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

Primary Purpose

Relapsed Malignant Mesothelioma

Status

Terminated

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

VS-5584 and VS-6063

About this trial

This is an interventional treatment trial for Relapsed Malignant Mesothelioma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Histopathologically-confirmed diagnosis of malignant mesothelioma (pleural or peritoneal). Must have disease that has relapsed following at least one prior line of chemotherapy.
Must have received at least 3 cycles of first-line chemotherapy.
Evaluable or measurable disease as assessed by Response Evaluation Criteria in Solid Tumors (RECIST).
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.
Performance status according to the Karnofsky Performance Scale ≥70%.
Fasting blood glucose of ≤ 140 mg/dL (7.8 mmol/L).
Adequate renal function (creatinine ≤ 1.5x upper limit of normal [ULN]) and/or glomerular filtration rate (GFR) of ≥50 mL/min.
Adequate hepatic function (total bilirubin ≤ 1.5x ULN; AST and ALT ≤ 3x ULN).
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:

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

Sites / Locations

The University of Chicago Medical Center
Memorial Sloane Kettering Cancer Center
University of Leicester
The Institute of Cancer Research

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

VS-5584 and VS-6063

Arm Description

Outcomes

Primary Outcome Measures

Incidence of dose-limiting toxicities (DLTs)

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

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

Secondary Outcome Measures

Pharmacokinetics of VS-5584 & VS-6063 maximum observed plasma concentration (Cmax)

Pharmacokinetics of VS-5584 & VS-6063 plasma area under the curve from time zero to last quantifiable concentration (AUClast)

Pharmacokinetics of VS-5584 & VS-6063 time to reach maximum observed concentration (Tmax)

Pharmacokinetics of VS-5584 & VS-6063 area under the curve from time zero to extrapolated infinite time (AUCO-inf)

Pharmacokinetics of VS-5584 & VS-6063 apparent oral clearance (CL/F)

Pharmacokinetics of VS-5584 & VS-6063 apparent volume of distribution (Vz/F)

Pharmacokinetics of VS-5584 & VS-6063 trough plasma concentration

Full Information

NCT ID

NCT02372227

First Posted

January 30, 2015

Last Updated

January 26, 2017

Sponsor

Verastem, Inc.

1. Study Identification

Unique Protocol Identification Number

NCT02372227

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

Study Type

Interventional

2. Study Status

Record Verification Date

January 2017

Overall Recruitment Status

Terminated

Study Start Date

January 2015 (undefined)

Primary Completion Date

October 2015 (Actual)

Study Completion Date

October 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Verastem, Inc.

4. Oversight

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Relapsed Malignant Mesothelioma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

21 (Actual)

8. Arms, Groups, and Interventions

Arm Title

VS-5584 and VS-6063

Arm Type

Experimental

Intervention Type

Drug

Intervention Name(s)

VS-5584 and VS-6063

Intervention Description

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.

Primary Outcome Measure Information:

Title

Incidence of dose-limiting toxicities (DLTs)

Description

Dose Escalation Phase: Frequency of DLTs at each dose level associated with administration of VS-5584 and VS-6063 in a 21 day cycle

Time Frame

6 months

Title

Safety and tolerability of the combination of VS-5584 and VS-6063

Description

Time Frame

16 months

Secondary Outcome Measure Information:

Title

Pharmacokinetics of VS-5584 & VS-6063 maximum observed plasma concentration (Cmax)

Time Frame

0-48 hours per patient

Title

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

Title

Pharmacokinetics of VS-5584 & VS-6063 time to reach maximum observed concentration (Tmax)

Time Frame

0-48 hours per patient

Title

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

Title

Pharmacokinetics of VS-5584 & VS-6063 apparent oral clearance (CL/F)

Time Frame

0-48 hours per patient

Title

Pharmacokinetics of VS-5584 & VS-6063 apparent volume of distribution (Vz/F)

Time Frame

0-48 hours per patient

Title

Pharmacokinetics of VS-5584 & VS-6063 trough plasma concentration

Time Frame

0-48 hours per patient

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Histopathologically-confirmed diagnosis of malignant mesothelioma (pleural or peritoneal). Must have disease that has relapsed following at least one prior line of chemotherapy. Must have received at least 3 cycles of first-line chemotherapy. Evaluable or measurable disease as assessed by Response Evaluation Criteria in Solid Tumors (RECIST). 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. Performance status according to the Karnofsky Performance Scale ≥70%. Fasting blood glucose of ≤ 140 mg/dL (7.8 mmol/L). Adequate renal function (creatinine ≤ 1.5x upper limit of normal [ULN]) and/or glomerular filtration rate (GFR) of ≥50 mL/min. Adequate hepatic function (total bilirubin ≤ 1.5x ULN; AST and ALT ≤ 3x ULN). 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: Have had a previous extra pleural pneumonectomy (EPP). Gastrointestinal condition which could interfere with the swallowing or absorption of study drug. Uncontrolled or severe concurrent medical condition (including uncontrolled brain metastases). Known history of stroke or cerebrovascular accident within 6 months prior to the first dose of study drug. Any evidence of serious active infection. Undergoing active treatment for a secondary malignancy. Cancer-directed therapy (chemotherapy, radiotherapy) within 21 days of the first dose of study drug or 5 half-lives, whichever is shorter. Major surgery within 28 days prior to the first dose of study drug. Acute or chronic pancreatitis. Diabetes mellitus requiring insulin treatment or subjects with a hemoglobin A1C (HbA1C) >7%. History or evidence of cardiac risk. Known history of malignant hypertension.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Hagop Youssoufian

Organizational Affiliation

Verastem, Inc.

Official's Role

Study Chair

Facility Information:

Facility Name

The University of Chicago Medical Center

City

Chicago

State/Province

Illinois

ZIP/Postal Code

60637

Country

United States

Facility Name

Memorial Sloane Kettering Cancer Center

City

New York

State/Province

New York

ZIP/Postal Code

10065

Country

United States

Facility Name

University of Leicester

City

Leicester

Country

United Kingdom

Facility Name

The Institute of Cancer Research

City

Sutton Surrey

Country

United Kingdom

12. IPD Sharing Statement

Learn more about this trial

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

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