Pre-Operative Radiation and Veliparib for Breast Cancer
- Conditions
- Breast Cancer
- Interventions
- Registration Number
- NCT01618357
- Lead Sponsor
- Richard Zellars
- Brief Summary
The investigators' primary aim is to determine the safety, tolerability and maximum tolerated dose (within 50 - 200mg/BID dose range) when combining veliparib and radiation.
The investigators' exploratory aim is to serially assess apoptosis/proliferation biomarkers, and gene and protein expression profiles for correlation with tumor response to POPI.
Study Plan:
It will be a standard 3+3 dose finding trial in which the MTD will be defined as the dose below the level at which \>1 DLT is observed in 3-6 patients. Women with node positive disease prior to NAC and \>1.0 cm residual breast disease and/or clinically positive nodal disease after NAC will be offered participation in the research phase of this study.
Women with residual disease \>1cm or +/-LN after NAC (Med Onc's choice) will be offered pre-operative Veliparib and concurrent whole breast and regional nodal irradiation. Four (4) dose levels of Veliparib will be evaluated with concurrent whole breast and regional nodal irradiation (WB/RNI). The starting dose of Veliparib will be 50 mg BID, will increase in 50 mg increments to a maximum of 200 mg BID and be delivered concurrently with 235 cGy QD x 16 to the breast and SCV/Axilla.
Accrual: Up to 41 patients
- Detailed Description
Neo adjuvant (Primary) chemotherapy has revolutionized the management of locally advanced breast. Two large prospective American studies have shown that NAC provides in vivo chemo-sensitivity information, and allows a greater percentage of women to have breast conserving therapy. Additionally and importantly, these two trials also showed that 20-30% of the women treated with NAC achieve a pathologic complete response (pCR) and have a better disease free and overall survival than those women who did not achieve pCR.
Unfortunately, 70-80% of patients receiving NAC do not achieve a pCR and many still must undergo a mastectomy due to an insufficient partial response. Researchers have attempted to increase the rate of pCR by adding radiation to NAC with mixed response rates. The varying rates of pCR in the above studies are likely due to the various chemotherapeutic agents used and timing of therapies yet also may represent the limitation of efficacy in combining these chemotherapy agents with radiation. What is needed is a better agent that can potentiate the effects of preoperative radiation.
One possible agent that may potentiate the effects of radiation is an inhibitor of Poly(ADP-ribose)-polymerase (PARP). PARP is a nuclear enzyme that recognizes deoxyribonucleic acid (DNA) damage and facilitates DNA repair. Cancer cells are often deficient in DNA repair. Deficiencies in DNA repair make these cancers more dependent on PARP. An inhibitor of PARP would further hamper the cancer cell's DNA repair capability. So theoretically, the efficacy of DNA damaging agents, such as radiation and chemotherapy, should be potentiated when these therapeutic modalities are combined with PARP inhibition.
Indeed, as expected, PARP inhibitors (PARPi), such as Veliparib, have been shown in pre-clinical studies to potentiate the effects of radiation and chemotherapy in several malignancies. Thus, we hypothesize that concurrent Veliparib and pre-operative breast irradiation, in women who have residual disease after NAC, will result in an increased tumor response rate. This improved tumor response will not only increase the rate of BCT, but possibly, by increasing the rate of pCRs, also improve overall survival.
However, before this hypothesis can be adequately tested, one must assess the safety of combining radiation and Veliparib. Consequently we propose a trial of Pre-Operative PARPi and Irradiation (POPI) in women with an incomplete response to NAC. It will be a standard 3+3 dose finding trial in which the MTD will be defined as the dose below the level at which \>1 DLT is observed in 3-6 patients. Women with node positive disease prior to NAC and \>1.0 cm residual breast disease and/or clinically positive nodal disease after NAC will be offered participation in this study. Four (4) dose levels of Veliparib will be evaluated with concurrent whole breast and regional nodal irradiation (WB/RNI). The starting dose of Veliparib will be 50 mg BID, will increase in 50 mg increments to a maximum of 200 mg BID and be delivered concurrently with 235 cGy QD x 16 to the breast and SCV/Axilla.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Female
- Target Recruitment
- 19
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Intervention Radiation All subjects will receive pre-operative Neo-Adjuvant Chemotherapy (NAC) but only those with an incomplete response to NAC will be treated with the PARPi experimental portion of the trial explained below. Those with a complete response will be treated per standard of care. Intervention Lumpectomy/Mastectomy All subjects will receive pre-operative Neo-Adjuvant Chemotherapy (NAC) but only those with an incomplete response to NAC will be treated with the PARPi experimental portion of the trial explained below. Those with a complete response will be treated per standard of care. Intervention Veliparib All subjects will receive pre-operative Neo-Adjuvant Chemotherapy (NAC) but only those with an incomplete response to NAC will be treated with the PARPi experimental portion of the trial explained below. Those with a complete response will be treated per standard of care.
- Primary Outcome Measures
Name Time Method POPI Safety, Tolerability, and MTD 1 year To determine the safety, tolerability and maximum tolerated dose (within 50 - 200 mg/BID dose range) when combining Veliparib and radiation.
- Secondary Outcome Measures
Name Time Method
Trial Locations
- Locations (6)
I U Health West
🇺🇸Avon, Indiana, United States
Indiana University Health Melvin and Bren Simon Cancer Center
🇺🇸Indianapolis, Indiana, United States
Indiana University Health Methodist Hospital
🇺🇸Indianapolis, Indiana, United States
Indiana University Health Hospital
🇺🇸Indianapolis, Indiana, United States
IU Schwarz Cancer Center
🇺🇸Carmel, Indiana, United States
Sidney and Lois Eskenazi Hospital
🇺🇸Indianapolis, Indiana, United States