RecruitingInterventionalPhase 1/Phase 2

A Phase 1/2, Open-label, First-in-human Study of the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of ETX-636, a Pan-mutant-selective PI3Kα Inhibitor, as Monotherapy and in Combination With Other Anticancer Therapies in Participants With Advanced Solid Tumors

NCT ID: NCT06993844Sponsor: Ensem TherapeuticsLast updated: 2026-05-06

Summary

Phase 1/2, open-label study of ETX-636 in participants with advanced solid tumors

Detailed description

Brief Summary: This is a Phase 1/2, open-label, multicenter, 3-part study to evaluate the safety, tolerability, PK, PD, and preliminary efficacy of ETX-636 in participants with advanced solid tumors harboring a PIK3CA mutation. Part A will evaluate escalating doses of ETX-636 as monotherapy in participants with advanced solid tumors. Part B will evaluate escalating doses of ETX-636 as combination therapy with fixed dose fulvestrant in participants with hormone receptor positive (HR+), HER2 negative (HER2-) locally advanced or metastatic breast cancer. Part C will be a combination therapy expansion in participants with HR+, HER2- locally advanced or metastatic breast cancer. Each study part will include a 28-day screening period, followed by treatment with ETX-636 monotherapy or combination therapy.

Arms & interventions

DrugETX-636 dose escalation
ETX-636 is a pan-mutant-selective PI3Kα Inhibitor and degrader in the form of an oral tablet that will be taken once per day in 28-day cycles, to evaluate escalating dose levels.
DrugETX-636 dose escalation in combination with fulvestrant
ETX-636 is a pan-mutant-selective PI3Kα Inhibitor and degrader in the form of an oral tablet. ETX-636 will be taken in combination with fulvestrant in 28-day cycles, to evaluate escalating dose levels. EXT-636 is an oral tablet that will be taken once per day. Fulvestrant will be administered as an injection 2 weeks apart in the first 28 days, followed by monthly injections.
DrugETX-636 dose expansion in combination with fulvestrant
ETX-636 is a pan-mutant-selective PI3Kα Inhibitor and degrader in the form of an oral tablet. ETX-636 will be taken in combination with fulvestrant in 28-day cycles, to expand selected dose levels. EXT-636 is an oral tablet that will be taken once per day. Fulvestrant will be administered as an injection 2 weeks apart in the first 28 days, followed by monthly injections.

Outcome measures

Primary

Evaluate Safety and Tolerability of ETX-636 monotherapy in Part A and ETX-636 plus fulvestrant combination therapy in Part B
Proportion of participants who experience at least 1 Dose Limiting Toxicity (DLT)
Time frame: First 28 days of treatment
Evaluate Safety and Tolerability of ETX-636 monotherapy in Part A and ETX-636 plus fulvestrant combination therapy in Part B
Incidence of AEs, treatment discontinuations due to AEs, changes from baseline in laboratory assessments, ECGs and vital signs.
Time frame: Average of 6 months
Select the Recommended Phase 2 Dose(s) (RP2D) in Part B to be further explored in Part C (combination therapy expansion)
Safety Parameters as described for primary outcomes
Time frame: Average of 6 months
Evaluate efficacy of ETX-636 plus fulvestrant combination therapy at the RP2D(s) in Part C
ORR and CBR according to RECIST v1.1
Time frame: Average of 6 months

Secondary

Characterize the Cmax (PK) of ETX-636 monotherapy in Part A and ETX-636 plus fulvestrant combination therapy in Part B
Time frame: First 2 treatment cycles (each cycle is 28 days)
Characterize the Tmax (PK) of ETX-636 monotherapy in Part A and ETX-636 plus fulvestrant combination therapy in Part B
Time frame: First 2 treatment cycles (each cycle is 28 days)
Characterize the AUC (PK) of ETX-636 monotherapy in Part A and ETX-636 plus fulvestrant combination therapy in Part B
Time frame: First 2 treatment cycles (each cycle is 28 days)
Measure PD effects of ETX-636 monotherapy in Part A and ETX-636 plus fulvestrant combination therapy in Part B and ETX-636 plus fulvestrant at the RP2D(s) in Part C
Time frame: First 3 cycles (each cycle is 28 days)
Changes in fasting blood glucose (All Parts)
Time frame: Average of 6 months
Changes in longitudinal glucose metabolism (All Parts)
Time frame: Average of 6 months
Assess preliminary efficacy of ETX-636 monotherapy in Part A and ETX-636 plus fulvestrant combination therapy in Part B
Time frame: Average of 6 months
Evaluate measures of efficacy of ETX-636 plus fulvestrant combination therapy at the RP2D(s) in Part C
Time frame: Average of 6 months
Evaluate additional measures of efficacy of ETX-636 plus fulvestrant combination therapy at the RP2D(s) in Part C
Time frame: Average of 6 months
Evaluate additional measures of efficacy of ETX-636 plus fulvestrant combination therapy at the RP2D(s) in Part C
Time frame: Average of 6 months
Evaluate additional measures of efficacy of ETX-636 plus fulvestrant combination therapy at the RP2D(s) in Part C
Time frame: Average of 6 months
Evaluate Safety of ETX-636 plus fulvestrant combination therapy at the RP2Ds in Part C
Time frame: Average of 6 months
Evaluate tolerability of ETX-636 plus fulvestrant combination therapy at the RP2Ds in Part C
Time frame: Average of 6 months
Characterize the PK of ETX-636 plus fulvestrant using population PK modeling (Part C, to be reported separately)
Time frame: First 2 treatment cycles (each cycle is 28 days)

Eligibility criteria

Sex: AllAge: 18 Years and olderHealthy volunteers: No

Key Inclusion Criteria: * Metastatic or locally advanced and unresectable solid tumor that has progressed on or after at least one available therapy. * Tumor harboring an activating PIK3CA mutation detected in either tumor tissue or ctDNA. * At least 1 measurable lesion or evaluable disease per RECIST v1.1. * An ECOG performance status score of 0 or 1. * Adequate organ function. Additional key inclusion criterion for Parts B and C: \- Confirmed metastatic or locally advanced HR+/HER2- breast cancer not amenable to surgical resection with curative intent and must have received at least 1 prior CDK4/6 inhibitor and at least 1 prior anti-estrogen therapy. Key Exclusion Criteria: * Has history (within ≤2 years before screening) of a solid tumor or hematological malignancy that is histologically distinct from the cancers being studied. * Has symptomatic brain or spinal metastases or a known or suspected history of untreated or uncontrolled central nervous system (CNS) involvement. * Has an established diagnosis of diabetes mellitus type 1 or has uncontrolled diabetes mellitus type 2. * Has received treatment with any local or systemic anticancer therapy or investigational anticancer agent within 14 days prior to start of treatment. * Has toxicities from previous anticancer therapies that have not resolved to baseline levels with the exception of alopecia and peripheral neuropathy. * Has had radiotherapy outside the target tumor lesions within 14 days prior to start of treatment.