| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Recurrent Low-Grade Serous Ovarian Cancer (LGSOC) |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10066697 |
| E.1.2 | Term | Ovarian cancer recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part A:
To determine the optimal regimen, either avutometinib monotherapy or avutometinib in combination with defactinib, for subsequent evaluation for efficacy in the expansion phase (Part B)
Part B:
To determine the efficacy of the optimal regimen identified from Part A
Part C:
To further evaluate the efficacy of the optimal regimen identified from Part A
Part D:
To evaluate the efficacy of a lower dose of avutometinib in combination with defactinib
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|
| E.2.2 | Secondary objectives of the trial |
1) To characterize the safety and toxicity profile of avutometinib as a monotherapy and in combination with defactinib in LGSOC
2)
Part A:
To evaluate additional efficacy parameters for avutometinib monotherapy and in combination with defactinib
Part B:
To evaluate additional efficacy parameters for the optimal regimen identified in Part A
Part C:
To evaluate additional efficacy parameters for the optimal regimen identified in Part A
Part D:
To evaluate additional efficacy parameters for a lower dose of avutometinib in combination with defactinib
3) To characterize the pharmacokinetics (PK) of avutometinib, defactinib, and relevant metabolites |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients may be eligible for inclusion in the study if they meet the following criteria:
1. Female patients ≥ 18 years of age
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.
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.
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.
5. Measurable disease according to RECIST 1.1.
6. An Eastern Cooperative Group (ECOG) performance status ≤ 1.
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.
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.
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.
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.
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| E.4 | Principal exclusion criteria |
Patients will be excluded from the study if they meet any of the following criteria.
1. Systemic anti-cancer therapy within 4 weeks of the first dose of study intervention.
2. Co-existing high-grade ovarian cancer or another histology.
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.
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).
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.
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).
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 both avutometinib 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.
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.
9. Known severe acute respiratory syndrome coronavirus 2 (SARS-Cov2) infection (clinical symptoms) ≤28 days prior to first dose of study intervention.
10. For patients with prior MEK exposure, Grade 4 toxicity deemed related to the MEK inhibitor.
11. Known hepatitis B, hepatitis C or human immunodeficiency virus infection that is active and/or requires therapy.
12. Active skin disorder that has required systemic therapy within the past year.
13. History of rhabdomyolysis.
14. Concurrent ocular disorders:
a. Patients with history of glaucoma that is considered a risk factor for MEK inhibitor-related toxicity, history of retinal vein occlusion (RVO), predisposing factors for RVO, including uncontrolled hypertension, uncontrolled diabetes.
b. Patients with history of retinal pathology or evidence of visible retinal pathology that is considered a risk factor for 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.
c. Patients with 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.
15. 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.
16. Patients with the inability to swallow oral medications or impaired gastrointestinal absorption due to gastrectomy or active inflammatory bowel disease.
17. Patients with a history of hypersensitivity to any of the active (avutometinib, defactinib) or inactive (hydroxypropylmethylcellulose, mannitol, magnesium stearate) ingredients of the investigational product.
18. Female patients who are pregnant or breastfeeding.
For full list of exclusion criteria please see protocol section 5.2 |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
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 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 |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Part A, B, C and D
1) Adverse events (AEs), serious AEs (SAEs), physical examinations, clinical laboratory values and tolerability (dose interruptions/reductions)
2)
- Duration of response (DOR)
- ORR as assessed by the Investigator
- 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)
3) PK parameters derived from plasma concentrations of avutometinib, defactinib, and relevant metabolites |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Avutometinib In Combination with Defactinib |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| United Kingdom |
| United States |
| Belgium |
| France |
| Italy |
| Spain |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
A patient is considered to have completed the study if he/she has completed the last scheduled procedure shown in the Schedule of Activities (SoA) (Table 2 in protocol), including the Survival Follow-up of up to 1 year after discontinuation of study intervention.
The end of the study is defined as the date of the last scheduled procedure shown in the SoA (Table 2) for the last patient in the study.
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 14 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 17 |
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