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
Overview
- Phase
- Phase 2
- Intervention
- Genomically Directed Monotherapy
- Conditions
- Malignant Neoplasm of Breast
- Sponsor
- Bryan Schneider, MD
- Enrollment
- 193
- Locations
- 29
- Primary Endpoint
- Percentage of Participants With Two-Year Disease-Free Survival (DFS)
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief 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.
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
Investigators
Bryan Schneider, MD
Sponsor-Investigator
Hoosier Cancer Research Network
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.
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.
Arms & Interventions
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: 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: Observation/Standard Therapy
Outcomes
Primary Outcomes
Percentage of Participants With Two-Year Disease-Free Survival (DFS)
Time Frame: From C1D1 until death or up to a maximum of 24 months.
Two-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. The survival probabilities for arm A and arm B were estimated as 2 year disease free survival. DFS is defined as the duration of time from randomization to time of a DFS event, defined as local failure (invasive), regional failure, distant failure, contralateral breast cancer (invasive or non-invasive), or death from any cause.
Secondary Outcomes
- Comparison Between Overall Disease-Free Survival(From C1D1 until death or up to a maximum of 58 months)
- Comparison Between One Year Disease Free Survival(From C1D1 until death or up to a maximum of 12 months)
- Five-Year Overall Survival (OS) Rate(From C1D1 until death or up to a maximum of 60 months)
- Number of Patients With Adverse Events as a Measure of Safety and Tolerability(From C1D1 until death or up to a maximum of 60 months)