Clinical trial NCT01204125: Two Regimens of SAR240550/Weekly Paclitaxel and Paclitaxel Alone as Neoadjuvant Therapy in Triple Negative Breast Cancer Patients
Official title: Randomized, Open-label, Phase 2 Study of the Efficacy and Safety of Weekly Paclitaxel Single-agent and Two Different Regimens of the PARP-1 Inhibitor SAR240550 (BSI-201) in Combination With Weekly Paclitaxel, as Neoadjuvant Therapy in Patients With Stage II-IIIA Triple Negative Breast Cancer (TNBC)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Breast Cancer Female
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
Collaborators: name: SOLTI Breast Cancer Research Group
First posted: 2010-09-17
Enrollment: 141
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: Primary Objective:

- to assess the pathological Complete Response (pCR) rate in the breast of patients treated in following combinations: SAR240550 twice-weekly + weekly paclitaxel, SAR240550 weekly+ weekly paclitaxel, and weekly paclitaxel single agent as calibrator.

Secondary objectives are:

* pCR rate in the breast and axilla,
* Radiological/clinical objective response rate (ORR), breast conservation rate, disease free survival (DFS), and overall survival (OS), in each treatment arm,
* Safety profiles of study combinations and of the single agent reference treatment,
* Molecular characteristics of the tumor tissue and peripheral blood mononuclear cells (PBMC) and any correlation between the biological activity of the study treatment and the disease outcome.

Based on data generated by BiPar/Sanofi, it is concluded that iniparib does not possess characteristics typical of the PARP inhibitor class. The exact mechanism has not yet been fully elucidated, however based on experiments on tumor cells performed in the laboratory, iniparib is a novel investigational anti-cancer agent that induces gamma-H2AX (a marker of DNA damage) in tumor cell lines, induces cell cycle arrest in the G2/M phase in tumor cell lines, and potentiates the cell cycle effects of DNA damaging modalities in tumor cell lines. Investigations into potential targets of iniparib and its metabolites are ongoing.

Detailed description: Active study treatment will be given either as twice weekly administration (Day 1 and Day 4) or as weekly administration (Day 1) for a maximum of 24 infusions for Arm A and for a maximum of 12 infusions for Arm B. In all study arms, treatment will be given until definitive surgery, the first sign of disease progression, unacceptable toxicity or withdrawal of patient consent.

Definitive surgery will be performed within 2 to 4 weeks after the last dose of study treatment.

Patients who complete all the study treatment or who withdraw consent or experience intolerable toxicity will undergo surgery according to local practices.

The cut-off date for the primary analyses will be 30 days after the last study treatment administration or the date of the definitive surgery, whichever comes last.

The maximum follow up for each individual patient will be until death or 5 years after the definitive surgery date whatever happens first.

Eligibility criteria: Inclusion criteria:

* Histologically confirmed Stage II-IIIA invasive breast cancer eligible for definitive surgery and Estrogen Receptor (ER)-negative, Progesterone receptor (PgR)-negative and Human epidermal growth factor receptor 2 (HER2) non-overexpressing by Immunohistochemistry (IHC) (0+, 1+) or fluorescence in situ hybridization (FISH negative, ratio \<1.8) or IHC (2+, 3+) /FISH-negative.
* The primary tumor must be \> 2cm in diameter measured by physical examination and mammography (mandatory) plus either echography or Magnetic Resonance Imaging (MRI)
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
* Adequate bone marrow reserve
* Adequate liver and renal function.
* Age \> or = 18 years

Exclusion criteria:

* Any prior treatment for primary breast cancer.
* Bilateral or multicentric breast cancer.
* Other primary tumors within the previous 5 years, except for adequately controlled limited basal cell carcinoma of the skin or carcinoma in situ of the cervix.
* Pre-existing peripheral neuropathy grade \> or = 2 as per National Cancer Institute Common Toxicity Criteria for Adverse Event (NCI CTCAE) at randomization.
* Any history of medical (e.g., cardiovascular, uncontrolled pulmonary, renal, or hepatic dysfunction, uncontrolled infection) or psychiatric condition or laboratory abnormality that, in the opinion of the investigator, may increase the risks associated with the study participation or administration of the investigational products, or that may interfere with the interpretation of the results
* Pregnancy or breastfeeding women.
* Women of childbearing potential (\<2 years after the last menstruation) not using effective, non-hormonal means of contraception during the study and for a period of 6 months following the last administration of study drug.
* Requirement for radiation therapy concurrent with study anticancer treatment. Patients who require breast or chest wall radiation therapy after surgery are eligible.
* Known hypersensitivity to any of the study drugs or excipients

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Primary outcomes:
measure: Pathological Complete Response (pCR) rate defined as the complete absence of invasive carcinoma on histological examination of the breast at the time of definitive surgery and confirmed by blinded centralized review
timeFrame: at the time of definitive surgery
Secondary outcomes:
measure: Pathological Complete Response (pCR) rate in the breast and axilla
timeFrame: at the time of definitive surgery
measure: Objective Response Rate(ORR) defined in the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) as complete response rate + partial response rate
timeFrame: at the time of definitive surgery
measure: Breast conservation rate
timeFrame: at the time of definitive surgery
measure: Disease Free Survival rate (DFS)
timeFrame: up to a maximum of 5 years after definitive surgery
measure: Overall Survival (OS)
timeFrame: up to a maximum of 5 years after definitive surgery
measure: Safety parameters (number of patients AE, SAE or AEPM)
timeFrame: up to a maximum of 5 years after definitive surgery
measure: Molecular-biological testing
timeFrame: 2 or 3 timepoints during treatment period
Other outcomes:
Locations:
city: Besancon Cedex
country: France
facility: Investigational Site Number 250001
city: Bordeaux
country: France
facility: Investigational Site Number 250004
city: Bron Cedex
country: France
facility: Investigational Site Number 250006
city: Paris Cedex 10
country: France
facility: Investigational Site Number 250003
city: Toulouse
country: France
facility: Investigational Site Number 250002
city: Villejuif
country: France
facility: Investigational Site Number 250005
city: Erlangen
country: Germany
facility: Investigational Site Number 276003
city: Hamburg
country: Germany
facility: Investigational Site Number 276004
city: Köln
country: Germany
facility: Investigational Site Number 276002
city: Mönchengladbach
country: Germany
facility: Investigational Site Number 276001
city: Barcelona
country: Spain
facility: Investigational Site Number 724001
city: Cáceres
country: Spain
facility: Investigational Site Number 724009
city: Córdoba
country: Spain
facility: Investigational Site Number 724013
city: Islas Baleares
country: Spain
facility: Investigational Site Number 724006
city: Jaén
country: Spain
facility: Investigational Site Number 724012
city: Lérida
country: Spain
facility: Investigational Site Number 724002
city: Madrid
country: Spain
facility: Investigational Site Number 724005
city: Madrid
country: Spain
facility: Investigational Site Number 724016
city: Reus
country: Spain
facility: Investigational Site Number 724007
city: Santiago De Compostela
country: Spain
facility: Investigational Site Number 724018
city: Sevilla
country: Spain
facility: Investigational Site Number 724017
city: Sevilla
country: Spain
facility: Investigational Site Number 724010
city: Torrevieja
country: Spain
facility: Investigational Site Number 724003
city: Valencia
country: Spain
facility: Investigational Site Number 724011
city: Valencia
country: Spain
facility: Investigational Site Number 724015
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
citation: Llombart-Cussac A, Bermejo B, Villanueva C, Delaloge S, Morales S, Balmana J, Amillano K, Bonnefoi H, Casas A, Manso L, Roche H, Gonzalez-Santiago S, Gavila J, Sanchez-Rovira P, Di Cosimo S, Harbeck N, Charpentier E, Garcia-Ribas I, Radosevic-Robin N, Aura C, Baselga J. SOLTI NeoPARP: a phase II randomized study of two schedules of iniparib plus paclitaxel versus paclitaxel alone as neoadjuvant therapy in patients with triple-negative breast cancer. Breast Cancer Res Treat. 2015 Nov;154(2):351-7. doi: 10.1007/s10549-015-3616-8. Epub 2015 Nov 4.