Trial to Evaluate Genomic Expression Profiles to Direct Preoperative Chemotherapy in Early Stage Breast Cancer

• ClinicalTrials.gov Identifier: NCT00636441
• Recruitment Status: Terminated
• First Posted: March 14, 2008
• Results First Posted: October 7, 2014
• Last Update Posted: December 11, 2015
• Sponsor: Duke University
• Collaborator: United States Department of Defense
• Information provided by (Responsible Party): Duke University

Tracking Information

• First Submitted Date: March 9, 2008
• First Posted Date: March 14, 2008
• Results First Submitted Date: May 7, 2014
• Results First Posted Date: October 7, 2014
• Last Update Posted Date: December 11, 2015
• Study Start Date: April 2008
• Actual Primary Completion Date: April 2013 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 6, 2014)

Pathologic Complete Response (pCR) Rate in Patients With HER2-negative Early-stage Breast Cancer [ Time Frame: 4-5 weeks after the fourth cycle of chemotherapy; approximately 16-17 weeks ]

Pathological complete response (pCR) was defined as the disappearance of all invasive disease in the breast or if only residual in situ or lymph node disease is found. The pCR rate is presented with its 95% confidence interval for the Guided and Non-guided arms.

Original Primary Outcome Measures (submitted: March 13, 2008)

• To determine in early stage breast cancer treated with PST whether genomic profiling for drug-sensitivity can improve the pCR rate as compared to random assignment of patients to therapy. [ Time Frame: 10 years ]
• To determine in early stage breast cancer treated with PST whether genomic profiling can identify drug-sensitive and drug-resistant patients including a comparison of subgroups for the two individual regimens (i.e. AC and TC). [ Time Frame: 10 years ]

Current Secondary Outcome Measures (submitted: October 6, 2014)

• Probabilities of Being Sensitive to AC and TC as Determined by the Patient's Genomic Signatures [ Time Frame: 10 years ]
  To determine in early stage breast cancer treated with PST whether genomic profiling can identify drug-sensitive and drug-resistant patients including a comparison of subgroups for the two individual regimens (i.e. AC and TC). To determine if the 60% cutoff for the genomic profiles is optimal in predicting the response to chemotherapy regimens.To describe the performance of the genomic profiles in assessing the relative responsiveness of: 1) Patients predicted to be resistant to both chemotherapy regimens; and 2) Patients randomly assigned to one treatment whose genomic profiles suggest receiving the other regimen (in both AC and TC subgroups).
• Percentage of Patients Who Had Breast-conserving Surgery With Negative Margins [ Time Frame: 6 months ]
  The percentage of patients who had breast-conserving surgery with negative margins, measured in patients with T2 and T3 tumors classified as requiring mastectomy at baseline.
• To Percentage of Patients Who Had Breast-conserving Surgery at First Attempt. [ Time Frame: 6 months ]
  The percentage of patients who had breast-conserving surgery at first attempt, measured only in patients with T2 tumors classified as potential candidates for breast conservation.
• Clinical Response Using WHO Criteria [ Time Frame: 12 weeks, 2-3 weeks after the fourth cycle of chemotherapy ]
  WHO criteria are based on the sum of the products of the longest axis and the longest perpendicular axis. Bi-dimensional measurements were taken of all breast lesions and axillary nodes using the best imaging modality performed after completion of assigned therapy. Clinical Complete Response (cCR): Disappearance of all target lesions by physical exam and best imaging modality. Clinical Partial Response (cPR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the sum LD at treatment initiation. Patients having a documented response with no reconfirmation of the response will be listed with stable disease. Progression (PD): At least a 20% increase in the sum of the LD of target lesions or the appearance of one or more new lesion.
• Disease-free Survival [ Time Frame: 2 years ]
  Disease-free survival is defined as the length of time from enrollment to local or distant disease recurrence, whichever comes first; disease-free deaths are censored. The 2-year disease-free survival rate is estimated with its 95% confidence interval.
• Sites of Recurrence [ Time Frame: 10 years ]
  Sites of Recurrence is a categorical outcome whose possible values are the organ-specific sites at which disease recurrence was observed. A patient may recur at more than one site.
• Overall Survival [ Time Frame: 2 years ]
  Overall survival is defined as the time from enrollment to death due to any cause. The 2-year overall survival rate is estimated with the Kaplan-Meier method.
• Economic Impact of Using Genomic Assessment to Guide Management. [ Time Frame: 5 years ]
  Economic Impact (i.e., cost of care) will be calculated by first assessing the quantity of clinical resources used by each patient in the study arm, and then assigning a cost to each resource using cost information derived from a costing study to be undertaken outside of this protocol.
• Patients' Perceptions of Participating in a Clinical Trial Evaluating Cancer Genomics for PST of Early-stage Breast Cancer. [ Time Frame: 1 year ]
  A short questionnaire was administered at baseline (the day chemotherapy was started) and following post-surgical medical oncology evaluation to assess the patient's understanding of the study being conducted, and the patient's expectations of the treatment. Due to space limitations, the full survey is presented in the Detailed Description.

Original Secondary Outcome Measures (submitted: March 13, 2008)

• To determine if the 60% cutoff for the genomic profiles is optimal in predicting the response to chemotherapy regimens. [ Time Frame: 10 years ]
• Describe the performance of the genomic profiles in assessing the relative responsiveness of patients predicted to be resistant to both chemotherapy regimens and patients randomly assigned to one treatment whose genomic profiles suggests other regimen [ Time Frame: 10 years ]
• To compare genomically-guided and non-genomically guided treatment assignments relative to the rates of improvement in surgical outcome as defined elsewhere. [ Time Frame: 10 years ]
• To correlate genomic profiles with clinical response, disease-free survival, sites of recurrence, and overall survival. [ Time Frame: 10 years ]
• To develop a specimen repository with clinical annotation from the study participants. [ Time Frame: 10 years ]
• To assess the economic impact of using genomic assessment to guide management. [ Time Frame: 5 years ]
• To assess patient perceptions of participating in a clinical trial evaluating cancer genomics for PST of early-stage breast cancer. [ Time Frame: 5 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Trial to Evaluate Genomic Expression Profiles to Direct Preoperative Chemotherapy in Early Stage Breast Cancer
• Official Title: A Randomized Phase II Trial Evaluating the Performance of Genomic Expression Profiles to Direct the Use of Preoperative Chemotherapy for Early Stage Breast Cancer
• Brief Summary: This multi-center randomized Phase II study assigned HER2-negative early-stage breast cancer patients to receive preoperative systemic chemotherapy in either a "genomic-guided" arm or a "non-guided arm." The "genomic-guided" method (Arm 1) used genomic expression profiling to assign the preoperative therapy (Doxorubicin/Cyclophosphamide (AC) versus Docetaxel/Cyclophosphamide (TC), while Arm 2 used random assignment to these two therapies.

Detailed Description

Primary Objective 1 was to test for an arm difference in pathological complete response rates. Secondary Objective 2 was to estimate and test the difference in pathologic complete response rates between drug-sensitive patients who received their preferred drug and drug-resistant patients randomized to AC or TC.

Secondary objectives included: to determine the 60% cutoff for the genomic profiles resulted in a larger pathologic CR rate for the guided arm than for the unguided arm; to compare the pathologic CR rates of patients whose genomic predictive probabilities indicated that they were resistant to both chemotherapy regimens with the pathologic CR rates of patients whose genomic predictive probabilities indicated that they were sensitive to only one treatment and who were then randomly assigned to a treatment for which they were resistant (combining AC and TC subgroups); Secondary Objective 3 in patients with T2 and T3 tumors classified as requiring mastectomy at baseline, compare the guided and non-guided treatment arms on rates of breast conserving surgery with negative final margins; Secondary Objective in patients with T2 tumors classified as potential candidates for breast conservation, compare the guided and non-guided arms on rates of breast conserving surgery at first attempt; Secondary Objectives 5, 6, 7 and 8 to correlate genomic profiles (i.e., genomic predictive probabilities) with clinical response, disease-free survival, sites of recurrence, and overall survival; Secondary Objective 9:to compare the mean cost of guided versus non-guided treatment; and Secondary Objective 10 to assess patient perceptions of participating in a clinical trial that evaluated cancer genomics for preoperative systemic therapy of early-stage breast cancer.

Objective 10 details: Due to space limitations in the Outcome Measure Description field, details are supplied here:

To assess patient motivation and participation for study participation in a clinical trial evaluating cancer genomics for treatment patients provided responses for the following questions at both baseline (the day of chemotherapy start) and following post-surgical medical oncology evaluation:

One of the goals of this study is to tailor your cancer treatments for you based upon a genomic analysis of your tumor. How much did the knowledge that the treatment is potentially tailored specifically for your tumor influence your decision to participate in this study? (Select One)

Response 1: I did not know that the treatment was tailored.

Response 2: I do not understand what "tailored treatment based upon genomic analysis of "my tumor" means.

Response 3: The information that this was a tailored treatment based upon genomic analysis of my tumor decreased my willingness to participate in this study.

Response 4: The information that this was a tailored treatment based upon genomic analysis of my tumor was of neutral value in the decision making process to participate in this study and did not influence my decision to participate.

Response 5: The information that this was a tailored treatment based upon genomic analysis of my tumor played a minor role in helping me decide to participate in the study.

Response 6: The information that this was a tailored treatment based upon genomic analysis of my tumor played a major role in helping me decide to participate in the study.

Response 7: The information that this was a tailored treatment based upon genomic analysis of my tumor was the primary reason that I decided to participate in the study.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Early-Stage Breast Cancer

Intervention

Drug: Doxorubicin/Cyclophosphamide (AC) or Docetaxel/Cyclophosphamide (TC)

Doxorubicin 60 mg/m² and Cyclophosphamide 600 mg/m² (AC) or Docetaxel 75 mg/m² and Cyclophosphamide 600 mg/m² (TC) every 3 weeks for 4 cycles as neoadjuvant therapy

Other Names:

• Adriamycin (Doxorubicin)
• Rubex (Doxorubicin)
• Taxotere (Docetaxel)
• Cytoxan (Cyclophosphamide)

Study Arms

• Active Comparator: Guided Arm

  Genomically-guided treatment allocation.

  This arm has the following cohorts:

  • AC sensitive patients [>60% probability of response to AC]
  • TC sensitive patients [>60% probability of response to TC]
  • Patients sensitive to neither AC nor TC; randomized to AC or TC
  Intervention: Drug: Doxorubicin/Cyclophosphamide (AC) or Docetaxel/Cyclophosphamide (TC)
• Active Comparator: Non-Guided Arm

  Non-genomically-guided treatment allocation.

  This arm has the following cohorts:

  • In patients randomly assigned to AC:

    • Patients sensitive to AC
    • Patients sensitive to TC
    • Patients sensitive to neither AC nor TC

  • In patients randomly assigned to TC:

    • Patients sensitive to AC
    • Patients sensitive to TC
    • Patients sensitive to neither AC nor TC
  Intervention: Drug: Doxorubicin/Cyclophosphamide (AC) or Docetaxel/Cyclophosphamide (TC)

Publications *

Potti A, Dressman HK, Bild A, Riedel RF, Chan G, Sayer R, Cragun J, Cottrill H, Kelley MJ, Petersen R, Harpole D, Marks J, Berchuck A, Ginsburg GS, Febbo P, Lancaster J, Nevins JR. Genomic signatures to guide the use of chemotherapeutics. Nat Med. 2006 Nov;12(11):1294-300. Epub 2006 Oct 22. Erratum in: Nat Med. 2007 Nov;13(11):1388. Nat Med. 2008 Aug;14(8):889. Retraction in: Potti A, Dressman HK, Bild A, Riedel RF, Chan G, Sayer R, Cragun J, Cottrill H, Kelley MJ, Petersen R, Harpole D, Marks J, Berchuck A, Ginsburg GS, Febbo P, Lancaster J, Nevins JR. Nat Med. 2011 Jan;17(1):135.

Retraction in:Potti A, Dressman HK, Bild A, Riedel RF, Chan G, Sayer R, Cragun J, Cottrill H, Kelley MJ, Petersen R, Harpole D, Marks J, Berchuck A, Ginsburg GS, Febbo P, Lancaster J, Nevins JR. Nat Med. 2011 Jan;17(1):135

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: October 6, 2014): 56
• Original Estimated Enrollment (submitted: March 13, 2008): 270
• Actual Study Completion Date: April 2013
• Actual Primary Completion Date: April 2013 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Histologic Documentation: Patients must have a histologic (i.e., not just cytologic) diagnosis of invasive breast cancer by core biopsy. Excisional biopsy or incisional biopsy is not allowed. All breast cancer histologic types are allowed.
2. Stage: Any patient with a clinical T1c (>1.5 cm) to T3 invasive breast cancer by the revised TNM staging system (AJCC 6th edition) will be eligible. Any N stage disease is allowed. No distant metastases allowed.
3. Tumor Site: Patients must have invasive cancer in the breast. Multifocal disease (i.e. confined to a single quadrant in the same breast) is allowed. Multicentric disease (i.e. disease in multiple breast quadrants) is not allowed. Determination of multifocal and multicentric disease status will be made by the evaluating surgeon; ambiguous cases will be reviewed by the principal investigator. Patients with synchronous contralateral invasive breast cancers are not eligible; prior contralateral breast cancer allowed as long as patient has not received prior chemotherapy or radiation therapy in the past 5 years.
4. Measurable Disease: Patients must have measurable disease in the breast by imaging studies (mammogram, ultrasound, or MRI), and must be greater than 1.5 cm in at least one dimension by one or more of the imaging assessments.
5. Conventional Biomarker Status: Standard clinical biomarkers for ER, PR, and HER2 must be obtained on the initial diagnostic core biopsy. The invasive cancer must be HER2 negative (i.e. immunohistochemistry score 1-2+ and/or FISH non-amplified). Any ER/PR status is allowed. Patients who are HER2 2+ on initial immunohistochemistry assessment will be further assessed by FISH. In this instance, patient will be consented and further screened for eligibility and have tissue acquired for genomic profiling. If the standard of care additional FISH testing is positive for HER2 gene amplification, the patient will not be randomized and will be treated in the same manner as screen failures.
6. Must be deemed a surgical candidate.
7. Fresh tissue biopsy material must be available for genomics analysis.
8. No prior chemotherapy, radiotherapy, or biologic/targeted therapy for the currently diagnosed breast cancer, or any other malignancy in the past 5 years, is allowed. No prior anthracycline or taxane therapy.
9. Prior malignancies are allowed if the patient is considered to be disease-free for 5 or more years and is deemed to be at low risk for recurrence. Patients with any prior diagnosis of in situ malignancies (melanoma, bladder, colon, cervical, basal cell, or squamous carcinoma) are eligible regardless of time from diagnosis.
10. Aged at least 18 years.
11. ECOG Performance Status 0-1.

12. Adequate Organ Function:

    1. Total bilirubin ≤1.0 x the institutional ULN
    2. Hepatic enzymes (AST (SGOT), ALT (SGPT)) ≤1.5x the institutional ULN
    3. Alkaline Phosphatase ≤2.5 x ULN
    4. Serum creatinine ≤2.0 mg/dl
    5. Neutrophil count (ANC or AGC) ≥1000/ μL
    6. Platelets ≥100,000/ μL
    7. Cardiac Ejection Fraction ≥50% by MUGA, Echo or MRI.
13. Significant cardiac disease that would preclude the use of anthracyclines: No myocardial infarction in the last 6 months; history of congestive heart failure, serious cardiac arrhythmia requiring medication, active coronary artery disease/angina pectoris requiring therapy, uncontrolled hypertension defined as BP >150/90 despite medication; any other unstable cardiac condition as perceived by treating physician or study PI.
14. No other serious medical or psychiatric illness.
15. Pregnancy: Patients may not be pregnant or nursing at the time of enrollment and other restrictions apply.
16. Signed written informed consent including HIPAA.

Exclusion Criteria:

1. Patients who have received investigational drugs within 4 weeks prior to starting study drug and/or who have not recovered from side effects of such therapy are not eligible.

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00636441
• Other Study ID Numbers: Pro00001345; W81XWH-07-1-0394; BC060228-W81XWH-07-1-0394
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Duke University
• Study Sponsor: Duke University
• Collaborators: United States Department of Defense

Investigators

• Principal Investigator: Paul K Marcom, MD; Duke Cancer Institute

• PRS Account: Duke University
• Verification Date: October 2014