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

• ClinicalTrials.gov Identifier: NCT02189174
• Recruitment Status: Terminated
• First Posted: July 14, 2014
• Last Update Posted: December 17, 2020
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

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

Condition or disease	Intervention/treatment	Phase
Advanced Solid Tumor	Drug: CLR457	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 157 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Multicenter, Open-label Study of CLR457, Administered Orally in Adult Patients With Advanced Solid Malignancies
• Actual Study Start Date: August 7, 2014
• Actual Primary Completion Date: November 12, 2015
• Actual Study Completion Date: November 12, 2015

Arms and Interventions

Arm	Intervention/treatment
Experimental: CLR457	Drug: CLR457

Outcome Measures

Primary Outcome Measures :

1. Incidence of DLT [ Time Frame: First 28 days of dosing ]
2. Objective response rate (ORR) as per RECIST v1.1 [ Time Frame: Baseline, every 8 weeks until discontinuation for an expected average of 4 months ]

Secondary Outcome Measures :

1. Incidence of Adverse Events (AEs) and Serious Advers Events (SAEs) [ Time Frame: Continously throughout the study until 30 days after treatment discontinuation ]
2. Severity of AEs and SAEs and dose reductions and interruptions [ Time Frame: Continously throughout the study until 30 days after treatment discontinuation ]
3. Duration of response (DOR) [ Time Frame: Baseline, every 8 weeks until discontinuation for an expected average of 4 months ]
   per RECIST v1.1
4. Progression free survival (PFS) [ Time Frame: Baseline, every 8 weeks until discontinuation for an expected average of 4 months ]
   per RECIST v1.1
5. Best overall response (BOR) [ Time Frame: Baseline and every 8 weeks for an expected average of 4 months ]
   per RECIST v1.1
6. 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 ]
   Parameters including but not limited to Cmax, Cmin, AUCinf, AUCtlast, AUCtau and T1/2
7. 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 ]
8. Pre- and post- treatment immunohistochemistry of PI3K pathway molecules in newly obtained paired tumor samples [ Time Frame: Baseline, C2D1 ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, Massachusetts

Massachusetts General Hospital SC-9

Boston, Massachusetts, United States, 02114

United States, New York

Memorial Sloan Kettering SC-4

New York, New York, United States, 10017

United States, Tennessee

Tennessee Oncology SC

Nashville, Tennessee, United States, 37203

Canada, Ontario

Novartis Investigative Site

Toronto, Ontario, Canada, M5G 1X6

Japan

Novartis Investigative Site

Kashiwa, Chiba, Japan, 277 8577

Singapore

Novartis Investigative Site

Singapore, Singapore, 169610

Spain

Novartis Investigative Site

Barcelona, Catalunya, Spain, 08035

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

More Information

Additional Information:

Results for CCLR457X2101 from the Novartis Clinical Trials website 

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02189174
• Other Study ID Numbers: CCLR457X2101
• First Posted: July 14, 2014
• Last Update Posted: December 17, 2020
• Last Verified: April 2019

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

Solid tumor,; breast cancer,; lung cancer,; endometrial cancer

Additional relevant MeSH terms:

Neoplasms