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

• One-Year Disease-Free Survival (DFS) Rate [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  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
• Five-Year Overall Survival (OS) Rate [ Time Frame: 60 months ] [ Designated as safety issue: No ]
  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
• Number of Patients with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: 24 months ] [ Designated as safety issue: Yes ]
  To determine the toxicities associated with genomically directed therapies in this population
• Clinical and Demographic Characteristics of Tumor Specimens [ Time Frame: 24 months ] [ Designated as safety issue: No ]
  To determine recurrence rates correlated with genomic characteristics in tumor specimens.
• Drug Specific Toxicity Rate [ Time Frame: 24 months ] [ Designated as safety issue: Yes ]
  Toxicity rates will be reported for each individual drug used in the study.

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.

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
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); Currently no standard therapy has proven efficacy in this patient population and thus follow-up alone would be considered standard of care. Additional therapy is permitted, however, if 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

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

• Triple Negative (ER-/PR-/HER2-) Invasive Breast Cancer
• Breast Cancer

• Drug: 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). The CGTB will assign therapy to each participant individually based on biomarkers/pathways identified by DNA sequencing:
• Other: Observation/Standard Therapy
  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.

• 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.
  Intervention: Drug: Genomically Directed Monotherapy
• Control Arm B (Observation/Standard Therapy)
  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.
  Intervention: Other: Observation/Standard Therapy

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:

  1. Residual Cancer Burden (RBC) classification II or III6
  2. 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.
  3. Residual invasive disease in the breast measuring at least 1cm with lymph node involvement (does not include metastases in lymph node which are only detected by immunohistochemistry).
• 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).
• 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.NOTE: 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.
• Participants must register within 84 days of surgery (for those participants who do not require radiation) or within 84 days of completion of radiation when radiation is required.
• 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 14 days prior to study registration. NOTE: Women are considered not of child bearing 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.

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 C.
• No clinically significant infections as judged by the treating physician.

• Vera Bradley Foundation for Breast Cancer
• Walther Cancer Institute
• Strategic Research Initiative Grant through IUSCC