IRB Study Number 24-233
Status Recruiting
Institutes Taussig Cancer Institute, Obstetrics and Gynecology and Women's Health Institute
Description
Primary Objective
To compare the progression-free survival (PFS) of the combination of avutometinib plus defactinib vs Investigator’s Choice of Treatment (ICT) in patients with recurrent LGSOC
Secondary Objectives
To compare the combination of avutometinib plus defactinib vs ICT in patients with recurrent LGSOC with regard to additional efficacy parameters
To characterize the safety and tolerability of combination avutometinib plus defactinib vs ICT in patients with recurrent LGSOC
To determine the exposure of avutometinib and defactinib in patients with recurrent LGSOC treated with combination of avutometinib plus defactinib
To assess the health-related quality of life and disease related symptoms in patients with recurrent LGSOC treated with combination avutometinib plus defactinib vs ICT
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.
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.
Suitable for treatment with at least one of the Investigator’s Choice of Treatments (ie, pegylated liposomal doxorubicin, paclitaxel, topotecan, 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.
At least one measurable lesion according to RECIST v1.1.
Eastern Cooperative Group (ECOG) performance status ≤ 1.
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.
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
Systemic anti-cancer therapy within 4 weeks of the first dose of study intervention. Note: Gonadotropin-releasing hormone (GnHR) and luteinizing hormone- releasing hormone (LHRH) modifying therapies prescribed for the intent of inducing menopause are permitted.
Co-existing high-grade ovarian cancer or another histology; LGSOC in conjunction with serous borderline tumor is permitted.
Prior treatment with avutometinib, defactinib, or other FAK inhibitors.
History of prior malignancy with recurrence < 3 years from the time of enrollment. Patients with basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, and in situ cervical cancer that has undergone potentially curative therapy with no evidence of disease recurrence for ≥ 1 year since completion of appropriate therapy may be included.
Known hepatitis B, hepatitis C, or human immunodeficiency virus infection that is active and/or requires therapy.
Appropriate candidates for optimal debulking surgery, in the opinion of their treating physician. These patients should preferentially receive surgery prior to consideration of trial therapy.
Major surgery within 4 weeks (excluding placement of vascular access), minor surgery within 2 weeks, or palliative radiotherapy within 1 week (7 days) of the first dose of study intervention.
Current warfarin use. Patients who are being treated with warfarin for deep vein thrombosis/pulmonary embolism may be eligible if their warfarin therapy can be converted to low molecular weight heparin or direct oral anticoagulants (DOACs).
Exposure to medications (with or without prescriptions), supplements, herbal remedies, or foods with potential for drug-drug interactions with avutometinib and/or defactinib within 5 half-lives (if known), or 14 days prior to the first dose of study intervention, including:
a. Strong CYP3A4 inhibitors or inducers
b. Strong CYP2C9 inhibitors or inducers
c. Strong P-glycoprotein (P-gp) inhibitors or inducers
d. Strong breast cancer resistance protein (BCRP) inhibitors or inducers
Known leptomeningeal or 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.
Severe toxicities deemed related to prior MEK or RAF exposure which qualify as discontinuation criteria in the current study. See Section 6.7.3 and Section 6.7.4.
Episode of symptomatic bowel obstruction related or unrelated to the underlying disease, within 3 months of signing informed consent.
Paracentesis within 4 weeks of signing informed consent.
Specific concurrent ocular disorders:
a. History of glaucoma, history of retinal vein occlusion (RVO), predisposing factors for RVO, including uncontrolled hypertension, uncontrolled diabetes.
b. History of retinal pathology or evidence of visible retinal pathology that is considered a risk factor for RVO, intraocular pressure > 21 mmHg as measured by tonometry, or other significant ocular pathology, such as anatomical abnormalities that increase the risk for RVO.
c. Active or chronic, visually significant corneal disorders, other active ocular conditions requiring ongoing therapy or clinically significant corneal disease that prevents adequate monitoring of drug-induced keratopathy. Examples of visually significant corneal disorders include corneal degeneration, active or recurrent keratitis, and other forms of serious ocular surface inflammatory conditions. Visually significant corneal disorders do NOT include dry eyes, blepharitis, and uncomplicated corneal erosions.
Concurrent congestive heart failure, prior history of class III/ IV cardiac disease (New York Heart Association), myocardial infarction within the last 6 months, unstable arrhythmias, unstable angina, or severe obstructive pulmonary disease.
Uncontrolled (persistent) hypertension: systolic blood pressure > 160 mmHg; diastolic blood pressure > 100 mmHg.
An active or past medical history of interstitial lung disease (ILD)/pneumonitis, including drug-induced or radiation ILD/pneumonitis, pulmonary fibrosis, or adult respiratory distress syndrome (ARDS).
Active, uncontrolled infection (bacterial, viral, or fungal) requiring systemic therapy, defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment. Subjects must be afebrile for > 48 hours off systemic therapy.
Inability to swallow oral medications or impaired gastrointestinal absorption due to gastrectomy or active inflammatory bowel disease.
History of hypersensitivity to any of the excipient ingredients found in avutometinib or defactinib (ie, hydroxypropylmethylcellulose, mannitol, magnesium stearate, lactose monohydrate, sodium starch glycolate, microcrystalline cellulose).
Pregnant or breastfeeding.
Any other medical condition (eg, cardiac, gastrointestinal [eg, severe heartburn, gastric ulcer, etc], pulmonary, psychiatric, neurological, genetic, GI bleeding, substance abuse, alcoholism, etc) within 3 months prior to enrollment that, in the opinion of the Investigator or Sponsor, would place the patient at unacceptably high risk for toxicity.
