Pre-Operative Radiation and Veliparib for Breast Cancer

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. Once the MTD is
determined we will further evaluate safety with an expansion cohort which will bring the
total number of patients treated at the MTD to 20.

Inclusion Criteria for Observation

- Patient must be female and 18 years of age or older.

- Patients must have histologically confirmed (by routine H&E staining) adenocarcinoma
of the breast with confirmed nodal metastasis.

- Patients must have an axillary nodal evaluation by fine needle aspiration (FNA),
sentinel node biopsy (SNB) or nodal dissection.

- Patients with squamous, or metaplastic carcinomas or sarcomas of the breast are NOT
eligible.

- Patient must have had a bilateral mammogram prior to NAC unless there is only one
breast.

- Patient must have a Medical Oncology consult and be recommended to receive neoadjuvant
chemotherapy for a stage IIB through IV carcinoma.

- Patients must not have received prior radiation therapy to the involved breast at any
time for any reason.

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 and/or clinically positive
residual nodal disease.

- Hematology:

1. Absolute Neutrophil Count (ANC) ≥ 1000/mm3

2. Platelet Count ≥ 100,000/mm3

3. Hemoglobin ≥ 9.0 g/dL (after transfusion if required)

- Renal Function:

a. Creatinine Serum ≤ 2.0 mg/dl or Creatinine Clearance ≥45mL/min

- Hepatic Function:

1. Bilirubin ≤ 1.5 mg/dL (≤ 3.0 mg/dL with liver metastasis)

2. Serum Glutamic-Oxaloacetic Transaminase (SGOT) ≤ 2.5 × ULN (≤ 5.0 × ULN with
liver metastasis)

3. Serum Glutamic-Pyruvic Transaminase (SGPT) ≤ 2.5 × ULN (≤ 5.0 × ULN with liver
metastasis) ULN = Upper normal limit of institution's normal range

4. If calculated creatinine clearance is < 45 mL/min, a 24-hour urine collection for
creatinine clearance may be performed.

5. Subjects with Gilbert's disease may have bilirubin up to 2.5 mg/dL (or 3.0 mg/dL
with liver (metastasis).

- 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).

- No 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.

- 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

1. Total abstinence from sexual intercourse (minimum one complete menstrual cycle)

2. A vasectomized partner

3. Hormonal contraceptives (oral, parenteral or transdermal) for at least 3 months
prior to study drug administration

4. Double-barrier method (condoms, contraceptive sponge, diaphragm or vaginal ring
with spermicidal jellies or cream)

- 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 14 days prior to protocol therapy (radiation and veliparib).

- 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:

1. Active uncontrolled infection

2. Symptomatic congestive heart failure, unstable angina pectoris, or cardiac
arrhythmia

3. 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.

- Unable to swallow and retain oral medications.

- History of seizure disorder.

- Known contraindication to enhanced MRI and CT, including but not limited to:

1. 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.

2. History of immediate or delayed hypersensitivity reaction or other
contraindication to contrast agents including but not limited to gadolinium and
iodine.

- 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.

- For 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.

- Anti-cancer Agents: Anti-cancer agents are not permitted within 21 days prior to start
of POPI. There are no limitations on the type or number of prior regimens. Hormonal
therapy and Traztusumab are permitted during POPI.

- Radiation: Prior treatment with breast irradiation is not allowed due to the potential
for cumulative toxicities.

- Surgery: Incident breast biopsies only permitted prior to POPI to confirm residual
disease after NAC.

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.