Study of Avutometinib (VS-6766) +Defactinib With Gemcitabine and Nab-paclitaxel in Patients With Pancreatic Cancer

Conditions

KRAS Activating Mutation, Malignant Neoplasm of Pancreas, Metastatic Cancer, Neoplasms Pancreatic, Pancreas Cancer

Keywords

avutometinib (VS-6766), Metastatic Cancer, KRAS Mutation, Pancreatic Cancer

Brief summary

This study will assess the safety and efficacy of avutometinib (VS-6766) and defactinib in combination with gemcitabine and nab-paclitaxel in patients with Pancreatic Ductal Adenocarcinoma (PDAC) who have been previously untreated.

Detailed description

This is a multicenter, non-randomized, open-label Phase 1/2 study designed to evaluate safety, tolerability and efficacy of avutometinib (VS-6766) and defactinib in combination with gemcitabine and nab-paclitaxel in patients previously untreated metastatic Pancreatic Ductal Adenocarcinoma (PDAC).

Kian‐Huat Lim, Rachael A. Safyan, Kimberly Perez, Kristen Spencer, Eileen M. O’Reilly et al. (19 authors)

Journal of Clinical Oncology2025-05-281 citations

10.1200/jco.2025.43.16_suppl.e16403

Avutometinib/defactinib and gemcitabine/nab-paclitaxel combination in first-line metastatic pancreatic ductal adenocarcinoma: Initial safety and efficacy of phase 1b/2 study (RAMP 205).

Kian‐Huat Lim, Kristen Spencer, Rachael A. Safyan, Vincent J. Picozzi, Anna M. Varghese et al. (14 authors)

Journal of Clinical Oncology2024-06-0112 citations

10.1200/jco.2024.42.16_suppl.4140

Abstract 2899: Combined inhibition of RAF, MEK and FAK increases PDAC responsiveness to cytotoxic- and immune therapy

Xiuting Liu, John Baer, Brett L. Knolhoff, Graham D. Hogg, Faiz Ahmad et al. (9 authors)

Cancer Research2024-03-22

10.1158/1538-7445.am2024-2899

Abstract A091: The RAF/MEK clamp avutometinib as the backbone of therapy for pancreatic cancer: Novel combinations with standard of care chemotherapy, FAK inhibitors, KRAS G12D inhibitors and/or autophagy inhibitors

Sílvia Coma, Xiuting Liu, Noah L. Pieper, Wen-Hsuan Chang, Kirsten L. Bryant et al. (8 authors)

Cancer Research2024-01-161 citations

10.1158/1538-7445.panca2023-a091

Abstract C003: RAMP 205: A phase 1b/2a study of gemcitabine, nab-paclitaxel, avutometinib, and defactinib in untreated metastatic pancreatic ductal adenocarcinoma

kian-Haut Lim, Manuel Hidalgo, Mark H. O’Hara, Kristen Spencer, Ignacio Garrido‐Laguna et al. (12 authors)

Cancer Research2024-01-16

10.1158/1538-7445.panca2023-c003

Interventions

DRUGavutometinib (VS-6766) and defactinib in combination with gemcitabine and nab-paclitaxel

The RP2D of avutometinib (VS-6766) and defactinib in combination with gemcitabine and nab-paclitaxel determined in Part A will be used in Part B dose expansion.

Study design

Allocation

NON_RANDOMIZED

Intervention model

SEQUENTIAL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

No

Inclusion criteria

* Male or female subjects ≥ 18 years of age * Histologic or cytologic evidence of metastatic pancreatic ductal adenocarcinoma. * An Eastern Cooperative Group (ECOG) performance status ≤ 1 * Measurable disease according to RECIST 1.1 * Adequate organ function * Adequate cardiac function * Agreement to use highly effective method of contraceptive

Exclusion criteria

* Patients with pancreatic neuroendocrine tumors * Prior or concomitant treatment for metastatic pancreatic ductal adenocarcinoma * Prior treatment with inhibitors of the RAS /MAPK pathway \[e.g. MEK inhibitors\] or inhibitors of FAK * History of prior malignancy, with the exception of curatively treated malignancies * Major surgery within 4 weeks (excluding placement of vascular access) * Concurrent heart disease or severe obstructive pulmonary disease * Concurrent ocular disorders * Active skin disorder that has required systemic therapy within the past 1 year * Patients with interstitial lung disease or pulmonary fibrosis or severe lung disease, pulmonary edema, and adult respiratory distress syndrome * Known SARS-Cov2 infection ≤28 days prior to first dose of study therapy

Design outcomes

Primary

Measure	Time frame	Description
Part A: To determine RP2D for avutometinib (VS-6766) and defactinib in combination gemcitabine and nab-paclitaxel	28 days	Assessment of Dose-limiting toxicities (DLTs)
To determine the efficacy of the RP2D identified in Part A	6 months	Confirmed overall response rate (ORR) (partial response \[PR\] + complete response \[CR\] defined according to Response Evaluation Criteria in Solid Tumors version 1.1 \[RECIST 1.1\])

Secondary

Measure	Time frame	Description
Progression Free Survival (PFS)	24 months	From the time of first dose of study intervention to PD as assessed per RECIST 1.1 or death from any cause
Overall Survival (OS)	Up to 5 years	From the time of first dose of study intervention to PD as assessed per RECIST 1.1 or death from any cause
Plasma Pharmacokinetics (PK) of avutometinib (VS-6766) and Defactinib and relevant metabolites, Tmax	10 weeks	Time to Maximum concentration (Tmax)
Duration of Response (DOR)	24 months	Time of first response to PD as assessed per RECIST 1.1
Plasma Pharmacokinetics (PK) of avutometinib (VS-6766) and Defactinib and relevant metabolites, Half-life	10 weeks	concentration Half-life (T1/2)
Frequency and severity adverse events (AEs) and Serious Adverse Events (SAEs)	24 months	Count of AE and SAEs by grade, based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grading scale
Number of abnormal laboratory values	24 months	Count of abnormal laboratory values by grade
Plasma Pharmacokinetics (PK) of avutometinib (VS-6766) and Defactinib and relevant metabolites, AUC	10 Weeks	Area under plasma Concentration (AUC) 0 to t
Disease Control Rate (DCR)	24 months	CR + PR + SD as assessed per RECIST 1.1

Countries

United States

Outcome results

None listed