A Phase I/II Study of BEZ235 in Patients With Advanced Solid Malignancies Enriched by Patients With Advanced Breast Cancer
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Purpose
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.
| Condition | Intervention | Phase |
|---|---|---|
|
Breast Cancer, Advanced Solid Tumors, Cowden Syndrome |
Drug: BEZ235 |
Phase 1 |
| Study Type: | Interventional |
| Study Design: | Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment |
| 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 |
- determine the maximum Tolerated Dose (MTD) of BEZ235 as single agent and in combination with trastuzumab (Dose escalation part) [ Time Frame: at end of study ] [ Designated as safety issue: Yes ]
- 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) [ Time Frame: at end of study ] [ Designated as safety issue: Yes ]
- assess the safety and tolerability of the various formulations of BEZ235 [ Time Frame: at end of study ] [ Designated as safety issue: Yes ]
- Asses the Pharmacokinetics of BEZ235 which includes AUC, Cmax, Tmax, t1/2 as endpoints [ Time Frame: at end of study ] [ Designated as safety issue: No ]
- Preliminary anti-tumor activity (tumor response) of BEZ235 SDS as single agent and in combination with trastuzumab [ Time Frame: end of study ] [ Designated as safety issue: No ]
| Enrollment: | 244 |
| Study Start Date: | December 2006 |
| Study Completion Date: | January 2013 |
| Primary Completion Date: | January 2013 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
| 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 |
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
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
Contacts and Locations| United States, California | |
| University of California at Los Angeles JonssonComprehensiveCancerCtr | |
| Los Angeles, California, United States, 90095 | |
| United States, Connecticut | |
| Yale University School of Medicine YaleCancerCtr-ClinTrialsOffice | |
| New Haven, Connecticut, United States, 06520 | |
| United States, Massachusetts | |
| Dana Farber Cancer Institute Clinical Trials ProjectManager | |
| Boston, Massachusetts, United States, 02115 | |
| United States, Nevada | |
| Nevada Cancer Institute NVCC - Huntsman | |
| Las Vegas, Nevada, United States, 89135 | |
| United States, South Carolina | |
| Cancer Centers of the Carolinas CCC Faris | |
| Greenville, South Carolina, United States, 29605 | |
| United States, Tennessee | |
| Sarah Cannon Research Institute Dept.ofSarahCannonCancerCtr(2) | |
| Nashville, Tennessee, United States, 37203 | |
| United States, Texas | |
| Baylor College of Medicine Baylor- Sammons | |
| Dallas, Texas, United States, 75246 | |
| MD Anderson Cancer Center/University of Texas Thoractic Head/Neck Med.Onc(2) | |
| Houston, Texas, United States, 77030-4009 | |
| Tyler Cancer Center TCC | |
| Tyler, Texas, United States, 75702 | |
| Germany | |
| Novartis Investigative Site | |
| Essen, Germany, 45147 | |
| Netherlands | |
| Novartis Investigative Site | |
| Amsterdam, Netherlands, 1066 CX | |
| Spain | |
| Novartis Investigative Site | |
| Barcelona, Cataluna, Spain, 08035 | |
| Novartis Investigative Site | |
| Valencia, Comunidad Valenciana, Spain, 46009 | |
| Novartis Investigative Site | |
| Valencia, Comunidad Valenciana, Spain, 46010 | |
| United Kingdom | |
| Novartis Investigative Site | |
| Manchester, United Kingdom, M20 9BX | |
| Study Director: | Novartis Pharmaceuticals | Novartis Pharmaceuticals |
More Information
No publications provided
| Responsible Party: | Novartis ( Novartis Pharmaceuticals ) |
| ClinicalTrials.gov Identifier: | NCT00620594 History of Changes |
| Other Study ID Numbers: | CBEZ235A2101, 2006-004353-23 |
| Study First Received: | February 8, 2008 |
| Last Updated: | March 4, 2013 |
| Health Authority: | United States: Food and Drug Administration Germany: BfArM (The Federal Institute for Drugs and Medical Devices) Netherlands: Dutch Health Care Inspectorate Spain: Agencia Espanola del Medicamento y Productos Sanitarios United Kingdom: Medicines and Healthcare Products Regulatory Agency |
Keywords provided by Novartis:
|
Neoplasms, breast neoplasms, breast diseases, solid tumors, BEZ235, |
breast cancer, PI3K Inhibitor, Phosphatidylinositol 3', kinase, advanced |
Additional relevant MeSH terms:
|
Breast Neoplasms Hamartoma Syndrome, Multiple Neoplasms by Site Neoplasms Breast Diseases |
Skin Diseases Hamartoma Neoplasms, Multiple Primary Neoplastic Syndromes, Hereditary Genetic Diseases, Inborn |
ClinicalTrials.gov processed this record on May 16, 2013