1. Iniparib plus Chemotherapy in Metastatic Triple-Negative Breast Cancer
The New England Journal of Medicine
January 20,2011 Vol.364 No.3
Prof. Beak Sun Kyung / R2 Hwang Jin Kyung
Kyung Hee University Medical Center

2. INTRODUCTION Triple-Negative Breast Cancer ? Negative Negative
Human epidermal growth factor receptor type 2 (HER2)
Estrogen-receptor
(ER)
Progesterone-receptor (PR)

3. INTRODUCTION
Metastatic triple-negative breast cancer
15 to 20% of all cases of breast cancer.
Aggressive subtype of breast cancer.
Higher rates of visceral and central nervous system metastases.
Median survival of approximately 1 year.
No standard-of-care therapy exists.
Related with dysregulation of BRCA1.
Critical roles in the homologous recombination–dependent DNA-repair pathway.
Methylation and over-expression of the negative regulators ID4 and HMG.
Aberrations of MRE11–RAD50–NBS1, ATM, p53, and PALB2 have also been implicated in the tumorigenesis.
 Providing a strong rationale for developing new agents that exploit DNA-repair defects in these cancers.

4. INTRODUCTION Poly Adenosine diphosphate–Ribose polymerase 1 (PARP1)
An important regulator of the DNA base-excision–repair pathway.
Iniparib (also known as BSI-201) is anticancer agent with PARP inhibitory activity.
Preclinical study
Clinical study
Phase 1-1b study
Phase 2 study
In this study
Iniparib
In vitro models
Enhances effects of carboplatin and gemcitabine.
Iniparib alone,
Iniparib + CTx
Advanced solid tumors
Mild toxicity, with no maximal dose.
Iniparib alone
Iniparib + CTx
acceptable toxicity levels
Metastatic breast cancer
Rates of response
26 ~ 34%.
Iniparib alone
Iniparib + CTx
acceptable toxicity levels
Metastatic triple negative breast cancer ?

5. METHODS Patients Female, age ≥ 18 years.
Metastatic triple negative breast cancer, histologically confirmed.
Eastern Cooperative Oncology Group performance status score `: 0~1.
0 : fully active and able to carry out predisease performance.
1 : restricted physically strenuous activity but ambulatory and light ~ sedentary nature able to carry out, adequate bone marrow, hepatic, and renal function.
Clinically stable CNS metastases without glucocorticoids or brain RTx.
Prior CTx regimens ≤ 2 for metastatic disease as adjuvant or neoadjuvant CTx.
Except gemcitabine, carboplatin, cisplatin, or a PARP inhibitor.
Immunohistochemistry for ER, PR, and HER2 and FISH for HER2, according to each institution’s standards with the archived-tissue specimens.
CTx : chemotherapy, RTx : radiotherapy, ER : estrogen receptor, PR: progesterone receptor,
HER2 : Human epidermal growth factor receptor type 2, FISH : fluorescence in situ hybridization

6. METHODS
Study design
Multicenter, open-label, randomized, phase 2 study.
Conducted at 20 centers within the US Oncology network.
Recruited September 2007~March 2009, randomly assigned, in a 1:1 ratio.
Gemcitabine + Carboplatin vs. Gemcitabine + Carboplatin + Iniparib.
Integrated web randomization system.
Primary end points
Rate of clinical benefit : percentage of CR, a PR, or SD for at least 6 months, as well as safety and tolerability of iniparib.
Secondary end points
Overall rate of response and progression-free survival, defined as the time from randomization to confirmation of disease progression or death.
Overall survival
Time of randomization ~ death was not prespecified as an end point.
Analyzed to explore the potential effect of iniparib on survival.

7. METHODS Treatment Patients received chemotherapy during 21-day.
20 patients of iniparib group
: 4.0 mg/kg (before Jan. 2008)  5.6 mg/kg (after Jan. 2008)
Chemotherapy-alone group
: cross over to receive iniparib + gemcitabine/carboplatin if disease progression occurred. D1 D8
IV Gemcitabine 1000 mg/m2 over a 30 min D1 D8
IV Carboplatin AUC of conc.-time over a 60 min D1 D4 D8
D11
IV Iniparib 4.0 mg/kg over a 60 min (before Jan. 2008)
IV Iniparib 5.6 mg/kg over a 60 min (after Jan. 2008)

8. METHODS Assessment Tumor response Safety Adverse event
Based on target and non-target lesions.
By CT or MRI imaging at baseline and every 6 weeks, in the absence of clinically evident disease progression.
Modified Response Evaluation Criteria in Solid Tumors, version 1.0.
Safety
Standard clinical and laboratory tests (hematologic tests, blood chemical tests, and urinalysis) throughout the study period until 30 days after the last dose.
Adverse event
Defined on the basis of the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0.
Serious adverse events
Monitored and reported to MedWatch and the ICON safety group by the primary investigator at each site.

9. METHODS Statistical Analysis Pearson chisquare test
Compare the rates of clinical benefit and the overall rates of response.
Kaplan–Meier method
95% confidence intervals were calculated.
Logrank test
Compare the distributions of progression-free and overall survival.
Adverse events and serious adverse events
Tabulated according to trial group and the Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class categorization and preferred terms.
Safety data reported after the crossover (chemothrapy-alone  iniparib group) were analyzed separately.

10. Enrollment, Randomization, and Follow-up of Study Patients.
51%

11. Baseline Characteristics of the Study Patients, According to Treatment Group.

12. Summary of Efficacy Measures in the Intention-to-Treat Population.

13. Kaplan-Meier Estimates of Progression-free and Overall Survival Rates, According to Treatment Group.

14. Common Adverse Events in the Safety Population

15. Conclusion
Iniparib + chemotherapy
in metastatic triple-negative breast cancer.
 Improved the clinical benefit and survival.
 No significantly increased toxic effects.