Triple-B Study;Carboplatin-cyclophosphamide Versus Paclitaxel With or Without Bevacizumab as First-line Treatment in Advanced Triple Negative Breast Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by The Netherlands Cancer Institute
Sponsor:
Collaborators:
Borstkanker Onderzoek Groep
Roche Pharma AG
Information provided by (Responsible Party):
The Netherlands Cancer Institute
ClinicalTrials.gov Identifier:
NCT01898117
First received: June 27, 2013
Last updated: May 22, 2014
Last verified: May 2014
  Purpose

Triple negative breast cancer (TNBC) is a difficult to treat molecular subtype with a poor survival. TNBC can be divided into at least two molecular entities; BRCA-like and non-BRCA-like. In this trial we would like to investigate whether a molecular subgroup exists within TNBCs that derives a benefit from bevacizumab added to first line chemotherapy.


Condition Intervention Phase
Breast Cancer
Drug: Carbo/cyclo
Drug: Carbo/cyclo + bevacizumab
Drug: Paclitaxel
Drug: Paclitaxel + Bevacizumab
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Factorial Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Biomarker Discovery Randomized Phase IIb Trial With Carboplatin-cyclophosphamide Versus Paclitaxel With or Without Bevacizumab as First-line Treatment in Advanced Triple Negative Breast Cancer

Resource links provided by NLM:


Further study details as provided by The Netherlands Cancer Institute:

Primary Outcome Measures:
  • Determine PFS in the different VEGFR2 levels [ Time Frame: Assessed up to 120 months ] [ Designated as safety issue: No ]
    Prospectively analyze whether VEGFR2 plasma levels at baseline predict for differential progression-free survival (PFS) benefit of bevacizumab added to first line palliative chemotherapy in triple-negative breast cancer (TNBC)

  • Validate the BRCA-like test [ Time Frame: assessed up to 120 months ] [ Designated as safety issue: No ]
    Validate the BRCA-like test in predicting differential PFS with first line alkylating and platinum agents when compared to paclitaxel in TNBC


Secondary Outcome Measures:
  • Improvement of PFS by adding bevacicumab [ Time Frame: assessed up to 120 months ] [ Designated as safety issue: No ]
    Validate that bevacizumab added to first line palliative chemotherapy improves PFS in TNBC

  • Define predictive biomarkers for PFS gain [ Time Frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 120 months ] [ Designated as safety issue: No ]
    Define predictive biomarkers for PFS gain of the addition of bevacizumab to first line chemotherapy; test VEGFA amplification vs no amplification and PFS stratified by chemotherapy regimen.

  • Determine PFS [ Time Frame: From date of randomization until dat of first documented progression or date of death, which ever comes first, assessed up to 120 months ] [ Designated as safety issue: No ]
    etermine PFS regarding the efficacy of the two different first line chemotherapeutic regimens, regardless of bevacizumab yes or no, in the whole study group, and in the BRCA-like and non-BRCA-like TNBCs subgroups separately

  • Overall survival (OS) [ Time Frame: assessed up to 120 months ] [ Designated as safety issue: No ]
    Evaluation of overall survival (OS) for all (sub)group comparisons as pre-specified for PFS

  • Toxicity of all study regimens [ Time Frame: Assessed at 1 year ] [ Designated as safety issue: Yes ]
    Adverse events will be graded according to NCI Common Toxicity Criteria version 4.03


Estimated Enrollment: 304
Study Start Date: July 2013
Estimated Study Completion Date: December 2029
Estimated Primary Completion Date: December 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Carbo/cyclo
Carboplatin AUC=5 Cyclophosphamide 600 mg/m2 Q 4 weeks
Drug: Carbo/cyclo
Other Names:
  • Carboplatin
  • Cyclophosphamide
Active Comparator: Carbo/cyclo + Bevacizumab
Carboplatin AUC=5 Cyclophosphamide 600 mg/m2 Bevacizumab 10 mg/kg d1, 15 Q 4 weeks
Drug: Carbo/cyclo + bevacizumab
Other Names:
  • Carboplatin
  • Cyclophosphamide
  • Bevazicumab
Active Comparator: Paclitaxel
Paclitaxel 90 mg/m2 d1, 8, 15 Q 4 weeks
Drug: Paclitaxel
Other Name: Paclitaxel
Active Comparator: Paclitaxel + bevacizumab
Paclitaxel 90 mg/m2 d1, 8, 15 Bevacizumab 10 mg/kg d1, 15 Q 4 weeks
Drug: Paclitaxel + Bevacizumab
Other Names:
  • Paclitaxel
  • evazicumab

Detailed Description:

In preclinical studies the addition of bevacizumab to chemotherapy improves drug access in the tumor. In humans, bevacizumab monotherapy normalizes the tumor vascularization. It is presently unknown what molecular subtype would derive a progression free survival (PFS) benefit of the addition of bevacizumab to first line chemotherapy. There are indications that patients with high VEFGA and/or VEFGR-2 plasma levels derive most benefit.

There are indications that TNBC that are BRCA-like are more sensitive to bifunctional alkylating and platinum agents than non-BRCA-like TNBCs, and relatively resistant to taxanes. Consequently, because TNBCs in general derive substantial benefit from taxanes, we anticipate that non-BRCA-like TNBCs are exquisitely sensitive to taxanes. Bevacizumab and paclitaxel are synergistic in preclinical models. Therefore we anticipate that bevacizumab added to paclitaxel confers a substantial progression-free survival benefit in non-BRCA-like patients. We would like to test these hypotheses in a prospective clinical trial.

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically confirmed triple negative breast cancer
  • Histological confirmation of triple negative breast cancer of a metastatic lesion is recommended
  • Histological or cytological confirmation of metastatic breast cancer is required in case of normal CA 15.3 levels
  • No previous cytotoxic therapy for metastatic disease
  • Disease-free interval of at least 12 months after completion of adjuvant taxane and/or platinum compound therapy
  • Measurable disease according to RECIST
  • Informative sVEGFR2 level test result in plasma baseline samples (taken before treatment started)
  • Informative BRCA-like test result on primary tumor or metastasis (up to 5% of patients with an unknown test result will be randomized)
  • WHO performance status of 0 or 1
  • Adequate bone marrow function: neutrophils ≥ 1.5 x 10E9 cells/l, platelets ≥100 x 10E9 cells/l, Hb ≥ 6.2 mmol/l.
  • Normal liver function: bilirubin < 1.5 x upper limit of the normal range (ULN); alkaline phosphatase < 2.5 x ULN (< 5 x ULN in case of liver metastases, and < 7 x ULN in case of bone metastases); transaminases (ASAT/ALAT) < 2.5 x ULN (and < 5 x ULN in case of liver metastases).
  • Normal renal function:

    • calculated (Cockcroft-Gault) or measured creatinine clearance > 50 mL/min
    • Urine dipstick for proteinuria < 2+. Patients with > 2+ proteinuria on dipstick urinalysis at baseline should undergo 24-hours urine collection and must demonstrate ≤1 g of protein/24hr.
  • INR < 1.5 and APTT normal, unless patient is on stable anti-coagulant treatment for at least two weeks with a low molecular weight heparin or coumarin, then an INR within the target range (usually between 2 and 3) is allowed.
  • Written informed consent

Exclusion Criteria:

  • Receptor conversion to hormone receptor positive (defined as >= 1% positive ER or PgR tumor cells) or HER2 positive
  • Another cancer except basal-cell carcinoma of the skin or in situ cervical cancer within the previous 5 years
  • Other antitumor therapy within the previous 21 days
  • Known CNS disease except for treated brain metastases.
  • Uncontrolled serious medical or psychiatric illness
  • Pre-existing peripheral neuropathy > grade 1 (NCI-CTC AE (version 4.03)) at inclusion
  • History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months of randomization
  • An infection requiring parenteral antibiotic
  • Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomization or anticipation of need for major surgical procedure during the course of the study
  • Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis within 6 months prior to randomization)
  • Non healing wound or non healing fracture
  • Arterial or venous thrombosis ≤ 12 months prior to registration
  • Inadequate controlled hypertension (systolic > 140 mm Hg and/or diastolic > 90 mm Hg)
  • Prior history of hypertensive crisis or hypertensive encephalopathy
  • New York Heart Association Class II or greater congestive heart failure. LVEF by MUGA or ultrasound must be ≥ 50% and should be performed within 4 weeks prior to randomization if cardiac failure is suspected.
  • History of myocardial infarction or unstable angina within 6 months prior to randomization
  • History of stroke or transient ischemic attack within 6 months prior to randomization
  • Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)
  • History of hemoptysis within 1 month prior to randomization
  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: NCT01898117

Contacts
Contact: Sabine C Linn, Prof. MD +3120512 ext 2870 s.linn@nki.nl
Contact: Ingrid A. Mandjes, MSc +3120512 ext 2667 i.mandjes@nki.nl

Locations
Netherlands
MCA Not yet recruiting
Alkmaar, Netherlands, 1815 JD
Contact: S Vrijaldenhoven, MD         
Principal Investigator: S Vrijaldenhoven, MD         
ZGT Not yet recruiting
Almelo, Netherlands, 7609 PP
Contact: I M Oving, MD       i.oving@zgt.nl   
Principal Investigator: I M Oving, MD         
Netherlands Cancer Institute Recruiting
Amsterdam, Netherlands, 1066 CX
Principal Investigator: Sabine C Linn, Prof. MD         
AZVU Not yet recruiting
Amsterdam, Netherlands, 1081 HV
Contact: I R Konings, MD       m.konings@vumc.nl   
Principal Investigator: I R Konings, MD         
BovenIJ Not yet recruiting
Amsterdam, Netherlands, 1034 CS
Contact: S E Dohmen, MD       s.dohmen@bovenij.nl   
Principal Investigator: S E Dohmen, MD         
Lievensberg ziekenhuis Not yet recruiting
Bergen op Zoom, Netherlands, 4624 VT
Contact: M M Troost, MD       M.Troost@lievensberg.nl   
Principal Investigator: M M Troost, MD         
Rode Kruis Ziekenhuis Not yet recruiting
Beverwijk, Netherlands, 1940 EB
Contact: R C Rietbroek, MD       rrietbroek@rkz.nl   
Principal Investigator: R C Rietbroek, MD         
IJsselland ziekenhuis Not yet recruiting
Capelle aan de IJssel, Netherlands, 2906 ZC
Contact: D F Kehrer, MD         
Principal Investigator: D F Kehrer, MD         
Haga Not yet recruiting
Den Haag, Netherlands, 2545 CH
Contact: J E Portielje, MD       j.portielje@hagaziekenhuis.nl   
Principal Investigator: J E Portielje, MD         
Deventer ziekenhuis Not yet recruiting
Deventer, Netherlands, 7416 SE
Contact: A L Imholz, MD       imholza@dz.nl   
Principal Investigator: A L Imholz, MD         
Nijsmellinghe Not yet recruiting
Drachten, Netherlands, 9202 NN
Contact: S Hovenga, MD       s.hovenga@nijsmellinghe.nl   
Principal Investigator: S Hovenga, MD         
Ziekenhuis Gelderse Vallei Not yet recruiting
Ede, Netherlands, 6716 RP
Contact: A W Haringhuizen, MD       haringhuizena@zgv.nl   
Principal Investigator: A W Haringhuizen, MD         
Maxima Medisch Centrum Not yet recruiting
Eindhoven, Netherlands, 5631 BM
Contact: M W Dercksen, MD         
Principal Investigator: M W Dercksen, MD         
Groene Hart Not yet recruiting
Gouda, Netherlands, 2803 HH
Contact: B C Tanis, MD       bea.tanis@ghz.nl   
Principal Investigator: B C Tanis, MD         
Spaarne ziekenhuis Not yet recruiting
Hoofddorp, Netherlands, 2134 TM
Contact: B de Valk, MD       bdevalk@spaarneziekenhuis.nl   
Principal Investigator: B de Valk, MD         
MCL Not yet recruiting
Leeuwarden, Netherlands, 8934 AD
Contact: H de Graaf, MD       graafhi@znb.nl   
Principal Investigator: H de Graaf, MD         
LUMC Not yet recruiting
Leiden, Netherlands, 2333 ZA
Contact: J R Kroep, MD       j.r.kroep@lumc.nl   
Principal Investigator: J R Kroep, MD         
MCH Not yet recruiting
Leidschendam, Netherlands, 2262 BA
Contact: H M Oosterkamp, MD       h.oosterkamp@mchaaglanden.nl   
Principal Investigator: H M Oosterkamp, MD         
Ikazia Not yet recruiting
Rotterdam, Netherlands, 3083 AN
Contact: F E de Jong, MD       fe.de.jongh@ikazia.nl   
Principal Investigator: F E de Jong, MD         
St. Fransicus Gasthuis Not yet recruiting
Rotterdam, Netherlands, 3045 PM
Contact: A P Hamberg, MD       p.hamberg@sfg.nl   
Principal Investigator: A P Hamberg, MD         
Vlietland ziekenhuis Not yet recruiting
Schiedam, Netherlands, 3118 JH
Contact: Q C van Rossum-Schornagel, MD         
Principal Investigator: Q C van Rossum-Schornagel, MD         
St. Elisabeth Not yet recruiting
Tilburg, Netherlands, 5022 GC
Contact: J M van Riel, MD       jmgriel@elisabeth.nl   
Principal Investigator: J M van Riel, MD         
Tweesteden ziekenhuis Not yet recruiting
Tilburg, Netherlands, 5042 AD
Contact: H Th Roerdink, MD       hroerdink@tsz.nl   
Principal Investigator: H Th Roerdink, MD         
Isala Klinieken Not yet recruiting
Zwolle, Netherlands, 8025 AB
Contact: A H. Honkoop, MD       a.h.honkoop@isala.nl   
Principal Investigator: A H Honkoop, MD         
Sponsors and Collaborators
The Netherlands Cancer Institute
Borstkanker Onderzoek Groep
Roche Pharma AG
  More Information

No publications provided

Responsible Party: The Netherlands Cancer Institute
ClinicalTrials.gov Identifier: NCT01898117     History of Changes
Other Study ID Numbers: M13TNB, 2013-001484-23, NL44403.031.13
Study First Received: June 27, 2013
Last Updated: May 22, 2014
Health Authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by The Netherlands Cancer Institute:
Triple negative
Metastatic

Additional relevant MeSH terms:
Triple Negative Breast Neoplasms
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Paclitaxel
Bevacizumab
Carboplatin
Cyclophosphamide
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Myeloablative Agonists

ClinicalTrials.gov processed this record on September 29, 2014