Study 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 types of drugs called kinase inhibitors. 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 four 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 standards 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)

Condition or Disease	Intervention/Treatment
Low Grade Serous Ovarian Cancer	Drug: avutometinib Drug: Defactinib Drug: Pegylated liposomal doxorubicin Drug: Paclitaxel Drug: Letrozole Drug: Anastrozole

Study Design

Study Type	Interventional
Anticipated Enrollment	270 participants
Design Allocation	Randomized
Interventional Model	Crossover Assignment
Masking	None (Open Label)
Primary Purpose	Treatment
Official Title	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)
Study Start Date	March 18, 2024
Anticipated Primary Completion Date	October 15, 2028
Anticipated Study Completion Date	February 9, 2031

Groups and Cohorts

Group/ Cohort	Intervention/ Treatment
avutometinib + defactinib Avutometinib 3.2 mg, PO, twice weekly 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.	Drug: avutometinib Avutometinib: administered orally Drug: Defactinib
Investigator Choice of Treatment (ICT) 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. 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.	Drug: Pegylated liposomal doxorubicin Drug: Paclitaxel Drug: Letrozole Drug: Anastrozole

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (PFS) per blinded independent central review (BICR) [Up to 24 months]
   Confirmed overall response rate per RECIST 1.1 per blinded independent central review (BICR)

Secondary Outcome Measures

1. 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
2. Progression Free Survival (PFS) per investigator assessment [24 months]
   From the time of first dose of study intervention to PD as assessed per RECIST 1.1 by Investigator or death from any cause
3. Objective response rate (ORR) [12 months]
   From the time of first dose of study intervention to PD as assessed per RECIST 1.1 by Investigator or death from any cause
4. Duration of Response (DOR) [12 months]
   From the time of first dose of study intervention to PD as assessed per RECIST 1.1 by Investigator or death from any cause
5. Disease Control Rate (DCR) [6 months]
   CR+PR+Stable disease
6. Frequency and severity adverse events (AEs) and Serious Adverse Events (SAEs) [25 months]
   Count of AE and SAEs by grade, based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grading scale
7. Area under the plasma concentration-time curve (AUC) of avutometinib, defactinib and relative metabolites [5 months]
   Area under plasma Concentration (AUC) 0 to t
8. Maximum plasma concentration (Cmax) of avutometinib, defactinib and relative metabolites [5 months]
   maximum plasma concentration
9. To assess the health-related quality of life and disease based on European Organization for Research and Treatment of Cancer (EORTC) Quality of life Questionnaire Core module C30 (QLQ-C30). [24 months]
   The EORTC QLQ-C30 is a validated questionnaire to assess the quality of life of ovarian cancer patients.
10. To assess the health-related quality of life and disease based on European Organization for Research and Treatment of Cancer (EORTC) Quality of life Questionnaire Ovarian Cancer module OV28 (QLQ-OV28). [24 months]
    The EORTC QLQ-OV28 is a validated questionnaire to assess the quality of life of ovarian cancer patients.
11. To assess the health-related quality of life and disease based on EuroQol-5 Dimension 5-level (EQ-5D-5L) [24 months]
    The EuroQol-5 Dimension 5-level (EQ-5D-5L) is a validated questionnaire used to measure a patient's overall health.

Eligibility Criteria

Ages Eligible for Study	18 Years and Older (Adult, Older Adult)
Sexes Eligible for Study	Female
Accepts Healthy Volunteers	No
Inclusion Criteria	Patients may be eligible for inclusion in the study if they meet the following criteria: Histologically proven LGSOC (ovarian, fallopian, peritoneal) Documented mutational status of KRAS by a validated tumor-tissue based diagnostic test. Suitable for treatment with at least one of the Investigator's Choice of Treatments:pegylated liposomal doxorubicin, paclitaxel, letrozole, anastrozole. Progression or recurrence of LGSOC after at least one prior systemic therapy for metastatic disease. Measurable disease according to RECIST v1.1. An Eastern Cooperative Group (ECOG) performance status ≤ 1. Adequate organ function. Adequate recovery from toxicities related to prior treatments. For patients with reproductive potential, a negative pregnancy test must be confirmed and agreement to use highly effective method of contraceptive. 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: Systemic anti-cancer therapy within 4 weeks of the first dose of study therapy. Co-existing high-grade serous ovarian cancer or mixed histology. Prior treatment with avutometinib, defactinib, or other FAK inhibitors. History of prior malignancy with recurrence <3 years from the time of enrollment. Major surgery within 4 weeks, minor surgery within 1 week, or palliative radiotherapy within 1 week of the first dose of study intervention. Symptomatic brain metastases requiring steroids or other interventions, known leptomeningeal metastases, or spinal cord compression. An active skin disorder that has required systemic therapy within one year of the first dose of study intervention. History of medically significant rhabdomyolysis. For subjects with prior MEK or RAF exposure, Grade 4 toxicity is deemed related to the MEK inhibitor. Symptomatic bowel obstruction within 3 months of the first dose of study intervention Concurrent ocular disorders. Concurrent heart disease or severe obstructive pulmonary disease. Active or past medical history of interstitial lung disease/pneumonitis, including drug-induced or radiation pneumonitis, pulmonary fibrosis, or adult respiratory distress syndrome (ARDS). Subjects with the inability to swallow oral medications. 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. Pregnant or breastfeeding. Active, uncontrolled infection (bacterial, viral, or fungal) requiring systemic therapy.

Contacts and Locations

Sponsors and Collaborators	Verastem, Inc., GOG Foundation, European Network of Gynaecological Oncological Trial Groups (ENGOT), Australia New Zealand Gynaecological Oncology Group
	GOG Foundation, European Network of Gynaecological Oncological Trial Groups (ENGOT), Australia New Zealand Gynaecological Oncology Group
Locations	HonorHealth | Phoenix, Arizona, United States, 85016 University of Arkansas | Little Rock, Arkansas, United States, 72205 UCLA Health | Los Angeles, California, United States, 90095 University of California, San Francisco | San Francisco, California, United States, 94143 Yale University | New Haven, Connecticut, United States, 06520 Florida Cancer Specialists - South | Fort Myers, Florida, United States, 33901 Mount Sinai | Miami Beach, Florida, United States, 33140 AdventHealth | Orlando, Florida, United States, 32804 Florida Cancer Specialists Research East | West Palm Beach, Florida, United States, 33401 Winship Cancer Institute at Emory University | Atlanta, Georgia, United States, 30322 NorthShore University HealthSystem | Evanston, Illinois, United States, 60201 Louisiana State University | New Orleans, Louisiana, United States, 70112 Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Baltimore, Maryland, United States, 21287 Karmanos Cancer Center | Detroit, Michigan, United States, 48201 Minnesota Oncology Hematology | Minneapolis, Minnesota, United States, 55404 Washington University School of Medicine | Saint Louis, Missouri, United States, 63110 Roswell Park Cancer Institute | Buffalo, New York, United States, 14263 Memorial Sloan Kettering Cancer Center | New York, New York, United States, 10065 Atrium Health | Charlotte, North Carolina, United States, 28203 Cleveland Clinic Foundation | Cleveland, Ohio, United States, 44195 Ohio State | Hilliard, Ohio, United States, 43026 University of Oklahoma Medical Center | Oklahoma City, Oklahoma, United States, 73104 Willamette Valley Cancer Institute | Eugene, Oregon, United States, 97401 Northwest Cancer Specialists | Portland, Oregon, United States, 97227 Asplundh Cancer Pavilion | Jefferson Health | Philadelphia, Pennsylvania, United States, 19090 Allegheny Health Network | Pittsburgh, Pennsylvania, United States, 15224 Texas Oncology Central | Austin, Texas, United States, 78731 Texas Oncology-Fort Worth Cancer Center | Fort Worth, Texas, United States, 76104 MD Anderson Cancer Center | Houston, Texas, United States, 77030 Texas Oncology | San Antonio, Texas, United States, 78229 Texas Oncology | The Woodlands, Texas, United States, 77380 Texas Oncology | Tyler, Texas, United States, 75702 Intermountain Medical Center | Murray, Utah, United States, 84107 University of Virginia Health System | Charlottesville, Virginia, United States, 22908 Virginia Cancer Specialists, PC | Gainesville, Virginia, United States, 20155 Prince of Wales Hospital | Randwick, New South Wales, Australia, 2031 Icon Cancer Centre Wesley | Auchenflower, Queensland, Australia, 4066 Cancer Research South Australia | Adelaide, South Australia, Australia, 5000 Peter MacCallum Cancer Centre | Melbourne, Victoria, Australia, 3000 Sir Charles Gairdner Hospital | Nedlands, Western Australia, Australia, 6009 Princess Margaret Cancer Center | Toronto, Ontario, Canada, M5G 1X6 McGill University Health Centre | Montreal, Quebec, Canada, H4A 3J1 Centre Hospitalier de l'Universite de Montreal (CHUM) | Montréal, Quebec, Canada, H2X 0C1 Centre Hospitalier de Besançon | Besançon, France, 25000 Institut Curie | Paris, France, European Institute of Oncology (IEO) | Milan, Italy, H. Vall d´ Hebron | Barcelona, Spain, H.U. Ramón y Cajal | Madrid, Spain, Greater Glasgow and Clyde (GGC) | Glasgow, Scotland, United Kingdom, G120YN University of Edinburgh Cancer Research Centre | Edinburgh, United Kingdom, Hope Cancer Trials Centre | Leicester, United Kingdom, LE2 7LX University College London Hospitals NHS Foundation Trust | London, United Kingdom, NW1 2PG Royal Marsden Hospital | London, United Kingdom, SW7 3RP The Christie NHS Foundation Trust | Manchester, United Kingdom, Royal Marsden Hospital | Sutton, United Kingdom, SM2 5PT
Investigators	Principal Investigator: Rachel Grisham, MD, GOG Foundation Principal Investigator: Susana Banerjee, MBBS, MA, PhD, European Network of Gynecological Oncological Trial Groups (ENGOT)

More Information

Additional Relevant MeSH Terms

• Ovarian Neoplasms
• Carcinoma, Ovarian Epithelial
• Endocrine Gland Neoplasms
• Neoplasms by Site
• Neoplasms
• Ovarian Diseases
• Adnexal Diseases
• Genital Diseases, Female
• Female Urogenital Diseases
• Female Urogenital Diseases and Pregnancy Complications
• Urogenital Diseases
• Genital Neoplasms, Female
• Urogenital Neoplasms
• Genital Diseases
• Endocrine System Diseases
• Gonadal Disorders
• Carcinoma
• Neoplasms, Glandular and Epithelial
• Neoplasms by Histologic Type