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

PHASE3RECRUITING

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.

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Study details:

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).

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

Inclusion 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

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.

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Eligibility

Age eligible for study : 18 and older

Healthy volunteers accepted : No

Gender eligible for study: Female

Things to know

Study dates

Study start: 2024-03-18

Primary completion: 2028-10-15

Study completion finish: 2031-02-09

Study type

TREATMENT

Phase

PHASE3

Trial ID

NCT06072781

Intervention or treatment

DRUG: avutometinib

DRUG: Defactinib

DRUG: Pegylated liposomal doxorubicin

DRUG: Paclitaxel

DRUG: Letrozole

DRUG: Anastrozole

Conditions

• Low Grade Serous Ovarian Cancer

Image related to Low Grade Serous Ovarian Cancer

Condition: Low Grade Serous Ovarian Cancer
DRUG: avutometinib and other drugs
Randwick, New South Wales, Australia and more
Sponsor: Verastem, Inc.

You may be eligible to participate in this trial based on your search. Check eligibility by answering some questions.

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Find a site

Closest Location:

Prince of Wales Hospital

Research sites nearby

Select from list below to view details:

Prince of Wales Hospital
Randwick, New South Wales, Australia
Icon Cancer Centre Wesley
Auchenflower, Queensland, Australia
Cancer Research South Australia
Adelaide, South Australia, Australia
Peter MacCallum Cancer Centre
Melbourne, Victoria, Australia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: 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
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. * 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 administered intravenously

Participant Group/Arm

Intervention/Treatment

EXPERIMENTAL: 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

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.
* 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

administered intravenously

What is the study measuring?

Primary outcome

Primary Outcome Measure	Primary Outcome Description	Primary Outcome 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

Secondary Outcome Measure	Secondary Outcome Description	Secondary Outcome 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 validated questionnaire to assess the quality of life of ovarian cancer 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 validated questionnaire to assess the quality of life of ovarian cancer patients.	24 months
To assess the health-related quality of life and disease based on EuroQol-5 Dimension 5-level (EQ-5D-5L)	The EuroQol-5 Dimension 5-level (EQ-5D-5L) is a validated questionnaire used to measure a patient's overall health.	24 months

Frequently Asked Questions

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References

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