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

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

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

Study Overview

• Status: Terminated
• Conditions: Advanced Solid Tumor
• Intervention / Treatment: Drug: CLR457

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X6
      • Novartis Investigative Site
• Japan
  • Chiba
    • Kashiwa, Chiba, Japan, 277 8577
      • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 169610
    • Novartis Investigative Site
• Spain
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital SC-9
  • New York
    • New York, New York, United States, 10017
      • Memorial Sloan Kettering SC-4
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology SC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CLR457	Drug: CLR457

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): August 7, 2014
• Primary Completion (Actual): November 12, 2015
• Study Completion (Actual): November 12, 2015

Study Registration Dates

• First Submitted: July 7, 2014
• First Submitted That Met QC Criteria: July 10, 2014
• First Posted (Estimate): July 14, 2014

Study Record Updates

• Last Update Posted (Actual): December 3, 2021
• Last Update Submitted That Met QC Criteria: December 2, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: endometrial cancer; breast cancer,; lung cancer,; Solid tumor,
• Additional Relevant MeSH Terms: Neoplasms
• Other Study ID Numbers: CCLR457X2101