A Phase 1 Dose Escalation Study of VS-5584 Administered in Combination With VS-6063, in Subjects With Relapsed Malignant Mesothelioma

• ClinicalTrials.gov Identifier: NCT02372227
• Recruitment Status: Terminated
• First Posted: February 26, 2015
• Last Update Posted: January 30, 2017
• Sponsor: Verastem, Inc.
• Information provided by (Responsible Party): Verastem, Inc.

Tracking Information

• First Submitted Date: January 30, 2015
• First Posted Date: February 26, 2015
• Last Update Posted Date: January 30, 2017
• Study Start Date: January 2015
• Actual Primary Completion Date: October 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 19, 2015)

• Incidence of dose-limiting toxicities (DLTs) [ Time Frame: 6 months ]
  Dose Escalation Phase: Frequency of DLTs at each dose level associated with administration of VS-5584 and VS-6063 in a 21 day cycle
• Safety and tolerability of the combination of VS-5584 and VS-6063 [ Time Frame: 16 months ]
  Dose Escalation Phase and Expansion Phase: A composite by dose level to include incidence of AEs, SAEs (overall and severity), laboratory abnormalities, ECGs, vital signs, Karnofsky Performance Status, dose interruptions and dose reductions as a measure of safety and tolerability

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: February 19, 2015)

• Pharmacokinetics of VS-5584 & VS-6063 maximum observed plasma concentration (Cmax) [ Time Frame: 0-48 hours per patient ]
• Pharmacokinetics of VS-5584 & VS-6063 plasma area under the curve from time zero to last quantifiable concentration (AUClast) [ Time Frame: 0-48 hours per patient ]
• Pharmacokinetics of VS-5584 & VS-6063 time to reach maximum observed concentration (Tmax) [ Time Frame: 0-48 hours per patient ]
• Pharmacokinetics of VS-5584 & VS-6063 area under the curve from time zero to extrapolated infinite time (AUCO-inf) [ Time Frame: 0-48 hours per patient ]
• Pharmacokinetics of VS-5584 & VS-6063 apparent oral clearance (CL/F) [ Time Frame: 0-48 hours per patient ]
• Pharmacokinetics of VS-5584 & VS-6063 apparent volume of distribution (Vz/F) [ Time Frame: 0-48 hours per patient ]
• Pharmacokinetics of VS-5584 & VS-6063 trough plasma concentration [ Time Frame: 0-48 hours per patient ]

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Phase 1 Dose Escalation Study of VS-5584 Administered in Combination With VS-6063, in Subjects With Relapsed Malignant Mesothelioma
• Official Title: A Phase 1 Dose Escalation Study of VS-5584, a Dual PI3K/mTOR Inhibitor, Administered With a Fixed Dose of VS-6063, a Focal Adhesion Kinase Inhibitor, in Subjects With Relapsed Malignant Mesothelioma
• Brief Summary: The purpose of this study is to evaluate rising dose levels of VS-5584 administered in combination with a fixed dose of VS-6063 in subjects with relapsed malignant mesothelioma to determine a recommended Phase 2 dose (RP2D) for further development of this combination in this indication.

Detailed Description

This study is comprised of 2 sequential parts: Part 1 (Dose Escalation of VS-5584) and Part 2 (Expansion). Up to 56 evaluable subjects (i.e., subjects who complete at least 1 cycle [21 days] of therapy) will be enrolled, assuming that:

• Up to 6 dose levels of VS-5584 are studied in Part 1 (Dose Escalation of VS-5584) in combination with a fixed dose of VS-6063 at 400 mg twice daily (BID) with a maximum of 6 subjects enrolled per VS-5584 dose level, for a total of up to 36 subjects (exclusive of replacement subjects).
• Up to an additional 20 evaluable subjects may be enrolled in Part 2, the expansion portion of the study. Subjects will be treated with VS-5584 at the RP2D and schedule determined in the dose escalation portion of the study in combination with a fixed dose of VS-6063.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Relapsed Malignant Mesothelioma

Intervention

Drug: VS-5584 and VS-6063

Starting dose of VS-5584 will be 20mg taken once daily, 3x/week of each 21 day cycle. All subjects will also receive 2x/day treatment with 400mg VS-6063 in 21 day cycles. Number of Cycles: until progression or unacceptable toxicity develops.

Study Arms

Experimental: VS-5584 and VS-6063

Intervention: Drug: VS-5584 and VS-6063

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: January 3, 2017): 21
• Original Estimated Enrollment (submitted: February 19, 2015): 56
• Actual Study Completion Date: October 2015
• Actual Primary Completion Date: October 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Histopathologically-confirmed diagnosis of malignant mesothelioma (pleural or peritoneal). Must have disease that has relapsed following at least one prior line of chemotherapy.
2. Must have received at least 3 cycles of first-line chemotherapy.
3. Evaluable or measurable disease as assessed by Response Evaluation Criteria in Solid Tumors (RECIST).
4. Must have archival tumor tissue available for biomarker analysis. A study-specific tumor core biopsy, pleural effusion or ascites sample must be obtained prior to treatment if archival tissue is not available.
5. Performance status according to the Karnofsky Performance Scale ≥70%.
6. Fasting blood glucose of ≤ 140 mg/dL (7.8 mmol/L).
7. Adequate renal function (creatinine ≤ 1.5x upper limit of normal [ULN]) and/or glomerular filtration rate (GFR) of ≥50 mL/min.
8. Adequate hepatic function (total bilirubin ≤ 1.5x ULN; AST and ALT ≤ 3x ULN).
9. Adequate bone marrow function (hemoglobin ≥9.0 g/dL; platelets ≥100 x10^9 cells/L; absolute neutrophil count ≥1.5x10^9 cells/L) without the use of hematopoietic growth factors.

Exclusion Criteria:

1. Have had a previous extra pleural pneumonectomy (EPP).
2. Gastrointestinal condition which could interfere with the swallowing or absorption of study drug.
3. Uncontrolled or severe concurrent medical condition (including uncontrolled brain metastases).
4. Known history of stroke or cerebrovascular accident within 6 months prior to the first dose of study drug.
5. Any evidence of serious active infection.
6. Undergoing active treatment for a secondary malignancy.
7. Cancer-directed therapy (chemotherapy, radiotherapy) within 21 days of the first dose of study drug or 5 half-lives, whichever is shorter.
8. Major surgery within 28 days prior to the first dose of study drug.
9. Acute or chronic pancreatitis.
10. Diabetes mellitus requiring insulin treatment or subjects with a hemoglobin A1C (HbA1C) >7%.
11. History or evidence of cardiac risk.
12. Known history of malignant hypertension.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United Kingdom, United States

Administrative Information

• NCT Number: NCT02372227
• Other Study ID Numbers: VS-6063-104
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Verastem, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Verastem, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Chair: Hagop Youssoufian; Verastem, Inc.

• PRS Account: Verastem, Inc.
• Verification Date: January 2017