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

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ClinicalTrials.gov Identifier: NCT02644278
Recruitment Status : Completed
First Posted : December 31, 2015
Last Update Posted : June 5, 2018
Sponsor:
Collaborator:
Merck KGaA
Information provided by (Responsible Party):
EMD Serono ( EMD Serono Research & Development Institute, Inc. )

Brief Summary:
The purpose of this study is 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 subjects with advanced solid tumors

Condition or disease Intervention/treatment Phase
Advanced Solid Tumor Drug: VX-984 Drug: IV pegylated liposomal doxorubicin (PLD) Phase 1

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 15 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : February 29, 2016
Actual Primary Completion Date : October 19, 2017
Actual Study Completion Date : October 19, 2017

Arm Intervention/treatment
Experimental: VX984/PLD
dose-escalation study in subjects with solid tumors (Part A) followed by an expansion phase in subjects with recurrent or metastatic endometrial cancer who have progressed on a prior platinum regimen (Part B).
Drug: VX-984
oral administration
Other Name: M9831

Drug: IV pegylated liposomal doxorubicin (PLD)



Primary Outcome Measures :
  1. Part A - Safety parameters, including adverse events (AEs), dose-limiting toxicities (DLTs), clinical laboratory values (serum chemistry and hematology), vital signs, echocardiogram, and electrocardiogram (ECG) assessments [ Time Frame: Up to day 30 after last dose ]
  2. Part A - maximum tolerated dose (MTD) of VX-984 in combination with pegylated liposomal doxorubicin (PLD) [ Time Frame: Up to Cycle 1 Day 28 ]
  3. Part B - Safety parameters, including AEs, clinical laboratory values (serum chemistry and hematology), vital signs, and ECG assessments [ Time Frame: Up to 30 days after last dose ]
  4. Part B - Objective response rate (ORR) as evaluated by CT scan per Response Criteria Evaluation (RECIST 1.1) [ Time Frame: Through study completion, approximately 2 years ]

Secondary Outcome Measures :
  1. Part A - Plasma Pharmacokinetics (PK) parameter estimates of VX-984: Area Under plasma Concentration (AUC) during a dosing interval [ Time Frame: on Day -12, and Day 4 ]
  2. Part A - Plasma PK parameter estimates of VX-984: Cmax (Maximum observed concentration) [ Time Frame: on Day -12, Day 2, and Day 4 ]
  3. Part A - Plasma PK parameter estimates of VX-984: tmax (time of the maximum concentration) [ Time Frame: on Day -12, Day 2, and Day 4 ]
  4. Part A - Plasma PK parameter estimates of VX-984: Cmin (minimum observed concentration during dosing interval) [ Time Frame: on Day -12, and Day 4 ]
  5. Part A - Plasma PK parameter estimates of PLD administered in combination with VX-984: AUC 0-96h (from time 0 to 96 hours post dose) [ Time Frame: on Day 1 ]
  6. Part A - Plasma PK parameter estimates of PLD administered in combination with VX-984: Cmax (maximum observed concentration from time 0 to 96 hours post dose ) [ Time Frame: on Day 1 ]
  7. Part A - Plasma PK parameter estimates of PLD administered in combination with VX-984: tmax (time of the maximum concentration from time 0 to 96 hours post dose) [ Time Frame: on Day 1 ]
  8. Part A - Preliminary evidence of anti-tumor activity, including tumor response as evaluated by Response Criteria Evaluation RECIST 1.1 and tumor markers [ Time Frame: Through study completion, approximately 2 years ]
  9. Part B - Progression Free Survival (PFS) [ Time Frame: An average of 1 year ]
  10. Part B - Response Duration (RD) [ Time Frame: Through study completion, approximately 2 years ]
  11. Part B - Overall Survival (OS) [ Time Frame: Through study completion, approximately 2 years ]
  12. Part B - Clinical Benefit (complete response(CR), partial response (PR), or stable disease (SD) of at least 4 months) [ Time Frame: Up to 1 year ]
  13. Part B - Plasma PK parameter estimates of VX-984 when administered in combination with PLD: AUC 0-8h (up to 8 hours) [ Time Frame: on day 4 ]
  14. Part B - Plasma PK parameter estimates of VX-984 when administered in combination with PLD: Cmax (maximum observed concentration). [ Time Frame: on day 4 ]
  15. Part B - Plasma PK parameter estimates of VX-984 when administered in combination with PLD: tmax (time of the maximum concentration) [ Time Frame: on day 4 ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subjects (male and female for Part A and female for Part B) will be at least 18 year of age.
  • Part A Subjects with histologically or cytologically confirmed malignant advanced solid tumors, who have 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. Subjects with histologically confirmed advanced primary endometrial cancer (locally advanced and incurable endometrial cancer that has 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. Subjects with uterine carcinosarcoma
    2. Prior anthracycline therapy
    3. More than 1 prior chemotherapy regimen (a subject who received first- line carboplatin and taxane and then receives the same taxane second- line will be 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 subjects who are pregnant or lactating at Screening, or plan to become pregnant while on study or within 6 months after the last dose of study drug
  • Female subjects of childbearing potential must adhere to contraception guidelines as outlined in the protocol. Female subjects will be considered to be of nonchildbearing potential if they have undergone surgical hysterectomy or bilateral oophorectomy or have 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 subjects with pregnant or lactating partners or partners who plan 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 subject 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02644278


Locations
United States, Arizona
Scottsdale, Arizona, United States, 85258
United States, Massachusetts
Boston, Massachusetts, United States, 02215
United States, Tennessee
Nashville, Tennessee, United States, 37203
United States, Texas
Dallas, Texas, United States, 75246
Houston, Texas, United States, 77030
Sponsors and Collaborators
EMD Serono Research & Development Institute, Inc.
Merck KGaA
Investigators
Study Director: Medical Responsible EMD Serono Research & Development Institute, Inc., a subsidiary of Merck KGaA, Darmstadt, Germany

Responsible Party: EMD Serono Research & Development Institute, Inc.
ClinicalTrials.gov Identifier: NCT02644278     History of Changes
Other Study ID Numbers: MS201926-0001
VX15-984-001 ( Other Identifier: Other )
First Posted: December 31, 2015    Key Record Dates
Last Update Posted: June 5, 2018
Last Verified: May 2018

Keywords provided by EMD Serono ( EMD Serono Research & Development Institute, Inc. ):
VX15-984-001
VX-984
M9831
Advanced Solid Tumor
Pegylated liposomal doxorubicin

Additional relevant MeSH terms:
Doxorubicin
Liposomal doxorubicin
Antibiotics, Antineoplastic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action