Trial: A Study of Avutometinib (VS-6766) + Def…

Trial Details

Sponsor: Verastem, Inc. (industry)

Phase: 3

Start date: March 18, 2024

Planned enrollment: 270

Trial ID: NCT06072781

More trial details at ClinicalTrials.gov

Show Summary from Sponsor

Investigational Drug AI Analysis

Show for: Defactinib (PF-04554878, VS-6063)

Overview

Defactinib (PF-04554878; VS-6063) is an oral small‑molecule inhibitor of focal adhesion kinase (FAK; PTK2) with additional activity against PYK2. It has been studied as monotherapy and in combinations across multiple solid tumors, including mesothelioma, ovarian cancer, and pancreatic cancer. In May 2025, the FDA granted accelerated approval to the combination of avutometinib (RAF/MEK clamp) plus defactinib for adults with KRAS‑mutated, recurrent low‑grade serous ovarian cancer (LGSOC) after prior systemic therapy. Defactinib itself remains investigational outside this co‑packaged combination. (pubmed.ncbi.nlm.nih.gov)

Mechanism of action

Target: Potent, selective inhibition of FAK and PYK2; recommended phase 2 monotherapy dose from first‑in‑human work was 425 mg twice daily. By blocking FAK signaling, defactinib can reduce tumor cell survival/invasion and modulate the tumor microenvironment. (pubmed.ncbi.nlm.nih.gov)
Tumor microenvironment and immunology: Preclinical studies indicate that FAK signaling supports stromal fibrosis and immunosuppression; FAK inhibition can enhance infiltration/efficacy of T‑cell checkpoint blockade in pancreatic models. (nature.com)

Efficacy

Low‑grade serous ovarian cancer (in combination with avutometinib)
Phase 2 (RAMP 201; ENGOT‑ov60/GOG‑3052): Confirmed ORR 31% overall (44% in KRAS‑mutant; 17% in KRAS‑wild‑type); median PFS 12.9 months overall. These data supported the FDA’s accelerated approval in KRAS‑mutant recurrent LGSOC. (ascopubs.org)
Phase 1/2 (FRAME, first‑in‑human combo): In LGSOC, ORR 42.3% and median PFS 20.1 months; in KRAS‑mutant LGSOC, ORR 58.3% and median PFS 30.8 months. (pubmed.ncbi.nlm.nih.gov)
Malignant pleural mesothelioma (maintenance monotherapy)
COMMAND randomized, double‑blind, phase 2 (post‑platinum maintenance; merlin‑stratified): No improvement versus placebo in PFS (4.1 vs 4.0 months) or OS (12.7 vs 13.6 months); results did not support use as maintenance therapy. (ascopubs.org)
Pancreatic ductal adenocarcinoma (investigator‑initiated combinations)
Phase I dose‑escalation/expansion of defactinib + pembrolizumab + gemcitabine in advanced PDAC: Among refractory patients (n=20), DCR 80% (1 PR, 15 SD); median PFS 3.6 months and OS 7.8 months. Maintenance cohort (post–gemcitabine/nab‑paclitaxel, n=10 evaluable): DCR 70% (1 PR). (pubmed.ncbi.nlm.nih.gov)
Early phase RAMP‑205 (first‑line PDAC; avutometinib + defactinib + gemcitabine/nab‑paclitaxel): Interim press‑release data reported high partial response rates in select dosing cohorts; confirmatory peer‑reviewed results are pending. (verastem.gcs-web.com)

Safety

Monotherapy (phase 1): Common adverse events included nausea (37%), fatigue (33%), vomiting (28%), diarrhea (22%), and headache (22%); dose‑limiting toxicities included headache, fatigue, and unconjugated hyperbilirubinemia. A maximum tolerated dose was not defined; 425 mg twice daily was recommended for phase 2. (pubmed.ncbi.nlm.nih.gov)
Mesothelioma maintenance (COMMAND): Most grade ≥3 events with defactinib were gastrointestinal or constitutional (e.g., nausea, diarrhea, fatigue); no survival benefit versus placebo. (ascopubs.org)
Combination with avutometinib in LGSOC:
RAMP 201: Most common adverse events included nausea, diarrhea, and elevated creatine phosphokinase; discontinuation for AEs occurred in about 10%. (ascopubs.org)
FRAME: Frequent AEs included rash and elevated CPK; discontinuation due to toxicity was uncommon. (pubmed.ncbi.nlm.nih.gov)
FDA label (co‑pack approval, May 8, 2025): For the avutometinib/defactinib co‑pack, common adverse reactions (≥25%) included CPK increased, nausea, fatigue, AST/ALT elevations, rash, diarrhea, edema, and hematologic changes. (fda.gov)

Additional notes

Biomarker development: NF2/merlin‑low status did not predict benefit in the COMMAND study, despite preclinical rationale. (ascopubs.org)
Ongoing trials: A confirmatory phase 3 study (RAMP 301) of avutometinib + defactinib versus investigator’s choice in recurrent LGSOC is in progress. Other early‑phase studies are exploring the combination with chemotherapy and/or immunotherapy in pancreatic and other solid tumors. (verastem.gcs-web.com)

Show for: Avutometinib (RO-5126766, CKI-27, CH-5126766, R-7304, RG-7304, VS-6766)

Overview

Avutometinib (also known as RO-5126766, CKI-27, CH-5126766, R-7304, RG-7304, VS-6766) is an oral, small‑molecule “RAF–MEK clamp” developed to inhibit the MAPK pathway by simultaneously blocking MEK activity and preventing RAF from phosphorylating and reactivating MEK via feedback. In May 2025, the FDA granted accelerated approval to avutometinib combined with the FAK inhibitor defactinib for adults with recurrent, KRAS‑mutated low‑grade serous ovarian cancer (LGSOC) after prior systemic therapy. (pubmed.ncbi.nlm.nih.gov)

Mechanism of action

Dual RAF/MEK inhibition: CH5126766/RO5126766 binds MEK allosterically, locks MEK in a conformation that forms a stable complex with RAF, and prevents RAF‑mediated phosphorylation of MEK, thereby suppressing ERK signaling and feedback reactivation that limits activity of MEK‑only inhibitors. This “clamp” effect yields deeper pathway inhibition in RAS/MAPK‑driven tumors. (pubmed.ncbi.nlm.nih.gov)
First‑in‑human PK/PD: Intermittent dosing was established due to on‑target toxicities (e.g., CPK elevations, rash) with a terminal half‑life ~60 hours and evidence of ERK pathway suppression in tumors. (aacrjournals.org)

Efficacy

Low‑grade serous ovarian cancer (LGSOC)

Phase 2, RAMP‑201 (ENGOT‑OV60/GOG‑3052): In the randomized selection/expansion study of recurrent LGSOC, avutometinib + defactinib achieved a confirmed ORR of 31% overall (44% in KRAS‑mutant; 17% in KRAS‑wild‑type), median PFS 12.9 months overall (≈31.0 months KRAS‑mutant; 12.8 months KRAS‑wild‑type) by blinded independent central review. These primary results were published in the Journal of Clinical Oncology in July 2025. (pmc.ncbi.nlm.nih.gov)
Regulatory endpoint subset: For FDA accelerated approval (May 8, 2025), efficacy was based on 57 patients with KRAS‑mutant recurrent LGSOC treated with the combination in RAMP‑201; confirmed ORR was 44% (95% CI 31–58) with DOR 3.3–31.1 months at cutoff. (fda.gov)
Earlier signal: The investigator‑initiated FRAME phase 1/2 trial reported ORR 42.3% and median PFS 20.1 months in all evaluable LGSOC patients; in KRAS‑mutant LGSOC, ORR 58.3% and median PFS 30.8 months. (investor.verastem.com)

Other tumor types (emerging data)

Metastatic pancreatic ductal adenocarcinoma (first‑line): Ongoing phase 1b/2 RAMP‑205 adds avutometinib/defactinib to gemcitabine/nab‑paclitaxel; early cohorts show combinability and preliminary activity (e.g., CA19‑9 reductions; partial responses in dose‑finding cohorts). Formal response rates are maturing. (ascopubs.org)

Confirmatory/ongoing trials

Phase 3 RAMP‑301 (GOG‑3097/ENGOT‑ov81): Randomized study of avutometinib + defactinib vs investigator’s choice in recurrent LGSOC (KRAS‑mutant or wild‑type); primary endpoint PFS; estimated primary completion 2028. (pubmed.ncbi.nlm.nih.gov)

Safety

Combination (RAMP‑201 primary analysis): Discontinuation due to AEs ~10%. Common AEs included nausea, diarrhea, and increased creatine phosphokinase; grade ≥3 rates were low to moderate for these events. (pmc.ncbi.nlm.nih.gov)
FDA label (accelerated approval population): Most common adverse reactions/laboratory abnormalities (≥25%) included increased CPK, nausea, fatigue, transaminase elevations, rash/dermatitis acneiform, diarrhea, musculoskeletal pain, edema, cytopenias, bilirubin/triglyceride elevations, and ocular events (e.g., vitreoretinal disorders/visual impairment). Recommended regimen: avutometinib 3.2 mg orally twice weekly (Days 1 and 4) plus defactinib 200 mg orally twice daily, both 3 weeks on/1 week off per 28‑day cycle until progression or unacceptable toxicity. (fda.gov)
Monotherapy experience (phase 1): On‑target toxicities include rash‑related disorders, CPK elevation, diarrhea, and ocular effects; half‑life ~60 hours supported intermittent dosing schedules. (aacrjournals.org)

TrialFetch AI Analysis

Goal: To compare the efficacy and safety of the investigational combination avutometinib plus defactinib versus investigator’s choice of standard therapies in patients with recurrent low-grade serous ovarian cancer (LGSOC) after prior platinum-based treatment, with a primary focus on improving progression-free survival.

Patients: Adults with histologically confirmed recurrent LGSOC (ovarian, fallopian tube, or primary peritoneal) who progressed after at least one prior systemic therapy for metastatic disease, have measurable disease by RECIST v1.1, ECOG 0–1, adequate organ function, and known KRAS mutational status. Key exclusions include mixed or high-grade histology, prior MEK/RAF clamp (avutometinib) or FAK inhibitor exposure, significant recent surgery or radiotherapy, active CNS involvement, significant pulmonary or cardiac disease, interstitial lung disease/pneumonitis, and pregnancy or uncontrolled infection.

Design: International, randomized, open-label, active-controlled Phase 3 trial. Approximately 270 participants will be randomized to investigational combination therapy or investigator’s choice of treatment. Crossover to the investigational combination is permitted for patients on the control arm at radiographic progression. Assessments include blinded independent central review for primary PFS.

Treatments: Experimental: Avutometinib 3.2 mg orally twice weekly, 21 days on/7 days off in 28-day cycles, plus defactinib 200 mg orally twice daily, 21 days on/7 days off. Avutometinib is a first-in-class dual RAF/MEK “clamp” that allosterically inhibits RAF and MEK and stabilizes inactive RAF–MEK complexes to prevent MEK rephosphorylation, thereby suppressing MAPK signaling. In Phase 2 LGSOC (RAMP 201), the combination with defactinib produced a 28% overall response rate versus 7% with avutometinib monotherapy, with high disease control rates and a manageable safety profile; common grade ≥3 AEs included elevated CPK, fatigue, and diarrhea. Defactinib is an oral focal adhesion kinase (FAK) and Pyk2 inhibitor that modulates tumor cell survival and the tumor microenvironment; it has shown tolerability across early-phase studies and is being developed primarily in combinations. Control: Investigator’s choice of pegylated liposomal doxorubicin, weekly paclitaxel, or endocrine therapy with anastrozole or letrozole per standard guidelines for recurrent LGSOC.

Outcomes: Primary: Progression-free survival by blinded independent central review per RECIST v1.1. Key secondary endpoints: overall survival; investigator-assessed PFS; objective response rate; duration of response; disease control rate; safety and tolerability (AEs/SAEs by CTCAE); pharmacokinetics of avutometinib, defactinib, and metabolites (AUC, Cmax); and patient-reported outcomes including EORTC QLQ-C30, QLQ-OV28, and EQ-5D-5L.

Burden on patient: Moderate. The trial involves standard oncology visit frequency with imaging for disease assessment similar to usual care in recurrent LGSOC. The investigational arm uses oral agents on a 28-day cycle with intermittent dosing schedules, requiring adherence and regular labs for safety monitoring, including CPK and hepatic panels given known toxicities. The control arm involves either IV chemotherapy with infusion visits (weekly for paclitaxel or every 4 weeks for pegylated liposomal doxorubicin) or daily oral endocrine therapy. Additional burden includes periodic PRO questionnaires and pharmacokinetic blood draws in a subset or at defined time points, which add extra visit time and venipunctures. No mandatory invasive tumor biopsies are specified, and crossover at progression may necessitate additional screening but aligns with patient interest in accessing the investigational combination.

Last updated: Oct 2025

Eligibility

Show Criteria

Inclusion Criteria:

Patients may be eligible for inclusion in the study if they meet the following criteria:

1. Histologically proven LGSOC (ovarian, fallopian, peritoneal)

2. Documented mutational status of KRAS by a validated tumor-tissue based diagnostic test.

3. Suitable for treatment with at least one of the Investigator's Choice of Treatments:pegylated liposomal doxorubicin, paclitaxel, letrozole, anastrozole.

4. Progression or recurrence of LGSOC after at least one prior systemic therapy for metastatic disease.

5. Measurable disease according to RECIST v1.1.

6. An Eastern Cooperative Group (ECOG) performance status ≤ 1.

7. Adequate organ function.

8. Adequate recovery from toxicities related to prior treatments.

9. For patients with reproductive potential, a negative pregnancy test must be confirmed and agreement to use highly effective method of contraceptive.

10. Willingness to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures.

Exclusion Criteria:

Patients will be excluded from the study if they meet any of the following criteria:

1. Systemic anti-cancer therapy within 4 weeks of the first dose of study therapy.

2. Co-existing high-grade serous ovarian cancer or mixed histology.

3. Prior treatment with avutometinib, defactinib, or other FAK inhibitors.

4. History of prior malignancy with recurrence \<3 years from the time of enrollment.

5. Major surgery within 4 weeks, minor surgery within 1 week, or palliative radiotherapy within 1 week of the first dose of study intervention.

6. Symptomatic brain metastases requiring steroids or other interventions, known leptomeningeal metastases, or spinal cord compression.

7. An active skin disorder that has required systemic therapy within one year of the first dose of study intervention.

8. History of medically significant rhabdomyolysis.

9. For subjects with prior MEK or RAF exposure, Grade 4 toxicity is deemed related to the MEK inhibitor.

10. Symptomatic bowel obstruction within 3 months of the first dose of study intervention

11. Concurrent ocular disorders.

12. Concurrent heart disease or severe obstructive pulmonary disease.

13. Active or past medical history of interstitial lung disease/pneumonitis, including drug-induced or radiation pneumonitis, pulmonary fibrosis, or adult respiratory distress syndrome (ARDS).

14. Subjects with the inability to swallow oral medications.

15. History of hypersensitivity to any of the active agents or ingredients of study intervention: peanut, soya, polyoxyl castor oil, etcetc.). Prior hypersensitivity to anthracyclines or anthracenediones if the use of pegylated liposomal doxorubicin (PLD) is planned.

16. Pregnant or breastfeeding.

17. Active, uncontrolled infection (bacterial, viral, or fungal) requiring systemic therapy.

Sites (105)

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Prince of Wales Hospital

Randwick, New South Wales, 2031, Australia

A Phase 3, Randomized, Open-Label Study of Combination Therapy With Avutometinib Plus Defactinib Versus Investigator's Choice of Treatment in Patients With Recurrent Low-Grade Serous Ovarian Cancer (LGSOC) (RAMP 301)

Trial Details

Show Summary from Sponsor

More details:

Investigational Drug AI Analysis

Show for: Defactinib (PF-04554878, VS-6063)

Overview

Mechanism of action

Efficacy

Safety

Additional notes

Further reading

Show for: Avutometinib (RO-5126766, CKI-27, CH-5126766, R-7304, RG-7304, VS-6766)

Overview

Mechanism of action

Efficacy

Safety

Further reading

TrialFetch AI Analysis

Eligibility

Show Criteria

Sites (105)

Prince of Wales Hospital

Icon Cancer Centre Wesley

Cancer Research South Australia

Peter MacCallum Cancer Centre

Sir Charles Gairdner Hospital

UZA

University Hospital Ghent

British of Columbia

Princess Margaret Cancer Center

Centre Hospitalier de l'Universite de Montreal (CHUM)

McGill University Health Centre

Aalborg U.H

Centre Hospitalier de Besançon

Centre Léon Bérard

Centre Oscar Lambret

Institut Curie

Site Georges François Leclerc

Charité - Universitätsmedizin Berlin

Kliniken Essen-Mitte

UMC Hamburg-Eppendorf

Universitätsfrauenkinik Ulm

Universitätsklinikum Carl Gustav Carus

Universitätsklinikum Mannheim GmbH

Agaplesion Markus Krankenhaus

St. James's Hospital

AO Cannizzaro

Centro di Riferimento Oncologico (CRO)

European Institute of Oncology (IEO)

Humanitas San Pio X

INT Napoli Hospital

IRCCS Gemelli

Istituti Fisioterapici Ospitalieri

Istituto Nazionale dei Tumori

Istituto Oncologico Veneto (IOV)

S.C.D.U. Oncologia

San Raffaele Hospital

Spedali Civili

Osaka Medical Center

The Jikei University Hospital

Tohoku University Hospital

The Mie University Hospital

Netherlands Cancer Insitute

Radboud UMC

Auckland City Hospital

Białostockie Centrum Onkologii

Gdański Uniwersytet Medyczny

Siedleckie Centrum Onkologii

Asan Medical Center

Gangnam Severance Hospital

Samsung Medical Center

Seoul National University Bundang Hospital

Yonsei University Severance Hospital

H. Vall d´ Hebron

H.U. Ramón y Cajal

Hospital Clínico Universitario de Santiago

Hospital Clínico Universitario de Valencia

Hospital Universitario Reina Sofía

Clínico Virgen de La Arrixaca