Phase Ib/II Trial of BEZ235 With Paclitaxel in Patients With HER2 Negative, Locally Advanced or Metastatic Breast Cancer
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Purpose
| Condition | Intervention | Phase |
|---|---|---|
| Inoperable Locally Advanced Breast Cancer Metastatic Breast Cancer (MBC) | Drug: BEZ235 + Paclitaxel | Phase 1 Phase 2 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Intervention Model: Single Group Assignment Masking: None (Open Label) Primary Purpose: Treatment |
| Official Title: | A Dose-finding Phase Ib Study Followed by an Open-label, Randomized Phase II Study of BEZ235 Plus Paclitaxel in Patients With HER2 Negative, Inoperable Locally Advanced or Metastatic Breast Cancer |
- Phase lb: Dose Limiting Toxicities (DLTs) the first cycle of treatment [ Time Frame: At first treatment intake (Cycle 1 Day 1 = C1D1), C1D8, C1D15, C1D22 and C2D1 [a cycle = 4 weeks = 28 days] ]
DLT is defined as treatment-related toxicity (classified according Common Toxicity Criteria for Adverse Events (CTCAE) Version 4) occurring during the first 28 treatment days and meeting specific protocol-predefined criteria.
The information will be integrated in a Bayesian logistic regression model with overdose control to estimate the maximum tolerated dose (MTD).
- Phase lb: Frequency and severity of adverse events [ Time Frame: At screening, every week (C1D1, C1D8, C1D15, C1D22, C2D1, C2D8, etc.) until 30-45 days after treatment discontinuation [estimated time frame: 18 months]. ]Incidence of adverse events (based on CTCAE Version 4) summarized by system organ class and/or preferred term, severity and relation to study treatment.
- Phase lb: Progression free survival (PFS) [ Time Frame: At first treatment intake, every 8 weeks (C3D1, C5D1, C7D1, etc.) until disease progression or death for any cause [estimated time frame: 18 months]. ]PFS is defined as the time from start of treatment to objective tumor progression or death from any cause. Radiological assessments will be performed every 8 weeks.
- Phase lb: Overall Response Rate (ORR) [ Time Frame: At first treatment intake, every 8 weeks (C3D1, C5D1, C7D1, etc.) during the study [estimated time frame: 18 months]. ]Proportion of patients with a best overall response of CR or PR according to RECIST 1.1
- Phase lb: Clinical Benefit Rate (CBR) [ Time Frame: At first treatment intake, every 8 weeks (C3D1, C5D1, C7D1, etc.) during the study [estimated time frame: 18 months]. ]Proportion of patients with a best overall response of CR, PR or SD with a duration of 24 weeks or longer according to RECIST 1.1
| Enrollment: | 18 |
| Study Start Date: | January 2012 |
| Study Completion Date: | May 2014 |
| Primary Completion Date: | May 2014 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: BEZ235 + paclitaxel (phase lb)
Increasing doses of oral BEZ235 administered on a continuous twice daily (BID) schedule + weekly paclitaxel infusion at a fixed dose of 80 mg/m2. Treatment will be organized into cycles of 28 days.
|
Drug: BEZ235 + Paclitaxel
Doses of oral BEZ235 (BID), supplied as 200mg, 300mg or 400mg in SDS sachets, together with standard weekly paclitaxel at a fixed dose (80mg/m²) during 1h by i.v. in infusion. The paclitaxel infusion will be given in the morning and directly thereafter the BEZ235 dose will be given. BEZ235 doses will be escalated in cohorts of 3 to 6 patients guided by an adaptive Bayesian logistic regression model with overdose control until MTD/RP2D has been established. The initial dose level for the first cohort will be 200mg (BID), and then based on the Bayesian model the dose may be escalated to 300mg, 400mg, 500mg or 600mg for the next cohorts. |
Eligibility
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| Ages Eligible for Study: | 18 Years and older (Adult, Senior) |
| Sexes Eligible for Study: | Female |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria (phase lb):
- Females with Breast cancer that is histologically or cytologically confirmed, HER2 negative and locally advanced or metastatic as confirmed by radiology
- ECOG performance status 0 and 1
- Adequate bone marrow and organ function
Exclusion Criteria (Phase lb):
- Previous treatment with PI3K and/or mTOR inhibitors
- Symptomatic Central Nervous System (CNS) metastases
- Concurrent malignancy or malignancy in the last 5 years prior to start of study treatment
- Wide field radiotherapy ≤ 28 days or limited field radiation for palliation ≤ 14 days prior to starting study drug
- Active cardiac disease (e.g. LVEF less than institutional lower limit of normal, QTcF > 480 msec, unstable angina pectoris, ventricular, supraventricular or nodal arrhythmias)
- Inadequately controlled hypertension
- Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of BEZ235 and/or paclitaxel
- Treatment at start of study treatment with drugs with a known risk to induce Torsades de Pointes, moderate and strong inhibitors or inducers of isoenzyme CYP3A4, warfarin and coumadin analogues, LHRH agonists
- Sensitivity to paclitaxel treatment
- Uncontrolled diabetes mellitus
- Pregnant or nursing (lactating) woman
Other protocol-defined inclusion/exclusion criteria may apply
Contacts and Locations
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01495247
| France | |
| Novartis Investigative Site | |
| Dijon Cedex, France, 21034 | |
| Novartis Investigative Site | |
| Saint-Herblain Cédex, France, 44805 | |
| Spain | |
| Novartis Investigative Site | |
| Hospitalet de LLobregat, Catalunya, Spain, 08907 | |
| Study Director: | Novartis Pharmaceuticals | Novartis Pharmaceuticals |
More Information
| Responsible Party: | Novartis Pharmaceuticals |
| ClinicalTrials.gov Identifier: | NCT01495247 History of Changes |
| Other Study ID Numbers: |
CBEZ235B2101 2011-002400-32 ( EudraCT Number ) |
| First Submitted: | September 30, 2011 |
| First Posted: | December 19, 2011 |
| Last Update Posted: | July 23, 2014 |
| Last Verified: | July 2014 |
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
|
Locally advanced metastatic breast cancer HER2 negative |
PI3K pathway paclitaxel mTOR inhibitor |
Additional relevant MeSH terms:
|
Breast Neoplasms Neoplasms by Site Neoplasms Breast Diseases Skin Diseases Paclitaxel Dactolisib |
Albumin-Bound Paclitaxel Antineoplastic Agents, Phytogenic Antineoplastic Agents Tubulin Modulators Antimitotic Agents Mitosis Modulators Molecular Mechanisms of Pharmacological Action |