Clinical Trials /

Pre-Operative Radiation and Veliparib for Breast Cancer

NCT01618357

Description:

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

Related Conditions:
  • Breast Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Pre-Operative Radiation and Veliparib for Breast Cancer
  • Official Title: Pre-Operative PARPi and Irradiation (POPI) in Women With an Incomplete Response to Neo-Adjuvant Chemotherapy for Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: J11155
  • SECONDARY ID: 1503214668
  • NCT ID: NCT01618357

Conditions

  • Breast Cancer

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

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.
    

Trial Arms

NameTypeDescriptionInterventions
InterventionExperimentalAll 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.

    Eligibility Criteria

            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.
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:Female
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:POPI Safety, Tolerability, and MTD
    Time Frame:1 year
    Safety Issue:
    Description:To determine the safety, tolerability and maximum tolerated dose (within 50 - 200 mg/BID dose range) when combining Veliparib and radiation.

    Secondary Outcome Measures

    Measure:Response Rate
    Time Frame:1 year
    Safety Issue:
    Description:To determine pathologic complete and partial response rate in patients treated with POPI.
    Measure:Biomarkers
    Time Frame:1 year
    Safety Issue:
    Description: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.
    Measure:POPI Toxicity
    Time Frame:1 year
    Safety Issue:
    Description:To determine the post-operative toxicity associated with POPI.

    Details

    Phase:Phase 1
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:Richard Zellars

    Trial Keywords

    • Veliparib
    • ABT-888
    • Radiation
    • POPI

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