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

Study Overview
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Brief Summary
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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.

Detailed Description
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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)

Official Title
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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)

Conditions
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Low Grade Serous Ovarian Cancer

Intervention / Treatment
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* Drug: avutometinib
* Drug: Defactinib
* Drug: Pegylated liposomal doxorubicin
* Drug: Paclitaxel
* Drug: Topotecan
* Drug: Letrozole
* Drug: Anastrozole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients may be eligible for inclusion in the study if they meet the following criteria: Histologically proven LGSOC (ovarian, fallopian, peritoneal) 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, 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 ovarian cancer or another 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. Symptomatic brain metastases or spinal cord compression. An active skin disorder that has required systemic therapy within one year of signing informed consent. History of medically significant rhabdomyolysis. For subjects with prior MEK exposure, Grade 4 toxicity deemed related to the MEK inhibitor. Symptomatic bowel obstruction within 3 months. Concurrent ocular disorders. Concurrent heart disease or severe obstructive pulmonary disease. Subjects with the inability to swallow oral medications. Active, uncontrolled infection (bacterial, viral, or fungal) requiring systemic therapy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: avutometinib + defactinib<br>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. | Drug: avutometinib<br>* Avutometinib: administered orally<br>* Other names: avutometinib (VS-6766);Drug: Defactinib<br>* Defactinib: administered orally<br>* Other names: defactinib (VS-6063);|
| Active Comparator: Investigator Choice of Treatment (ICT)<br>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. | Drug: Pegylated liposomal doxorubicin<br>* administered intravenously<br>* Other names: Caelyx, Doxil, Lipodox;Drug: Paclitaxel<br>* administered intravenously<br>* Other names: Nov-Onxol, Onxol, Navaplus, Taxol;Drug: Topotecan<br>* administered intravenously<br>* Other names: Hycamtin;Drug: Letrozole<br>* administered orally<br>* Other names: Femara;Drug: Anastrozole<br>* administered orally<br>* Other names: Arimidex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) per blinded independent central review (BICR) | Confirmed overall response rate per RECIST 1.1 per blinded independent central review (BICR) | Up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | From the time of first dose of study intervention to PD as assessed per RECIST 1.1 or death from any cause | Up to 5 years | 
| Progression Free Survival (PFS) per investigator assessment | From the time of first dose of study intervention to PD as assessed per RECIST 1.1 by Investigator or death from any cause | 24 months | 
| Objective response rate (ORR) | From the time of first dose of study intervention to PD as assessed per RECIST 1.1 by Investigator or death from any cause | 12 months | 
| Duration of Response (DOR) | From the time of first dose of study intervention to PD as assessed per RECIST 1.1 by Investigator or death from any cause | 12 months | 
| Disease Control Rate (DCR) | CR+PR+Stable disease | 6 months | 
| Frequency and severity adverse events (AEs) and Serious Adverse Events (SAEs) | Count of AE and SAEs by grade, based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grading scale | 25 months | 
| Area under the plasma concentration-time curve (AUC) of avutometinib, defactinib and relative metabolites | Area under plasma Concentration (AUC) 0 to t | 5 months | 
| Maximum plasma concentration (Cmax) of avutometinib, defactinib and relative metabolites | maximum plasma concentration | 5 months | 
| 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). | The EORTC QLQ-C30 is a questionnaire to assess quality of life of ovarian cancer patients. It is composed of 30 questions. An overall scoring range is from 0 to 100. A high scales score represents a higher response level. Thus, a high score for a functional scale represents a high/healthy level of function, a high score for the global health status/QOL represents a high QOL, but a high score for a symptom scale/item represents a high level of symptomatology/problems. Quality of life measured by EORTC QLQ-C30. These are validated questionnaires to be answered by patients. | 24 months | 
| 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). | The EORTC QLQ-OV28 is a questionnaire to assess quality of life of ovarian cancer patients. It is composed of 28 questions. An overall scoring range is from 0 to 100. A high scales score represents a higher response level. Thus, a high score for a functional scale represents a high/healthy level of function, a high score for the global health status/QOL represents a high QOL, but a high score for a symptom scale/item represents a high level of symptomatology/problems. | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Low Grade Serous Ovarian Cancer, KRAS, KRAS wt, KRAS mt