Randomized Controlled Trial of Genomically Directed Therapy in Patients With Triple Negative Breast Cancer
Condition: Malignant Neoplasm of Breast; Breast Cancer
MeSH terms: Breast Neoplasms; Triple Negative Breast Neoplasms; Neoplasms
Intervention: Genomically Directed Monotherapy; Observation/Standard Therapy
Intervention description: 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). The CGTB will assign therapy to each participant individually based on biomarkers/pathways identified by DNA sequencing:; Currently 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.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Factorial Assignment
Masking: None (Open Label)
Enrollment: 193.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Genomically-Directed Therapy; DNA Sequencing; RNA Sequencing

Summary:

      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.
    

Eligibility criteria:

        Inclusion Criteria:

        -Written informed consent and HIPAA authorization for release of personal health
        information.

        NOTE: 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.

          -  Age ≥ 18 years at the time of consent.

          -  ECOG Performance Status 0 or 1 within 14 days prior to study registration.

          -  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.

        NOTE: Women are considered not of childbearing potential if they are surgically sterile
        (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy),
        or they are postmenopausal for at least 12 consecutive months.

          -  Women must not be breastfeeding.

          -  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 III^6

               -  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.

               -  Participants with a primary tumor > 5 cm or involvement of ≥4 lymph nodes who
                  require a mastectomy must also have radiotherapy pre- or post-operatively at the
                  discretion of the treating physician. 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. Registration must occur within 84 days
                  of the completion of the last local therapy.

               -  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.

          -  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 untreated hepatitis C.

          -  Adequate laboratory values must be obtained within 14 days prior to study
             registration.

               -  Hemoglobin (Hgb) >/= 9.0 g/dL

               -  Platelets >/= 100 K/mm^3

               -  Absolute neutrophile count (ANC) >/= 1.5 K/mm^3

               -  Calculated creatinine clearance of >/= 50 cc/min using the Cockcroft-Gault
                  formula:

                    -  Males: (140-Age in years) x Actual body weight in kg / 72 x Serum creatinine
                       (mg/dL)

                    -  Females: Estimated creatinine clearaNCE FOR MALES X 0.85

               -  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

          -  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 infections as judged by the treating physician.

          -  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

          -  No clinically significant arrhythmia or baseline ECG abnormalities in the opinion of
             the treating physician.

        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.