Advanced solid malignancies MedDRA version: 17.1 Level: LLT Classification code 10065147 Term: Malignant solid tumor System Organ Class: 100000004864
Conditions
Interventions
Product Name: CLR457
Product Code: CLR457
Pharmaceutical Form: Capsule, hard
Current Sponsor code: CLR457
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 2.5-
Prod
Sponsors
Novartis Pharma Services AG
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Written informed consent must be obtained prior to any screening procedures 2. Patient (male or female) = 18 years of age 3. 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 + 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: patients with non-small cell lung cancer harboring cMET activation and/or EGFR mutation 4. Up to 3 chemotherapies in advanced/metastatic setting allowed for Phase II patients. 5. ECOG Performance Status = 2. 6. Availability of a representative formalin fixed paraffin embedded tumor tissue sample. If archival tumor specimen is not available, a newly obtained tumor specimen needs to be submitted instead. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 110 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 53
Exclusion criteria
Exclusion criteria: 1. Brain metastasis unless treated and neurologically stable 2. 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) and alanine aminotransferase (ALT= 2.5 x ULN) • Patients with tumor involvement of the liver must have AST and/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 480 msec on screening ECG or congenital long QT syndrome • Acute myocardial infarction (AMI) or unstable angina pectoris = 3 months prior to study entry 3. Peripheral neuropathy CTCAE Grade = 2. 4. History of pancreatitis of any grade. 5. 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 6. 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 pomp inhibitors unless these medications can be discontinued at least a week prior to start of treatment.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 1. To estimate the MTD or RP2D of CLR457 (dose escalation phase) 2. To investigate the anti-tumor activity of CLR457 (Phase II);Secondary Objective: 1. To characterize the safety and tolerability of CLR457 treatment 2. To determine the single and multiple dose PK profile of CLR457 3. To further investigate the anti-tumor activity of CLR457 4. To assess the PI3K pathway inhibition by CLR457;Primary end point(s): 1- Incidence of DLT 2- Objective response rate (ORR) per RECIST v1.1 by investigator assessment;Timepoint(s) of evaluation of this end point: 1- First 28 days of dosing 2- Baseline and every 8 weeks | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1- Safety: Incidence and severity of AEs and SAEs, including changes in laboratory values, vital signs and ECGs Tolerability: Dose interruptions and reductions 2- Plasma concentration of CLR457 and PK parameters including but not limited to Cmax, Cmin, AUCinf, AUCtlast, AUCtau and T1/2 3- Best overall response (BOR), duration of response (DOR), progression free survival (PFS) per RECIST v1.1 by investigator assessment 4- Changes from baseline in glucose metabolism markers (fasting glucose and insulin) Pre- and post- treatment immunohistochemistry of PI3K pathway molecules (e.g. p-S6, p-AKT) in newly obtained tumor samples;Timepoint(s) of evaluation of this end point: 1- Continuously throughout the study until 30 days after safety follow up 2- During phase I: Baseline; Cycle 1 Day 1, 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 3- Baseline and every 8 weeks 4- Blood for glucose metabolism markers collected on C1D1, C1D2, C1D15, C1D16, C2D1 and C2D2. Paired newly obtained tumor samples collected at baseline and at C2D1. | — |
Countries
Australia, Austria, Canada, France, Germany, Hong Kong, Israel, Italy, Japan, Singapore, Spain, United States
Contacts
Public ContactInformation&Communication Médicale
Novartis Pharma S.A.S.
Outcome results
None listed