06 (-9.92 to -0.20)
Change at Cycle 43: Day 1-7.08 (-14.53 to 0.37)
Change at Cycle 45: Day 1-5.94 (-27.36 to 15.47)
Change at Cycle 47: Day 1-6.22 (-25.11 to 12.66)
Change at Cycle 49: Day 1-8.58 (-90.11 to 72.95)
End of Treatment-7.09 (-10.98 to -3.20)
SecondaryChange From Baseline in Trial Outcome Index (TOI): Phase 2 at Day 1 of Cycle 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49 and End of Treatment

FACT is a modular approach to assess participant's health-related quality of life. TOI total score was derived from the sum of the 3 sub-scale scores: physical well-being, functional well-being (both sub-scales consisting of 7 items ranging from 0 to 28, where higher scores indicating better quality of life) and breast cancer subscale (consists of 9 items and ranging from 0 to 36, where higher scores indicating better quality of life). Each individual item was rated on a 5-point Likert scale, ranging from 0 (not at all good) to 4 (very well), where higher scores indicating better quality of life. TOI total score range was of 0 (not at all good) to 92 (very well), where higher scores indicating better quality of life.

Time frame:
Baseline (Day 1 of Cycle 1), Day 1 of Cycle 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, End of treatment (up to 1526 days)
Reported as:
Mean · units on a scale
Change From Baseline in Trial Outcome Index (TOI): Phase 2 at Day 1 of Cycle 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49 and End of Treatment
units on a scalePD-0332991 125 mg+ Letrozole 2.5 mg: Expanded Cohort
Baseline71.52 (68.36 to 74.69)
Change at Cycle 2: Day 1-1.17 (-3.24 to 0.89)
Change at Cycle 3: Day 1-2.20 (-4.74 to 0.35)
Change at Cycle 5: Day 1-2.54 (-5.25 to 0.16)
Change at Cycle 7: Day 1-3.63 (-6.44 to -0.82)
Change at Cycle 9: Day 1-3.31 (-6.03 to -0.60)
Change at Cycle 11: Day 1-2.30 (-5.06 to 0.45)
Change at Cycle 13: Day 1-3.93 (-7.31 to -0.56)
Change at Cycle 15: Day 1-2.49 (-5.09 to 0.11)
Change at Cycle 17: Day 1-3.18 (-6.02 to -0.34)
Change at Cycle 19: Day 1-4.32 (-8.01 to -0.63)
Change at Cycle 21: Day 1-3.56 (-6.83 to -0.28)
Change at Cycle 23: Day 1-3.19 (-7.11 to 0.73)
Change at Cycle 25: Day 1-2.13 (-5.51 to 1.26)
Change at Cycle 27: Day 1-2.50 (-5.77 to 0.77)
Change at Cycle 29: Day 1-3.70 (-7.36 to -0.03)
Change at Cycle 31: Day 1-1.95 (-5.23 to 1.33)
Change at Cycle 33: Day 1-4.30 (-7.65 to -0.95)
Change at Cycle 35: Day 1-4.65 (-8.68 to -0.62)
Change at Cycle 37: Day 1-4.84 (-8.77 to -0.92)
Change at Cycle 39: Day 1-3.47 (-7.09 to 0.15)
Change at Cycle 41: Day 1-2.27 (-7.62 to 3.08)
Change at Cycle 43: Day 1-7.00 (-13.83 to -0.17)
Change at Cycle 45: Day 1-3.00 (-22.40 to 16.40)
Change at Cycle 47: Day 1-4.00 (-12.96 to 4.96)
Change at Cycle 49: Day 1-2.00 (-14.71 to 10.71)
End of Treatment-6.03 (-9.61 to -2.45)
SecondaryPresence of Tumor Tissue Biomarker- Ki67: Phase 2

Tumor tissue biomarker, Ki67 was analyzed to investigate possible associations with resistance or sensitivity to treatment with study drugs and was selected based on its known relevance to mechanisms involved in cell cycle regulation. Number of participants with less than or equal to and greater than 20 percent of Ki67 tumor tissue biomarker were reported.

Time frame:
Baseline (Day 1)
Reported as:
Number · participants
Presence of Tumor Tissue Biomarker- Ki67: Phase 2
participantsPD-0332991 125 mg+ Letrozole 2.5 mg: Expanded Cohort
<=20 percent19
>20 percent23
SecondaryPresence of Tumor Tissue Biomarkers- Estrogen Receptor (ER) H-Score, Retinoblastoma (Rb) H-Score, B-cell Lymphoma-1 (BCL-1) H-Score, P16 H-Score: Phase 2

Tumor tissue biomarkers ER, Rb, BCL-1 and P16 were analyzed to investigate possible associations with resistance or sensitivity to treatment with study drugs and were selected based on their known relevance to mechanisms involved in cell cycle regulation. Number of participants with positive ER (H-Score), Rb (H-Score), BCL-1 (H-Score) and P16 (H-Score) tumor tissue biomarkers were reported. The H-score is a method of assessing the extent of nuclear immunoreactivity, applicable to steroid receptors.

Time frame:
Baseline (Day 1)
Reported as:
Number · participants
Presence of Tumor Tissue Biomarkers- Estrogen Receptor (ER) H-Score, Retinoblastoma (Rb) H-Score, B-cell Lymphoma-1 (BCL-1) H-Score, P16 H-Score: Phase 2
participantsPD-0332991 125 mg+ Letrozole 2.5 mg: Expanded Cohort
ER (H-Score)41
Rb (H-Score)41
BCL-1 (H-Score)42
P16 (H-Score)41

Adverse events

Collected over Part 1 Phase 1: Lead-in period (Day -7) up to 28 days after last dose of study drug (up to 308 days), Part 2 Phase 1: Baseline (Day 1) up to 28 days after last dose of study drug (up to 1673 days), Phase 2: Baseline (Day 1) up to 28 days after last dose of study drug (up to 1526 days). Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
PD-0332991 100 mg: Dose Escalation Cohort—0/6 (0%)6/6 (100%)
PD-0332991 125 mg: Dose Escalation Cohort—0/6 (0%)6/6 (100%)
PD-0332991 125 mg+ Letrozole 2.5 mg: MTD Cohort—2/6 (33.3%)6/6 (100%)
PD-0332991 125 mg+ Letrozole 2.5 mg: Expanded Cohort—4/42 (9.5%)42/42 (100%)
Most frequent serious events
Most frequent serious events
EventPD-0332991 100 mg: Dose Escalation CohortPD-0332991 125 mg: Dose Escalation CohortPD-0332991 125 mg+ Letrozole 2.5 mg: MTD CohortPD-0332991 125 mg+ Letrozole 2.5 mg: Expanded Cohort
Gastrointestinal perforationGastrointestinal disorders0/60/61/60/42
Supraventricular tachycardiaCardiac disorders0/60/61/60/42
Febrile NeutropeniaBlood and lymphatic system disorders0/60/60/61/42
VomitingGastrointestinal disorders0/60/60/61/42
MalaiseGeneral disorders0/60/60/61/42
Cerebral HaemorrhageNervous system disorders0/60/60/61/42
DizzinessNervous system disorders0/60/60/61/42
Subarachnoid HaemorrhageNervous system disorders0/60/60/61/42
OsteoarthritisMusculoskeletal and connective tissue disorders0/60/60/61/42
Most frequent other events
Showing 10 of 116
Most frequent other events
EventPD-0332991 100 mg: Dose Escalation CohortPD-0332991 125 mg: Dose Escalation CohortPD-0332991 125 mg+ Letrozole 2.5 mg: MTD CohortPD-0332991 125 mg+ Letrozole 2.5 mg: Expanded Cohort
Neutrophil count decreasedInvestigations5/64/66/634/42
White blood cell count decreasedInvestigations4/65/66/630/42
StomatitisGastrointestinal disorders0/62/61/632/42
FallInjury, poisoning and procedural complications0/60/64/69/42
Platelet count decreasedInvestigations1/62/64/69/42
DiarrhoeaGastrointestinal disorders1/64/64/65/42
Lymphocyte count decreasedInvestigations1/63/60/62/42
NasopharyngitisInfections and infestations1/60/62/619/42
AnaemiaBlood and lymphatic system disorders0/62/60/610/42
ConstipationGastrointestinal disorders1/62/62/612/42

Baseline characteristics

Safety analysis set included all enrolled participants who received at least 1 dose of study drug (PD-0332991).

Age, Categorical
Age, Categorical(Participants)PD-0332991 100 mg: Dose Escalation CohortPD-0332991 125 mg: Dose Escalation CohortPD-0332991 125 mg+ Letrozole 2.5 mg: MTD CohortPD-0332991 125 mg+ Letrozole 2.5 mg: Expanded CohortTotal
<=18 years00000
Between 18 and 65 years4542639
>=65 years2121621
Sex: Female, Male
Sex: Female, Male(Participants)PD-0332991 100 mg: Dose Escalation CohortPD-0332991 125 mg: Dose Escalation CohortPD-0332991 125 mg+ Letrozole 2.5 mg: MTD CohortPD-0332991 125 mg+ Letrozole 2.5 mg: Expanded CohortTotal
Female5264255
Male14005
08

Study locations

16 sites
  • Aichi Cancer Center Hospital
    Nagoya, Aichi 464-8681, Japan
  • National Cancer Center Hospital East
    Kashiwa, Chiba 277-8577, Japan
  • National Hospital Organization Hokkaido Cancer Center
    Sapporo, Hokkaido 003-0804, Japan
  • Kumamoto Shinto General Hospital
    Kumamoto-city, Kumamoto 862-8655, Japan
  • Saitama Cancer Center
    Kita-adachi-gun, Saitama 362-0806, Japan
  • National Cancer Center Hospital
    Chuo-Ku, Tokyo 104-0045, Japan
  • Chiba Cancer Center
    Chiba, 260-8717, Japan
  • National Hospital Organization Shikoku Cancer Center
    Ehime, 791-0280, Japan
  • National Hospital Organization Kyushu Cancer Center
    Fukuoka, 811-1395, Japan
  • Hiroshima City Hiroshima Citizens Hospital
    Hiroshima, 730-8518, Japan
  • Iwate Medical University Hospital
    Iwate, 020-8505, Japan
  • Hakuaikai Medical Corporation Sagara Hospital
    Kagoshima, 892-0833, Japan
  • Kumamoto University Hospital
    Kumamoto, 860-8556, Japan
  • Kumamoto City Hospital
    Kumamoto, 862-8505, Japan
  • Kyoto University Hospital
    Kyoto, 606-8507, Japan
  • National Hospital Organization Osaka National Hospital
    Osaka, 540-0006, Japan
09

References and documents

Publications

  • Takahashi M, Masuda N, Nishimura R, Inoue K, Ohno S, Iwata H, Hashigaki S, Muramatsu Y, Umeyama Y, Toi M. Palbociclib-letrozole as first-line treatment for advanced breast cancer: Updated results from a Japanese phase 2 study. Cancer Med. 2020 Jul;9(14):4929-4940. doi: 10.1002/cam4.3091. Epub 2020 May 18. PubMed 32420697 ↗
  • Masuda N, Mukai H, Inoue K, Rai Y, Ohno S, Mori Y, Hashigaki S, Muramatsu Y, Umeyama Y, Iwata H, Toi M. Neutropenia management with palbociclib in Japanese patients with advanced breast cancer. Breast Cancer. 2019 Sep;26(5):637-650. doi: 10.1007/s12282-019-00970-7. Epub 2019 May 24. Erratum In: Breast Cancer. 2019 Sep;26(5):651. doi: 10.1007/s12282-019-00984-1. PubMed 31127500 ↗
  • Tamura K, Mukai H, Naito Y, Yonemori K, Kodaira M, Tanabe Y, Yamamoto N, Osera S, Sasaki M, Mori Y, Hashigaki S, Nagasawa T, Umeyama Y, Yoshino T. Phase I study of palbociclib, a cyclin-dependent kinase 4/6 inhibitor, in Japanese patients. Cancer Sci. 2016 Jun;107(6):755-63. doi: 10.1111/cas.12932. Epub 2016 May 11. PubMed 26991823 ↗

Individual participant data

Plan to share: Yes — Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Nov 23, 2020, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT01684215
Lead sponsor
Pfizer
Responsible party
Sponsor
First posted
Sep 12, 2012
Start date
Oct 19, 2012
Primary completion
Mar 4, 2016
Completion
Oct 25, 2018
Results posted
May 2, 2017
Last update
Nov 23, 2020

Study contacts

Pfizer CT.gov Call Center
study director · Pfizer

Oversight

Data monitoring committee
No
View the source record on ClinicalTrials.gov ↗

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This study is completed, as verified in Oct 2020. You cannot join it, but the record below documents what was studied.

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Discussion

Questions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.

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Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.

Other studies in this condition

Breast Neoplasms→

Other studies from this sponsor

Pfizer

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