Clinical trial NCT00938652: A Phase 3, Multi-Center Study of Gemcitabine/Carboplatin, With or Without BSI-201, in Patients With ER-, PR-, and Her2-Negative Metastatic Breast Cancer
Official title: A Phase 3, Multi-Center, Open-Label, Randomized Study of Gemcitabine/Carboplatin, With or Without BSI-201, in Patients With ER-, PR-, and Her2-Negative Metastatic Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Breast Cancer
Keywords: triple negative breast cancer
metastatic breast cancer
Triple negative metastatic breast cancer
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2009-07-14
Enrollment: 519
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: The goal of this study was to determine the effect on overall survival and progression free survival by adding iniparib (BSI-201/SAR240550) to the combination of gemcitabine/carboplatin in adult patients with triple negative breast cancer (estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and human epidermal growth factor receptor 2 (HER2)-negative).

Based on data generated by BiPar/Sanofi, it is concluded that iniparib does not possess characteristics typical of the poly (ADP-ribose) polymerase (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: Participants were treated for 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal. After treatment discontinuation, participants were followed until end of study or death or receipt of new anticancer therapy, whichever was first.

Eligibility criteria: Inclusion Criteria:

- Histologically documented breast cancer (either primary or metastatic site) that is ER-negative, PR-negative, and HER2 non-overexpressing by immunohistochemistry (0, 1) or fluorescence in situ hybridization (FISH).

Triple-negative tumors were defined by the following criteria:

* HER2-non-overexpressing: FISH-negative (defined by ratio \<2.2) or, immunohistochemical (IHC) 0, IHC 1+ or, IHC 2+ or IHC 3+ and FISH-negative.
* ER- and PR-negative: \<10% tumor staining by immunohistochemistry (IHC).

  * Never having received chemotherapy for metastatic disease or, having received 1 or 2 prior chemotherapy regimens in the metastatic setting (Prior adjuvant/neoadjuvant therapy was allowed);
  * Metastatic breast cancer (Stage IV) with measurable disease by RECIST 1.1 criteria;
  * Female, ≥18 years of age;
  * Eastern Cooperative Oncology Group (ECOG) performance status of 0-1;
  * Organ and marrow function as follows: absolute neutrophil count (ANC) ≥1500/mm3, platelets ≥100,000/dL, hemoglobin ≥9 g/dL, bilirubin ≤1.5 mg/dL, serum creatinine ≤1.5 mg/dL or creatinine clearance ≥60 mL/min, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 times the upper limit of normal if no liver involvement or ≤5 times the upper limit of normal with liver involvement;
  * Radiation therapy completed at least 14 days before study dosing on day 1; radiated lesions may not have served as measurable disease;
  * Central nervous system metastases allowed if subject did not require steroids, whole brain radiation therapy (XRT), gamma/cyber knife, and brain metastases were clinically stable without symptomatic progression;
  * For women of child bearing potential, documented negative pregnancy test within two weeks of study entry and agreement to acceptable birth control during the duration of the study therapy;
  * Tissue block (primary or metastatic) or readily available fresh frozen tumor tissue for PARP expression and other pharmacogenomic studies recommended (although its absence will not exclude subjects from participating);
  * No other diagnosis of malignancy (with exception of non melanoma skin cancer or a malignancy diagnosed ≥5 years ago);
  * Obtained informed consent;
  * Capability to understand and comply with the protocol and signed informed consent document.

Exclusion Criteria:

* Systemic anticancer therapy within 14 days of the first dose of study drug;
* Prior treatment with gemcitabine, carboplatin, cisplatin or iniparib
* Had not recovered to grade ≤1 from adverse events (AEs) per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v3.0 or to within 10% of baseline values due to investigational drugs or other medications administered more than 30 days prior to study enrollment;
* Major medical conditions that might have affected study participation (e.g. uncontrolled pulmonary, renal, or hepatic dysfunction, uncontrolled infection, cardiac disease);
* Concurrent radiation therapy intended to treat primary tumor not permitted throughout the course of the study; palliative radiation was acceptable;
* Leptomeningeal disease or brain metastases requiring steroids or other therapeutic intervention;
* Pregnancy or breastfeeding;
* Inability or unwillingness to abide by the study protocol or cooperate fully with the investigator or designee.

Primary outcomes:
measure: progression free survival
timeFrame: until cut-off date established from deaths rate
measure: Overall survival
timeFrame: until cut-off date established from deaths rate
Secondary outcomes:
measure: Best overall response
timeFrame: until treatment discontinuation (assessment at the end of cycle 2 then every other cycle)
measure: Objective response rate
timeFrame: until treatment discontinuation (assessment at the end of cycle 2 then every other cycle)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Research Site
state: Alabama
city: Sedona
country: United States
facility: Research Site
state: Arizona
city: Jonesboro
country: United States
facility: Research Site
state: Arkansas
city: Alhambra
country: United States
facility: Research Site
state: California
city: Bakersfield
country: United States
facility: Research Site
state: California
city: Campbell
country: United States
facility: Research Site
state: California
city: Fullerton
country: United States
facility: Research Site
state: California
city: Lancaster
country: United States
facility: Research Site
state: California
city: Long Beach
country: United States
facility: Research Site
state: California
city: Los Angeles
country: United States
facility: Research Site
state: California
city: Nothridge
country: United States
facility: Research Site
state: California
city: Oxnard
country: United States
facility: Research Site
state: California
city: Palo Alto
country: United States
facility: Research Site
state: California
city: Pomona
country: United States
facility: Research Site
state: California
city: Redondo Beach
country: United States
facility: Research Site
state: California
city: San Francisco
country: United States
facility: Research Site
state: California
city: Santa Barbara
country: United States
facility: Research Site
state: California
city: Santa Maria
country: United States
facility: Research Site
state: California
city: Sylmar
country: United States
facility: Research Site
state: California
city: Vallejo
country: United States
facility: Research Site
state: California
city: Westlake Village
country: United States
facility: Research Site
state: California
city: Whittier
country: United States
facility: Research Site
state: California
city: Denver
country: United States
facility: Research Site
state: Colorado
city: Grand Junction
country: United States
facility: Research Site
state: Colorado
city: Washington
country: United States
facility: Research Site
state: District of Columbia
city: Bonita Springs
country: United States
facility: Research Site
state: Florida
city: Gainesville
country: United States
facility: Research Site
state: Florida
city: Hollywood
country: United States
facility: Research Site
state: Florida
city: Jacksonville
country: United States
facility: Research Site
state: Florida
city: Miami
country: United States
facility: Research Site
state: Florida
city: Ocala
country: United States
facility: Research Site
state: Florida
city: Ocoee
country: United States
facility: Research Site
state: Florida
city: Orange Park
country: United States
facility: Research Site
state: Florida
city: Orlando
country: United States
facility: Research Site
state: Florida
city: Port St Lucie
country: United States
facility: Research Site
state: Florida
city: Albany
country: United States
facility: Research Site
state: Georgia
city: Athens
country: United States
facility: Research Site
state: Georgia
city: Atlanta
country: United States
facility: Research Site
state: Georgia
city: Augusta
country: United States
facility: Research Site
state: Georgia
city: Lawrenceville
country: United States
facility: Research Site
state: Georgia
city: Macon
country: United States
facility: Research Site
state: Georgia
city: Marietta
country: United States
facility: Research Site
state: Georgia
city: Savannah
country: United States
facility: Research Site
state: Georgia
city: Coeur D'alene
country: United States
facility: Research Site
state: Idaho
city: Chicago
country: United States
facility: Research Site
state: Illinois
city: Indianapolis
country: United States
facility: Research Site
state: Indiana
city: Overland Park
country: United States
facility: Research Site
state: Kansas
city: Westwood
country: United States
facility: Research Site
state: Kansas
city: Baltimore
country: United States
facility: Research Site
state: Maryland
city: Chevy Chase
country: United States
facility: Research Site
state: Maryland
city: Westminster
country: United States
facility: Research Site
state: Maryland
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: Ann Arbor
country: United States
facility: Research Site
state: Michigan
city: Royal
country: United States
facility: Research Site
state: Michigan
city: Minneapolis
country: United States
facility: Research Site
state: Minnesota
city: Rochester
country: United States
facility: Research Site
state: Minnesota
city: Jackson
country: United States
facility: Research Site
state: Mississippi
city: Columbia
country: United States
facility: Research Site
state: Missouri
city: St Louis
country: United States
facility: Research Site
state: Missouri
city: Billings
country: United States
facility: Reserach Site
state: Montana
city: Grand Island
country: United States
facility: Research Site
state: Nebraska
city: Las Vegas
country: United States
facility: Research Site
state: Nevada
city: Hooksett
country: United States
facility: Research Site
state: New Hampshire
city: Morristown
country: United States
facility: Research Site
state: New Jersey
city: Sparta
country: United States
facility: Research Site
state: New Jersey
city: Santa Fe
country: United States
facility: Research Site
state: New Mexico
city: Amsterdam
country: United States
facility: Research Site
state: New York
city: East Setauket
country: United States
facility: Research Site
state: New York
city: New York City
country: United States
facility: Research Site
state: New York
city: Chapel Hill
country: United States
facility: Research Site
state: North Carolina
city: Charlotte
country: United States
facility: Research Site
state: North Carolina
city: Durham
country: United States
facility: Research Site
state: North Carolina
city: Durham
country: United States
facility: Reserach Site
state: North Carolina
city: Greensboro
country: United States
facility: Research Site
state: North Carolina
city: Raleigh
country: United States
facility: Research Site
state: North Carolina
city: Winston-salem
country: United States
facility: Research Site
state: North Carolina
city: Cincinnati
country: United States
facility: Research Site
state: Ohio
city: Toledo
country: United States
facility: Research Site
state: Ohio
city: Portland
country: United States
facility: Research Site
state: Oregon
city: Philadelphia
country: United States
facility: Research Site
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Research Site
state: Pennsylvania
city: Columbia
country: United States
facility: Reserach Site
state: South Carolina
city: Chattanooga
country: United States
facility: Research Site
state: Tennessee
city: Memphis
country: United States
facility: Research Site
state: Tennessee
city: Nashville
country: United States
facility: Research Site
state: Tennessee
city: Austin
country: United States
facility: Research Site
state: Texas
city: Bedford
country: United States
facility: Research Site
state: Texas
city: Dallas
country: United States
facility: Research Site
state: Texas
city: Fort Worth
country: United States
facility: Research Site
state: Texas
city: Fredericksburg
country: United States
facility: Research Site
state: Texas
city: Houston
country: United States
facility: Research Site
state: Texas
city: Tyler
country: United States
facility: Research Site
state: Texas
city: Salt Lake City
country: United States
facility: Research Site
state: Utah
city: Fairfax
country: United States
facility: Research Site
state: Virginia
city: Norfolk
country: United States
facility: Research Site
state: Virginia
city: Richmond
country: United States
facility: Research Site
state: Virginia
city: Roanoke
country: United States
facility: Research Site
state: Virginia
city: Suffolk
country: United States
facility: Research Site
state: Virginia
city: Kennewick
country: United States
facility: Research Site
state: Washington
city: Seattle
country: United States
facility: Research Sites
state: Washington
city: Vancouver
country: United States
facility: Research Site
state: Washington
city: Yakima
country: United States
facility: Research Site
state: Washington
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
citation: O'Shaughnessy J, Schwartzberg L, Danso MA, Miller KD, Rugo HS, Neubauer M, Robert N, Hellerstedt B, Saleh M, Richards P, Specht JM, Yardley DA, Carlson RW, Finn RS, Charpentier E, Garcia-Ribas I, Winer EP. Phase III study of iniparib plus gemcitabine and carboplatin versus gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer. J Clin Oncol. 2014 Dec 1;32(34):3840-7. doi: 10.1200/JCO.2014.55.2984. Epub 2014 Oct 27.