PF-06804103 Dose Escalation in HER2 Positive and Negative (Negative Only in Part 2) Solid Tumors

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• Breast Neoplasms 12,520

Keywords

• HER2
• PF-06804103
• ADC
• breast cancer
• neoplasms
• solid tumors
• human epidermal growth receptor 2

Study arms

• Experimental
  PF-06804103

  Study Treatment

  Drug: PF-06804103

• Experimental
  PF-06804103+Combination Regimen

  Study Treatment

  Drug: PF-06804103 + Palbociclib +Letrozole

Interventions

• DrugPF-06804103

  Dose Escalation Part - 1A Dose Expansion Part - 2A

• DrugPF-06804103 + Palbociclib +Letrozole

  Dose Escalation - Part 1B Dose Expansion - Part 2B

Primary outcomes

1. Number of Participants With Cycle 1 (21 Days) Dose-Limiting Toxicities (DLTs) in Part 1A

   A DLT was any of the following adverse events(AEs) in the first cycle of treatment (within 21 days of first dose). (1) Hematologic: Grade 4 neutropenia lasting \>7 days; febrile neutropenia; Grade \>＝3 neutropenic infection; Grade \>＝3 thrombocytopenia with bleeding; thrombocytopenia; (2) Non-hematologic: Grade \>=3 toxicities that were considered clinically significant; delayed by more than 2 weeks in receiving the next scheduled cycle due to persisting treatment related toxicities; concurrent AST or ALT \>3x ULN and total bilirubin \>2x ULN; any Grade 5 event.

   Time frame: First cycle, Day 1 up to Day 21

2. Number of Participants Wth Cycle 1 (28 Days) Dose-Limiting Toxicities (DLTs) in Part 1B

   A DLT was any of the following adverse events(AEs) in the first cycle of treatment (within 28 days of first dose). (1) Hematologic: including a delay greater than 1 week in administration of the next scheduled dose of study treatment due to persistent treatment-related toxicities; Grade 4 neutropenia lasting \>7 days; febrile neutropenia; Grade \>=3 neutropenic infection; Grade \>=3 thrombocytopenia with bleeding; thrombocytopenia. (2) Non-hematologic: including Grade \>=3 toxicities that are considered clinically significant; Grade 3 QTc prolongation despite correction of reversible causes; delayed by \>2 week in receiving the next scheduled dose of any study treatment due to persisting treatment-related toxicities; inability to administer at least 80% of the planned palbociclib or letrozole or 100% of the planned PF-06804103 doses during Cycle 1 due to toxicity related to the study treatment; concurrent AST or ALT \>3x ULN and total bilirubin \>2x ULN; any Grade 5 event.

   Time frame: First Cycle, Day 1 up to Day 28

3. Number of Participants With All-Causality Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Event (SAEs), Treatment-Related TEAEs and SAEs

   An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (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. Treatment-emergent AEs (TEAEs) were defined as those with initial onset or increasing in severity after the first dose of study medication. A treatment-related AE was any untoward medical occurrence attributed to the study drug in a participant who received study drug. Relatedness to study drug was assessed by the investigator.

   Time frame: From the first dose of study treatment up to a minimum of 28 calendar days after the last dose of study treatment (maximum duration between first and last dose: 89.3 weeks for Part 1A, 49.4 weeks for Part 2A, 53.7 weeks for Part 1B)

4. Number of Participants With Laboratory Abnormalities-Hematology

   Participants who experienced hematology laboratory test abnormalities were summarized according to worst toxicity grade observed for each hematology laboratory test. Laboratory abnormalities were graded by NCI CTCAE version 4.03 (Grade 0: no change from normal or reference range; Grade 1: mild AE; Grade 2: moderate AE; Grade 3: severe AE; Grade 4: life-threatening consequences, urgent intervention indicated). This outcome measure calculated the number of participants with hematology laboratory abnormalities that were shifted from \<=Grade 2 at baseline to Grade 3 or above, including the following parameters: anemia, INR increased, lymphocyte count decreased, neutrophil count decreased, white blood cell decreased.

   Time frame: From baseline to end of treatment (maximum treatment duration: 89.3 weeks for Part 1A, 49.4 weeks for Part 2A, 53.7 weeks for Part 1B)

5. Number of Participants With Laboratory Abnormalities-Chemistries

   Participants who experienced chemistry laboratory test abnormalities were summarized according to worst toxicity grade observed for each chemistry laboratory test. Laboratory abnormalities were graded by NCI CTCAE version 4.03 (Grade 0: no change from normal or reference range; Grade 1: mild AE; Grade 2: moderate AE; Grade 3: severe AE; Grade 4: life-threatening consequences, urgent intervention indicated). This outcome measure calculated the number of participants with chemistry laboratory abnormalities that were shifted from \<=Grade 2 at baseline to Grade 3 or above, including the following parameters: alanine aminotransferase (ALT) increased, alkaline phosphatase (ALP) increased, aspartate aminotransferase (AST) increased, hyperglycemia, hypermagnesemia, hypocalcemia, hypokalemia, hyponatremia, hypophosphatemia, lipase increased, serum amylase increased.

   Time frame: From baseline to end of treatment (maximum treatment duration: 89.3 weeks for Part 1A, 49.4 weeks for Part 2A, 53.7 weeks for Part 1B)

6. Number of Participants With Laboratory Abnormalities-Urinalysis

   Participants who experienced urinalysis laboratory test abnormalities were summarized according to worst toxicity grade observed for each urinalysis laboratory test. Laboratory abnormalities were graded by NCI CTCAE version 4.03 (Grade 0: no change from normal or reference range; Grade 1: mild AE; Grade 2: moderate AE; Grade 3: severe AE; Grade 4: life-threatening consequences, urgent intervention indicated). This outcome measure calculated the number of participants with urinalysis laboratory abnormalities that were shifted from \<=Grade 2 at baseline to Grade 3 or above.

   Time frame: From baseline to end of treatment (maximum treatment duration: 89.3 weeks for Part 1A, 49.4 weeks for Part 2A, 53.7 weeks for Part 1B)

7. Number of Participants With Vital Signs Data Meeting Pre-Defined Criteria

   Blood pressure (BP), including systolic BP (SBP) and diastolic BP (DBP), and pulse rate were recorded in a supine or seated position.

   Time frame: From baseline up to follow up (at least 28 days and no more than 35 days after discontinuation of treatment), maximum treatment duration: 89.3 weeks for Part 1A, 49.4 weeks for Part 2A, 53.7 weeks for Part 1B

8. Percentage of Participants With Objective Response in Part 2

   Percentage of participants with objective response based on assessment of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis \<10 mm). No new lesions. PR was defined as \>=30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions.

   Time frame: Baseline, every 6 weeks from the start of treatment until disease progression, death, or permanent discontinuation of study treatment (maximum treatment duration: 49.4 weeks)

9. Duration of Response (DR) in Part 2

   Duration of response (DR) was the time from first documentation of PR or CR to date of first documentation of progressive disease (PD) or death due to any cause. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis \<10 mm). No new lesions. PR was defined as \>=30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions. PD was defined as at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of one or more new lesions.

   Time frame: Baseline, every 6 weeks from the start of treatment until disease progression, death, or permanent discontinuation of study treatment (maximum treatment duration: 49.4 weeks)

10. Progression-Free Survival (PFS) in Part 2

    Progression-free survival (PFS) was the time from randomization date to date of first documentation of PD or death due to any cause. PD was defined as at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of one or more new lesions.

    Time frame: Baseline, every 6 weeks from the start of treatment until disease progression, death, or permanent discontinuation of study treatment (maximum treatment duration: 49.4 weeks)

11. Time to Tumor Progression (TTP) in Part 2

    Time to progression (TTP) was the time from start date to the date of the first documentation of PD. PD was defined as at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of one or more new lesions.

    Time frame: Baseline, every 6 weeks from the start of treatment until disease progression, death, or withdrawal from treatment (maximum treatment duration: 49.4 weeks)

Secondary outcomes

1. Percentage of Participants With Objective Response in Part 1

   Percentage of participants with objective response based on assessment of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis \<10 mm). No new lesions. PR was defined as \>=30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions.

   Time frame: Baseline, every 6 weeks (for Part 1A) or every 8 weeks (for Part 1B) from the start of treatment until disease progression, death, or permanent discontinuation of study treatment (maximum treatment duration: 89.3 weeks for Part 1A, 53.7 weeks for Part 1B)

2. Duration of Response (DR) in Part 1

   Duration of response (DR) was the time from first documentation of PR or CR to date of first documentation of progressive disease (PD) or death due to any cause. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis \<10 mm). No new lesions. PR was defined as \>=30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions. PD was defined as at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of one or more new lesions.

   Time frame: Baseline, every 6 weeks (for Part 1A) or every 8 weeks (for Part 1B) from the start of treatment until disease progression, death, or permanent discontinuation of study treatment (maximum treatment duration: 89.3 weeks for Part 1A, 53.7 weeks for Part 1B)

3. Progression-Free Survival (PFS) in Part 1

   Progression-free survival (PFS) was the time from randomization date to date of first documentation of PD or death due to any cause. PD was defined as at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of one or more new lesions.

   Time frame: Baseline, every 6 weeks (for Part 1A) or every 8 weeks (for Part 1B) from the start of treatment until disease progression, death, or permanent discontinuation of study treatment (maximum treatment duration: 89.3 weeks for Part 1A, 53.7 weeks for Part 1B)

4. Time to Tumor Progression (TTP) in Part 1

   Time to progression (TTP) was the time from start date to the date of the first documentation of PD. PD was defined as at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of one or more new lesions.

   Time frame: Baseline, every 6 weeks (for Part 1A) or every 8 weeks (for Part 1B) from the start of treatment until disease progression, death, or permanent discontinuation of study treatment (maximum treatment duration: 89.3 weeks for Part 1A, 53.7 weeks for Part 1B)

5. Number of Participants With Anti-Drug Antibodies (ADA) and Neutralizing Antibody (NAb) Against PF-06804103

   To evaluate the immunogenicity as measured by presence of ADA and NAb in participants treated with PF-06804103.

   Time frame: Prior to the start of treatment on Day 1 of Cycle 1 up to end of treatment (maximum treatment duration: 89.3 weeks for Part 1A, 49.4 weeks for Part 2A, 53.7 weeks for Part 1B)

6. Number of Participants With HER2 Positivity Based on Tumor Tissue Analysis

   Tumor tissues from archived tissue biopsy were analyzed for HER2 mutations.

   Time frame: Baseline

7. Maximum Observed Concentration (Cmax) of PF-06804103 Antibody-Drug Conjugate (ADC)

   Cmax is maximum observed serum concentration. Cmax for PF-06804103 ADC was observed directly from data. Part 2A used a sparse pharmacokinetic (PK) sampling schedule leaving very limited data for PK parameter estimation, so PK parameters from Part 2A were not reported. Only part 1A and part 1B treatment groups were included in this outcome measure.

   Time frame: Pre-dose, 1, 4, 24, 72, 168, 336 hours post-dose of Cycle 1 & 4 Day 1 for Part 1A; pre-dose, 1, 4, 24, 72, 168 hours post-dose of Cycle 1 & 4 Day 1 for Part 1B

8. Terminal Serum Half-Life (t1/2) of PF-06804103 ADC

   Terminal serum half-life (t1/2) is the time measured for the serum concentration of drug to decrease by one half. Part 2A used a sparse PK sampling schedule leaving very limited data for PK parameter estimation, so PK parameters from Part 2A were not reported. Only part 1A and part 1B treatment groups were included in this outcome measure.

   Time frame: Pre-dose, 1, 4, 24, 72, 168, 336 hours post-dose of Cycle 1 & 4 Day 1 for Part 1A; pre-dose, 1, 4, 24, 72, 168 hours post-dose of Cycle 1 & 4 Day 1 for Part 1B

9. Area Under The Serum Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-06804103 ADC

   AUCinf is the area under the serum concentration-time profile from time zero extrapolated to infinite time. Part 2A used a sparse PK sampling schedule leaving very limited data for PK parameter estimation, so PK parameters from Part 2A were not reported. Only part 1A and part 1B treatment groups were included in this outcome measure.

   Time frame: Pre-dose, 1, 4, 24, 72, 168, 336 hours post-dose of Cycle 1 Day 1 for Part 1A; pre-dose, 1, 4, 24, 72, 168 hours post-dose of Cycle 1 Day 1 for Part 1B

10. Area Under the Concentration-Time Profile From Time Zero to Time Tau (AUCtau) of PF-06804103 ADC

    Tau refers to the dosing interval and it equals to 504 hours for Part 1A and 336 hours for Part 1B. AUCtau is the area under the concentration-time profile from time zero to time tau. AUCtau for PF-06804103 ADC was determined using linear/log trapezoidal method. Part 2A used a sparse PK sampling schedule leaving very limited data for PK parameter estimation, so PK parameters from Part 2A were not reported. Only part 1A and part 1B treatment groups were included in this outcome measure.

    Time frame: Pre-dose, 1, 4, 24, 72, 168, 336 hours post-dose of Cycle 4 Day 1 for Part 1A; pre-dose, 1, 4, 24, 72, 168 hours post-dose of Cycle 4 Day 1 for Part 1B

11. Clearance (CL) of PF-06804103 ADC

    Clearance (CL) is a quantitative measure of the rate at which a drug substance is removed from the body. Clearance for PF-06804103 ADC was calculated as dose/AUCinf for single dose and dose/AUCtau for multiple dose, where AUCinf was the area under the serum concentration-time profile from time zero extrapolated to infinite time and AUCtau was the area under the concentration-time profile from time zero to time tau (tau equals to 504 hours for Part 1A and 336 hours for Part 1B). Part 2A used a sparse PK sampling schedule leaving very limited data for PK parameter estimation, so PK parameters from Part 2A were not reported. Only part 1A and part 1B treatment groups were included in this outcome measure.

    Time frame: Pre-dose, 1, 4, 24, 72, 168, 336 hours post-dose of Cycle 1 & 4 Day 1 for Part 1A; pre-dose, 1, 4, 24, 72, 168 hours post-dose of Cycle 1 & 4 Day 1 for Part 1B

12. Volume of Distribution at Steady State (Vss) of PF-06804103 ADC

    Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state. Part 2A used a sparse PK sampling schedule leaving very limited data for PK parameter estimation, so PK parameters from Part 2A were not reported. Only part 1A and part 1B treatment groups were included in this outcome measure.

    Time frame: Pre-dose, 1, 4, 24, 72, 168, 336 hours post-dose of Cycle 4 Day 1 for Part 1A; pre-dose, 1, 4, 24, 72, 168 hours post-dose of Cycle 4 Day 1 for Part 1B

13. Observed Accumulation Ratio (Rac) of PF-06804103 ADC

    Rac is defined as observed accumulation ratio based on dose normalized AUCtau (AUCtau\[dn\]), where AUCtau is the area under the concentration-time profile from time zero to time tau (tau equals to 504 hours for Part 1A and 336 hours for Part 1B). Rac=\[Cycle 4 Day 1 AUCtau(dn) (multiple dose)\] /\[Cycle 1 Day 1 AUCtau(dn) (single Dose)\] for Part 1A, Rac=\[Cycle 3 Day 1 AUCtau(dn) (multiple dose)\] /\[Cycle 1 Day 1 AUCtau(dn) (single Dose)\] for Part 1B. Part 2A used a sparse PK sampling schedule leaving very limited data for PK parameter estimation, so PK parameters from Part 2A were not reported. Only part 1A and part 1B treatment groups were included in this outcome measure.

    Time frame: Pre-dose, 1, 4, 24, 72, 168, 336 hours post-dose of Cycle 1 & 4 Day 1 for Part 1A; pre-dose, 1, 4, 24, 72, 168 hours post-dose of Cycle 1 Day 1, pre-dose, 1 hour post-dose of Cycle 3 Day 1 for Part 1B

14. Cmax of PF-06804103 Total Antibody

    Cmax is maximum observed serum concentration. Cmax for PF-06804103 total antibody was observed directly from data. Part 2A used a sparse PK sampling schedule leaving very limited data for PK parameter estimation, so PK parameters from Part 2A were not reported. Only part 1A and part 1B treatment groups were included in this outcome measure. Total antibody means PF-06804103 with or without PF-06380101 conjugated. Both the antibody and small molecule components of the ADC are critical to its activity, requiring assays suited to measuring these disparate components. Each analyte provides unique information regarding ADC behavior in vivo and, singly or in combination, facilitates understanding of ADC PK.

    Time frame: Pre-dose, 1, 4, 24, 72, 168, 336 hours post-dose of Cycle 1 & 4 Day 1 for Part 1A; pre-dose, 1, 4, 24, 72, 168 hours post-dose of Cycle 1 & 4 Day 1 for Part 1B

15. t1/2 of PF-06804103 Total Antibody

    Terminal serum half-life (t1/2) is the time measured for the serum concentration of drug to decrease by one half. Part 2A used a sparse PK sampling schedule leaving very limited data for PK parameter estimation, so PK parameters from Part 2A were not reported. Only part 1A and part 1B treatment groups were included in this outcome measure.

    Time frame: Pre-dose, 1, 4, 24, 72, 168, 336 hours post-dose of Cycle 1 & 4 Day 1 for Part 1A; pre-dose, 1, 4, 24, 72, 168 hours post-dose of Cycle 1 & 4 Day 1 for Part 1B

16. AUCinf of PF-06804103 Total Antibody

    AUCinf is the area under the serum concentration-time profile from time zero extrapolated to infinite time. Part 2A used a sparse PK sampling schedule leaving very limited data for PK parameter estimation, so PK parameters from Part 2A were not reported. Only part 1A and part 1B treatment groups were included in this outcome measure.

    Time frame: Pre-dose, 1, 4, 24, 72, 168, 336 hours post-dose of Cycle 1 Day 1 for Part 1A; pre-dose, 1, 4, 24, 72, 168 hours post-dose of Cycle 1 Day 1 for Part 1B

17. AUCtau of PF-06804103 Total Antibody

    Tau refers to the dosing interval and it equals to 504 hours for Part 1A and 336 hours for Part 1B. AUCtau is the area under the concentration-time profile from time zero to time tau. AUCtau for PF-06804103 total antibody was determined using linear/log trapezoidal method. Part 2A used a sparse PK sampling schedule leaving very limited data for PK parameter estimation, so PK parameters from Part 2A were not reported. Only part 1A and part 1B treatment groups were included in this outcome measure.

    Time frame: Pre-dose, 1, 4, 24, 72, 168, 336 hours post-dose of Cycle 4 Day 1 for Part 1A; pre-dose, 1, 4, 24, 72, 168 hours post-dose of Cycle 4 Day 1 for Part 1B

18. CL of PF-06804103 Total Antibody

    Clearance (CL) is a quantitative measure of the rate at which a drug substance is removed from the body. Clearance for PF-06804103 total antibody was calculated as dose/AUCinf for single dose and dose/AUCtau for multiple dose, where AUCinf was the area under the serum concentration-time profile from time zero extrapolated to infinite time and AUCtau was the area under the concentration-time profile from time zero to time tau (tau equals to 504 hours for Part 1A and 336 hours for Part 1B). Part 2A used a sparse PK sampling schedule leaving very limited data for PK parameter estimation, so PK parameters from Part 2A were not reported. Only part 1A and part 1B treatment groups were included in this outcome measure.

    Time frame: Pre-dose, 1, 4, 24, 72, 168, 336 hours post-dose of Cycle 1 & 4 Day 1 for Part 1A; pre-dose, 1, 4, 24, 72, 168 hours post-dose of Cycle 1 & 4 Day 1 for Part 1B

19. Vss of PF-06804103 Total Antibody

    Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state. Part 2A used a sparse PK sampling schedule leaving very limited data for PK parameter estimation, so PK parameters from Part 2A were not reported. Only part 1A and part 1B treatment groups were included in this outcome measure.

    Time frame: Pre-dose, 1, 4, 24, 72, 168, 336 hours post-dose of Cycle 4 Day 1 for Part 1A; pre-dose, 1, 4, 24, 72, 168 hours post-dose of Cycle 4 Day 1 for Part 1B

20. Rac of PF-06804103 Total Antibody

    Rac is defined as observed accumulation ratio based on dose normalized AUCtau (AUCtau\[dn\]), where AUCtau is the area under the concentration-time profile from time zero to time tau (tau equals to 504 hours for Part 1A and 336 hours for Part 1B). Rac=\[Cycle 4 Day 1 AUCtau(dn) (multiple dose)\] /\[Cycle 1 Day 1 AUCtau(dn) (single Dose)\] for Part 1A, Rac=\[Cycle 3 Day 1 AUCtau(dn) (multiple dose)\] /\[Cycle 1 Day 1 AUCtau(dn) (single Dose)\] for Part 1B. Part 2A used a sparse PK sampling schedule leaving very limited data for PK parameter estimation, so PK parameters from Part 2A were not reported. Only part 1A and part 1B treatment groups were included in this outcome measure.

    Time frame: Pre-dose, 1, 4, 24, 72, 168, 336 hours post-dose of Cycle 1 & 4 Day 1 for Part 1A; pre-dose, 1, 4, 24, 72, 168 hours post-dose of Cycle 1 Day 1, pre-dose, 1 hour post-dose of Cycle 3 Day 1 for Part 1B

21. Cmax of PF-06380101 Unconjugated Payload

    Cmax is maximum observed serum concentration. Cmax for PF-06380101 unconjugated payload was observed directly from data. Part 2A used a sparse PK sampling schedule leaving very limited data for PK parameter estimation, so PK parameters from Part 2A were not reported. Only part 1A and part 1B treatment groups were included in this outcome measure. Small molecule components (PF-06380101) of the ADC are critical to its activity, requiring assays suited to measuring these disparate components. Each analyte provides unique information regarding ADC behavior in vivo and, singly or in combination, facilitates understanding of ADC PK.

    Time frame: Pre-dose, 1, 4, 24, 72, 168, 336 hours post-dose of Cycle 1 & 4 Day 1 for Part 1A; pre-dose, 1, 4, 24, 72, 168 hours post-dose of Cycle 1 & 4 Day 1 for Part 1B

22. Time for Cmax (Tmax) of PF-06380101 Unconjugated Payload

    Tmax is the time for Cmax. Tmax for PF-06380101 unconjugated payload was observed directly from data as time of first occurrence.Part 2A used a sparse PK sampling schedule leaving very limited data for PK parameter estimation, so PK parameters from Part 2A were not reported. Only part 1A and part 1B treatment groups were included in this outcome measure.

    Time frame: Pre-dose, 1, 4, 24, 72, 168, 336 hours post-dose of Cycle 1 & 4 Day 1 for Part 1A; pre-dose, 1, 4, 24, 72, 168 hours post-dose of Cycle 1 & 4 Day 1 for Part 1B

23. t1/2 of PF-06380101 Unconjugated Payload

    Terminal serum half-life (t1/2) is the time measured for the serum concentration of drug to decrease by one half. Part 2A used a sparse PK sampling schedule leaving very limited data for PK parameter estimation, so PK parameters from Part 2A were not reported. Only part 1A and part 1B treatment groups were included in this outcome measure.

    Time frame: Pre-dose, 1, 4, 24, 72, 168, 336 hours post-dose of Cycle 1 & 4 Day 1 for Part 1A; pre-dose, 1, 4, 24, 72, 168 hours post-dose of Cycle 1 & 4 Day 1 for Part 1B

24. AUCinf of PF-06380101 Unconjugated Payload

    AUCinf is the area under the serum concentration-time profile from time zero extrapolated to infinite time. Part 2A used a sparse PK sampling schedule leaving very limited data for PK parameter estimation, so PK parameters from Part 2A were not reported. Only part 1A and part 1B treatment groups were included in this outcome measure.

    Time frame: Pre-dose, 1, 4, 24, 72, 168, 336 hours post-dose of Cycle 1 Day 1 for Part 1A; pre-dose, 1, 4, 24, 72, 168 hours post-dose of Cycle 1 Day 1 for Part 1B

25. AUCtau of PF-06380101 Unconjugated Payload

    Tau refers to the dosing interval and it equals to 504 hours for Part 1A and 336 hours for Part 1B. AUCtau is the area under the concentration-time profile from time zero to time tau. AUCtau for PF-06804103 total antibody was determined using linear/log trapezoidal method. Part 2A used a sparse PK sampling schedule leaving very limited data for PK parameter estimation, so PK parameters from Part 2A were not reported. Only part 1A and part 1B treatment groups were included in this outcome measure.

    Time frame: Pre-dose, 1, 4, 24, 72, 168, 336 hours post-dose of Cycle 4 Day 1 for Part 1A; pre-dose, 1, 4, 24, 72, 168 hours post-dose of Cycle 4 Day 1 for Part 1B

26. Rac of PF-06380101 Unconjugated Payload

    Rac is defined as observed accumulation ratio based on dose normalized AUCtau (AUCtau\[dn\]), where AUCtau is the area under the concentration-time profile from time zero to time tau (tau equals to 504 hours for Part 1A and 336 hours for Part 1B). Rac=\[Cycle 4 Day 1 AUCtau(dn) (multiple dose)\]/\[Cycle 1 Day 1 AUCtau(dn) (single Dose)\] for Part 1A, Rac=\[Cycle 3 Day 1 AUCtau(dn) (multiple dose)\]/\[Cycle 1 Day 1 AUCtau(dn) (single Dose)\] for Part 1B. Part 2A used a sparse PK sampling schedule leaving very limited data for PK parameter estimation, so PK parameters from Part 2A were not reported. Only part 1A and part 1B treatment groups were included in this outcome measure.

    Time frame: Pre-dose, 1, 4, 24, 72, 168, 336 hours post-dose of Cycle 1 & 4 Day 1 for Part 1A; pre-dose, 1, 4, 24, 72, 168 hours post-dose of Cycle 1 Day 1, pre-dose, 1 hour post-dose of Cycle 3 Day 1 for Part 1B

Baseline characteristics

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Study documents

• Study protocol · Jan 24, 2020
• Statistical analysis plan · Aug 23, 2021

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Individual participant data

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