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

Overview

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.

Interventions

• Drug ETX-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.
• Drug ETX-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.
• Drug ETX-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.

Primary outcome measures

• Evaluate Safety and Tolerability of ETX-636 monotherapy in Part A and ETX-636 plus fulvestrant combination therapy in Part B [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 [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) [Time frame: Average of 6 months]
• Evaluate efficacy of ETX-636 plus fulvestrant combination therapy at the RP2D(s) in Part C [Time frame: Average of 6 months]

Secondary outcome measures (12)

• 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]

Eligibility criteria

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.

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 10 centers

• Hoag Memorial Hospital Presbyterian — Newport Beach
• UCSF Helen Diller Family Comprehensive Cancer Center — San Francisco
• Yale University, Yale Cancer Center — New Haven
• Beth Israel Deaconess Medical Center — Boston
• Dana-Farber Cancer Institute — Boston
• Carolina BioOncology Institute — Huntersville
• The University of Texas MD Anderson Cancer Center — Houston
• START — San Antonio
• … and 2 more centers

China · 5 centers

• Beijing Luhe Hospital,Capital Medical University — Beijing
• Fujian Cancer Hospital — Fuzhou
• Sun Yat-sen University Cancer Center — Guangzhou
• Shandong Cancer Hospital&Institute — Shandong
• Fudan University Shanghai Cancer Hospital — Shanghai

Identifiers

NCT: NCT06993844 · ETX636-C-001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗