Know Cancer

forgot password

Pre-Operative PARPi and Irradiation (POPI) in Women With an Incomplete Response to Neo-Adjuvant Chemotherapy for Breast Cancer

Phase 1
18 Years
Open (Enrolling)
Breast Cancer

Thank you

Trial Information

Pre-Operative PARPi and Irradiation (POPI) in Women With an Incomplete Response to Neo-Adjuvant Chemotherapy for 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

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.

Inclusion Criteria:

Primary Study Subjects (Consent A) Inclusion Criteria for Observation

- Patient must be 18 years of age or older

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

- Patients must have an axillary nodal evaluation either by FNA or SNB in accordance
with their institutional guidelines.

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

- Patient must have a history and physical within 8 weeks prior to the start of any
protocol therapy

- Patient must have had a bilateral mammogram prior to surgery unless there is only one

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

- Patients must have a performance status 0 or 1 by ECOG criteria (Appendix)

- Patients 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

- Patient must have > 1.0 cm residual in-breast cancer and/or clinically positive
residual nodal disease.

- Hematology:

Absolute Neutrophil Count (ANC) ≥ 1000/mm3 Platelet Count ≥ 100,000/mm3 Hemoglobin
≥ 9.0 g/dL (after transfusion if required)

- Renal Function: Creatinine Serum ≤ 2.0 mg/dl or Creatinine Clearance ≥45mL/min

- Hepatic Function: Bilirubin ≤ 1.5 mg/dL (≤ 3.0 mg/dL with liver metastasis) Serum
Glutamic-Oxaloacetic Transaminase (SGOT) ≤ 2.5 × ULN (≤ 5.0 × ULN with liver metastasis)
Serum Glutamic-Pyruvic Transaminase (SGPT) ≤ 2.5 × ULN (≤ 5.0 × ULN with liver
metastasis) ULN = Upper normal limit of institution's normal range

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

2. 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 six weeks prior to start of protocol therapy.

- 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

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)

- 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.

Exclusion Criteria:

- Women who were cT1-2 and cN0 before NAC and already planned to have a mastectomy.
(This group would likely not receive radiation standardly)

- Last dose of chemotherapy, immunotherapy, biologic therapy, or investigational
therapy, was less than 14 days prior to enrollment on POPI.

- Bisphosphonates, hormone modification therapy, and trastuzumab are permitted without

- 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

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.

- 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

- Previous 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.

- 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 14 days prior to
start of POPI. There are no limitations on the type or number of prior regimens.

- 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.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

POPI participant treatment outcomes

Outcome Description:

To determine the safety (within 50 - 200 mg/BID dose range) when combining Veliparib and radiation.

Outcome Time Frame:

1 year

Safety Issue:


Principal Investigator

Richard Zellars, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins


United States: Food and Drug Administration

Study ID:




Start Date:

September 2012

Completion Date:

April 2016

Related Keywords:

  • Breast Cancer
  • Veliparib
  • ABT-888
  • Radiation
  • Non Inflammatory
  • Invasive
  • Breast Neoplasms



The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore, Maryland  21231