A Phase 1b/2 Study of Serabelisib in Combination With Canagliflozin in Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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This study aims to test the hypothesis that combining serabelisib, a PI3K alpha isoform inhibitor, with an SGLT2 inhibitor, canagliflozin will improve efficacy in the treatment of patients with advanced solid tumors.

Detailed Description
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This study aims to test the hypothesis that controlling the glucose/insulin feedback will enhance the efficacy of PI3K inhibition in treating solid tumors. The treatment consists of serabelisib, a PI3K alpha isoform (PI3Kα) inhibitor, combined with the sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin. The study will assess the safety and efficacy of the combination in adult patients with advanced solid tumors harboring mutations that may be dependent on PI3Kα activity: PIK3CA mutations and KRAS mutations.

Official Title
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A Phase 1b/2 Study of Serabelisib in Combination With Canagliflozin in Patients With Advanced Solid Tumors With PIK3CA or KRAS Mutations

Conditions
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Breast Cancer, Endometrial Cancer, Lung Cancer, Colo-rectal Cancer, Head and Neck Cancer

Intervention / Treatment
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* Drug: Serabelisib
* Drug: Canagliflozin 300mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have histologically or cytologically confirmed locally advanced or metastatic solid tumors. Have a tumor harboring a mutation in PIK3CA or KRAS genes. Have received prior therapy and have recurrent or persistent disease without standard therapies available, or are ineligible to receive standard therapies. Have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Have Eastern Cooperative Oncology Group performance status (ECOG PS) of ≤2 Have adequate organ function. Have adequate birth control during the course of the study. 12. Are able to receive canagliflozin Exclusion Criteria: Diagnosis of primary brain tumor Untreated brain metastasis or history of leptomeningeal disease Have received prior chemotherapy within 28 days or other anticancer agents within 28 days of 5 half lives (whichever is the shorter duration) before the first administration of study drug. The exception is patients in Cohort 4 (PIK3CA-mutated breast cancer) are allowed to receive ongoing endocrine therapy. Have diabetes mellitus requiring insulin therapy Have diabetes mellitus requiring insulin secretagogue therapy Have poorly controlled diabetes mellitus defined as glycosylated hemoglobin A1c (HbA1c) >7.5% Have a secondary malignancy requiring therapy or are unstable without therapy. Known impaired cardiac function or clinically significant cardiac disease. Myocardial infarction or unstable angina within 6 months before the first administration of study drug. Pregnant (positive serum pregnancy test) or breastfeeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Serabelisib<br>Part 1 is dose escalation of Serabelisib Cohort 1 = 600mg; Cohort 2 = 900mg; Cohort 3 = 1200mg Part 2 is expansion of mutational cohorts with selected dose as follows: Cohort 4 = PIK3CA-mutated breast cancer; Cohort 5 = PIK3CA-mutated Non breast cancer; Cohort 6 = KRAS mutated | Drug: Serabelisib<br>* Subjects will be dosed with Serabelisib on 3 consecutive days a week in a 28 day cycle until tumor progression. in combination with Canagliflozin 300mg, both are oral medications<br>Drug: Canagliflozin 300mg<br>* All subjects will be dosed with 300 mg canagliflozin in combination with serabelisib<br>* Other names: Invokana;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Adverse Events | Safety of serabelisib in combination with canagliflozin as evaluated by incidence of drug-related adverse events (AEs), serious adverse events (SAEs), adverse events leading to discontinuation, deaths and clinical laboratory test abnormalities. | 30 days after last dose | 
| Rate of Laboratory Abnormalities | Safety of serabelisib in combination with canagliflozin as evaluated by incidence of clinical laboratory abnormalities | 30 days after last dose | 
| Dose confirmation | To confirm the appropriate dose of serabelisib to be coadministered with canagliflozin | 6 months | 
| Tumor Assessments by RESIST | To assess efficacy of serabelisib in combination with canagliflozin in patients with solid tumors with PIK3CA or KRAS mutations | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax Pharmacokinetic assessment | Maximum observed plasma concentration (Cmax) of serabelisib | Day 1 and 8 of Cycle 1: pre-dose and then post-dose at 1.5 hours, 3 hours, 6 hours, 9 hours, 12 hours, and 24 hours | 
| Tmax Pharmacokinetic assessment | Time of maximum observed plasma concentration (Tmax) of serabelisib | Day 1 and 8 of Cycle 1: pre-dose and then post-dose at 1.5 hours, 3 hours, 6 hours, 9 hours, 12 hours, and 24 hours | 
| AUC Pharmacokinetic assessment | Area under the plasma concentration time curve in the dosing interval AUC of serabelisib | Day 1 and 8 of Cycle 1: pre-dose and then post-dose at 1.5 hours, 3 hours, 6 hours, 9 hours, 12 hours, and 24 hours |