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About
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
Full 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.
Enrollment
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Inclusion and exclusion criteria
Inclusion Criteria for Observation
Inclusion Criteria for Treatment with Veliparib and Radiation
Patient must have a history and physical within 2 weeks prior to the start of any protocol therapy (radiation and veliparib).
Patient must have > 1.0 cm residual in-breast cancer (via positive biopsy) or clinically positive residual nodal disease. Incident breast biopsies only permitted prior to POPI to confirm residual disease after NAC.
Hematology:
Renal Function:
a. Creatinine Serum ≤ 2.0 mg/dl or Creatinine Clearance ≥45mL/min
Hepatic Function:
Patients must not be pregnant due to the potential for fetal harm as a result of this treatment regimen. Women of child-bearing potential must also have a negative pregnancy test within 2 weeks prior to start of protocol therapy (radiation and veliparib).
Women of childbearing potential must agree to use adequate contraception (one of the following listed below) prior to study entry, for the duration of study participation and up to 2 months following completion of protocol therapy
Patients must not have a serious medical or psychiatric illness which prevents informed consent or compliance with treatment.
All patients must be informed of the investigational nature of this study and given written informed consent in accordance with institutional and federal guidelines.
Patients must have a performance status 0 or 1 by ECOG criteria (Appendix I)
Exclusion Criteria for Consent B
Women who have a < 1.0 cm and are cN0 after NAC are not eligible.
Last dose of chemotherapy, immunotherapy, biologic therapy, or investigational therapy, was less than 21 days prior to protocol therapy (radiation and veliparib). There are no limitations on the type or number of prior regimens. Hormonal therapy and Traztusumab are permitted during POPI.
Bisphosphonates, hormone modification therapy, and trastuzumab are permitted without restriction.
Unresolved or unstable, serious toxicity from prior administration of another investigational drug and/or prior anti-cancer treatment.
If female, subject is pregnant or breast-feeding
Clinically significant and uncontrolled major cardiac, respiratory, renal, hepatic, gastrointestinal, hematologic or neurological/psychiatric disease or disorder, including but not limited to:
Unable to swallow and retain oral medications.
History of seizure disorder.
Known contraindication to enhanced MRI and CT, including but not limited to:
Previous enrollment on another study involving the investigation of veliparib (ABT- 888), with the exception of receiving a single dose of study drug.
Consideration by the Investigator, for any reason, that the subject is an unsuitable candidate to receive veliparib (ABT-888) and/or breast irradiation.
Inclusion of Underrepresented Populations Individuals of all races and ethnic groups are eligible for this trial. There is no bias towards age or race in the clinical trial outlined. This trial is open to the accrual of women only.
Primary purpose
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Interventional model
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19 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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