Phase 3 Randomized Open-Label Study of Avutometinib and Defactinib Versus Standard Treatment in Recurrent Low-Grade Serous Ovarian Cancer
- Trial ID
- 2023-508204-38-00
- Protocol
- VS-6766-301
- Sponsor
- Verastem Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the **progression-free survival** (PFS) of the combination therapy of avutometinib plus defactinib versus the Investigator’s Choice of Treatment (ICT) in patients with recurrent Low-Grade Serous Ovarian Cancer (LGSOC). This is clinically relevant as it aims to determine the efficacy of the combination therapy in delaying disease progression or death, which is a critical endpoint in cancer treatment.
Secondary objectives include:
- Evaluating if the combination of avutometinib and defactinib is superior in prolonging PFS compared to standard care treatments for LGSOC.
- Describing the efficacy and duration of the treatment with avutometinib and defactinib compared to standard care treatments.
- Assessing the safety profile of avutometinib and defactinib in comparison to standard care treatments.
- Measuring the pharmacokinetics (PK) of avutometinib, defactinib, and related compounds in the blood at various time points.
- Understanding the impact of the treatment on the quality of life of participants compared to standard care treatments.
Participants
The clinical trial involves a total of **125 participants** diagnosed with **Recurrent Low-Grade Serous Ovarian Cancer (LGSOC)**. The study population is exclusively female, with an age range of **18 years and older**. Participants were selected based on specific inclusion criteria, including adequate recovery from prior treatment toxicities, documented progression or recurrence of LGSOC, and suitable organ function. The trial does not include a vulnerable population. Participants are required to have a histologically confirmed diagnosis of LGSOC and must have documented mutational status of KRAS. Lifestyle considerations such as diet and physical activity are not specified in the trial data. The selection process ensures that participants are suitable for treatment with at least one of the Investigator’s Choice of Treatments, considering their medical history and prior treatments. The trial aims to compare the progression-free survival of the combination of avutometinib plus defactinib versus the Investigator’s Choice of Treatment in this specific patient population.
Plans and Procedures
The clinical trial is a **randomized**, open-label study designed to evaluate the efficacy of combination therapy with **avutometinib** plus **defactinib** compared to the investigator's choice of treatment in patients with recurrent low-grade serous ovarian cancer (LGSOC). The primary objective is to compare progression-free survival (PFS) between the two treatment groups. The trial is expected to commence recruitment on June 28, 2024, and conclude by November 30, 2030, with an estimated duration of participant involvement of up to four months, depending on individual response and treatment tolerance.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, recovery from prior treatment toxicities, and adequate organ function. Following randomization, participants will receive either the combination therapy or one of the investigator's choice treatments, which may include **pegylated liposomal doxorubicin**, **paclitaxel**, **topotecan**, **letrozole**, or **anastrozole**. The study will include regular follow-up visits to monitor treatment response, adverse events, and overall health status. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
Early termination from the study may occur if participants experience unacceptable toxicity, disease progression, or withdrawal of consent. The trial will employ both blinded independent central review (BICR) and investigator assessments to evaluate primary and secondary endpoints, including overall survival, objective response rate, and disease control rate. Participants are required to comply with scheduled visits, treatment plans, and laboratory tests throughout the study duration.
Treatment
The clinical trial involves the administration of several **experimental medications** and comparator treatments. The primary experimental medication is **avutometinib**, marketed under the name VS-6766, which is provided in a hard capsule form. Each capsule contains 2 mg of avutometinib, and the medication is administered orally. The maximum daily dose is 2 mg, with a treatment period of up to 4 weeks. Participant compliance is monitored through regular assessments and pill counts.
Another experimental medication used in the trial is **defactinib**, marketed as VS-6063. This medication is available in tablet form, with each tablet containing 200 mg of defactinib. It is administered orally, with a maximum daily dose of 200 mg, and the treatment period is also up to 4 weeks. Compliance is monitored similarly to avutometinib.
The trial also includes several comparator treatments. **Letrozole** is provided in film-coated tablet form, with each tablet containing 2.5 mg of the active substance. It is administered orally, with a maximum daily dose of 2.5 mg, and a treatment period of up to 4 weeks. Compliance is monitored through patient diaries and pill counts.
**Anastrozole** is another comparator treatment, available as a film-coated tablet containing 1 mg of the active substance. It is administered orally, with a maximum daily dose of 1 mg, and a treatment period of up to 4 weeks. Compliance is monitored through similar methods as other oral medications.
**Paclitaxel** is administered as a solution for infusion, with a concentration of 6 mg/ml. The maximum daily dose is 80 mg/m², and the treatment period is up to 4 weeks. Infusion administration is conducted under clinical supervision to ensure accurate dosing and participant safety.
**Doxorubicin hydrochloride**, available as a pegylated liposomal concentrate for solution for infusion, is administered with a maximum daily dose of 40 mg/m². The treatment period is up to 4 weeks, and administration is conducted under clinical supervision.
**Topotecan** is provided as a solution for infusion, with a concentration of 1 mg/ml. The maximum daily dose is 4 mg/m², and the treatment period is up to 4 weeks. Infusion administration is conducted under clinical supervision to ensure accurate dosing and participant safety.
**Doxorubicin hydrochloride, liposomal** is administered as a concentrate for dispersion for infusion, with a maximum daily dose of 40 mg/m². The treatment period is up to 4 weeks, and administration is conducted under clinical supervision.
Participant compliance with the treatment regimen is monitored through a combination of methods, including pill counts, patient diaries, and clinical assessments. The trial aims to compare the progression-free survival of the combination of avutometinib plus defactinib versus the investigator's choice of treatment in patients with recurrent low-grade serous ovarian cancer.
Efficacy
The efficacy of the clinical trial will be assessed primarily through **Progression-Free Survival (PFS)**, evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. This assessment will be conducted by a blinded independent central review (BICR). Secondary endpoints include Overall Survival (OS), PFS per Investigator Assessment, Objective Response Rate (ORR), Duration of Response (DoR), and Disease Control Rate (DCR). The DCR is defined as achieving a best response of complete response (CR), partial response (PR), or stable disease (SD) documented at or beyond Week 24.
All tumor response-based endpoints will be analyzed using both BICR and Investigator assessments. The trial aims to compare the efficacy of the combination therapy of avutometinib plus defactinib against the Investigator’s Choice of Treatment in patients with recurrent Low-Grade Serous Ovarian Cancer (LGSOC). The trial is designed to ensure rigorous and objective evaluation of the treatment's efficacy, with assessments scheduled at predefined intervals throughout the study duration.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age ≥ 18 years
- Histologically proven LGSOC (ovarian, fallopian, peritoneal) a. No mixed histology; LGSOC in conjunction with serous borderline tumor is permitted b. Adequate tumor tissue (as defined in the lab manual) must be available for central confirmation of LGSOC. Adequate tumor tissue (as defined in the lab manual) must be received by the central laboratory prior to randomization. If the patient does not have adequate archived tumor tissue or the archived tumor was obtained more than 5 years from informed consent, then a fresh tumor sample will be needed to support eligibility. Central pathological confirmation does not need to be completed prior to randomization.
- Suitable for treatment with at least one of the Investigator’s Choice of Treatments (ie, pegylated liposomal doxorubicin, paclitaxel, letrozole, anastrozole) as determined by the Investigator, given the medical history, prior treatment(s), availability, and approval within a given country, and other relevant factors.
- Documented progression (radiographic or clinical) or recurrence of LGSOC after at least one platinum-based chemotherapy regimen. Allowed prior treatments and therapies include: a. Prior systemic therapy for metastatic disease (International Federation of Gynecology and Obstetrics [FIGO] stage II-IV) may consist of chemotherapy administered with or without bevacizumab, with or without maintenance therapy; or hormonal therapy. b. One prior line of treatment with a MEK and/or RAF inhibitor is permitted only if there was prior clinical benefit (objective response or stable disease ≥ 6 months) and not received within 6 months of signing informed consent.
- Adequate organ function, defined by the following laboratory parameters: a. Adequate hematologic function, including hemoglobin [Hb] ≥ 9.0 g/dL; platelets ≥ 100,000/mm3; and absolute neutrophil count [ANC] ≥ 1500/mm3. If a red blood cell transfusion or erythropoiesis-stimulating agent has been administered the Hb must remain stable and ≥ 9 g/dL for at least 1 week prior to first dose of study intervention. b. Adequate hepatic function: (i) total bilirubin ≤ 1.5 × upper limit of normal [ULN] for the institution; patients with Gilbert syndrome may enroll if total bilirubin is < 3.0 mg/dL (51 μmol/L); (ii) alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN (or < 5 x ULN in patients with liver metastases). c. Adequate renal function with creatinine clearance rate of ≥ 50 mL/min, as calculated by the Cockcroft-Gault formula or serum creatinine of ≤ 1.5 x ULN. d. International normalized ratio (INR) ≤ 1.5 and partial thromboplastin time (PTT) ≤ 1.5 x ULN in the absence of anticoagulation or therapeutic levels in the presence of anticoagulation. e. Albumin ≥ 3.0 g/dL (451 μmol/L). f. Creatine phosphokinase (CPK) ≤ 2.5 x ULN. g. Adequate cardiac function with left ventricular ejection fraction ≥ 55% by echocardiography (ECHO) or multiple-gated acquisition (MUGA) scan.
- Baseline QTc interval ≤ 460 ms using Fredericia’s QT correction formula. NOTE: This criterion does not apply to patients with a right or left bundle branch block.
- Documented mutational status of KRAS by an approved diagnostic test (eg, CDx, CE marked etc) from tumor tissue (Section 8.4.10). Adequate tumor tissue and matched normal (as defined in the lab manual) must be received by the central laboratory prior to randomization. If the patient does not have adequate archived tumor tissue or the archived tumor was obtained more than 5 years from informed consent, then a fresh tumor sample will be needed to support eligibility. Central confirmation of mutational status does not need to be completed prior to randomization.
- At least one measurable lesion according to RECIST v1.1.
- Eastern Cooperative Group (ECOG) performance status ≤ 1.
- Adequately recovered (Grade ≤ 1 by CTCAE v 5.0) from any toxicities related to prior treatments except alopecia or hypothyroidism.
- For patients with reproductive potential, a negative serum pregnancy test (β human chorionic gonadoptropnin [β-hCG]) no more than 7 days prior to randomization, verified by the treating physician.
- For patients with reproductive potential, agreement to use highly effective method of contraceptive (per Clinical Trial Facilitation Group [CFTG] recommendations) during the trial and for 30 days following the last dose of study intervention
- Willingness to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures.
Exclusion Criteria
- Received a systemic (targets the entire body) cancer treatment within 4 weeks of the first dose of study therapy;
- Have had symptomatic bowel blockage within 3 months prior to treatment;
- Currently have eye disorders;
- Currently have heart disease or severe obstructive pulmonary disease;
- Are not able to swallow medicines given by mouth; or Have active, uncontrolled infections (bacterial, viral, or fungal) requiring systemic therapy.
- Currently have high-grade ovarian cancer or another ovarian cancer subtype;
- Have had prior treatment with avutometinib, defactinib, or other FAK kinase inhibitors similar to defactinib;
- Have a history of prior cancer that came back less than 3 years from the time of enrollment;
- Had a major surgery within 4 weeks prior to treatment;
- Have symptomatic brain cancer or a spinal cord involvement;
- Have an active skin disorder that has required a systemic treatment within 1 year of signing informed consent;
- Have a history of medically significant rhabdomyolysis (rare muscle injury where the muscles break down);
- Have had a serious reaction to a MEK (mitogen-activated protein kinase kinase) inhibitor in the past;
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Recruiting | 28 Jun 2024 | 25 |
 Denmark | Recruiting | 28 Jun 2024 | 10 |
 France | Recruiting | 28 Jun 2024 | 25 |
 Germany | Recruiting | 28 Jun 2024 | 20 |
 Ireland | Recruiting | 28 Jun 2024 | 3 |
 Italy | Recruiting | 28 Jun 2024 | 60 |
 The Netherlands | Recruiting | 28 Jun 2024 | — |
 Poland | Recruiting | 28 Jun 2024 | 15 |
 Spain | Recruiting | 28 Jun 2024 | 20 |
| Netherlands | — | — | 5 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
ZOLSKETIL pegylated liposomal 2 mg/mL concentrate for dispersion for infusion | Comparator | CONCENTRATE FOR DISPERSION FOR INFUSION | INFUSION | 40 | 4 | PRD9743762 |
Paclitaxel Ribosepharm 6 mg/ml Konzentrat zur Herstellung einer Infusionslösung | Comparator | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INFUSION | 80 | 4 | PRD6701803 |
Caelyx pegylated liposomal 2 mg/ml concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INFUSION | 40 | 4 | PRD9162338 |
Letrozol STADA® 2,5 mg Filmtabletten | Comparator | FILMTABLETTEN | ORAL USE | 2.5 | 4 | PRD389191 |
Anastrozol STADA® 1 mg Filmtabletten | Comparator | FILMTABLETTEN | ORAL USE | 1 | 4 | PRD514712 |
VS-6063 | Test | TABLET | ORAL | 200 | 4 | PRD871319 |
Paclitaxel AqVida 6 mg/ml Konzentrat zur Herstellung einer Infusionslösung | Comparator | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INFUSION | 80 | 4 | PRD5797516 |
LETRO-cell® 2,5 mg Filmtabletten | Comparator | FILMTABLETTEN | ORAL USE | 2.5 | 4 | PRD1953066 |
VS-6766 | Test | CAPSULE, HARD | ORAL USE | 2 | 4 | PRD8431568 |
Topotecan HEXAL 1 mg/ml Konzentrat zur Herstellung einer Infusionslösung | Comparator | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INFUSION | 4 | 4 | PRD759857 |