First-in-Human Study of the Safety, Tolerability, and Pharmacokinetic/Pharmacodynamic Profile of VX-984 in Combination With Chemotherapy

Keywords

• VX15-984-001
• VX-984
• M9831
• Advanced Solid Tumor
• Pegylated liposomal doxorubicin

Lead sponsor

EMD Serono Research & Development Institute, Inc. is the lead sponsor of 87 studies on the registry; 8 are open to participants now.

Of its 46 completed or terminated interventional studies of FDA-regulated products, 38 (83%) have results posted.

First submitted after EMD Serono Research & Development Institute, Inc. became part of Merck KGaA, Darmstadt, Germany.

Study arms

• Experimental
  VX-984 120 mg + PLD 40 mg/m^2

  Drug: VX-984 120 mg + PLD 40 mg/m^2

• Experimental
  VX-984 240 mg + PLD 40 mg/m^2

  Drug: VX-984 240 mg + PLD 40 mg/m^2

• Experimental
  VX-984 480 mg + PLD 40 mg/m^2

  Drug: VX-984 480 mg + PLD 40 mg/m^2

• Experimental
  VX-984 720 mg + PLD 40 mg/m^2

  Drug: VX-984 720 mg + PLD 40 mg/m^2

Interventions

• DrugVX-984 120 mg + PLD 40 mg/m^2

  Participants received VX-984 orally 120 milligram (mg) orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 120 mg in combination with pegylated liposomal doxorubicin (PLD) 40 milligram per square meter (mg/m\^2) administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m\^2.

  Also known as: M9831

• DrugVX-984 240 mg + PLD 40 mg/m^2

  Participants received VX-984 orally 240 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 240 mg in combination with PLD 40 mg/m\^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m\^2.

• DrugVX-984 480 mg + PLD 40 mg/m^2

  Participants received VX-984 orally 480 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 480 mg in combination with PLD 40 mg/m\^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m\^2.

• DrugVX-984 720 mg + PLD 40 mg/m^2

  Participants received VX-984 orally 720 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 720 mg in combination with PLD 40 mg/m\^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m\^2.

Primary outcomes

1. Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs

   An adverse event (AE) was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious AE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Treatment-Emergent adverse events (TEAEs) were defined as AEs that were reported or worsened on or after the start of study drug dosing through the 28-day Safety Follow-up visit. TEAEs included both Serious TEAEs and non-serious TEAEs.

   Time frame: Baseline up to 28 days after the last dose of study treatment, assessed up to 53.1 weeks

2. Part A: Number of Participants Who Experienced Dose Limiting Toxicity (DLT)

   DLT was defined using National cancer Institute Common Toxicity Criteria for Adverse Events Version 4.0 as any of the following toxicities: Grade 4 neutropenia for more than 7 days; Grade greater than or equal to (\>=) 3 febrile neutropenia; Grade 4 or Grade 3 thrombocytopenia with bleeding. Grade \>= 3 uncontrolled nausea/vomiting and/or diarrhea despite adequate and optimal treatment and Grade \>= 3 any non- hematological adverse event (AE), except the aforementioned gastrointestinal events and alopecia.

   Time frame: Cycle 1 (each cycle is 28 days)

3. Part A: Number of Participants With Toxicity Grade 3 or Higher in Laboratory Abnormalities

   The laboratory measurements included hematology and serum chemistry. It had been graded according to National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 into Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (Life-threatening) and Grade 5 = death. Participants with grade 3 or higher were reported.

   Time frame: Baseline up to 28 days after the last dose of study treatment, assessed up to 53.1 weeks

4. Part A: Maximum Tolerated Dose (MTD) of VX-984 in Combination With Pegylated Liposomal Doxorubicin (PLD)

   The MTD was defined as the combination dose associated with the highest probability that Dose limiting toxicity (DLT) events will occur in 16.6 percent to less than 33.3 percent participants as the combination dose that not exceeded the overdose criterion (more than 25 percent probability that DLT events occurred less than or equal to (\>=) 33 percent of participants. DLT was defined using National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.0.

   Time frame: Up to Cycle 1 Day 28 (each cycle is 28 days)

5. Part A: Number of Participants With Clinical Significant Abnormalities in Vital Signs

   Vital signs assessment included blood pressure, pulse rate and body temperature. Clinical significance was determined by the investigator. Number of participants with clinical significant abnormalities in vital Signs reported here.

   Time frame: Baseline up to 28 days after the last dose of study treatment, assessed up to 53.1 weeks

6. Part A: Number of Participants With Clinical Significant Abnormalities Echocardiograms

   Echocardiogram is a graphic outline of the heart's movement. Clinical significance was determined by the investigator. Number of participants with clinical significant abnormalities in Echocardiograms reported here.

   Time frame: Baseline up to 28 days after the last dose of study treatment, assessed up to 53.1 weeks

7. Part A: Number of Participants With Clinical Significant Abnormalities in Electrocardiogram(ECG) Parameters

   ECG parameters included heart rate, pulse rate, QRS,QT, RR, QTcB and QTcF. Clinical significance was determined by the investigator. Number of participants with clinical significant abnormalities in ECG parameters reported here.

   Time frame: Baseline up to 28 days after the last dose of study treatment, assessed up to 53.1 weeks

Secondary outcomes

1. Part A: Area Under Plasma Concentration (AUC) During a Dosing Interval of VX-984

   AUC is the area under the plasma concentration curve within 1 dosing interval.

   Time frame: Pre-dose and at 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day -12 and Day 4 in Cycle 1; Pre-dose and at 0.5, 1, 2, 4 hours post-dose on Day 2 in Cycle 1 (each Cycle is of 28 days)

2. Part A: Maximum Observed Plasma Concentration (Cmax) of VX-984

   Pharmacokinetic PK parameter Cmax was obtained directly from the concentration versus time curve.

   Time frame: Pre-dose and at 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day -12 and Day 4 in Cycle 1; Pre-dose and at 0.5, 1, 2, 4 hours post-dose on Day 2 in Cycle 1 (each Cycle is of 28 days)

3. Part A: Time to Reach Maximum Plasma Concentration (Tmax) of VX-984

   Time to reach the maximum plasma concentration (Tmax) was obtained directly from the concentration versus time curve.

   Time frame: Pre-dose and at 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day -12 and Day 4 in Cycle 1; Pre-dose and at 0.5, 1, 2, 4 hours post-dose on Day 2 in Cycle 1 (each Cycle is of 28 days)

4. Part A: Minimum Observed Plasma Concentration During Dosing Interval (Cmin) of VX-984

   Cmin is minimum observed plasma concentration obtained directly from the concentration versus time curve.

   Time frame: Pre-dose and at 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day -12 and Day 4 in Cycle 1; Pre-dose and at 0.5, 1, 2, 4 hours post-dose on Day 2 in Cycle 1 (each Cycle is of 28 days)

5. Part A: Area Under the Plasma Concentration Curve From Time Zero to 96 Hours Post Dose AUC(0-96h) of Pegylated Liposomal Doxorubicin

   The AUC(0-96h) was estimated by determining the total area under the curve of the concentration versus curve extrapolated from 0 to 96 hours.

   Time frame: Pre-infusion and at 1, 2, 4, 6, 24, 72 and 96 hours after infusion in Cycle 1 (each Cycle is of 28 days)

6. Part A: Maximum Observed Plasma Concentration (Cmax0-96h) From Time Zero to 96 Hours Post Dose of Pegylated Liposomal Doxorubicin

   Cmax is the maximum observed plasma concentration obtained directly from concentration versus time curve from zero to 96 hours

   Time frame: Pre-infusion and at 1, 2, 4, 6, 24, 72 and 96 hours after infusion in Cycle 1 (each Cycle is of 28 days)

7. Part A: Time to Reach Maximum Plasma Concentration From Zero to 96 Hours Post Dose (tmax0-96h) of Pegylated Liposomal Doxorubicin

   Tmax is time to reach maximum observed plasma concentration obtained directly from the concentration versus time curve from zero to 96 hours post dose.

   Time frame: Pre-infusion and at 1, 2, 4, 6, 24, 72 and 96 hours after infusion in Cycle 1 (each Cycle is of 28 days)

8. Part A: Number of Participants With Best Overall Response Evaluated by Response Criteria Evaluation (RECIST 1.1)

   The best overall response was defined as the number of participants who had achieved complete response (CR) or partial response (PR) as the best overall response according to radiological assessments as adjudicated by the IRC from randomization until the first occurrence of progressive disease (PD). CR: Complete Response (CR) defined as disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Partial response (PR) defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started.

   Time frame: Up to 2 years

Baseline characteristics

Study documents

• Study protocol · Aug 21, 2017
• Statistical analysis plan · Jan 26, 2018

Documents are hosted by the registry — open the source record to download them.