A Study of Avutometinib (VS-6766) + Defactinib (VS-6063) in Recurrent Low-Grade Serous Ovarian Cancer (RAMP 301)

Verastem

Status and phase: Enrolling; Phase 3

Conditions: Low Grade Serous Ovarian Cancer

Treatments: Drug: Defactinib; Drug: Letrozole; Drug: avutometinib; Drug: Topotecan; Drug: Paclitaxel; Drug: Anastrozole; Drug: Pegylated liposomal doxorubicin

Study type: Interventional

Funder types: Other; NETWORK; Industry

Identifiers

NCT06072781

VS-6766-301

GOG-3097 (Other Identifier)

ENGOT-ov81 (Other Identifier)

Details and patient eligibility

About

This study will assess the safety and efficacy of avutometinib (VS-6766) in combination with defactinib versus Investigator's choice of treatments (ICT) in subjects with recurrent LGSOC who have progressed on a prior platinum-based therapy.

Full description

This international, randomized, open-label, Phase 3 study will compare the investigational combination of avutometinib plus defactinib versus Investigator's Choice of Treatments (ICT) in patients with recurrent LGSOC who have progressed on a prior platinum-based therapy. Avutometinib and defactinib are both a type of drug called a kinase inhibitor. Kinase inhibitors block cancer cell growth. The study will compare the progression-free survival (PFS) of the combination of avutometinib plus defactinib versus ICT. The study will also evaluate the effect of the combination on safety, overall survival, other efficacy endpoints, and health-related quality of life and disease related symptoms. The study is being conducted by gynecological cancer specialists. Patients who are eligible and agree to participate in this study will be treated with either a combination of avutometinib with defactinib, or with one of five standard of care NCCN and ESMO treatment recommendations for recurrent LGSOC, and then with subsequent follow up appointments. Patients who originally received one of the standard of care treatments who are determined to have progressive disease may be eligible to crossover to receive the investigational combination avutometinib plus defactinib.Avutometinib and defactinib are investigational drugs that have not been approved by the U.S. Food and Drug Administration (FDA)

Enrollment: 270 estimated patients

Sex: Female

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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. Progression or recurrence of LGSOC after at least one prior systemic therapy for metastatic disease.
3. Measurable disease according to RECIST v1.1.
4. An Eastern Cooperative Group (ECOG) performance status ≤ 1.
5. Adequate organ function
6. Adequate recovery from toxicities related to prior treatments.
7. For patients with reproductive potential, Agreement to use highly effective method of contraceptive.
8. 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 ovarian cancer or another 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.
6. Symptomatic brain metastases or spinal cord compression.
7. An active skin disorder that has required systemic therapy within one year of signing informed consent.
8. History of medically significant rhabdomyolysis.
9. For subjects with prior MEK exposure, Grade 4 toxicity deemed related to the MEK inhibitor.
10. Symptomatic bowel obstruction within 3 months.
11. Concurrent ocular disorders.
12. Concurrent heart disease or severe obstructive pulmonary disease.
13. Subjects with the inability to swallow oral medications.
14. Active, uncontrolled infection (bacterial, viral, or fungal) requiring systemic therapy.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: None (Open label)

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270 participants in 2 patient groups

avutometinib + defactinib

Experimental group

Description:

Avutometinib 3.2 mg, PO, twice weekly (eg, Monday/Thursday, Tuesday/Friday, or Wednesday/Saturday) for 21 days on, 7 days off in a 28-day (4 weeks) cycle in combination with defactinib 200 mg, PO, twice daily for 21 days on, 7 days off in a 28-day(4 week) cycle.

Treatment:

Drug: avutometinib

Drug: Defactinib

Investigator Choice of Treatment (ICT)

Active Comparator group

Description:

Patients will receive one of the following therapies as determined by the Investigator: * Pegylated liposomal doxorubicin: 40 mg/m2 IV on Day 1 of each 28-day (4 week) cycle. * Paclitaxel: 80 mg/m2 IV on Days 1, 8, and 15 of each 28-day (4 week) cycle. * Topotecan: 4 mg/m2 IV on Days 1, 8, and 15 of each 28-day (4 week) cycle. * Anastrozole: 1 mg, PO, once daily of each 28-day (4 week) cycle. * Letrozole: 2.5 mg, PO, once daily of each 28-day (4 week) cycle.

Treatment:

Drug: Pegylated liposomal doxorubicin

Drug: Anastrozole

Drug: Paclitaxel

Drug: Topotecan

Drug: Letrozole