Study of CLR457 Administered Orally in Adult Patients With Advanced Solid Malignancies

Study Overview
=================
Brief Summary
-----------------
To estimate the maximum tolerated dose (MTD) or recommended dose for phase II (RP2D) of CLR457 and to investigate the anti-tumor activity of CLR457

Official Title
-----------------
A Phase I/II Multicenter, Open-label Study of CLR457, Administered Orally in Adult Patients With Advanced Solid Malignancies

Conditions
-----------------
Advanced Solid Tumor

Intervention / Treatment
-----------------
* Drug: CLR457


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Written informed consent must be obtained prior to any screening procedures Phase I: Patients with advanced/metastatic solid tumors, with measurable or non-measurable disease as determined by modified RECIST version 1.1 who have progressed despite standard therapy or be intolerant of standard therapy, or for whom no standard therapy exists, who have tumors harboring one of the following: confirmed PIK3CA mutation or amplification, PTEN loss of function, EGFR mutation, cMET activation and/or HER2 overexpression. Endometrial carcinoma will not be selected for any molecular status. Phase II: Patients with advanced/metastatic solid tumors, with at least one measurable lesion as determined by modified RECIST version 1.1, who progressed despite standard therapy or be intolerant of standard therapy, or for whom no standard therapy exists, fitting in one of the following groups: Group 1: patients with PIK3CA mutated or amplified ER positive (ER+) breast cancer ; Group 2: patients with endometrial carcinoma (not selected for any molecular status); Group 3: patients with solid tumors (with the exception of PIK3CA mutant/amplified ER+ breast cancer and endometrial carcinoma) harboring PIK3CA mutation or amplification/any PTEN status; Group 4: patients with solid tumors (with the exception of endometrial carcinoma) harboring PTEN loss of function/ PIK3CA wild type; Group 5: non-small cell lung cancer harboring cMET activation and/or EGFR mutation. Up to 3 lines of chemotherapy allowed in advanced/metastatic setting. ECOG Performance Status ≤ 2. Availability of a representative formalin fixed paraffin embedded tumor tissue sample. If archival tumor sample is not available, a newly obtained tumor sample needs to be submitted instead. Exclusion Criteria: Brain metastasis unless treated and neurologically stable Patient having out of range laboratory values defined as: Hepatic and renal function: Serum total Bilirubin ≥ 1.5 x ULN (upper limit of normal) or aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 2.5 x ULN For patients with tumor involvement of the liver AST or ALT > 5 x ULN For patients with Gilbert's syndrome total bilirubin > 2.5 x ULN Serum creatinine > 1.5 x ULN and/or measured or calculated creatinine clearance < 75% LLN (lower limit of normal) Bone marrow function: Platelets < 100 x 109/L Hemoglobin (Hgb) < 9 g/dL Absolute Neutrophil Count (ANC) < 1.5 x 109/L Cardiac function: Clinically significant and/or uncontrolled heart disease such as congestive heart failure (CHF) requiring treatment (NYH grade ≥2), hypertension or arrhythmia Left ventricular ejection fraction (LVEF) < 45% as determined by MUGA scan or ECHO QTcF >480 msec on screening ECG or congenital long QT syndrome Acute myocardial infarction (AMI) or unstable angina pectoris < 3 months prior to study entry Peripheral neuropathy CTCAE Grade ≥2 History of pancreatitis of any grade Patients with diabetes mellitus requiring insulin treatment and/or with clinical signs or with Fasting Plasma Glucose (FPG) ≥ 140 mg/dL / 7.8 mmol/L Patients receiving treatment with medications that are known to be 1) strong inhibitors or inducers of CYP3A4/5; 2) CYP2C9 substrate with narrow therapeutic index; 3) QT prolonging agents; 4) proton pump inhibitors unless these medications can be discontinued at least a week prior to start of treatment. Other protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Phase ll part of the study was not conducted as Novartis decided to terminate the study considering safety and tolerability concerns and limited clinical activity.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CLR457<br> | Drug: CLR457<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of DLT |  | First 28 days of dosing | 
| Objective response rate (ORR) as per RECIST v1.1 |  | Baseline, every 8 weeks until discontinuation for an expected average of 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events (AEs) and Serious Advers Events (SAEs) |  | Continously throughout the study until 30 days after treatment discontinuation | 
| Severity of AEs and SAEs and dose reductions and interruptions |  | Continously throughout the study until 30 days after treatment discontinuation | 
| Duration of response (DOR) | per RECIST v1.1 | Baseline, every 8 weeks until discontinuation for an expected average of 4 months | 
| Progression free survival (PFS) | per RECIST v1.1 | Baseline, every 8 weeks until discontinuation for an expected average of 4 months | 
| Best overall response (BOR) | per RECIST v1.1 | Baseline and every 8 weeks for an expected average of 4 months | 
| Plasma concentration and Pharmacokinetics (PK) parameters of CLR457 | Parameters including but not limited to Cmax, Cmin, AUCinf, AUCtlast, AUCtau and T1/2 | During phase I: Baseline; Cycle 1 (C1) Day 1 (D1), 2, 8, 15, 16 and 22; Cycle 2 Day 1, 2, from Cycle 3 to cycle 6 on Day 1 During Phase II: Baseline; Cycle 1 Day 1, 2, 8, 15, 16 and 22 | 
| Changes from baseline in glucose metabolism markers (fasting glucose and insulin) |  | For Phase I and II C1D1, C1D2, C1D15, C1D16 and for Phase I only C2D1 and C2D2 | 
| Pre- and post- treatment immunohistochemistry of PI3K pathway molecules in newly obtained paired tumor samples |  | Baseline, C2D1 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Solid tumor,, breast cancer,, lung cancer,, endometrial cancer