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 kinase inhibitor developed primarily for cancer treatment. Although still investigational in many tumor types, it is no longer wholly investigational in the United States: on May 8, 2025, the FDA granted accelerated approval to defactinib combined with avutometinib for adults with previously treated, KRAS-mutated recurrent low-grade serous ovarian cancer (LGSOC). Defactinib monotherapy is not FDA-approved. (fda.gov)

Mechanism of action

Defactinib inhibits focal adhesion kinase (FAK/PTK2) and the related kinase PYK2/PTK2B. These non-receptor tyrosine kinases transmit signals from integrins and growth-factor receptors that can promote tumor-cell survival, proliferation, migration and invasion. FAK inhibition may also affect cancer stem-like cells and the tumor microenvironment. In combination with avutometinib, defactinib is intended to suppress adaptive FAK signaling that may limit responses to RAF–MEK pathway inhibition. (pubmed.ncbi.nlm.nih.gov)

Efficacy

KRAS-mutated recurrent LGSOC: In the phase II RAMP-201 trial, 57 previously treated patients receiving avutometinib plus defactinib had a blinded independent-review objective response rate (ORR) of 44% (95% CI 31%–58%). Response duration ranged from 3.3 to 31.1 months. These results supported accelerated FDA approval; confirmatory evidence remains required. (fda.gov)
Earlier LGSOC evidence: In the phase I FRAME trial, the combination produced an ORR of 42.3% (11/26) and median progression-free survival (PFS) of 20.1 months. Outcomes appeared stronger in KRAS-mutated disease, although subgroup numbers were small. (pmc.ncbi.nlm.nih.gov)
NF2-altered tumors, monotherapy: NCI-MATCH Subprotocol U reported one partial response among 30 evaluable patients (ORR 3.3%), stable disease in 40%, and median PFS of approximately 1.9 months, indicating limited activity across an unselected group of NF2-altered tumors. (pmc.ncbi.nlm.nih.gov)
Pleural mesothelioma, monotherapy: In the randomized phase II COMMAND trial, maintenance defactinib did not improve median PFS versus placebo (4.1 vs 4.0 months) or median overall survival (12.7 vs 13.6 months), including in the proposed merlin-low subgroup. (ascopubs.org)
Early solid-tumor study: No radiographic responses occurred in the initial 46-patient phase I monotherapy trial; 6 of 37 patients receiving at least 100 mg twice daily had disease stabilization at approximately 12 weeks. (pubmed.ncbi.nlm.nih.gov)

Overall, meaningful clinical efficacy has been demonstrated principally when defactinib is combined with avutometinib in KRAS-mutated LGSOC; single-agent activity has generally been limited.

Safety

In the initial monotherapy phase I trial, common adverse events included nausea (37%), fatigue (33%), vomiting (28%), diarrhea (22%) and headache (22%). Reversible dose-limiting toxicities included headache, fatigue and unconjugated hyperbilirubinemia. (pubmed.ncbi.nlm.nih.gov)

For avutometinib plus defactinib, frequent adverse reactions and laboratory abnormalities included increased creatine phosphokinase, gastrointestinal symptoms, fatigue, rash, edema, musculoskeletal pain, elevated liver enzymes or bilirubin, cytopenias and ocular effects including vitreoretinal disorders and visual impairment. Because these data concern combination treatment, individual events cannot necessarily be attributed to defactinib alone. (fda.gov)

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

Overview

Avutometinib (RO5126766/CH5126766/VS-6766) is an oral small-molecule RAF/MEK inhibitor developed for RAS–RAF–MEK–ERK pathway-driven cancers. Although still investigational in most settings, it is no longer wholly investigational in the United States: on May 8, 2025, the FDA granted accelerated approval to avutometinib plus the FAK inhibitor defactinib for adults with KRAS-mutated recurrent low-grade serous ovarian cancer (LGSOC) previously treated with systemic therapy. (fda.gov)

Mechanism of action

Avutometinib is described as a RAF/MEK clamp. It binds allosterically to MEK1/2, inhibits MEK activity, and stabilizes an inactive RAF–MEK complex in which MEK cannot be phosphorylated and released by RAF. This suppresses both MEK activity and the compensatory RAF reactivation that can limit conventional MEK inhibitors, thereby reducing downstream ERK signaling. (pmc.ncbi.nlm.nih.gov)

Defactinib inhibits focal adhesion kinase (FAK), an adaptive signaling pathway that may become activated after RAF/MEK inhibition. This provides the rationale for combining the two drugs. (pubmed.ncbi.nlm.nih.gov)

Efficacy

The principal clinical evidence comes from the phase II RAMP-201 study of avutometinib plus defactinib in 115 heavily pretreated patients with recurrent LGSOC:

Confirmed objective response rate (ORR): 31% overall
ORR by tumor genotype: 44% in KRAS-mutated and 17% in KRAS-wild-type disease
Median duration of response: 31.1 months
Median progression-free survival (PFS): 12.9 months overall, with longer PFS in the KRAS-mutated subgroup. (pubmed.ncbi.nlm.nih.gov)

At approximately two years of follow-up, median duration of response remained 31.1 months and median PFS was 12.9 months overall. Median PFS was 19.6 months in KRAS-mutated and 12.7 months in KRAS-wild-type disease. (pubmed.ncbi.nlm.nih.gov)

The FDA approval population comprised 57 patients with KRAS-mutated LGSOC; blinded independent review found a 44% ORR (95% CI, 31%–58%), with responses lasting 3.3 to 31.1 months at the analysis cutoff. (fda.gov)

Earlier phase I monotherapy testing in 52 patients with advanced solid tumors produced three partial responses—two in BRAF-mutated melanoma and one in NRAS-mutated melanoma—and tumor shrinkage in approximately 40% of patients, although this was not a tumor-specific response rate. (pubmed.ncbi.nlm.nih.gov)

Safety

In the 115-patient RAMP-201 combination cohort, the most frequent grade 3 or higher treatment-related adverse events were:

Increased creatine phosphokinase: 24%–26%
Diarrhea: 8%
Anemia: 5%–7%

Approximately 10%–12% discontinued treatment because of adverse events, and no treatment-related deaths were reported in the two-year analysis. (pubmed.ncbi.nlm.nih.gov)

Other commonly reported toxicities include rash or acneiform dermatitis, nausea, fatigue, liver-enzyme elevations, edema, musculoskeletal symptoms, gastrointestinal effects and ocular or vitreoretinal disorders. Early monotherapy studies also identified creatine phosphokinase elevation and blurred vision as dose-limiting toxicities. (fda.gov)

TrialFetch AI Analysis

Goal: Determine whether avutometinib plus defactinib improves progression-free survival compared with investigator-selected treatment in recurrent low-grade serous ovarian cancer (LGSOC), while assessing safety and other clinical outcomes.

Patients: Patients with measurable, histologically confirmed recurrent ovarian, fallopian tube, or peritoneal LGSOC after prior systemic therapy, including prior platinum-based treatment. KRAS status must be documented; ECOG performance status must be 0–1. Key exclusions include mixed or high-grade serous histology, prior avutometinib or FAK inhibitor treatment, and significant active ocular, cardiac, pulmonary, or skin conditions.

Design: International, randomized, open-label comparison of the combination against investigator's choice of treatment. Patients assigned to investigator's choice who develop progressive disease may be eligible to cross over to the combination.

Treatments: The experimental arm receives oral avutometinib 3.2 mg twice weekly plus oral defactinib 200 mg twice daily, both for 21 days followed by 7 days off in 28-day cycles. Avutometinib inhibits RAF–MEK signaling, while defactinib inhibits FAK-mediated adaptive signaling. In the earlier single-arm RAMP-201 study, the combination achieved a 31% objective response rate overall and 44% in KRAS-mutated LGSOC; these are not comparative results from this trial. The combination received US accelerated approval in 2025 for previously treated KRAS-mutated recurrent LGSOC. Investigator's choice comprises standard options: pegylated liposomal doxorubicin or paclitaxel intravenously, or oral letrozole or anastrozole.

Outcomes: The primary endpoint is RECIST 1.1 progression-free survival by blinded independent central review, assessed over up to 24 months. Secondary measures include overall survival, investigator-assessed progression-free survival, response and disease control, adverse events, drug pharmacokinetics, and quality of life and symptoms using EORTC and EQ-5D-5L questionnaires.

Burden on patient: Moderate. Treatment requires repeated 28-day cycles, study visits, laboratory tests, imaging, questionnaires, and pharmacokinetic blood sampling during the first 5 months, with longer-term follow-up. The experimental regimen is taken at home but requires adherence to an intermittent dosing schedule; comparator-arm patients receiving intravenous therapy need infusion visits. No mandatory research biopsy is specified.

Last updated: Sep 2026

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)

Sort by distance to:

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

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

H. de Donostia