Advanced Breast Cancer, Advanced Solid Tumors
Conditions
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
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.
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.
Sponsors
Ensem Therapeutics
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Fulvestrant
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Evaluate Safety and Tolerability of ETX-636 monotherapy in Part A and ETX-636 plus fulvestrant combination therapy in Part B | First 28 days of treatment | Proportion of participants who experience at least 1 Dose Limiting Toxicity (DLT) |
| Select the Recommended Phase 2 Dose(s) (RP2D) in Part B to be further explored in Part C (combination therapy expansion) | Average of 6 months | Safety Parameters as described for primary outcomes |
| Evaluate efficacy of ETX-636 plus fulvestrant combination therapy at the RP2D(s) in Part C | Average of 6 months | ORR and CBR according to RECIST v1.1 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Characterize the Cmax (PK) of ETX-636 monotherapy in Part A and ETX-636 plus fulvestrant combination therapy in Part B | First 2 treatment cycles (each cycle is 28 days) | Maximum observed plasma concentration (Cmax) of ETX-636 |
| Characterize the Tmax (PK) of ETX-636 monotherapy in Part A and ETX-636 plus fulvestrant combination therapy in Part B | First 2 treatment cycles (each cycle is 28 days) | Calculated time to reach maximum observed plasma concentration of ETX-636 |
| Characterize the AUC (PK) of ETX-636 monotherapy in Part A and ETX-636 plus fulvestrant combination therapy in Part B | First 2 treatment cycles (each cycle is 28 days) | Calculated area under the plasma concentration curve (AUC) of ETX-636 |
| 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 | First 3 cycles (each cycle is 28 days) | Change from baseline in ctDNA levels; Change from baseline in PD markers in paired biopsies |
| Changes in fasting blood glucose (All Parts) | Average of 6 months | Measured by fasting blood glucose |
| Changes in longitudinal glucose metabolism (All Parts) | Average of 6 months | Measured by HbA1c |
| Assess preliminary efficacy of ETX-636 monotherapy in Part A and ETX-636 plus fulvestrant combination therapy in Part B | Average of 6 months | Objective response rate (ORR) and clinical benefit rate (CBR) based on RECIST v1.1 |
| Evaluate measures of efficacy of ETX-636 plus fulvestrant combination therapy at the RP2D(s) in Part C | Average of 6 months | Time to response (TTR) according to RECIST v1.1 |
| Evaluate additional measures of efficacy of ETX-636 plus fulvestrant combination therapy at the RP2D(s) in Part C | Average of 6 months | Duration of response (DoR) according to RECIST v1.1 |
| Evaluate Safety of ETX-636 plus fulvestrant combination therapy at the RP2Ds in Part C | Average of 6 months | Incidence of adverse events graded according to CTCAE v5.0 |
| Evaluate tolerability of ETX-636 plus fulvestrant combination therapy at the RP2Ds in Part C | Average of 6 months | Incidence of adverse events graded according to CTCAE v5.0 |
| Characterize the PK of ETX-636 plus fulvestrant using population PK modeling (Part C, to be reported separately) | First 2 treatment cycles (each cycle is 28 days) | Plasma concentrations |
Countries
China, United States
Contacts
CONTACTJanaki Parameswaran, MD
CONTACTMelinda Snyder
Outcome results
None listed