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

Primary Purpose

Inoperable Locally Advanced Breast Cancer, Metastatic Breast Cancer (MBC)

Status

Terminated

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

BEZ235

Paclitaxel

About this trial

This is an interventional treatment trial for Inoperable Locally Advanced Breast Cancer focused on measuring Locally advanced, metastatic, breast cancer, HER2 negative, PI3K pathway, paclitaxel, mTOR inhibitor

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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

Sites / Locations

Novartis Investigative Site
Novartis Investigative Site
Novartis Investigative Site

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

BEZ235 100 mg bid + paclitaxel 80 mg (phase lb)

BEZ235 200 mg bid + paclitaxel 80 mg (phase lb)

Arm Description

Increasing doses of oral BEZ235 100 mg administered on a continuous twice daily (BID) schedule + weekly paclitaxel infusion at a fixed dose of 80 mg/m2. Treatment was organized into cycles of 28 days.

Increasing doses of oral BEZ235 200 mg administered on a continuous twice daily (BID) schedule + weekly paclitaxel infusion at a fixed dose of 80 mg/m2. Treatment was organized into cycles of 28 days

Outcomes

Primary Outcome Measures

Phase lb: Dose Limiting Toxicities (DLTs) the first cycle of treatment

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

Phase lb: Frequency and severity of adverse events

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)

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)

Proportion of patients with a best overall response of CR or PR according to RECIST 1.1

Phase lb: Clinical Benefit Rate (CBR)

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

Full Information

NCT ID

NCT01495247

First Posted

September 30, 2011

Last Updated

December 6, 2020

Sponsor

Novartis Pharmaceuticals

1. Study Identification

Unique Protocol Identification Number

NCT01495247

Brief Title

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

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 Type

Interventional

2. Study Status

Record Verification Date

September 2020

Overall Recruitment Status

Terminated

Why Stopped

Study did not meet Phase Ib primary objective to establish the maximum tolerated dose/recommended dose for Phase II

Study Start Date

January 30, 2012 (Actual)

Primary Completion Date

May 19, 2014 (Actual)

Study Completion Date

May 19, 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Novartis Pharmaceuticals

4. Oversight

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Inoperable Locally Advanced Breast Cancer, Metastatic Breast Cancer (MBC)

Keywords

Locally advanced, metastatic, breast cancer, HER2 negative, PI3K pathway, paclitaxel, mTOR inhibitor

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Sequential Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

18 (Actual)

8. Arms, Groups, and Interventions

Arm Title

BEZ235 100 mg bid + paclitaxel 80 mg (phase lb)

Arm Type

Experimental

Arm Description

Arm Title

BEZ235 200 mg bid + paclitaxel 80 mg (phase lb)

Arm Type

Experimental

Arm Description

Increasing doses of oral BEZ235 200 mg administered on a continuous twice daily (BID) schedule + weekly paclitaxel infusion at a fixed dose of 80 mg/m2. Treatment was organized into cycles of 28 days

Intervention Type

Drug

Intervention Name(s)

BEZ235

Intervention Description

Doses of oral BEZ235 (BID), supplied as 50mg, 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.

Intervention Type

Drug

Intervention Name(s)

Paclitaxel

Intervention Description

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 Measure Information:

Title

Phase lb: Dose Limiting Toxicities (DLTs) the first cycle of treatment

Description

Time Frame

At first treatment intake (Cycle 1 Day 1 = C1D1), C1D8, C1D15, C1D22 and C2D1 [a cycle = 4 weeks = 28 days]

Secondary Outcome Measure Information:

Title

Phase lb: Frequency and severity of adverse events

Description

Incidence of adverse events (based on CTCAE Version 4) summarized by system organ class and/or preferred term, severity and relation to study treatment.

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].

Title

Phase lb: Progression free survival (PFS)

Description

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.

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].

Title

Phase lb: Overall Response Rate (ORR)

Description

Proportion of patients with a best overall response of CR or PR according to RECIST 1.1

Time Frame

At first treatment intake, every 8 weeks (C3D1, C5D1, C7D1, etc.) during the study [estimated time frame: 18 months].

Title

Phase lb: Clinical Benefit Rate (CBR)

Description

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

Time Frame

At first treatment intake, every 8 weeks (C3D1, C5D1, C7D1, etc.) during the study [estimated time frame: 18 months].

10. Eligibility

Sex

Female

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Novartis Pharmaceuticals

Organizational Affiliation

Novartis Pharmaceuticals

Official's Role

Study Director

Facility Information:

Facility Name

Novartis Investigative Site

City

Dijon Cedex

ZIP/Postal Code

21034

Country

France

Facility Name

Novartis Investigative Site

City

Saint-Herblain Cédex

ZIP/Postal Code

44805

Country

France

Facility Name

Novartis Investigative Site

City

Hospitalet de LLobregat

State/Province

Catalunya

ZIP/Postal Code

08907

Country

Spain

12. IPD Sharing Statement

Links:

URL

https://www.novctrd.com/ctrdweb/trialresult/trialresults/pdf?trialResultId=13703

Description

Results for CBEZ235B2101 can be found on the Novartis Clinical Trial Results Website

Learn more about this trial

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

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