Clinical Trials /

Randomized Controlled Trial of Genomically Directed Therapy in Patients With Triple Negative Breast Cancer

NCT02101385

Description:

This study will test the theory that therapy designed for each individual's tumor will improve outcomes over standard of care in a population that needs a better standard.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Randomized Controlled Trial of Genomically Directed Therapy in Patients With Triple Negative Breast Cancer
  • Official Title: A Phase II Randomized Controlled Trial of Genomically Directed Therapy After Preoperative Chemotherapy in Patients With Triple Negative Breast Cancer: Hoosier Oncology Group BRE12-158

Clinical Trial IDs

  • ORG STUDY ID: BRE12-158
  • NCT ID: NCT02101385

Conditions

  • Malignant Neoplasm of Breast
  • Breast Cancer

Interventions

DrugSynonymsArms
Genomically Directed MonotherapyArm A (Genomically Directed Monotherapy)

Purpose

This study will test the theory that therapy designed for each individual's tumor will improve outcomes over standard of care in a population that needs a better standard.

Detailed Description

      OUTLINE: This is a multi-center trial.

      SEQUENCING:

      DNA from archived tumor samples collected at the time of surgery (residual disease post
      neoadjuvant chemotherapy) will be extracted and sequenced. The resulting sequencing data will
      be interrogated for known genomic drivers of sensitivity or resistance to existing FDA
      approved agents.

      CANCER GENOMICS TUMOR BOARD (CGTB):

      Realizing that optimal treatment recommendations cannot be made based on sequencing data
      alone, the CGTB will be responsible for the final treatment recommendation. The CGTB will
      consider the genomic data along with the patient's prior treatment history, ongoing
      toxicities, and comorbidities. Preference will be given to the treatment identified by the
      sequencing data unless a significant clinical or safety contraindication exists for that
      therapy. All participants and investigators will be blinded to sequencing results and CGTB
      deliberations until the time of relapse.

      PARTICIPANTS WITH A CGTB TREATMENT RECOMMENDATION:

      Participants with a CGTB recommendation will be randomized to Experimental Arm A (genomically
      directed monotherapy) or Control Arm B (standard therapy).

      EXPERIMENTAL ARM A (GENOMICALLY DIRECTED MONOTHERAPY):

      Participants randomized to Experimental Arm A will receive an FDA approved drug at standard
      dose for four cycles (12-16 weeks total duration, depending on cycle length). Clinical and
      laboratory monitoring and dose-reductions will follow the FDA package insert guidelines.

      TOP GENOMIC ACTIONABLE BIOMARKERS/PATHWAYS AND DRUG RECOMMENDATIONS:

        1. PIK3CA, PTEN: Everolimus

        2. TOP2A: Doxorubicin

        3. PARP1, BRCA1: Cisplatin and Olaparib

        4. VEGFA: Bevacizumab

        5. TYMP: Capecitabine

        6. SSTR2: Octreotide

        7. MGMT: Temozolomide

        8. MYC: Paclitaxel

        9. EGFR: Cetuximab

       10. COX2: Celecoxib

       11. hENT: Gemcitabine

       12. MET: Crizotinib

      CONTROL ARM B (STANDARD THERAPY); Recently, a randomized phase III trial of over 900
      HER2-negative patients demonstrated an improvement in disease-free survival (DFS) and overall
      survival (OS) for the addition of 8 cycles of capecitabine in the post-neoadjuvant setting.
      The hazard ratios were also significant in the triple negative subgroup. Thus, capecitabine
      can be considered a standard option in this setting. As this represents only a single trial
      (with prior data not demonstrating benefit for the addition of capecitabine in the
      neoadjuvant nor adjuvant settings in unselected patients), observation can be considered an
      option as directed by the treating physician. While not recommended, other therapies can be
      used as deemed appropriate by the treating physician.

      In the event of disease progression on the control arm, patient sequencing results will be
      forwarded to the treating physician.

      PARTICIPANTS WITH NO CGTB RECOMMENDATION:

      Participants may have no CGTB recommendation either because 1) sequencing did not identify a
      matched drug or 2) the matched drug was contraindicated. These participants will be assigned
      to Control Arm B and treated as described above for Control Arm B. As the outcome of
      participants without an 'actionable' genomically directed therapy may differ, the primary
      analysis will include only participants randomized to Control Arm B.

      Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 14 days prior
      to study registration

      Life Expectancy: Not Specified

      Adequate laboratory values must be obtained within 14 days prior to study registration:

      Hematopoietic:

        -  Hemoglobin (Hgb) ≥ 9.0 g/dL

        -  Platelets ≥ 100 K/mm3

        -  Absolute neutrophil count (ANC) ≥ 1.5 K/mm3

      Hepatic:

        -  Bilirubin ≤ 1.5 x ULN (except in participants with documented Gilbert's disease, who
           must have a total bilirubin ≤ 3.0 mg/dL)

        -  Aspartate aminotransferase (AST, SGOT) ≤ 2.5 x ULN

        -  Alanine aminotransferase (ALT, SGPT) ≤ 2.5 x ULN

      Renal:

        -  Calculated creatinine clearance of ≥ 50 cc/min using the Cockcroft-Gault formula

      Cardiac:

        -  Left ventricular ejection fraction within normal limits obtained within 30 days prior to
           study registration. NOTE: Participants with an unstable angina or myocardial infarction
           within 12 months of study registration are excluded.

        -  No clinically significant arrhythmia or baseline ECG abnormalities in the opinion of the
           treating physician
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (Genomically Directed Monotherapy)ExperimentalParticipants randomized to Experimental Arm A will receive an FDA approved drug at standard dose for four cycles (12-16 weeks total duration, depending on cycle length). Clinical and laboratory monitoring and dose-reductions will follow the FDA package insert guidelines.
  • Genomically Directed Monotherapy
Control Arm B (Observation/Standard Therapy)OtherCurrently no standard therapy has proven efficacy in this patient population and thus observation alone would be considered standard of care. Additional therapy is permitted, however, if deemed appropriate by the treating physician.

    Eligibility Criteria

            Inclusion Criteria:
    
              -  Must have histologically or cytologically confirmed triple negative (ER-/PR-/HER2-)
                 invasive breast cancer, clinical stage I-III at diagnosis (AJCC 6th edition) based on
                 initial evaluation by physical examination and/or breast imaging prior to study
                 registration. NOTE: ER, PR and HER2 status will be confirmed by central pathology
                 review prior to randomization. ER and PR will be considered negative if ≤ 1% of cells
                 stain weakly positive. HER2 will be considered negative if scored 0 or 1+ by
                 immunohistochemistry (IHC) or 2+ by IHC associated with a fluorescence in situ
                 hybridization (FISH) ratio of < 2.0 or < 6 copies per cell.
    
              -  Must have completed preoperative (neoadjuvant) chemotherapy. NOTE: Acceptable
                 preoperative regimens include an anthracycline or a taxane, or both. Participants who
                 received preoperative therapy as part of a clinical trial may enroll. Participants may
                 not have received adjuvant chemotherapy after surgery prior to randomization.
                 Bisphosphonate use is allowed.
    
              -  Must have completed definitive resection of primary tumor. The most recent surgery for
                 breast cancer must have been completed at least 14 days prior (but no more than 84
                 days prior) to study registration. NOTE: Negative margins for both invasive and ductal
                 carcinoma in situ (DCIS) are desirable, however participants with positive margins may
                 enroll if the treatment team believes no further surgery is possible and patient has
                 received radiotherapy. Participants with margins positive for lobular carcinoma in
                 situ (LCIS) are eligible. Either mastectomy or breast conserving surgery (including
                 lumpectomy or partial mastectomy) is acceptable.
    
              -  Must have significant residual invasive disease at the time of definitive surgery
                 following preoperative chemotherapy. Significant residual disease is defined as at
                 least one of the following:
    
                   -  Residual Cancer Burden (RBC) classification II or III6
    
                   -  Residual invasive disease in the breast measuring at least 2 cm. The presence of
                      DCIS without invasion does not qualify as residual disease in the breast.
    
                   -  Residual invasive disease in the breast measuring at least 1cm with any lymph
                      node involvement (does not include metastases in lymph node which are only
                      detected by immunohistochemistry).
    
                   -  Any lymph node involvement that results in 20% cellularity or greater regardless
                      of primary tumor site involvement (includes no residual disease in the breast).
    
              -  Must have an FFPE tumor block with tumor cellularity of 20% or greater. NOTE: Prior to
                 randomization, the tumor cellularity will be confirmed by central pathology review and
                 percent values will be double checked at Paradigm (a Next Generation Sequencing
                 Company).
    
              -  BREAST RADIOTHERAPY:
    
                   -  Whole breast radiotherapy is required for participants who underwent
                      breast-conserving therapy, including lumpectomy or partial mastectomy.
                      Participants must have completed radiotherapy at least 14 days prior (but no more
                      than 84 days prior) to study registration.
    
                   -  Post-mastectomy radiotherapy is required for all participants with a primary
                      tumor ≥ 5 cm or involvement of ≥ 4 lymph nodes. For participants with primary
                      tumors < 5 cm or with < 4 involved lymph nodes, provision of post-mastectomy
                      radiotherapy is at the discretion of the treating physician. Study registration
                      must occur within 84 days of completion of radiation.
    
                   -  For radiation required prior to surgery, the participant must register within 84
                      days of surgery. Also, participants in this situation would not be required to
                      have additional post-mastectomy radiation therapy.
    
                   -  For those participants who do not require radiation, registration must be within
                      84 days of surgery.
    
              -  Age ≥ 18 years at the time of consent.
    
              -  Written informed consent and HIPAA authorization for release of personal health
                 information. HIPAA authorization may be included in the informed consent or may be
                 obtained separately. NOTE: Central pathology review may be conducted any time after
                 definitive surgery. Consenting participants may be pre-registered to the study and
                 proceed with central pathology review before full eligibility has been confirmed.
                 However ALL of the eligibility criteria must be met and formal study registration
                 completed prior to submission of the sample for sequencing.
    
              -  Must consent to allow submission of adequate archived tumor tissue sample from
                 definitive surgery for genomic assessment of tumor.
    
              -  Must consent to collection of whole blood samples for genomic analysis
    
              -  Women and men of childbearing potential must be willing to use an effective method of
                 contraception (e.g. hormonal or barrier method of birth control; abstinence) from the
                 time consent is signed until 4 weeks after protocol therapy discontinuation.
    
              -  Women of childbearing potential must have a negative pregnancy test within 30 days
                 prior to study registration. Women should be counseled regarding acceptable birth
                 control methods to utilize from the time of screening to start of treatment. If prior
                 to treatment after discussion with the subject it is felt by the treating physician
                 there is a possibility the subject is pregnant a pregnancy test should be repeated.
    
            Women of childbearing potential must have a negative pregnancy test within 30 days prior to
            study registration.
    
              -  Women must not be breastfeeding.
    
            Exclusion Criteria:
    
              -  No stage IV (metastatic) disease, however no specific staging studies are required in
                 the absence of symptoms or physical exam findings that would suggest distant disease.
    
              -  No treatment with any investigational agent within 30 days prior to study
                 registration.
    
              -  No history of chronic hepatitis B or or untreated hepatitis C.
    
              -  No clinically significant infections as judged by the treating physician.
    
              -  No active second malignancy (except non-melanomatous skin cancer or incidental
                 prostate cancer found on cystectomy): Active second malignancy is defined as a current
                 need for cancer therapy or a high possibility (> 30%) of recurrence during the study.
                 Previous contralateral breast cancer is allowable unless it meets "active" criteria as
                 stated above.
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Two-Year Disease-Free Survival (DFS) Rate
    Time Frame:24 months
    Safety Issue:
    Description:To compare 2-year disease-free survival (DFS) in participants with confirmed triple negative breast cancer (TNBC) treated with a genomically directed therapy or standard of care following preoperative chemotherapy

    Secondary Outcome Measures

    Measure:One-Year Disease-Free Survival (DFS) Rate
    Time Frame:12 months
    Safety Issue:
    Description:To compare overall DFS and 1-year DFS in participants with confirmed triple negative breast cancer (TNBC) treated with a genomically directed therapy or standard of care following preoperative chemotherapy
    Measure:Five-Year Overall Survival (OS) Rate
    Time Frame:60 months
    Safety Issue:
    Description:To determine 5-year overall survival (OS) in participants with confirmed triple negative breast cancer (TNBC) treated with a genomically directed therapy or standard of care following preoperative chemotherapy
    Measure:Number of Patients with Adverse Events as a Measure of Safety and Tolerability
    Time Frame:24 months
    Safety Issue:
    Description:To determine the toxicities associated with genomically directed therapies in this population
    Measure:Clinical and Demographic Characteristics of Tumor Specimens
    Time Frame:24 months
    Safety Issue:
    Description:To determine recurrence rates correlated with genomic characteristics in tumor specimens.
    Measure:Drug Specific Toxicity Rate
    Time Frame:24 months
    Safety Issue:
    Description:Toxicity rates will be reported for each individual drug used in the study.

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:Bryan Schneider, MD

    Trial Keywords

    • Genomically-Directed Therapy
    • DNA Sequencing
    • RNA Sequencing

    Last Updated

    May 2, 2017