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

• Register: ClinicalTrials.gov
• Last refreshed on: 13 December 2021
• Main ID: NCT02189174
• Date of registration: 07/07/2014
• Prospective Registration: Yes
• Primary sponsor: Novartis Pharmaceuticals
• Public title: Study of CLR457 Administered Orally in Adult Patients With Advanced Solid Malignancies
• Scientific title: A Phase I/II Multicenter, Open-label Study of CLR457, Administered Orally in Adult Patients With Advanced Solid Malignancies
• Date of first enrolment: August 7, 2014
• Target sample size: 31
• Recruitment status: Terminated
• URL: https://clinicaltrials.gov/show/NCT02189174
• Study type: Interventional
• Study design: Allocation: N/A. Intervention model: Single Group Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 1

Countries of recruitment

Australia, Austria, Canada, France, Hong Kong, Israel, Italy, Japan, Singapore, Spain, Switzerland, United States

Contacts

• Name: Novartis Pharmaceuticals
• Affiliation: Novartis Pharmaceuticals

Key inclusion & exclusion 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.



Age minimum: 18 Years
Age maximum: N/A
Gender: All

Health Condition(s) or Problem(s) studied

Advanced Solid Tumor

Intervention(s)

Drug: CLR457

Primary Outcome(s)

Objective response rate (ORR) as per RECIST v1.1 [Time Frame: Baseline, every 8 weeks until discontinuation for an expected average of 4 months]

Incidence of DLT [Time Frame: First 28 days of dosing]

Secondary Outcome(s)

Progression free survival (PFS) [Time Frame: Baseline, every 8 weeks until discontinuation for an expected average of 4 months]

Plasma concentration and Pharmacokinetics (PK) parameters of CLR457 [Time Frame: 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]

Best overall response (BOR) [Time Frame: Baseline and every 8 weeks for an expected average of 4 months]

Changes from baseline in glucose metabolism markers (fasting glucose and insulin) [Time Frame: For Phase I and II C1D1, C1D2, C1D15, C1D16 and for Phase I only C2D1 and C2D2]

Incidence of Adverse Events (AEs) and Serious Advers Events (SAEs) [Time Frame: Continously throughout the study until 30 days after treatment discontinuation]

Pre- and post- treatment immunohistochemistry of PI3K pathway molecules in newly obtained paired tumor samples [Time Frame: Baseline, C2D1]

Duration of response (DOR) [Time Frame: Baseline, every 8 weeks until discontinuation for an expected average of 4 months]

Severity of AEs and SAEs and dose reductions and interruptions [Time Frame: Continously throughout the study until 30 days after treatment discontinuation]

Secondary ID(s)

CCLR457X2101

Source(s) of Monetary Support

Please refer to primary and secondary sponsors