Clinical trial NCT01471847: A Phase Ib/II Study of BEZ235 and Trastuzumab in Patients With HER2-positive Breast Cancer Who Failed Prior to Trastuzumab
Official title: A Phase Ib/Randomized Phase II Study of BEZ235 and Trastuzumab Versus Lapatinib and Capecitabine in Patients With HER2-positive Locally Advanced or Metastatic Breast Cancer Who Failed Prior to Trastuzumab
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Locally Advance Breast Cancer (LABC)
Metastatic Breast Cancer (MBC)
Keywords: Locally advanced
metastatic
breast cancer
HER2 positive
PI3K
mTOR
trastuzumab
targeted therapy
LABC
MBC
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2011-11-16
Enrollment: 5
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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+ breast cancer. The first part (phase Ib) will investigate the MTD/ RP2D of the combination therapy of BEZ235 BID and weekly trastuzumab using a Bayesian model. Once MTD/ RP2D is established the second part (phase II) will start. Phase II will evaluate the efficacy and the safety of weekly trastuzumab plus BEZ235 BID compared to capecitabine and lapatinib.


Eligibility criteria: Inclusion Criteria:

* Patient is a female ≥ 18 years of age
* Patient has a histologically and/or cytologically confirmed diagnosis of HER2-positive invasive breast cancer with inoperable locally advanced or metastatic disease
* Patients with controlled or asymptomatic CNS metastases are eligible
* Patient has adequate bone marrow and organ functions, and has recovery from all clinically significant toxicities related to prior anti-neoplastic therapies
* Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
* Platelets ≥ 100 x 109/L
* Hemoglobin (Hgb) ≥ 9.0 g/dL
* INR ≤ 2
* Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN (or ≤ 5.0 x ULN if liver metastases are present)
* Total serum bilirubin ≤ 1.5 x ULN (in patients with known Gilbert Syndrome, a total bilirubin ≤ 3.0 x ULN, with direct bilirubin ≤ 1.5 x ULN)
* Serum creatinine ≤ 1.5 x ULN
* Fasting plasma glucose (FPG) ≤ 140mg/dL \[7.8 mmol/L\]
* HbA1c ≤ 8%
* Patient has received prior trastuzumab (alone or in combination) but NO more than 3 prior cytotoxic chemotherapy lines
* Prior endocrine and radiotherapy allowed
* Patient has ECOG performance status of 0-2 (Phase Ib) or 0-1 (Phase II)

Additional inclusion criteria for phase II:

* Available tumor tissue (archival or fresh) for biomarker analysis; known PI3K activation status
* At least one measurable lesion as per RECIST 1.1
* Patient has received prior treatment with a taxane
* Patient has "trastuzumab-resistance disease" defined as:
* Recurrence while on trastuzumab (or T-DM1) or within 12 months since the last infusion in the adjuvant setting
* Progression while on or within 4 weeks since the last infusion of trastuzumab (or T-DM1) in the locally advanced or metastatic setting

Exclusion Criteria:

* Previous treatment with PI3K and/or mTOR inhibitors
* Symptomatic/uncontrolled Central Nervous System (CNS) metastases
* Concurrent malignancy or malignancy in the last 3 years prior to enrollment
* 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
* 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
* Intolerance or contraindications to trastuzumab treatment
* Pregnant or nursing (lactating) woman

Additional exclusion criteria for phase II:

* Prior treatment with capecitabine and lapatinib
* Intolerance or contraindications to capecitabine and lapatinib
* Previous treatment with HER-2 targeted agents other than trastuzumab or T-DM1
* Peripheral neuropathy ≥ Grade 2

Primary outcomes:
measure: Incidence of Dose Limiting Toxicities (DLT) in the first cycle - phase lb
timeFrame: First treatment cycle (28 days)
measure: Progression Free Survival (PFS) based on local radiological assessment - phase ll
timeFrame: Randomization, disease progression or start of of new anti-neoplastic therapy (expected average: 12 months)
Secondary outcomes:
measure: Progression Free Survival (PFS) - Phase lb
timeFrame: Randomization, Randomization, disease progression or start of of new anti-neoplastic therapy (expected average: 12 months)
measure: Overall Response Rate (ORR)- Phase lb
timeFrame: 12 months
measure: Clinical Benefit Rate (CBR) (Phase lb)
timeFrame: 12 months
measure: Frequency and severity of Adverse Events - Phase lb
timeFrame: until 30 days after treatment discontinuation
measure: BEZ235 plasma and trastuzumab serum concentrations - phase lb
timeFrame: Pre-dose (cycle 1 through 9) and 4-6 hours post-dose (cycle 1 and 2)
measure: Overall Response Rate (ORR) - phase ll
timeFrame: 12 months
measure: Clinical Benefit Rate (CBR) - phase ll
timeFrame: 12 months
measure: Time to overall response (TTR) - phase ll
timeFrame: 12 months
measure: Duration of overall response (DR) - phase ll
timeFrame: 12 months
measure: Median overall survival (OS) (phase ll)
timeFrame: Randomization, death (expected average:24 months)
measure: PFS based on central radiological assessment (phase ll)
timeFrame: Randomization, disease progression or start of of new anti-neoplastic therapy (expected average: 12 months)
measure: Frequency and severity of adverse events (phase ll)
timeFrame: Until 30 days after treatment discontinuation
measure: Efficacy in subgroups of patients with activated/non-activated PI3K pathway (phase ll)
timeFrame: 12 months
Other outcomes:
Locations:
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Leicester
country: United Kingdom
facility: Novartis Investigative Site
city: Manchester
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: