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

• ClinicalTrials.gov Identifier: NCT06072781
• Recruitment Status: Recruiting
• First Posted: October 10, 2023
• Last Update Posted: May 20, 2024
• Sponsor: Verastem, Inc.
• Collaborators: GOG Foundation; European Network of Gynaecological Oncological Trial Groups (ENGOT)
• Information provided by (Responsible Party): Verastem, Inc.

Tracking Information

• First Submitted Date: October 2, 2023
• First Posted Date: October 10, 2023
• Last Update Posted Date: May 20, 2024
• Actual Study Start Date: March 18, 2024
• Estimated Primary Completion Date: October 15, 2028 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 2, 2023)

Progression Free Survival (PFS) per blinded independent central review (BICR) [ Time Frame: Up to 24 months ]

Confirmed overall response rate per RECIST 1.1 per blinded independent central review (BICR)

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: October 12, 2023)

• Overall Survival (OS) [ Time Frame: 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
• Progression Free Survival (PFS) per investigator assessment [ Time Frame: 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
• Objective response rate (ORR) [ Time Frame: 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
• Duration of Response (DOR) [ Time Frame: 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
• Disease Control Rate (DCR) [ Time Frame: 6 months ]
  CR+PR+Stable disease
• Frequency and severity adverse events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: 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
• Area under the plasma concentration-time curve (AUC) of avutometinib, defactinib and relative metabolites [ Time Frame: 5 months ]
  Area under plasma Concentration (AUC) 0 to t
• Maximum plasma concentration (Cmax) of avutometinib, defactinib and relative metabolites [ Time Frame: 5 months ]
  maximum plasma concentration
• 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). [ Time Frame: 24 months ]
  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.
• 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). [ Time Frame: 24 months ]
  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.

Original Secondary Outcome Measures (submitted: October 2, 2023)

• Overall Survival (OS) [ Time Frame: 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
• Progression Free Survival (PFS) per investigator assessment [ Time Frame: 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
• Objective response rate (ORR) [ Time Frame: 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
• Duration of Response (DOR) [ Time Frame: 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
• Disease Control Rate (DCR) [ Time Frame: 6 months ]
  CR+PR+Stable disease
• Frequency and severity adverse events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: 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
• Area under the plasma concentration-time curve (AUC) of avutometinib, defactinib and relative metabolites [ Time Frame: 5 months ]
  Area under plasma Concentration (AUC) 0 to t
• Maximum plasma concentration (Cmax) of avutometinib, defactinib and relative metabolites [ Time Frame: 5 months ]
  Time until maximum plasma concentration
• To assess the health-related quality of life and disease based on European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 [ Time Frame: 24 months ]
  Changes over time in (EORTC) QLQ-C30
• To assess the health-related quality of life and disease based on European Organization for Research and Treatment of Cancer (EORTC) QLQ-OV28 [ Time Frame: 24 months ]
  Changes over time in (EORTC) QLQ-OV28

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Avutometinib (VS-6766) + Defactinib (VS-6063) in Recurrent Low-Grade Serous Ovarian Cancer
• 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)
• Brief Summary: 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: 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)
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Low Grade Serous Ovarian Cancer

Intervention

• Drug: avutometinib
  Avutometinib: administered orally
  Other Name: avutometinib (VS-6766)
• Drug: Defactinib
  Defactinib: administered orally
  Other Name: defactinib (VS-6063)
• Drug: Pegylated liposomal doxorubicin
  administered intravenously
  Other Name: Caelyx, Doxil, Lipodox
• Drug: Paclitaxel
  administered intravenously
  Other Name: Nov-Onxol, Onxol, Navaplus, Taxol
• Drug: Topotecan
  administered intravenously
  Other Name: Hycamtin
• Drug: Letrozole
  administered orally
  Other Name: Femara
• Drug: Anastrozole
  administered orally
  Other Name: Arimidex

Study Arms

• Experimental: avutometinib + defactinib
  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.
  Interventions:

  • Drug: avutometinib
  • Drug: Defactinib
• Active Comparator: 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.
  • 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.
  Interventions:

  • Drug: Pegylated liposomal doxorubicin
  • Drug: Paclitaxel
  • Drug: Topotecan
  • Drug: Letrozole
  • Drug: Anastrozole

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: October 2, 2023): 270
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: February 9, 2031
• Estimated Primary Completion Date: October 15, 2028 (Final data collection date for primary outcome measure)

Eligibility 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. 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.

Sex/Gender

• Sexes Eligible for Study: Female
• Gender Based Eligibility: Yes

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Verastem Call Center; 781-292-4204; clinicaltrials@verastem.com

• Listed Location Countries: Australia, United States

Administrative Information

• NCT Number: NCT06072781
• Other Study ID Numbers: VS-6766-301; GOG-3097 ( Other Identifier: The GOG Foundation, Inc. ); ENGOT-ov81 ( Other Identifier: ENGOT )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Verastem, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Verastem, Inc.
• Original Study Sponsor: Same as current

Collaborators

• GOG Foundation
• European Network of Gynaecological Oncological Trial Groups (ENGOT)

Investigators

• Principal Investigator: Rachel Grisham, MD; GOG Foundation
• Principal Investigator: Susana Banerjee, MBBS, MA, PhD; European Network of Gynecological Oncological Trial Groups (ENGOT)
• Study Director: MD Verastem; Verastem, Inc.

• PRS Account: Verastem, Inc.
• Verification Date: May 2024