Phase Ib Study of Avutometinib, Defactinib, and Everolimus in RAS Pathway Mutant Endometrial Cancer
Overview
- Phase
- Phase 1
- Status
- Not yet recruiting
- Sponsor
- M.D. Anderson Cancer Center
- Enrollment
- 31
- Locations
- 1
- Primary Endpoint
- Safety and adverse events (AEs).
Overview
Brief Summary
To find the recommended dose of the combination of avutometinib, defactinib, and everolimus in patients with endometrial cancer that is recurrent and has abnormal RAS activity. The safety and effects of this combination will also be studied.
Detailed Description
Primary Objectives To identify the recommended phase 2 dosing (RP2D) of the combination of avutometinib, defactinib and everolimus in participants with recurrent, RAS pathway mutant endometrial cancer.
Secondary Objectives To evaluate the tolerability of the RP2D of avutometinib, defactinib and everolimus including dose limiting toxicities that occur during cycle 1.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- Female
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Eligibility Criteria
- •Participants must have histologically or cytologically confirmed recurrent RAS mutant endometrial cancer. RAS pathway gene activating mutations include KRAS, NRAS, HRAS, BRAF, MEK1, and MEK2 activating mutations. Any endometrial histology is permitted, including endometrioid, clear cell, mesonephric, and serous.
- •Participants must have received prior immune checkpoint inhibition treatment alone or in combination.
- •Unlimited prior systemic therapies are allowed, including any number of prior MEK inhibitor therapies is allowed.
- •Ability to understand and the willingness to sign a written informed consent document.
- •Willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
- •ECOG performance status of 0-1
- •The effects of avutometinib and defactinib on the developing human fetus are unknown. For this reason, women of child-bearing potential must have a negative urine or serum pregnancy test within 72 hours of starting study and agree to use adequate contraception prior to study entry, for the duration of study participation, and for 3 months after the last does of study drug. (Refer to Pregnancy Assessment Policy MD Anderson Institutional Policy # CLN1114). This includes all female participants, between the onset of menses (as early as 8 years of age) and 55 years unless the participant presents with an applicable exclusionary factor which may be one of the following:
- •Postmenopausal (no menses in greater than or equal to 12 consecutive months).
- •History of hysterectomy or bilateral salpingo-oophorectomy.
Exclusion Criteria
- •Participants who are pregnant or lactating.
- •Participants with sarcoma components of their endometrial cancer, except carcinosarcoma.
- •Radiation, chemotherapy, or immunotherapy or any other anticancer therapy ≤2 weeks prior to cycle 1 day
- •Participation in an interventional anti-cancer study (clinical trial) within 3 weeks prior to cycle 1 day 1
- •Major surgery within four weeks before cycle 1 day
- •A history of congestive heart failure (CHF) of NYHA Class ≥3, or history of myocardial infarction (MI) within 3 months.
- •Participants with a history of severe obstructive pulmonary disease, pulmonary hypertension, and/or pulmonary fibrosis in the opinion of treating MD
- •History of medically significant rhabdomyolysis in the opinion of treating MD.
- •For participants with prior MEK inhibitors, any history of or ongoing Grade 4 toxicity deemed related to MEK inhibitor
- •Uncontrolled infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose; participants with controlled infection in the opinion of treating MD or on prophylactic antibiotics are permitted in the study.
Arms & Interventions
Dose Escalation
To be administered per dose level during Days 1-21
Intervention: Everolimus (Drug)
Dose Expansion
To be administered per identified RP2D during Days 1-2
Intervention: Avutometinib (Drug)
Dose Expansion
To be administered per identified RP2D during Days 1-2
Intervention: defactinib (Drug)
Dose Expansion
To be administered per identified RP2D during Days 1-2
Intervention: Everolimus (Drug)
Dose Escalation
To be administered per dose level during Days 1-21
Intervention: Avutometinib (Drug)
Dose Escalation
To be administered per dose level during Days 1-21
Intervention: defactinib (Drug)
Outcomes
Primary Outcomes
Safety and adverse events (AEs).
Time Frame: Through study completion; an average of 1 year
Incidence of Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 5.0
Secondary Outcomes
No secondary outcomes reported