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

Purpose

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	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: 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

Resource links provided by NLM:

Genetics Home Reference related topics: breast cancer

MedlinePlus related topics: Breast Cancer Cancer

Drug Information available for: Paclitaxel

U.S. FDA Resources

Further study details as provided by Novartis:

Primary Outcome Measures:

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] ] [ Designated as safety issue: Yes ]
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 [ 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]. ] [ Designated as safety issue: Yes ]
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]. ] [ Designated as safety issue: No ]
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]. ] [ Designated as safety issue: No ]
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]. ] [ Designated as safety issue: No ]
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.

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


Ages Eligible for Study:	18 Years and older (Adult, Senior)
Genders Eligible for Study:	Female
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01495247

Locations


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

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators


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
Study First Received:	September 30, 2011
Last Updated:	July 22, 2014
Health Authority:	United States: Food and Drug Administration Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica Australia: Department of Health and Ageing Therapeutic Goods Administration Brazil: National Health Surveillance Agency Belgium: Federal Agency for Medicinal Products and Health Products France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis) Germany: Federal Institute for Drugs and Medical Devices Hong Kong: Department of Health Italy: National Institute of Health Korea: Food and Drug Administration Russia: Ministry of Health of the Russian Federation Singapore: Health Sciences Authority Spain: Spanish Agency of Medicines Taiwan: Department of Health Thailand: Food and Drug Administration Turkey: Ministry of Health United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Novartis:


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 Albumin-Bound Paclitaxel	Antineoplastic Agents, Phytogenic Antineoplastic Agents Tubulin Modulators Antimitotic Agents Mitosis Modulators Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 23, 2016