Clinical trial NCT06993844: Phase 1/2 Study of ETX-636 in Participants With Advanced Solid Tumors
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Advanced Solid Tumors
Advanced Breast Cancer
Keywords: cancer
breast cancer
solid tumors
PIK3CA
PI3Kα inhibitor
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
HER2-negative breast cancer
HR-positive breast cancer
Gynecologic cancer
Endometrial cancer
Ovarian cancer
Cervical cancer
Head and neck cancer
Head and neck squamous cell carcinoma
Fulvestrant
Antineoplastic Agents
PI3Kα
PI3K alpha
PI3Kα mutation
Alpelisib
Estrogen Receptor Antagonists
Estrogen Antagonists
Hormone Receptor Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
PIK3CA mutation
Lead sponsor: Ensem Therapeutics
Sponsor class: INDUSTRY
First posted: 2025-05-29
Enrollment: 233
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Fulvestrant
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Evaluate Safety and Tolerability of ETX-636 monotherapy in Part A and ETX-636 plus fulvestrant combination therapy in Part B
timeFrame: First 28 days of treatment
measure: Evaluate Safety and Tolerability of ETX-636 monotherapy in Part A and ETX-636 plus fulvestrant combination therapy in Part B
timeFrame: Average of 6 months
measure: Select the Recommended Phase 2 Dose(s) (RP2D) in Part B to be further explored in Part C (combination therapy expansion)
timeFrame: Average of 6 months
measure: Evaluate efficacy of ETX-636 plus fulvestrant combination therapy at the RP2D(s) in Part C
timeFrame: Average of 6 months
Secondary outcomes:
measure: Characterize the Cmax (PK) of ETX-636 monotherapy in Part A and ETX-636 plus fulvestrant combination therapy in Part B
timeFrame: First 2 treatment cycles (each cycle is 28 days)
measure: Characterize the Tmax (PK) of ETX-636 monotherapy in Part A and ETX-636 plus fulvestrant combination therapy in Part B
timeFrame: First 2 treatment cycles (each cycle is 28 days)
measure: Characterize the AUC (PK) of ETX-636 monotherapy in Part A and ETX-636 plus fulvestrant combination therapy in Part B
timeFrame: First 2 treatment cycles (each cycle is 28 days)
measure: 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
timeFrame: First 3 cycles (each cycle is 28 days)
measure: Changes in fasting blood glucose (All Parts)
timeFrame: Average of 6 months
measure: Changes in longitudinal glucose metabolism (All Parts)
timeFrame: Average of 6 months
measure: Assess preliminary efficacy of ETX-636 monotherapy in Part A and ETX-636 plus fulvestrant combination therapy in Part B
timeFrame: Average of 6 months
measure: Evaluate measures of efficacy of ETX-636 plus fulvestrant combination therapy at the RP2D(s) in Part C
timeFrame: Average of 6 months
measure: Evaluate additional measures of efficacy of ETX-636 plus fulvestrant combination therapy at the RP2D(s) in Part C
timeFrame: Average of 6 months
measure: Evaluate additional measures of efficacy of ETX-636 plus fulvestrant combination therapy at the RP2D(s) in Part C
timeFrame: Average of 6 months
measure: Evaluate additional measures of efficacy of ETX-636 plus fulvestrant combination therapy at the RP2D(s) in Part C
timeFrame: Average of 6 months
measure: Evaluate Safety of ETX-636 plus fulvestrant combination therapy at the RP2Ds in Part C
timeFrame: Average of 6 months
measure: Evaluate tolerability of ETX-636 plus fulvestrant combination therapy at the RP2Ds in Part C
timeFrame: Average of 6 months
measure: Characterize the PK of ETX-636 plus fulvestrant using population PK modeling (Part C, to be reported separately)
timeFrame: First 2 treatment cycles (each cycle is 28 days)
Other outcomes:
Locations:
city: Fairfax
country: United States
facility: NEXT
state: Virginia
Study officials:
References: