Combination of Avutometinib, Defactinib, and Letrozole for the Treatment of Low-Grade Serous Ovarian Cancer
This phase II trial studies how well the combination of avutometinib, defactinib, and letrozole works in treating patients with low-grade serous ovarian cancer. Avutometinib and defactinib are in a class of medications called kinase inhibitors. They work by blocking the action of an abnormal protein (the kinase protein) that signals tumor cells to multiply. This helps slow or stop the spread of tumor cells. Letrozole is in a class of medications called nonsteroidal aromatase inhibitors. It works by decreasing the amount of estrogen produced by the body. This can slow or stop the growth of some types of cancer cells that need estrogen to grow. Giving avutometinib, defactinib, and letrozole may work better in treating patients with low-grade serous ovarian cancer.
Inclusion Criteria
- Female patients ≥ 18 years of age
- Histologically-confirmed LGSOC (ovarian, peritoneal) by tissue biopsy read by pathology at study institution. NOTE: Patients with a prior history of serous borderline tumors without prior systemic (cytotoxic or hormonal) treatment but a new diagnosis of low-grade serous ovarian cancer are eligible
- Determination that the patient is not a primary surgical candidate by a gynecologic oncologist surgeon; or has undergone an attempted primary debulking with residual RECIST measurable disease
- Measurable disease according to RECIST 1.1. Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension. Each lesion must be .10mm when measured by CT or MRI. Lymph nodes must be >= 15mm by short axis when measured by CT or MRI
- An Eastern Cooperative Group (ECOG) performance status of ≤ 1. Patients with an ECOG performance status of 2 are permitted on trial if this is deemed to be secondary to cancer but not to other comorbidities
- Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression. Patients with asymptomatic brain metastases that do not require intervention are also eligible
- HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
- Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on anti-HCV treatment, they are eligible if they have an undetectable HCV viral load
- Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
- Female patients with reproductive potential agree to use highly effective method of contraceptive during the trial and for 1 month following the last dose of study intervention, unless surgical menopause is conferred. Women of child-bearing potential must have a negative pregnancy test within 14 days prior to commencement of study treatment. Non-hormonal methods of highly effective contraception include: * Intrauterine device (IUD) * Bilateral tubal occlusion * Vasectomized partner * Sexual abstinence
- Patients must have adequate cardiac function with left ventricular ejection fraction ≥ 50% by echocardiography (ECHO) or multiple-gated acquisition (MUGA) scan
- Baseline corrected QT (QTc) interval < 460 ms (Common Terminology Criteria for Adverse Events [CTCAE] grade 1) using Fredericia’s QT correction formula. NOTE: This criterion does not apply to patients with a right or left bundle branch block
- Hemoglobin (Hb) ≥ 9.0 g/dL. If a red blood cell transfusion has been administered the Hb must remain stable and ≥ 9.0 g/dL for at least 1 week prior to first dose of study intervention
- Platelets ≥ 100,000/mm^3
- Absolute neutrophil count (ANC) ≥ 1000/mm^3
- Total bilirubin ≤ 1.5 × upper limit of normal (ULN) for the institution; patients with Gilbert syndrome may enroll if total bilirubin is < 3.0mg/dL (51 umole/L) upon discussion with Memorial Sloan Kettering (MSK) principal investigator (PI)
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN (or < 5 xULN in patients with liver metastases)
- Creatinine clearance rate of ≥ 50 mL/min as calculated by the Cockcroft-Gault formula or serum creatinine of ≤ 1.5 x ULN
- Creatine phosphokinase (CPK) ≤ 2.5 x ULN
Exclusion Criteria
- Patients who are deemed in the opinion of their treating physician to be appropriate candidates for a primary debulking surgery are not eligible for this trial, unless measurable disease remains after a primary cytoreductive surgery
- Prior systemic anti-cancer therapy for LGSOC or serous borderline disease
- Major surgery within 4 weeks, minor surgery within 2 weeks, or palliative radiotherapy within 1 week of the first dose of study intervention. Open and close laparotomy and/or laparoscopy will be considered minor surgery
- Treatment with warfarin. Patients on warfarin for deep vein thrombosis/pulmonary embolism can be converted to low-molecular-weight heparin or direct oral anticoagulants (DOACs)
- Patients with the inability to swallow oral medications or impaired gastrointestinal absorption due to gastrectomy or drainage percutaneous endoscopic (PEG) tube. Patients with diagnosis of bowel obstruction < 3 months from study enrollment will be excluded unless surgically cured or approved by study PI
- Symptomatic brain metastases requiring steroids or other interventions. Patients with new asymptomatic CNS metastases detected during the screening period must receive radiation therapy and/or surgery for CNS metastases. Following treatment, these patients may then be eligible if all other criteria are met
- Patients with history of retinal pathology or evidence of visible retinal pathology that is considered a risk factor for retinal vein occlusion (RVO), intraocular pressure > 21 mm Hg as measured by tonometry, or other significant ocular pathology, such as anatomical abnormalities that increase the risk for RVO
- Patients with a history of corneal erosion (instability of corneal epithelium), corneal degeneration, active or recurrent keratitis, and other forms of serious ocular surface inflammatory conditions
- History of rhabdomyolysis
- Patients with a history of hypersensitivity to any of the active (avutometinib, defactinib) or inactive (hydroxypropylmethylcellulose, mannitol, magnesium stearate) ingredients of the investigational product
- Female patients who are breastfeeding
- Any other medical condition (e.g., cardiac, gastrointestinal, pulmonary, psychiatric, neurological, genetic, etc.) that in the opinion of the Investigator would places the patient at unacceptably high risk for toxicity
- Exposure to medications (with or without prescriptions), supplements, herbal remedies, or foods with potential for drug-drug interactions with study interventions within 14 days prior to the first dose of study intervention and during the course of therapy, including: * Strong CYP3A4 inhibitors or inducers, due to potential drug-drug interactions with both Avutometinib and defactinib. * Strong CYP2C9 inhibitors or inducers, due to potential drug-drug interactions with defactinib. * P-glycoprotein (P-gp) inhibitors or inducers, due to potential drug-drug interactions with defactinib
Additional locations may be listed on ClinicalTrials.gov for NCT06394804.
Locations matching your search criteria
United States
Georgia
Atlanta
New Jersey
Basking Ridge
Middletown
Montvale
New York
Commack
New York
Uniondale
West Harrison
PRIMARY OBJECTIVE:
I. To determine the clinical efficacy, in terms of best overall response (complete or partial response) within 9 months of treatment with avutometinib, defactinib, plus letrozole therapy, as determined by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) in patients with newly-diagnosed low-grade serous ovarian cancer (LGSOC) who are not surgical candidates or who have measurable residual disease after attempt at primary cytoreduction.
SECONDARY OBJECTIVES:
I. To characterize the safety and toxicity profile of avutometinib and defactinib in combination with letrozole as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v) .5.0.
II. To evaluate the ability to proceed with attempt at interval cytoreduction, and the number of neoadjuvant cycles of study treatment required prior to attempt at surgical cytoreduction.
III. To describe surgical outcomes (rates of complete gross resection, rates of ostomy formation, blood loss, operative time) at interval cytoreduction.
IV. To describe progression free survival (PFS) in patients treated with avutometinib and defactinib with letrozole, defined as time from day 1 of study treatment to time of progression via RECIST 1.1.
V. To determine best overall response on treatment (up to 21 cycles).
EXPLORATORY OBJECTIVE:
I. To describe efficacy of avutometinib and defactinib in combination with letrozole in patients with biomarkers of interest including KRAS and/or MAPK pathway alterations, CDKN2A loss, ESR1 alterations, ER/PR expression and Ki-67 index.
OUTLINE: Patients are assigned to 1 of 2 arms.
ARM I (FOLLOWING PRIMARY DEBULKING SURGERY): Patients receive avutometinib orally (PO) twice a week (BIW) and defactinib PO twice daily (BID) for 3 weeks, and letrozole PO once daily (QD) of each cycle. Treatment repeats every 28 days for up to 21 cycles in the absence of disease progression or unacceptable toxicity. Patients may also receive leuprolide acetate subcutaneously (SC) every 4 weeks or every 3 months on study. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography (ECHO) or multigated acquisition (MUGA) scan during screening. Patients also undergo computed tomography (CT), magnetic resonance imaging (MRI), and bone density scan throughout the study.
ARM II (NOT YET UNDERGONE PRIMARY DEBULKING SURGERY): Patients receive avutometinib PO BIW and defactinib PO BID for 3 weeks, and letrozole PO QD of each cycle. Treatment repeats every 28 days for up to 9 cycles in the absence of disease progression or unacceptable toxicity. After 3-9 cycles, patients may undergo debulking surgery. Treatment resumes with avutometinib PO BIW and defactinib PO BID for 3 weeks, and letrozole PO QD of each cycle 2-8 weeks after surgery. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients may also receive leuprolide acetate SC every 4 weeks or every 3 months on study. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA scan during screening. Patients also undergo CT, MRI, and bone density scan throughout the study.
After completion of study treatment, patients are followed up at 30 days and then every 6 months for 3 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationMemorial Sloan Kettering Cancer Center
Principal InvestigatorRachel Nicole Grisham
- Primary ID24-014
- Secondary IDsNCI-2024-03865
- ClinicalTrials.gov IDNCT06394804