A Phase 3, Randomized, Open-Label Study of Combination Therapy with Avutometinib plus Defactinib Versus Investigator’s Choice of Treatment in Patients with Recurrent Low-Grade Serous Ovarian Cancer (LGSOC) (RAMP301)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Verastem Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Female

Therapeutic area

Diseases [C] - Female Urogenital Diseases and Pregnancy Complications [C13]

Trial duration

2 Jul 2024 → ongoing

Decision date (initial)

2024-05-22

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Verastem Inc

External identifiers

EU CT number

2023-508204-38-00

ClinicalTrials.gov

NCT06072781

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Efficacy, Therapy, Safety

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 5

1. Find out if the combination of avutometinib and defactinib is better at prolonging the time it takes for LGSOC to grow or the patient to survive (also called progression-free survival or PFS) compared with standard of care treatment options for LGSOC.
2. Describe how well and how long the treatment with avutometinib and defactinib works compared with the standard of care treatments for LGSOC.
3. Understand the safety of avutometinib and defactinib compared with the standard of care treatments for LGSOC.
4. Measure the amount of avutometinib, defactinib, and compounds related to the 2 study drugs in the blood at different times (this is called pharmacokinetics or PK).
5. Understand how the treatment with avutometinib and defactinib impacts quality of life in participants compared with the standard of care treatments used for LGSOC.

Conditions and MedDRA coding

Recurrent Low-Grade Serous Ovarian Cancer (LGSOC)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Age ≥ 18 years
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. At least one measurable lesion according to RECIST v1.1.
9. Eastern Cooperative Group (ECOG) performance status ≤ 1.
10. Adequately recovered (Grade ≤ 1 by CTCAE v 5.0) from any toxicities related to prior treatments except alopecia or hypothyroidism.
11. 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.
12. 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
13. Willingness to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures.

Exclusion criteria 13

1. Received a systemic (targets the entire body) cancer treatment within 4 weeks of the first dose of study therapy;
2. Have had symptomatic bowel blockage within 3 months prior to treatment;
3. Currently have eye disorders;
4. Currently have heart disease or severe obstructive pulmonary disease;
5. Are not able to swallow medicines given by mouth; or Have active, uncontrolled infections (bacterial, viral, or fungal) requiring systemic therapy.
6. Currently have high-grade ovarian cancer or another ovarian cancer subtype;
7. Have had prior treatment with avutometinib, defactinib, or other FAK kinase inhibitors similar to defactinib;
8. Have a history of prior cancer that came back less than 3 years from the time of enrollment;
9. Had a major surgery within 4 weeks prior to treatment;
10. Have symptomatic brain cancer or a spinal cord involvement;
11. Have an active skin disorder that has required a systemic treatment within 1 year of signing informed consent;
12. Have a history of medically significant rhabdomyolysis (rare muscle injury where the muscles break down);
13. Have had a serious reaction to a MEK (mitogen-activated protein kinase kinase) inhibitor in the past;

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, per blinded independent central review (BICR)

Secondary endpoints 1

1. Unless otherwise specified, all tumor response-based endpoints will be analyzed using both BICR and Investigator assessments. • Overall Survival (OS) • PFS according to RECIST v1.1, per Investigator Assessment • Objective response rate (ORR) • Duration of response (DoR) • Disease control rate (DCR), defined as having achieved a best response of complete response (CR) or partial response (PR), or stable disease (SD) documented at ≥ Week 24

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Comparator 10

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Verastem Inc.

Sponsor organisation

Verastem Inc.

Address

117 Kendrick Street Suite 500

City

Needham

Postcode

02494-2730

Country

United States

Scientific contact point

Organisation

Verastem Inc.

Contact name

Hagop Youssoufian

Public contact point

Organisation

Verastem Inc.

Contact name

Elizabeth Noble

Third parties 1

Locations

9 EU/EEA countries · 45 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 162 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

19 submissions — initial application plus substantial / non-substantial modifications