Avutometinib for Low-grade serous ovarian cancer (recurrent)

Inclusion criteria

• {"criterion_text":"- 1. Female patients ≥ 18 years of age\n- 10. Female patients with reproductive potential agree to use highly effective method of contraceptive (per Clinical Trial Facilitation Group [CFTG] recommendations in Section 11.4) during the trial and for 1 month following the last dose of study intervention.\n- 2. Histologically proven LGSOC (ovarian, peritoneal) a. The Sponsor's Medical Monitor must review the pathology report prior to the start of treatment b. Adequate pathology material (as defined in the lab manual) must be available prior to enrollment to be used for central confirmation. Central pathological confirmation does not need to be completed prior to enrollment.\n- 3. Tumor with known KRAS mutational status using a validated testing method (blood or tissue) prior to treatment assignment. Adequate material (as defined in the lab manual) must be available for central confirmation prior to treatment assignment.\n- 4. Progression (radiographic or clinical) or recurrence of LGSOC after at least one prior systemic therapy for metastatic disease. Below are additional prior treatments that are allowed once the requirement of prior platinum therapy is satisfied. a. Prior systemic therapy for metastatic disease (International Federation of Gynecology and Obstetrics [FIGO]stage II-IV) may consist of chemotherapy administered as single-agent or a platinum or another chemotherapy doublet with or without bevacizumab, with or without maintenance therapy or radiation therapy; hormonal therapy; and/or MEK/RAF inhibitor therapy. b. Only one prior line of MEK/RAF inhibitor therapy is allowed.\n- 5. Measurable disease according to RECIST 1.1.\n- 6. An Eastern Cooperative Group (ECOG) performance status ≤ 1.\n- 7.Must have 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 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) upon discussion with Medical Monitor: (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 ≥ 50% by echocardiography (ECHO) or multiple-gated acquisition (MUGA) scan.\n- 8. Baseline QTc interval < 460 ms (average of triplicate readings) (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.\n- 9. Adequate recovery from toxicities related to prior treatments to at least Grade 1 by CTCAE v 5.0. Exceptions include alopecia and peripheral neuropathy Grade ≤2. Patients with other toxicities that are stable on supportive therapy may be allowed to participate with prior approval by the Sponsor."}

Exclusion criteria

• {"criterion_text":"- 1. Systemic anti-cancer therapy within 4 weeks of the first dose of study intervention.\n- 10. For patients with prior MEK exposure, Grade 4 toxicity deemed related to the MEK inhibitor.\n- 11. Known hepatitis B, hepatitis C or human immunodeficiency virus infection that is active and/or requires therapy.\n- 12. Active skin disorder that has required systemic therapy within the past year.\n- 13. History of rhabdomyolysis.\n- 2. Co-existing high-grade ovarian cancer or another histology.\n- 3. 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. Patients with other malignancies associated with very low risk of metastasis or death may be included upon discussion with the Medical Monitor\n- 4. Patients who are deemed in the opinion of their treating physician to be appropriate candidates for a debulking surgery. These patients should preferentially receive surgery prior to consideration of trial therapy.\n- 5. 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.\n- 6. 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).\n- 7. Exposure to medications (with or without prescriptions), supplements, herbal remedies, or foods with potential for drug-drug interactions with study interventions within 5 half-lives (if known) or 14 days prior to the first dose of study intervention, including: a. Strong CYP3A4 inhibitors or inducers, due to potential drug-drug interactions with bothavutometinib and defactinib. b. Strong CYP2C9 inhibitors or inducers, due to potential drug-drug interactions with defactinib. Not applicable if and when patients randomized to avutometinib monotherapy. c. Strong P-glycoprotein (P-gp) inhibitors or inducers, due to potential drug-drug interactions with both avutometinib and defactinib. d. Strong breast cancer resistance protein (BCRP) inhibitors or inducers, due to potential drug-drug interactions with avutometinib or defactinib.\n- 8. Symptomatic brain metastases requiring steroids or other interventions. Patients with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to study entry, have discontinued corticosteroid treatment for these metastases for at least 2 weeks prior to first dose of study intervention, and are neurologically stable, with no evidence of interim progression. 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.\n- 9. Known severe acute respiratory syndrome coronavirus 2 (SARS-Cov2) infection (clinical symptoms) </= 28 days prior to first dose of study intervention."}

Primary endpoints

• {"endpoint_text":"- Part A: Confirmed overall response rate (ORR; partial response [PR] + complete response [CR] defined according to Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST 1.1]) as assessed by the blinded independent radiology review committee (BIRC) Part B: Confirmed ORR defined according to RECIST 1.1 as assessed by the BIRC Part C: Confirmed ORR defined according to RECIST 1.1 as assessed by the BIRC Part D: Confirmed ORR defined according to RECIST 1.1 as assessed by the BIRC","definition_or_measurement_approach":"ORR = confirmed PR + CR per RECIST 1.1, assessments performed and confirmed by a blinded independent radiology review committee (BIRC)."}

Secondary endpoints

• {"endpoint_text":"- Part A, B, C and D: 1) Adverse events (AEs), serious AEs (SAEs), physical examinations, clinical laboratory values and tolerability (dose interruptions/reductions)","definition_or_measurement_approach":"Safety and tolerability assessed by recording AEs/SAEs, physical exams, lab values and dose modifications per CTCAE criteria."}
• {"endpoint_text":"- 2) - Duration of response (DOR) - ORR as assessed by the Investigator - Progression free survival (PFS), defined as the time from first dose of study intervention to the first documentation of progressive disease (PD), or death from any cause - Disease control rate (DCR), defined as CR+PR+ stable disease (SD) - Overall survival (OS)","definition_or_measurement_approach":"DOR, Investigator-assessed ORR, PFS (time from first dose to PD or death), DCR (CR+PR+SD), and OS measured per RECIST 1.1 and time-to-event analyses."}
• {"endpoint_text":"- 3) PK parameters derived from plasma concentrations of avutometinib, defactinib, and relevant metabolites","definition_or_measurement_approach":"Pharmacokinetic parameters calculated from plasma concentration measurements of avutometinib, defactinib and metabolites (e.g., Cmax, AUC) as specified in the protocol PK analysis plan."}

Spain

Earliest CTIS Part Ii Submission Date

30-08-2024

Latest Decision Or Authorization Date

30-09-2024

Processing Time Days

31

Number Of Sites

4

Number Of Participants

15

Italy

Earliest CTIS Part Ii Submission Date

30-08-2024

Latest Decision Or Authorization Date

14-10-2024

Processing Time Days

45

Number Of Sites

2

Number Of Participants

10

France

Earliest CTIS Part Ii Submission Date

30-08-2024

Latest Decision Or Authorization Date

15-10-2024

Processing Time Days

46

Number Of Sites

4

Number Of Participants

30

Belgium

Earliest CTIS Part Ii Submission Date

30-08-2024

Latest Decision Or Authorization Date

01-10-2024

Processing Time Days

32

Number Of Sites

3

Number Of Participants

20

Primary sponsor

Full Name

Verastem Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

Parexel International (IRL) Limited

Responsibilities

Multiple sponsor duties including codes [1,10,12,15 (Medical Imaging),2,6,7,8] (as listed in sponsorDuties)

Name

Charles River Laboratories Inc.

Responsibilities

sponsorDuties code [4]

Name

Endpoint Clinical Inc.

Responsibilities

sponsorDuties code [3]

Third parties

• {"country":"United States","full_name":"Dcl Pathology LLC","duties_or_roles":"sponsorDuties codes: [4]","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Charles River Laboratories Inc.","duties_or_roles":"sponsorDuties codes: [4]","organisation_type":"Pharmaceutical company"}
• {"country":"Ireland","full_name":"Parexel International (IRL) Limited","duties_or_roles":"sponsorDuties codes: [1,10,12,15 (Medical Imaging),2,6,7,8]","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Azenta Germany GmbH","duties_or_roles":"sponsorDuties codes: [15] - Samples storage and shipments to Sponsor labs","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Endpoint Clinical Inc.","duties_or_roles":"sponsorDuties codes: [3]","organisation_type":"Pharmaceutical company"}