Trial record 1 of 1 for:    NCT01618357
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Pre-Operative Radiation and Veliparib for Breast Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by Sidney Kimmel Comprehensive Cancer Center
Sponsor:
Collaborator:
Breast Cancer Research Foundation
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center
ClinicalTrials.gov Identifier:
NCT01618357
First received: January 20, 2012
Last updated: August 22, 2014
Last verified: August 2014
  Purpose

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 (MTD) (within 50-200 mg/BID dose range) when combining Veliparib and radiation, as well as to identify side effects and their intensity at different 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:

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. 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.

Accrual: Up to 44 patients


Condition Intervention Phase
Breast Cancer
Radiation: Radiation
Procedure: Lumpectomy/Mastectomy
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Pre-Operative PARPi and Irradiation (POPI) in Women With an Incomplete Response to Neo-Adjuvant Chemotherapy for Breast Cancer

Resource links provided by NLM:


Further study details as provided by Sidney Kimmel Comprehensive Cancer Center:

Primary Outcome Measures:
  • POPI Safety, Tolerability, and MTD [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
    To determine the safety, tolerability and maximum tolerated dose (within 50 - 200 mg/BID dose range) when combining Veliparib and radiation.


Secondary Outcome Measures:
  • Response Rate [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    To determine pathologic complete and partial response rate in patients treated with POPI.

  • Biomarkers [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    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.

  • POPI Toxicity [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
    To determine the post-operative toxicity associated with POPI.


Estimated Enrollment: 44
Study Start Date: September 2012
Estimated Study Completion Date: April 2016
Estimated Primary Completion Date: April 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Intervention
All subjects will receive pre-operative Neo-Adjuvant Chemotherapy (NAC) but only those with an incomplete response to NAC will be treated with the PARPi experimental portion of the trial explained below. Those with a complete response will be treated per standard of care.
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.
Procedure: Lumpectomy/Mastectomy
Resection of breast cancer.

Detailed 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. 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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 with confirmed nodal metastasis. Patients must have an axillary nodal evaluation by FNA , 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, Renal Function, and Hepatic Function within accepted limits.
  • 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
  • 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.
  • Unable to swallow and retain oral medications.
  • History of seizure disorder.
  • Known contraindication to enhanced MRI and CT.
  • 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01618357

Contacts
Contact: Richard Zellars, M.D. 410-502-1421 zellari@jhmi.edu
Contact: Shirley DiPasquale, R.N. 410-614-1598 sdipasq1@jhmi.edu

Locations
United States, Maryland
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Recruiting
Baltimore, Maryland, United States, 21231
Principal Investigator: Richard Zellars, M.D.         
Sub-Investigator: Pedram Argani, M.D.         
Sub-Investigator: Emad Boctor, Ph.D.         
Sub-Investigator: Deborah Frassica, M.D.         
Sub-Investigator: Mehran Habibi, M.D.         
Sub-Investigator: Michael Jacobs, Ph.D.         
Sub-Investigator: Lisa Jacobs, M.D.         
Sub-Investigator: Julie Lange, M.D.         
Sub-Investigator: Vered Stearns, M.D.         
Sub-Investigator: Antonio Wolff, M.D.         
Sub-Investigator: Fariba Asrari, M.D.         
Sub-Investigator: Nagi Khouri, M.D.         
Sub-Investigator: Melissa Camp, M.D.         
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center
Breast Cancer Research Foundation
Investigators
Principal Investigator: Richard Zellars, M.D. The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
  More Information

No publications provided

Responsible Party: Sidney Kimmel Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT01618357     History of Changes
Other Study ID Numbers: J11155, NA_00048362
Study First Received: January 20, 2012
Last Updated: August 22, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Sidney Kimmel Comprehensive Cancer Center:
Veliparib
ABT-888
Radiation
POPI

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases

ClinicalTrials.gov processed this record on August 28, 2014