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

NCT01495247 | Terminated Phase 1

• 2 other identifiers: CBEZ235B21012011-002400-32
• Study Type: interventional
• Target: 18
• Locations: 2 countries
• Sites: 3

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.

Conditions

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

Keywords

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

Outcome Measures

Primary Outcomes (1)

• 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).

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

Secondary Outcomes (4)

• Phase lb: Frequency and severity of adverse events

  At screening, every week (C1D1, C1D8, C1D15, C1D22, C2D1, C2D8, etc.) until 30-45 days after treatment discontinuation [estimated time frame: 18 months].

• Phase lb: Progression free survival (PFS)

  At first treatment intake, every 8 weeks (C3D1, C5D1, C7D1, etc.) until disease progression or death for any cause [estimated time frame: 18 months].

• Phase lb: Overall Response Rate (ORR)

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

• Phase lb: Clinical Benefit Rate (CBR)

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

Study Arms (2)

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

EXPERIMENTAL

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.

Drug: BEZ235; Drug: Paclitaxel

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

EXPERIMENTAL

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

Drug: BEZ235; Drug: Paclitaxel

Interventions

BEZ235 DRUG

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.

BEZ235 100 mg bid + paclitaxel 80 mg (phase lb); BEZ235 200 mg bid + paclitaxel 80 mg (phase lb)

Paclitaxel DRUG

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.

BEZ235 100 mg bid + paclitaxel 80 mg (phase lb); BEZ235 200 mg bid + paclitaxel 80 mg (phase lb)

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (3)

Novartis Investigative Site

Dijon, 21034, France

Location

Novartis Investigative Site

Saint-Herblain Cédex, 44805, France

Location

Novartis Investigative Site

L'Hospitalet de Llobregat, Catalonia, 08907, Spain

Location

Related Links

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

MeSH Terms

Conditions

Breast Neoplasms; Neoplasm Metastasis

Interventions

dactolisib; Paclitaxel

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 30, 2011
• First Posted: December 19, 2011
• Study Start: January 30, 2012
• Primary Completion: May 19, 2014
• Study Completion: May 19, 2014
• Last Updated: December 8, 2020

Record last verified: 2020-09

Locations

FR (2); ES (1)