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.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
POPI participant treatment outcomes
To determine the safety (within 50 - 200 mg/BID dose range) when combining Veliparib and radiation.
Richard Zellars, M.D.
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
United States: Food and Drug Administration
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