Pancreatic Cancer
Conditions
Brief summary
The purpose of this study is to evaluate increasing dose levels of VS-4718 administered in combination with gemcitabine and nab-paclitaxel in subjects with advanced cancer and to determine a recommended Phase 2 dose (RP2D) for further development of this combination in subjects with untreated advanced pancreatic cancer.
Detailed description
The study is comprised of 2 sequential parts: Part A (Dose Escalation of VS-4718) in subjects with advanced cancer and Part B (Expansion) in subjects with untreated advanced pancreatic cancer. Up to 60 evaluable subjects (i.e., subjects who complete at least 1 cycle (28 days) of therapy) will be enrolled, assuming that: 1. Part A: The maximum sample size will be 6 subjects up to 4 dose levels (exclusive of replacement subjects). However, additional subjects may be added if exploration of intermediate dose level(s) of VS 4718 is warranted. The starting dose of VS-4718 will be 200mg BID. 2. Part B: Up to 36 additional subjects may be enrolled at the RP2D. These subjects will be randomized at a 1:1 ratio to 1 of 2 treatment cohorts: * Cohort 1: IV treatment in 28-day cycles (nab-paclitaxel 125 mg/m2 over 30 minutes on Days 1, 8, and 15 and gemcitabine at 1000 mg/m2 over 30 minutes on Days 1, 8, and 15) and oral VS 4718 BID continuously starting on Day 1 of Cycle 1 * Cohort 2: IV treatment for the first 2 cycles, followed by IV treatment and oral VS-4718 BID continuously starting on Day 1 of Cycle 3
Interventions
DRUGPart B, Cohort 1- VS-4718, nab-paclitaxel, gemcitabine
IV treatment in 28-day cycles (nab-paclitaxel 125 mg/m2 over 30 minutes on Days 1, 8, and 15 and gemcitabine at 1000 mg/m2 over 30 minutes on Days 1, 8, and 15) and oral VS 4718 BID continuously starting on Day 1 of Cycle 1
DRUGPart B, Cohort 2- VS4718, nab-paclitaxel, gemcitabine
IV treatment for the first 2 cycles, followed by IV treatment and oral VS-4718 BID continuously starting on Day 1 of Cycle 3
DRUGPart A- VS-4718, nab-paclitaxel, gemcitabine
Part A- intravenous (IV) treatment in 28-day cycles (nab-paclitaxel 125 mg/m2 over 30 minutes on Days 1, 8, and 15 and gemcitabine at 1000 mg/m2 over 30 minutes on Days 1, 8, and 15) and oral VS 4718 twice-daily (BID) continuously starting on Cycle 1 Day 2. The starting dose of VS-4718 will be 200 mg BID.
Sponsors
Verastem, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥ 18 years * Histologically or cytologically confirmed diagnosis of an advanced nonhematological malignancy (Part A) or advanced pancreatic adenocarcinoma (Part B) that is not surgically resectable * Eligible for treatment with nab-paclitaxel and gemcitabine on Days 1, 8, and 15 in 28-day cycles as standard therapy * Evaluable or measurable disease, as assessed by RECIST v1.1 * ECOG performance status of ≤ 1 * Adequate renal function (creatinine ≤ 1.5×ULN \[upper limit of normal\]) or glomerular filtration rate of ≥ 60 mL/min * Adequate hepatic function (total bilirubin ≤ 1.5×ULN for the institution; aspartate transaminase and alanine transaminase ≤ 2.5×ULN, or ≤ 5×ULN if due to liver involvement by tumor; albumin ≥ 3 g/dL) * Adequate bone marrow function (hemoglobin ≥ 9.0 g/dL; unsupported platelets ≥ 100×109 cells/L; absolute neutrophil count \[ANC\] ≥ 1.5×109 cells/L without the use of hematopoietic growth factors) * Corrected QT interval (QTc) \< 470 ms * Willing and able to participate in the trial and comply with all trial requirements
Exclusion criteria
* Gastrointestinal (GI) condition that could interfere with the swallowing or absorption of study medication * Uncontrolled or severe concurrent medical condition (including uncontrolled brain metastases). * History of upper gastrointestinal bleeding, ulceration, or perforation within 6 months prior to the first dose of protocol therapy * Known history of stroke or cerebrovascular accident within 6 months prior to the first dose of protocol therapy. * Part B only: Prior therapy (including investigational agents) for pancreatic cancer * Chemotherapy or radiotherapy within 14 days prior to first dose of protocol therapy * Active treatment for a secondary malignancy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of dose-limiting toxicities (DLTs) | 6 months | Dose Escalation Phase: Frequency of DLTs at each dose level associated with administration of VS-4718 in combination with gemcitabine and nab-paclitaxel |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Response rate (RR) | Every 8 weeks from baseline through the end of treatment, an expected average of 5 months] | RR is measured as the best overall response using Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1. |
| Pharmacokinetics of VS-4718 in combination with nab-paclitaxel and gemcitabine: Clearance | Time points on Day 1, 2,15, 16, and 22 in Cycle 1; Day 1 of each subsequent cycle | — |
| Pharmacokinetics of VS-4718 in combination with nab-paclitaxel and gemcitabine: Plasma concentration | Time points on Day 1, 2,15, 16, and 22 in Cycle 1; Day 1 of each subsequent cycle | — |
| Progression Free Survival | From the date of first treatment to the date of progression including death from any cause, expected average at least 5 months | — |
| Pharmacokinetics of VS-4718 in combination with nab-paclitaxel and gemcitabine: Maximum observed plasma concentration (Cmax) | Time points on Day 1, 2,15, 16, and 22 in Cycle 1; Day 1 of each subsequent cycle | — |
| Pharmacokinetics of VS-4718 in combination with nab-paclitaxel and gemcitabine: Time to reach maximum observed concentration (Tmax) | Time points on Day 1, 2,15, 16, and 22 in Cycle 1; Day 1 of each subsequent cycle | — |
| Pharmacokinetics of VS-4718 in combination with nab-paclitaxel and gemcitabine: Half life (T1/2) | Time points on Day 1, 2,15, 16, and 22 in Cycle 1; Day 1 of each subsequent cycle | — |
| Pharmacokinetics of VS-4718 in combination with nab-paclitaxel and gemcitabine: Area under the plasma concentration versus time curve (AUC) | Time points on Day 1, 2,15, 16, and 22 in Cycle 1; Day 1 of each subsequent cycle | — |
Countries
United States
Outcome results
None listed