Pre-Operative Radiation With Incomplete Neo-Adjuvant Chemotherapy for Breast Cancer
The investigators' primary aim is to determine the number of participants who can handle the treatment within specific safety parameters, determine the number of participants who can handle safely the maximum tolerated dose (MTD) (within 50-200 mg/BID dose range) when combining Veliparib and radiation, as well as to identify side effects and their intensity at different dosing levels.
The investigators' secondary aim is to determine the number of participants with post-operative adverse events associated with POPI as well as the pathologic complete and partial response rate in patients treated with POPI.
The investigators' exploratory aim is to serially assess apoptosis/proliferation biomarkers, and gene and protein expression profiles for correlation with tumor response to POPI. This will be primarily evaluated in the expansion cohort.
Women with residual disease >1cm after NAC (Med Onc's choice) will be offered pre-operative Veliparib and concurrent whole breast and regional nodal irradiation. This is a standard 3 3 dose finding study in which 3 dose levels of Veliparib will be explored. The MTD is defined as 2 of 6 patients with grade IV radiation dermatitis. There are 2 parts to this study. In part A Veliparib will be combined with whole breast only irradiation and in part B Veliparib will be combined with whole breast and supraclavicular irradiation.
Accrual: Up to 36 patients
Drug: Neo-Adjuvant Chemotherapy
Procedure: Resection of breast cancer
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Pre-Operative PARPi and Irradiation (POPI) in Women With an Incomplete Response to Neo-Adjuvant Chemotherapy for Breast Cancer|
- POPI participant treatment outcomes [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]To determine the safety (within 50 - 200 mg/BID dose range) when combining Veliparib and radiation.
- POPI treatment tolerance outcomes [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]To determine the tolerability (within 50 - 200 mg/BID dose range) when combining Veliparib and radiation.
- Maximum POPI Tolerated Dose [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]To determine the maximum tolerated dose (within 50 - 200 mg/BID dose range) when combining Veliparib and radiation.
- Post-Operative POPI associated adverse events [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]To determine the post-operative toxicity associated with POPI.
- Response Rate [ Time Frame: 1 year ] [ Designated as safety issue: No ]To determine pathologic complete and partial response rate in patients treated with POPI.
- Biomarkers [ Time Frame: 1 year ] [ Designated as safety issue: No ]To serially assess apoptosis/proliferation biomarkers, and gene and protein expression profiles for correlation with tumor response to POPI. This will be primarily evaluated in the expansion cohort.
|Study Start Date:||September 2012|
|Estimated Study Completion Date:||April 2016|
|Estimated Primary Completion Date:||April 2015 (Final data collection date for primary outcome measure)|
All subjects will receive preoperative Neo-Adjuvant Chemotherapy (NAC)treatment but only those with an incomplete response to NAC will be treated with the Preoperative experimental portion of the trial explained below. Those with a complete response will be treated per standard of care in the control arm of this trial.
Residual disease after surgery then Breast biopsy. If residual disease then Radiation with Veliparib.
Patients will receive radiation therapy at a dose of 2.35 Gy per fraction to the breast and regional nodal region for 16 fractions to a total dose of 37.5 Gy. Treatments will be given Monday through Friday. Radiation therapy will start on day 1 of Veliparib.Radiation: Radiation
Whole breast radiation delivered as standard of care concurrent with Veliparib.
Patients who have a complete response after the administration of preoperative Neo-Adjuvant Chemotherapy (NAC) (per the recommendation by the treating medical oncologist) will go to the control arm of this trial. That control arm will include surgery followed by more Neo-Adjuvant (NAC) treatment if residual disease is still present.
Drug: Neo-Adjuvant Chemotherapy
All subjects will be treated with NAC, at the discretion of the treating Medical Oncologist. For chemotherapy related questions please contact Dr. Vered Stearns at 443-287-6489 or Antonio Wolff at 410-614-4192.Procedure: Resection of breast cancer
Resection of breast cancer
Neo adjuvant (Primary) chemotherapy has revolutionized the management of locally advanced breast. Two large prospective American studies have shown the 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, the investigators 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, the investigators 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 2/6 patients with grade IV radiation dermatitis or other grade IV hematologic/systemic toxicity. Women with >1.0 cm residual breast or clinically positive nodal disease after NAC will be offered participation in this study. Four 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. Once the MTD is determined the investigators will further evaluate safety with an expansion cohort which will bring the total number of patients treated at the MTD to 20.
|Contact: Richard Zellars, M.D.||firstname.lastname@example.org|
|Contact: Shirley DiPasquale, R.N.||email@example.com|
|United States, Maryland|
|The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins||Recruiting|
|Baltimore, Maryland, United States, 21231|
|Principal Investigator: Richard Zellars, M.D.|
|Sub-Investigator: Pedram Argani, M.D.|
|Sub-Investigator: Emad Boctor, Ph.D.|
|Sub-Investigator: Deborah Frassica, M.D.|
|Sub-Investigator: Mehran Habibi, M.D.|
|Sub-Investigator: Michael Jacobs, Ph.D.|
|Sub-Investigator: Lisa Jacobs, M.D.|
|Sub-Investigator: Julie Lange, M.D.|
|Sub-Investigator: Vered Stearns, M.D.|
|Sub-Investigator: Theodore Tsangaris, M.D.|
|Sub-Investigator: Antonio Wolff, M.D.|
|Principal Investigator:||Richard Zellars, M.D.||The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins|