Phase I Dose Escalation Study of VS-5584 in Subjects With Advanced Non-Hematologic Malignancies or Lymphoma

• ClinicalTrials.gov Identifier: NCT01991938
• Recruitment Status: Terminated
• First Posted: November 25, 2013
• Last Update Posted: January 27, 2017
• Sponsor: Verastem, Inc.
• Information provided by (Responsible Party): Verastem, Inc.

Tracking Information

• First Submitted Date: November 18, 2013
• First Posted Date: November 25, 2013
• Last Update Posted Date: January 27, 2017
• Study Start Date: November 2013
• Actual Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 22, 2013)

• Assess the safety and tolerability of VS-5584 in subjects with advanced non-hematologic malignancies or lymphoma [ Time Frame: From start of treatment to end of treatment, an expected average of 6 weeks ]
  Serious Adverse events, Adverse events and their frequency, duration and severity, physical examination, laboratory parameters, vital signs and ECGs as determined based on CTCAE (Common Toxicity Criteria for Adverse Effects) V4.03. A Safety Monitoring Committee will review safety information.
• Determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) and schedule of VS-5584 administered to subjects with advanced non-hematologic malignancies or lymphoma [ Time Frame: From start of treatment to end of Cycle 1 (21 day cycles) ]
  The RP2D will be determined based on the MTD of VS-5584 as determined by number of participants with dose limiting toxicities related to VS-5584. Observations related to pharmacokinetics, pharmacodynamics, and any VS-5584 related toxicities may be included in the rationale supporting the RP2D and schedule and will not exceed the MTD.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: November 22, 2013)

Assess the pharmacokinetics of VS-5584 [ Time Frame: Time points on Day 1, 2, 3, 17, 18 ]

PK (pharmacokinetics) parameters, including but not limited to plasma concentration, clearance, AUC (Area Under Curve, 0-24 and 0-t), Cmax, Tmax, and T1/2

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: November 22, 2013)

• Evaluate the efficacy of VS-5584 [ Time Frame: Every 6 weeks to end of treatment, expected average of 6 weeks ]
  Response rate and progression-free survival as determined by Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1 or by the Revised Response Criteria for Malignant Lymphoma
• Evaluate the time to new lesion [ Time Frame: Expected average of 6 weeks from start of treatment to end of treatment ]
• Evaluate duration of response to VS-5584 compared with duration of response to prior therapy [ Time Frame: Expected average of 6 weeks from start of treatment to end of treatment ]
• Examine the pharmacodynamic effect of VS-5584 on target proteins in platelet rich plasma and tumor biopsies [ Time Frame: Platelet rich plasma time points: Day 1, 2, 8, 17; Tumor biopsies time points: Screening, Day 22, and at the time of progression ]
  Pharmacodynamic and predictive response biomarkers intended to demonstrate inhibition of the molecular target and determination of the mechanism of action will be assessed in archival tissue and tumor biopsies and platelet rich plasma samples.
• Examine if tumor genetic alterations and/or plasma biomarkers correlate with response to VS-5584 therapy [ Time Frame: start of treatment to end of treatment, an expected average of 6 weeks ]
  Tumor genetic alterations and/or plasma biomarkers compared with response to VS-5584, as determined by Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1 or Revised Response Criteria for Malignant Lymphoma

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: Phase I Dose Escalation Study of VS-5584 in Subjects With Advanced Non-Hematologic Malignancies or Lymphoma
• Official Title: A Phase I Dose Escalation Study of VS-5584, a Dual PI3K/mTOR Inhibitor, in Subjects With Advanced Non-Hematologic Malignancies or Lymphoma
• Brief Summary: This is a Phase I, open-label, multicenter, dose-escalation trial of VS-5584, a PI3K/mTOR kinase inhibitor, in subjects with advanced non-hematologic malignancies or lymphoma. This clinical study is comprised of 2 sequential parts: Part 1 (Dose Escalation) and Part 2 (Expansion). The purpose of this study is to evaluate the safety (including the recommended Phase II dose), pharmacokinetics (the amount of VS-5584 in subject's blood) and the anti-cancer activity of VS-5584. Biomarkers (genes or proteins that may predict or show how subject's body may respond to VS-5584) will also be assessed in archival tumor tissue, tumor biopsies (in consenting subjects), and blood samples.
• Detailed Description: Not Provided
• 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

• Non Hematologic Cancers
• Metastatic Cancer
• Lymphoma

• Intervention: Drug: VS-5584

Study Arms

Experimental: VS-5584

Oral VS-5584 administered once daily on Day 1, 3, 5, 8, 10, 12, 15, 17 and 19 of each cycle

Intervention: Drug: VS-5584

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: December 23, 2016): 75
• Original Estimated Enrollment (submitted: November 22, 2013): 62
• Actual Study Completion Date: December 2016
• Actual Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Able to provide signed and dated informed consent prior to initiation of any study procedures.
2. Age ≥ 18 years.
3. Subjects must have a histopathologically confirmed diagnosis of an advanced non-hematologic malignancy or lymphoma or indolent NHL/CLL.
4. Subjects must have no alternate therapy of proven benefit or have refused standard therapy.
5. All clinically significant toxicities from prior chemotherapy must be ≤ Grade 1.
6. ECOG performance status of 0 or 1, measured at screening and immediately before the start of treatment.
7. Predicted life expectancy of ≥ 3 months.
8. Fasting blood glucose of ≤ 140 mg/dL (7.8 mmol/L).
9. Adequate renal function [creatinine ≤ 1.5x ULN (upper limit of normal)] or GFR of ≥ 60mL/min.
10. Adequate hepatic function (total bilirubin ≤ 1.5x ULN for the institution; AST [aspartate transaminase] and ALT [alanine transaminase] ≤ 3x ULN).
11. Adequate bone marrow function (hemoglobin ≥ 9.0 g/dL; platelets ≥ 75 x10^9 cells/L; absolute neutrophil count ≥ 1.0x10^9 cells/L).
12. Corrected QT interval (QTc) < 470 ms (as calculated by the Fridericia correction formula).
13. Negative pregnancy test for women of child-bearing potential.
14. Men and women of child bearing potential must agree to use adequate birth control throughout their participation in the study and for 60 days following the last study treatment.
15. Willing and able to participate in the trial and comply with all trial requirements.
16. Subjects must have archival tumor tissue available for mutational analysis. A study specific biopsy can be performed if archival tissue is not available.
17. Stable brain metastases either treated or being treated with a stable dose of steroids/ anticonvulsants, with no dose change within 28 days prior to the first dose of study drug, will be allowed.

Exclusion Criteria:

1. Gastrointestinal (GI) condition which could interfere with the swallowing or absorption of study medication.
2. Uncontrolled or severe concurrent medical condition including cardiovascular disease (e.g., myocardial infarct, unstable angina, New York Heart Association (NYHA) Class II or greater congestive heart failure, serious arrhythmias requiring medication for treatment, clinically significant pericardial disease, cardiac amyloidosis, transient ischemic attacks, CVA, coronary artery or other vascular stents).
3. A past history of, or current uncontrolled hypertension. Blood pressure must be adequately controlled prior to dosing with VS-5584.
4. Prior history of a hypertensive reaction to a kinase inhibitor
5. History of upper gastrointestinal bleeding, ulceration, or perforation within 12 months prior to the first dose of study drug.
6. Subjects with known infection with human immunodeficiency virus (HIV) or Acquired Immune Deficiency Syndrome (AIDS) (testing not required).
7. Subjects with known active Hepatitis A, B or C (testing not required).
8. Subjects being actively treated for a secondary malignancy.
9. Cancer-directed therapy (chemotherapy, radiotherapy, hormonal therapy with the exception of LHRH agonists for prostate cancer, biologic or immunotherapy, etc.) within 21 days of the first dose of study drug or 5 half-lives, whichever is shorter. Palliative radiotherapy is allowed prior to initiating treatment if associated toxicity resolved to ≤ Grade 1.
10. Subjects currently taking medications known to be strong CYP3A4 inhibitors.
11. Major surgery within 28 days prior to the first dose of study drug.
12. Subjects with acute or chronic pancreatitis.
13. Subjects with diabetes mellitus requiring insulin treatment or subjects with a HbA1C > 7.
14. Use of an investigational drug within 28 days or 5 half-lives (whichever is shorter) prior to the first dose of study drug. A minimum of 14 days between termination of the investigational drug and administration of the study treatment is required. In addition, any drug-related toxicity except alopecia should have recovered to grade 1 or less.
15. Women who are pregnant or breastfeeding.
16. Any evidence of serious active infections.
17. Uncontrolled intercurrent illness involving any other organ system or a social situation that would, in investigator's opinion, place the subject at unacceptable risk, limit compliance, or confound interpretation of safety or other results.

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: NCT01991938
• Other Study ID Numbers: VS-5584-101
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• 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, MD; Verastem, Inc.

• PRS Account: Verastem, Inc.
• Verification Date: January 2016