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Phase Ib/II Trial of BEZ235 With Paclitaxel in Patients With HER2 Negative, Locally Advanced or Metastatic Breast Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01495247
Recruitment Status : Completed
First Posted : December 19, 2011
Last Update Posted : July 23, 2014
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
This is a prospective, multi-center, open-label, phase Ib/ II study (two parts) with patients that have locally advanced or metastatic HER2 negative breast cancer. The first part (phase Ib) will investigate the MTD / Recommended Phase 2 Dose (RP2D) of the combination therapy of BEZ235 twice daily (b.i.d.) and weekly paclitaxel using a Bayesian model. When MTD/ RP2D is established the second part (phase II) will start. Phase II will evaluate the efficacy and the safety of weekly paclitaxel alone compared to weekly paclitaxel plus BEZ235 bid.

Condition or disease Intervention/treatment Phase
Inoperable Locally Advanced Breast Cancer Metastatic Breast Cancer (MBC) Drug: BEZ235 + Paclitaxel Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 18 participants
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
Study Start Date : January 2012
Actual Primary Completion Date : May 2014
Actual Study Completion Date : May 2014

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer
Drug Information available for: Paclitaxel

Arm Intervention/treatment
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.

Primary Outcome Measures :
  1. 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).

Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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

  4. 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

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
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

Information from the National Library of Medicine

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 identifier (NCT number): NCT01495247

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Novartis Investigative Site
Dijon Cedex, France, 21034
Novartis Investigative Site
Saint-Herblain Cédex, France, 44805
Novartis Investigative Site
Hospitalet de LLobregat, Catalunya, Spain, 08907
Sponsors and Collaborators
Novartis Pharmaceuticals
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals

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Responsible Party: Novartis Pharmaceuticals Identifier: NCT01495247     History of Changes
Other Study ID Numbers: CBEZ235B2101
2011-002400-32 ( EudraCT Number )
First Posted: December 19, 2011    Key Record Dates
Last Update Posted: July 23, 2014
Last Verified: July 2014
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Locally advanced
breast cancer
HER2 negative
PI3K pathway
mTOR inhibitor
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Albumin-Bound Paclitaxel
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action