Clinical trial NCT02644278: First-in-Human Study of the Safety, Tolerability, and Pharmacokinetic/Pharmacodynamic Profile of VX-984 in Combination With Chemotherapy
Official title: An Open-Label, Phase 1, First-in-Human Study of the Safety, Tolerability, and Pharmacokinetic/Pharmacodynamic Profile of VX-984 in Combination With Chemotherapy in Subjects With Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Advanced Solid Tumor
Keywords: VX15-984-001
VX-984
M9831
Advanced Solid Tumor
Pegylated liposomal doxorubicin
Lead sponsor: EMD Serono
Sponsor class: INDUSTRY
Collaborators: name: Merck KGaA, Darmstadt, Germany
First posted: 2015-12-31
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: The purpose of this study was to evaluate the safety and tolerability of VX-984 (M9831) administered alone and in combination with pegylated liposomal doxorubicin (PLD), and to determine the maximum tolerated dose (MTD) and preliminary evidence of efficacy of VX-984 in combination with PLD in participants with advanced solid tumors.


Eligibility criteria: Inclusion Criteria:

* Participants (male and female for Part A and female for Part B) were at least 18 year of age.
* Part A Participants with histologically or cytologically confirmed malignant advanced solid tumors, who had progressed on at least 1 prior chemotherapy, and for whom either

  1. No standard care available
  2. PLD at the dose and schedule being used might be considered standard of care
* Part B

  1. Participants with histologically confirmed advanced primary endometrial cancer (locally advanced and incurable endometrial cancer that had been treated with surgery and/or radiation or is ineligible for such treatment), or recurrent or metastatic endometrial cancer, and
  2. Completed 1 line of chemotherapy treatment with a platinum-containing regimen in the advanced setting
* Measurable disease according to RECIST criteria (Version 1.1)
* Life expectancy of at least 12 weeks
* Hematological and biochemical indices within acceptable ranges shown at screening.
* Normal left ventricular ejection fraction on screening assessed by transthoracic echocardiogram or multiple gated acquisition (MUGA) scan

Exclusion Criteria:

* Previous radiotherapy (unless brachytherapy), endocrine therapy, chemotherapy, or exposure to investigational medicinal products during the 4 weeks (6 weeks for nitrosoureas and Mitomycin-C) or 4 drug half-lives before the planned administration of the first dose of study drug, whichever is greater. Previous immunotherapy during the 4 weeks before the planned administration of the first dose of study drug.
* For Part B only:

  1. Participants with uterine carcinosarcoma
  2. Prior anthracycline therapy
  3. More than 1 prior chemotherapy regimen (a participant was received first- line carboplatin and taxane and then received the same taxane second- line were considered to have had 1 prior chemotherapy regimen)
* Unresolved toxicity of Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 or greater from previous anti-cancer therapy or radiotherapy
* History of spinal cord compression or brain metastases, unless asymptomatic, treated, stable, and not requiring treatment with steroids for at least 4 weeks before the planned administration of the first dose of study drug. Any history of leptomeningeal metastases.
* Female participants who was pregnant or lactating at Screening, or planned to become pregnant while on study or within 6 months after the last dose of study drug
* Female participants of childbearing potential were adhere to contraception guidelines as outlined in the protocol. Female participants were considered to be of nonchildbearing potential if they had undergone surgical hysterectomy or bilateral oophorectomy or had been amenorrheic for more than 2 years with a screening serum follicle-stimulating hormone (FSH) level within the laboratory's reference range for postmenopausal females
* Male participants with pregnant or lactating partners or partners who planned to become pregnant while on study or within 6 months after the planned administration of the last dose of study drug
* Major surgery ≤4 weeks before first dose of study drug, or incomplete recovery from a prior major surgical procedure
* Cardiac conditions
* Prior bone marrow transplant
* Extensive radiotherapy (to greater than 15% of bone marrow)
* Any other condition that in the investigator's opinion would not make the participant a good candidate for the clinical study,
* Part B: Current active malignancies of other types, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin. Prior cancer in remission for 2 years or more would not be excluded.

Primary outcomes:
measure: Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs
timeFrame: Baseline up to 28 days after the last dose of study treatment, assessed up to 53.1 weeks
measure: Part A: Number of Participants Who Experienced Dose Limiting Toxicity (DLT)
timeFrame: Cycle 1 (each cycle is 28 days)
measure: Part A: Number of Participants With Toxicity Grade 3 or Higher in Laboratory Abnormalities
timeFrame: Baseline up to 28 days after the last dose of study treatment, assessed up to 53.1 weeks
measure: Part A: Maximum Tolerated Dose (MTD) of VX-984 in Combination With Pegylated Liposomal Doxorubicin (PLD)
timeFrame: Up to Cycle 1 Day 28 (each cycle is 28 days)
measure: Part A: Number of Participants With Clinical Significant Abnormalities in Vital Signs
timeFrame: Baseline up to 28 days after the last dose of study treatment, assessed up to 53.1 weeks
measure: Part A: Number of Participants With Clinical Significant Abnormalities Echocardiograms
timeFrame: Baseline up to 28 days after the last dose of study treatment, assessed up to 53.1 weeks
measure: Part A: Number of Participants With Clinical Significant Abnormalities in Electrocardiogram(ECG) Parameters
timeFrame: Baseline up to 28 days after the last dose of study treatment, assessed up to 53.1 weeks
Secondary outcomes:
measure: Part A: Area Under Plasma Concentration (AUC) During a Dosing Interval of VX-984
timeFrame: 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)
measure: Part A: Maximum Observed Plasma Concentration (Cmax) of VX-984
timeFrame: 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)
measure: Part A: Time to Reach Maximum Plasma Concentration (Tmax) of VX-984
timeFrame: 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)
measure: Part A: Minimum Observed Plasma Concentration During Dosing Interval (Cmin) of VX-984
timeFrame: 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)
measure: Part A: Area Under the Plasma Concentration Curve From Time Zero to 96 Hours Post Dose AUC(0-96h) of Pegylated Liposomal Doxorubicin
timeFrame: Pre-infusion and at 1, 2, 4, 6, 24, 72 and 96 hours after infusion in Cycle 1 (each Cycle is of 28 days)
measure: Part A: Maximum Observed Plasma Concentration (Cmax0-96h) From Time Zero to 96 Hours Post Dose of Pegylated Liposomal Doxorubicin
timeFrame: Pre-infusion and at 1, 2, 4, 6, 24, 72 and 96 hours after infusion in Cycle 1 (each Cycle is of 28 days)
measure: Part A: Time to Reach Maximum Plasma Concentration From Zero to 96 Hours Post Dose (tmax0-96h) of Pegylated Liposomal Doxorubicin
timeFrame: Pre-infusion and at 1, 2, 4, 6, 24, 72 and 96 hours after infusion in Cycle 1 (each Cycle is of 28 days)
measure: Part A: Number of Participants With Best Overall Response Evaluated by Response Criteria Evaluation (RECIST 1.1)
timeFrame: Up to 2 years
Other outcomes:
Locations:
city: Scottsdale
country: United States
state: Arizona
city: Boston
country: United States
state: Massachusetts
city: Nashville
country: United States
state: Tennessee
city: Dallas
country: United States
state: Texas
city: Houston
country: United States
state: Texas
Study officials:
affiliation: EMD Serono Research & Development Institute, Inc., a subsidiary of Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References: