Locally Advance Breast Cancer (LABC)Phase 1NCT01471847

A Phase Ib/II Study of BEZ235 and Trastuzumab in Patients With HER2-positive Breast Cancer Who Failed Prior to Trastuzumab

A Phase 1 study testing BEZ235 + Trastuzumab Phase l/Phase ll) and Lapatinib + Capecitabine (Phase II) in people with Locally Advance Breast Cancer (LABC) and Metastatic Breast Cancer (MBC), run by Novartis Pharmaceuticals at 3 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 18 years and older, women only
Conditions the study is for: Locally Advance Breast Cancer (LABC), Metastatic Breast Cancer (MBC)
What is being tested?: BEZ235 + Trastuzumab Phase l/Phase ll) and Lapatinib + Capecitabine (Phase II)
Type of treatment: Pill or oral medicine
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 5 participants
Where: 3 sitesin 2 countries
Study dates: Feb 2012to Jun 2012
Phase: Phase 1
Are there results?: None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
Women only
No healthy volunteers
Adult, Older adult

Who may be able to join

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

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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

Who cannot join

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

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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

Trial locations and contacts

3 sites in 2 countries.

Country

City, postcode or hospital

3 sites in 2 countries

United Kingdom2 sites

Novartis Investigative Site
Leicester, LE1 5WW
Novartis Investigative Site
Manchester, M20 2BX

Other trials in United Kingdom

Spain1 site

Novartis Investigative Site
Madrid, 28050

Other trials in Spain

About this study

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

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.

Conditions: Locally Advance Breast Cancer (LABC), Metastatic Breast Cancer (MBC)
Being tested: BEZ235 + Trastuzumab Phase l/Phase ll), Lapatinib + Capecitabine (Phase II)
Keywords: Locally advanced, metastatic, breast cancer, HER2 positive, PI3K, mTOR, trastuzumab, targeted therapy, LABC, MBC
Medical subject headings: Breast Neoplasms, Neoplasm Metastasis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

BEZ235 + Trastuzumab Phase l/Phase ll)Drug
Phase l: Patients will receive increasing doses of oral BEZ235 (BID) together with standard weekly trastuzumab at a fixed dose. 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.
Phase ll: If randomized to the trastuzumab + BEZ235 arm, patients will receive standard weekly trastuzumab in combination with oral BEZ235 (BID) at the MTD or RP2D and will continue on study treatment until PD, unacceptable toxicity or until other pre-defined discontinuation criteria are met. They will have regular safety assessments and will be evaluated for response to treatment according to RECIST every 2 cycles for the first 36 weeks then every 12 weeks until disease progression (or start of new anti-neoplastic therapy).
Lapatinib + Capecitabine (Phase II)Drug
If randomized to the lapatinib + capecitabine treatment arm, patients will receive standard lapatinib plus capecitabine until PD, unacceptable toxicity or until other pre-defined discontinuation criteria are met.
Patients will have regular safety assessments and will be evaluated for response to treatment according to RECIST every 2 cycles for the first 36 weeks then every 12 weeks until disease progression (or start of new anti-neoplastic therapy). After progression, survival f-up will continue.
All patients participating in the Phase II part of the study will be required to have available archival or fresh tumor tissue for biomarker analysis prior to treatment start

Study groups in NCT01471847
Study group	Role	What they receive
BEZ235 + Trastuzumab (Phase l /Phase ll)	Experimental	Phase l: Eligible patients will receive increasing doses of oral BEZ235 administered on a continuous twice daily (BID) schedule + weekly trastuzumab at a fixed dose of 2 mg/kg. Treatment will be organized into cycles of 28 days. Phase ll: Eligible patients will receive weekly trastuzumab (2 mg/kg) + oral BEZ235 on a continuous twice daily (BID schedule) at the MTD or RP2D. Treatment will be organized into cycles of 21 days. Receives: Drug: BEZ235 + Trastuzumab Phase l/Phase ll)
Lapatinib + Capecitabine (Phase II)	Active comparator	Eligible patients will receive lapatinib (1250 mg given orally once daily on days 1 through 21) in combination with capecitabine (2000 mg/m2/day administered orally in 2 doses approximately 12 hours apart on days 1 through 14). Treatment will be organized into cycles of 21 days . Receives: Drug: Lapatinib + Capecitabine (Phase II)

What is being measured

The primary outcome is the main question the study is designed to answer.

Incidence of Dose Limiting Toxicities (DLT) in the first cycle - phase lb
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)
Measured: First treatment cycle (28 days)
Progression Free Survival (PFS) based on local radiological assessment - phase ll
PFS is defined as the time from randomization until objective tumor progression or death from any cause. Radiological assessments will be performed every 6 weeks for the first 36 weeks after treatment start, then every 12 weeks.
Measured: Randomization, disease progression or start of of new anti-neoplastic therapy (expected average: 12 months)

Secondary outcomes (13)

Progression Free Survival (PFS) - Phase lb
Time from treatment start until objective tumor progression or death from any cause. Radiological assessments will be performed every 8 weeks for the first 32 weeks after treatment start, then every 12 weeks.
Measured: Randomization, Randomization, disease progression or start of of new anti-neoplastic therapy (expected average: 12 months)
Overall Response Rate (ORR)- Phase lb
Proportion of patients with a best overall response of complete response (CR) or partial response (PR) according to RECIST 1.1
Measured: 12 months
Clinical Benefit Rate (CBR) (Phase lb)
Proportion of patients with a best overall response of CR, PR or stable disease (SD) with a duration of 24 weeks or longer according to RECIST 1.1
Measured: 12 months
Frequency and severity of Adverse Events - Phase lb
Incidence of adverse events (based on common terminology criteria for adverse events (CTCAE) Version 4) summarized by system organ class and/or preferred term, severity and relation to study treatment.
Measured: until 30 days after treatment discontinuation
BEZ235 plasma and trastuzumab serum concentrations - phase lb
BEZ235 plasma and trastuzumab serum concentrations obtained during the two sampling windows (pre-dose and post-dose). No pharmacokinetic parameters will be calculated and no formal statistical analysis will be performed.
Measured: Pre-dose (cycle 1 through 9) and 4-6 hours post-dose (cycle 1 and 2)
Overall Response Rate (ORR) - phase ll
Proportion of patients with a best overall response of CR or PR according to RECIST 1.1
Measured: 12 months
Clinical Benefit Rate (CBR) - phase ll
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
Measured: 12 months
Time to overall response (TTR) - phase ll
Time from randomization until first documented response.
Measured: 12 months
Duration of overall response (DR) - phase ll
Time between the first documented response and first documented progression or death due to underlying cancer.
Measured: 12 months
Median overall survival (OS) (phase ll)
Time from randomization to the date of death due to any cause.
Measured: Randomization, death (expected average:24 months)
PFS based on central radiological assessment (phase ll)
Time from randomization until objective tumor progression or death from any cause. Radiological assessments will be performed every 6 weeks for the first 36 weeks after treatment start, then every 12 weeks, centrally collected and read.
Measured: Randomization, disease progression or start of of new anti-neoplastic therapy (expected average: 12 months)
Frequency and severity of adverse events (phase ll)
Incidence of adverse events (based on CTCAE Version 4) summarized by system organ class and/or preferred term, severity and relation to study treatment.
Measured: Until 30 days after treatment discontinuation
Efficacy in subgroups of patients with activated/non-activated PI3K pathway (phase ll)
Efficacy (e.g. PFS, ORR, CBR) according to PI3K activation and treatment group.
Measured: 12 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Feb 2012Jun 2012

First posted16 Nov 2011 (estimated)
Study startFeb 2012
Primary completionJun 2012
Study completionJun 2012

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Other trials for Locally Advance Breast Cancer (LABC)Studies of the same condition, open and under way.
More trials run by Novartis PharmaceuticalsThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: None (open label)
Enrolment: 5 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01471847
Sponsor's protocol ID: CBEZ235B2203
Status last verified: Feb 2018
First submitted: 10 Oct 2011
Last updated: 9 Dec 2020
Results posted: No

Study at a glance

From the registry record, last updated by the sponsor on 9 Dec 2020. Recruitment status is as the sponsor reported it: confirm with the study team.

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
ClinicalTrials.gov ID: NCT01471847
Acronym / sponsor ID: CBEZ235B2203
Conditions: Locally Advance Breast Cancer (LABC), Metastatic Breast Cancer (MBC)
Keywords: Locally advanced, metastatic, breast cancer, HER2 positive, PI3K, mTOR, trastuzumab, targeted therapy
Phase: Phase 1
Study type: Interventional
Recruitment status: Completed
Enrolment: 5 participants (actual)
Lead sponsor: Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
Study start: Feb 2012
Primary completion: Jun 2012 (actual)
Study completion: Jun 2012 (actual)
First posted: 16 Nov 2011 (estimated)
Results: Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: None (open label)
Number of arms: 2

Arm	Type	Receives
BEZ235 + Trastuzumab (Phase l /Phase ll)	Experimental	Drug: BEZ235 + Trastuzumab Phase l/Phase ll)Phase l: Eligible patients will receive increasing doses of oral BEZ235 administered on a continuous twice daily (BID) schedule + weekly trastuzumab at a fixed dose of 2 mg/kg. Treatment will be organized into cycles of 28 days. Phase ll: Eligible patients will receive weekly trastuzumab (2 mg/kg) + oral BEZ235 on a continuous twice daily (BID schedule) at the MTD or RP2D. Treatment will be organized into cycles of 21 days.
Lapatinib + Capecitabine (Phase II)	Active comparator	Drug: Lapatinib + Capecitabine (Phase II)Eligible patients will receive lapatinib (1250 mg given orally once daily on days 1 through 21) in combination with capecitabine (2000 mg/m2/day administered orally in 2 doses approximately 12 hours apart on days 1 through 14). Treatment will be organized into cycles of 21 days .

Who may qualify

Ages: 18 years and older
Sex: Female only
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (23 listed)

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

Key exclusion criteria (15 listed)

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)

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
BEZ235 + Trastuzumab Phase l/Phase ll)Phase l: Patients will receive increasing doses of oral BEZ235 (BID) together with standard weekly trastuzumab at a fixed dose. 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. Phase ll: If randomized to the trastuzumab + BEZ235 arm, patients will receive standard weekly trastuzumab in combination with oral BEZ235 (BID) at the MTD or RP2D and will continue on study treatment until PD, unacceptable toxicity or until other pre-defined discontinuation criteria are met. They will have regular safety assessments and will be evaluated for response to treatment according to RECIST every 2 cycles for the first 36 weeks then every 12 weeks until disease progression (or start of new anti-neoplastic therapy).	Drug	BEZ235 + Trastuzumab (Phase l /Phase ll)
Lapatinib + Capecitabine (Phase II)If randomized to the lapatinib + capecitabine treatment arm, patients will receive standard lapatinib plus capecitabine until PD, unacceptable toxicity or until other pre-defined discontinuation criteria are met. Patients will have regular safety assessments and will be evaluated for response to treatment according to RECIST every 2 cycles for the first 36 weeks then every 12 weeks until disease progression (or start of new anti-neoplastic therapy). After progression, survival f-up will continue. All patients participating in the Phase II part of the study will be required to have available archival or fresh tumor tissue for biomarker analysis prior to treatment start	Drug	Lapatinib + Capecitabine (Phase II)

Primary outcome

Incidence of Dose Limiting Toxicities (DLT) in the first cycle - phase lb
Time frame: First treatment cycle (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)
Progression Free Survival (PFS) based on local radiological assessment - phase ll
Time frame: Randomization, disease progression or start of of new anti-neoplastic therapy (expected average: 12 months)
PFS is defined as the time from randomization until objective tumor progression or death from any cause. Radiological assessments will be performed every 6 weeks for the first 36 weeks after treatment start, then every 12 weeks.

13 secondary outcomes

Progression Free Survival (PFS) - Phase lb
Time frame: Randomization, Randomization, disease progression or start of of new anti-neoplastic therapy (expected average: 12 months)
Overall Response Rate (ORR)- Phase lb
Time frame: 12 months
Clinical Benefit Rate (CBR) (Phase lb)
Time frame: 12 months
Frequency and severity of Adverse Events - Phase lb
Time frame: until 30 days after treatment discontinuation
BEZ235 plasma and trastuzumab serum concentrations - phase lb
Time frame: Pre-dose (cycle 1 through 9) and 4-6 hours post-dose (cycle 1 and 2)
Overall Response Rate (ORR) - phase ll
Time frame: 12 months
Clinical Benefit Rate (CBR) - phase ll
Time frame: 12 months
Time to overall response (TTR) - phase ll
Time frame: 12 months
Duration of overall response (DR) - phase ll
Time frame: 12 months
Median overall survival (OS) (phase ll)
Time frame: Randomization, death (expected average:24 months)
PFS based on central radiological assessment (phase ll)
Time frame: Randomization, disease progression or start of of new anti-neoplastic therapy (expected average: 12 months)
Frequency and severity of adverse events (phase ll)
Time frame: Until 30 days after treatment discontinuation
Efficacy in subgroups of patients with activated/non-activated PI3K pathway (phase ll)
Time frame: 12 months

Results and safety

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 9 Dec 2020.
Results for CBEZ235B2203 can be found on the Novartis Clinical Trials WebsiteLink provided by the sponsor.

Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Novartis Pharmaceuticals study director

Novartis Pharmaceuticals

3 sites in 2 countries: see every site and its status.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 23 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 9 Dec 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in United Kingdom, Spain. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Incidence of Dose Limiting Toxicities (DLT) in the first cycle - phase lb (time frame: First treatment cycle (28 days)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01471847.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Dec 2020.