Pre-Operative PARPi and Irradiation (POPI) in Women with an Incomplete Response to Neo-Adjuvant Chemotherapy for Breast Cancer
Johns Hopkins Kimmel Cancer Center in Baltimore
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 (within 50-200 mg/BID dose range) when combining Veliparib and radiation, as well as to identify side effects and their intensity at differenet 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. Study Plan: Women with residual disease greater than 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
Inclusion Criteria: Primary Study Subjects (Consent A) Inclusion Criteria for Observation ï¿½Patient must be 18 years of age or older ï¿½Patients must have histologically confirmed (by routine H&E staining) adenocarcinoma of the breast. ï¿½Patients must have an axillary nodal evaluation either by FNA or SNB in accordance with their institutional guidelines. ï¿½Patients with squamous, or metaplastic carcinomas or sarcomas of the breast are NOT eligible ï¿½Patient must have a history and physical within 8 weeks prior to the start of any protocol therapy ï¿½Patient must have had a bilateral mammogram prior to surgery unless there is only one breast. ï¿½Patient must have a Medical Oncology consult and be recommended to receive neoadjuvant chemotherapy for a stage II through IV carcinoma. ï¿½Patients must have a performance status 0 or 1 by ECOG criteria (Appendix) ï¿½Patients must not have received prior radiation therapy to the involved breast at any time for any reason. Secondary Study Subjects (Consent B) Inclusion Criteria for Treatment with Veliparib and Radiation ï¿½Patient must have greater than 1.0 cm residual in-breast cancer and/or clinically positive residual nodal disease. ï¿½Adequate Hematology - Adequate Renal Function- Adequate Hepatic Function ï¿½Patients 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 six weeks prior to start of protocol therapy. ï¿½No other prior malignancy is allowed except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or any other cancer from which the patient has been disease-free for 5 years. ï¿½Women 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 a. Total abstinence from sexual intercourse (minimum one complete menstrual cycle) b. A vasectomized partner c. Hormonal contraceptives (oral, parenteral or transdermal) for at least 3 months prior to study drug administration d. Double-barrier metho (condoms, contraceptive sponge, diaphragm or vaginal ring with spermicidal jellies or cream) ï¿½Patients must not have a serious medical or psychiatric illness which prevents informed consent or compliance with treatment. ï¿½All patients must be informed of the investigational nature of this study and given written informed consent in accordance with institutional and federal guidelines. Exclusion Criteria: ï¿½Women who were cT1-2 and cN0 before NAC and already planned to have a mastectomy. (This group would likely not receive radiation standardly) ï¿½Last dose of chemotherapy, immunotherapy, biologic therapy, or investigational therapy, was less than 14 days prior to enrollment on POPI. ï¿½Bisphosphonates, hormone modification therapy, and trastuzumab are permitted without restriction. ï¿½Unresolved or unstable, serious toxicity from prior administration of another investigational drug and/or prior anti-cancer treatment. ï¿½If female, subject is pregnant or breast-feeding ï¿½Clinically significant and uncontrolled major cardiac, respiratory, renal, hepatic, gastrointestinal, hematologic or neurological/psychiatric disease or disorder,including but not limited to: a.active uncontrolled infection b.symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia c.any other illness condition(s) that could exacerbate potential toxicities, confound safety assessments, require excluded therapy for management, or limit compliance with study requirements. Questions regarding inclusion of individual subjects should be directed to the PI. ï¿½Unable to swallow and retain oral medications. ï¿½Known contraindication to enhanced MRI and CT, including but not limited to: a.Presence of metal objects within the body such as a cardiac pacemaker, implanted cardiac defibrillator, brain aneurysm clips, cochlear implant, ocular foreign body, or shrapnel. b.History of immediate or delayed hypersensitivity reaction or other contraindication to contrast agents including but not limited to gadolinium and iodine. ï¿½Previous enrollment in this study or another study involving the investigation of Veliparib (ABT-888), with the exception of receiving a single dose of study drug. ï¿½Consideration by the Investigator, for any reason, that the subject is an unsuitable candidate to receive Veliparib (ABT-888) and/or breast irradiation. ï¿½For purposes of this protocol, anti-tumor treatment may be defined as, but is not limited to, anti-cancer agents (cytotoxic chemotherapy, immunotherapy, biologic therapy), radiotherapy, and investigational agents. An investigational agent is any drug or therapy not currently approved for use in humans.
Radiation: Radiation 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. Drug: N-acetyl-cysteine (NAC) 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. Radiation: Radiation Whole breast radiation delivered as standard of care concurrent with Veliparib. Procedure/Surgery: Resection of breast cancer Resection of breast cancer
07/30/2016 05:03 AM