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

Phase 1

• Conditions: Endometrial Cancer; Lung Cancer; Colo-rectal Cancer; Breast Cancer; Head and Neck Cancer
• Interventions: Drug: Serabelisib; Drug: Canagliflozin 300mg

• Registration Number: NCT04073680
• Lead Sponsor: Petra Pharma

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2019-08-26
• Study First Submitted QC: 2019-08-27
• Study First Posted: 2019-08-29
• Status Verified: 2020-05
• Last Update Submitted: 2020-05-20
• Last Update Posted: 2020-05-21
• Study Start: 2020-09-01
• Primary Completion: 2021-07-15
• Study Completion: 2021-12-30

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

1. Have histologically or cytologically confirmed locally advanced or metastatic solid tumors.

2. Have a tumor harboring a mutation in PIK3CA or KRAS genes.

3. Have received prior therapy and have recurrent or persistent disease without standard therapies available, or are ineligible to receive standard therapies.

4. Have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

5. Have Eastern Cooperative Oncology Group performance status (ECOG PS) of ≤2

6. Have adequate organ function.

7. Have adequate birth control during the course of the study.

8. Are able to receive canagliflozin

Exclusion Criteria

1. Diagnosis of primary brain tumor
2. Untreated brain metastasis or history of leptomeningeal disease
3. 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.
4. Have diabetes mellitus requiring insulin therapy
5. Have diabetes mellitus requiring insulin secretagogue therapy
6. Have poorly controlled diabetes mellitus defined as glycosylated hemoglobin A1c (HbA1c) >7.5%
7. Have a secondary malignancy requiring therapy or are unstable without therapy.
8. Known impaired cardiac function or clinically significant cardiac disease.
9. Myocardial infarction or unstable angina within 6 months before the first administration of study drug.
10. Pregnant (positive serum pregnancy test) or breastfeeding

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Serabelisib	Serabelisib	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
Serabelisib	Canagliflozin 300mg	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

Primary Outcome Measures

Name	Time	Method
Rate of Laboratory Abnormalities	30 days after last dose	Safety of serabelisib in combination with canagliflozin as evaluated by incidence of clinical laboratory abnormalities
Dose confirmation	6 months	To confirm the appropriate dose of serabelisib to be coadministered with canagliflozin
Rate of Adverse Events	30 days after last dose	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.
Tumor Assessments by RESIST	2 years	To assess efficacy of serabelisib in combination with canagliflozin in patients with solid tumors with PIK3CA or KRAS mutations

Secondary Outcome Measures

Name	Time	Method
AUC Pharmacokinetic assessment	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	Area under the plasma concentration time curve in the dosing interval AUC of serabelisib
Tmax Pharmacokinetic assessment	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	Time of maximum observed plasma concentration (Tmax) of serabelisib
Cmax Pharmacokinetic assessment	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	Maximum observed plasma concentration (Cmax) of serabelisib