Clinical trial NCT00620594: A Phase I/II Study of BEZ235 in Patients With Advanced Solid Malignancies Enriched by Patients With Advanced Breast Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Breast Cancer
Advanced Solid Tumors
Cowden Syndrome
Keywords: Neoplasms
breast neoplasms
breast diseases
solid tumors
BEZ235
breast cancer
PI3K Inhibitor
Phosphatidylinositol 3
kinase
advanced
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2008-02-21
Enrollment: 183
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: determine the maximum Tolerated Dose (MTD) of BEZ235 as single agent and in combination with trastuzumab (Dose escalation part)
timeFrame: at end of study
measure: 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)
timeFrame: at end of study
Secondary outcomes:
measure: assess the safety and tolerability of the various formulations of BEZ235
timeFrame: at end of study
measure: Asses the Pharmacokinetics of BEZ235 which includes AUC, Cmax, Tmax, t1/2 as endpoints
timeFrame: at end of study
measure: Preliminary anti-tumor activity (tumor response) of BEZ235 SDS as single agent and in combination with trastuzumab
timeFrame: end of study
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of California at Los Angeles JonssonComprehensiveCancerCtr
state: California
city: New Haven
country: United States
facility: Yale University School of Medicine YaleCancerCtr-ClinTrialsOffice
state: Connecticut
city: Boston
country: United States
facility: Dana Farber Cancer Institute Clinical Trials ProjectManager
state: Massachusetts
city: Las Vegas
country: United States
facility: Nevada Cancer Institute NVCC - Huntsman
state: Nevada
city: Greenville
country: United States
facility: Cancer Centers of the Carolinas CCC Faris
state: South Carolina
city: Nashville
country: United States
facility: Sarah Cannon Research Institute Dept.ofSarahCannonCancerCtr(2)
state: Tennessee
city: Dallas
country: United States
facility: Baylor Health Care System/Sammons Cancer Center Baylor- Sammons
state: Texas
city: Houston
country: United States
facility: University of Texas/MD Anderson Cancer Center Thoractic Head/Neck Med.Onc(2)
state: Texas
city: Tyler
country: United States
facility: Tyler Cancer Center TCC
state: Texas
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Amsterdam
country: Netherlands
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Valencia
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: Valencia
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: Manchester
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: