A Phase I/II Study of BEZ235 in Patients With Advanced Solid Malignancies Enriched by Patients With Advanced Breast Cancer

A Phase I/II, Multi-center, Open-label Study of BEZ235, Administered Orally on a Continuous Daily Dosing Schedule in Adult Patients With Advanced Solid Malignancies Including Patients With Advanced Breast Cancer

This is a first-in-human, phase I/Ib clinical research study with BEZ235, an inhibitor of phosphatidylinositol 3'-kinase (PI3K). The study consists of a dose escalation part followed by a safety dose expansion part:

Dose escalation part (advanced solid tumors, including patients with breast cancer being treated with trastuzumab):

Patients receive oral BEZ235 once daily on days 1-28 of the first course. Courses will repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of at least 3 patients receive escalating doses of BEZ235, as single agent or in combination with trastuzumab, until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose expected to produce during the first course of treatment dose-limiting toxicity in 33% of patients.

Once the MTD has been defined, the safety expansion parts of the trial will be opened for enrollment.

Safety dose expansion part (advanced solid tumors, including patients with breast cancer being treated with trastuzumab):

Patients will be treated with BEZ235, as single agent or in combination with trastuzumab, given at the MTD, once daily. Treatment of patients will continue until disease progression or occurrence of unacceptable side effects.

Study Overview

• Status: Completed
• Conditions: Breast Cancer; Advanced Solid Tumors; Cowden Syndrome
• Intervention / Treatment: Drug: BEZ235

• Study Type: Interventional
• Enrollment (Actual): 183
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Essen, Germany, 45147
    • Novartis Investigative Site
• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • Novartis Investigative Site
• Spain
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
  • Comunidad Valenciana
    • Valencia, Comunidad Valenciana, Spain, 46010
      • Novartis Investigative Site
    • Valencia, Comunidad Valenciana, Spain, 46009
      • Novartis Investigative Site
• United Kingdom
  • Manchester, United Kingdom, M20 9BX
    • Novartis Investigative Site
• United States
  • California
    • Los Angeles, California, United States, 90095
      • University of California at Los Angeles JonssonComprehensiveCancerCtr
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University School of Medicine YaleCancerCtr-ClinTrialsOffice
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute Clinical Trials ProjectManager
  • Nevada
    • Las Vegas, Nevada, United States, 89135
      • Nevada Cancer Institute NVCC - Huntsman
  • South Carolina
    • Greenville, South Carolina, United States, 29605
      • Cancer Centers of the Carolinas CCC Faris
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute Dept.ofSarahCannonCancerCtr(2)
  • Texas
    • Dallas, Texas, United States, 75246
      • Baylor Health Care System/Sammons Cancer Center Baylor- Sammons
    • Houston, Texas, United States, 77030-4009
      • University of Texas/MD Anderson Cancer Center Thoractic Head/Neck Med.Onc(2)
    • Tyler, Texas, United States, 75702
      • Tyler Cancer Center TCC

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:

[Single agent dose escalation arm]: Patients with histologically-confirmed, advanced unresectable solid tumors including CS patients who have progressed on (or not been able to tolerate) standard therapy within three months before screening visit or for whom no standard anticancer therapy exists.

[Combination part]: Patients with metastatic HER2+ Breast Cancer, after failure of trastuzumab treatment. Eligible patients will have to have tumors carrying molecular alterations of PIK3CA and/or PTEN.

[Single agent safety expansion arm]: Patients with histologically-confirmed, advanced unresectable solid tumors including CS patients who have progressed on (or not been able to tolerate) standard therapy within three months before screening visit or for whom no standard anticancer therapy exists. Patients will be prescreened for molecular alterations affecting PIK3CA and/or PTEN. Patients with NSCLC will also be pre-screened for EGFR mutation.

Exclusion Criteria:

• Patients who have brain metastases, which are progressive and/or requiring medical intervention for symptom control
• Prior treatment with a PI3K inhibitor
• Acute or chronic liver disease or renal disease
• Acute or chronic pancreatitis
• Patients with unresolved diarrhea ≥ CTCAE grade 2
• Impaired cardiac function or clinically significant cardiac diseases
• Patients with diabetes mellitus requiring insulin treatment
• Patients with known coagulopathies
• Patients with a history of photosensitivity reactions to other drugs
• Any of the following ophthalmological findings:
• Progressive eye disease that could lead to severe loss of visual acuity or visual field
• loss during the study period
• Inability to perform the ophthalmic procedures required in this protocol
• Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol.

Other protocol-defined inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BEZ235 Alone, Dose Escalation	Drug: BEZ235
Experimental: BEZ235 + trastuzumab, Dose Escalation	Drug: BEZ235
Experimental: BEZ235 Alone, MTD Expansion	Drug: BEZ235
Experimental: BEZ235 + Trastuzumab, MTD Expansion	Drug: BEZ235

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
determine the maximum Tolerated Dose (MTD) of BEZ235 as single agent and in combination with trastuzumab (Dose escalation part)	at end of study
assess the safety & tolerability of BEZ235 SDS as single agent and in combination with trastuzumab administered to patients at the MTD level (Safety expansion part)	at end of study

Secondary Outcome Measures

Outcome Measure	Time Frame
assess the safety and tolerability of the various formulations of BEZ235	at end of study
Asses the Pharmacokinetics of BEZ235 which includes AUC, Cmax, Tmax, t1/2 as endpoints	at end of study
Preliminary anti-tumor activity (tumor response) of BEZ235 SDS as single agent and in combination with trastuzumab	end of study

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• Results for CBEZ235A2101 can be found on the Novartis Clinical Trial Results Website

Study record dates

Study Major Dates

• Study Start (Actual): December 21, 2006
• Primary Completion (Actual): January 8, 2013
• Study Completion (Actual): January 8, 2013

Study Registration Dates

• First Submitted: February 8, 2008
• First Submitted That Met QC Criteria: February 20, 2008
• First Posted (Estimate): February 21, 2008

Study Record Updates

• Last Update Posted (Actual): December 9, 2020
• Last Update Submitted That Met QC Criteria: December 6, 2020
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Keywords: breast cancer; Neoplasms; solid tumors; breast neoplasms; advanced; kinase; BEZ235; PI3K Inhibitor; breast diseases; Phosphatidylinositol 3
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Genetic Diseases, Inborn; Neoplastic Syndromes, Hereditary; Hamartoma; Neoplasms, Multiple Primary; Breast Neoplasms; Hamartoma Syndrome, Multiple; Antineoplastic Agents; Dactolisib
• Other Study ID Numbers: CBEZ235A2101; 2006-004353-23 (EudraCT Number)