DCP CHEMOPREVENTION PROTOCOL TEMPLATE



COVER PAGE

Protocol #: This number will be assigned by UCSF IRB.

Local Protocol #: Insert your local protocol # for this study. If a local protocol number has not been assigned, indicate ‘pending’. DEFINITION: The local protocol number is assigned by the participating organization according to local institutional conventions.

Protocol Title: I-SPY 2 TRIAL (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis 2)

Organization Name: University of California, San Francisco

Protocol Principal

Investigator: Laura Esserman, MD, MBA

Dept of Surgery M2 Box 1610

San Francisco, CA 94143

Tel: (415) 885-7691 Fax: (415) 353-9571

laura.esserman@

Organization: Organization name (TBA following completion of sites selection)

Co-Investigator(s): Co-Investigator’s Name

Investigator’s Specialty

Address

Address

Telephone

Fax

E-mail address

Organization: University of Texas, MDACC

Statistician: Donald Berry, PhD

1515 Holcombe Ave

Houston, TX 77030-4009

Tel: (713) 745-5509 Fax: (713)792-4252

dberry@

NOTE: If this is a multi-institution study:

1. The protocol title page(s) must include the name and address of each participating institution and any affiliates participating in the study.

2. The protocol title page(s) must include the names of all investigators at each institution; his/her telephone, Fax, and e-mail address.

3. Indicate the protocol lead investigator responsible for the study at each institution; his/her telephone, Fax, and e-mail address.

IND Sponsor: FNIH

9650 Rockville Pike, Bethesda MD 20814-3999

(301) 402-5311

IND# ____ 105,139__________________

Agent(s)/Supplier: Study Agent(s)/Supplier Name

Protocol Version Date: _____ 07/31/09 _____

Protocol Revision or

Amendment # None, Original Protocol

SCHEMA

I-SPY 2 TRIAL (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis 2)

[pic]

I-SPY 2 Adaptive TRIAL Schema: Screening Eligibility & Randomization

[pic]

I-SPY 2 TRIAL, Adaptive Overall Study Schema

[pic]

Schedule of Study Procedures

|Pre-Treatment |Early Paclitaxel |Inter-Regimen |Pre- Surgery/ Surgery |

| | | |(Time Point 4) |

|(Time Point 1) |(Time Point 2) |(Time Point 3) | |

|MRI |MRI |MRI |MRI |

|(prior to randomization) |(end of wk 3, prior to cycle |(prior to AC, at least 1 wk |(prior to Surgery, at least 2-3 |

| |4) |after last paclitaxel,) |wks after AC) |

|Core Biopsy |Core Biopsy | |Surgical Tissue |

|(prior to randomization) |(end of wk 3, prior to cycle |---- ---- ---- |(at time of Surgery) |

| |4) | | |

|Blood Draw |Blood Draw |Blood Draw |Blood Draw |

|(prior to randomization) |(end of wk 3, prior to cycle |(prior to AC, at least 1 wk |(prior to Surgery, at least 2-3 |

| |4) |after last paclitaxel,) |wks after AC) |

TABLE OF CONTENTS

COVER PAGE i

SCHEMA iii

TABLE OF CONTENTS v

LIST OF ABBREVIATIONS viiviii

1. OBJECTIVES 1

1.1 Primary Objective 1

1.2 Secondary Objectives 1

1.2.1 Predictive and Prognostic Indices 1

1.2.2 Biological Specimen Resource and Imaging Data Base 1

1.2.3 Relapse-Free Survival 1

2. BACKGROUND 1

2.1 Breast Cancer 1

2.1.1 Neoadjuvant Therapy for Breast Cancer 2

2.2. The I-SPY TRIAL 4

2.2.1. Results 4

2.3 Rationale: Neoadjuvant Adaptive Design Approach 9

2.4 Study Agent Rationale 11

2.4.1 Drug Selection 11

2.4.2 Designation of Tier 1 versus Tier 2 Agents for the I-SPY 2 TRIAL Process 12

2.4.3 Plan to incorporate Biomarkers (Additional Detail in Section 7) 12

2.4.4 Proposed I-SPY 2 Investigational Tier 1 Agents 12

2.5 General Approach in Evaluating Drug(s) 13

3. SUMMARY OF STUDY PLAN 14

4. PARTICIPANT SELECTION 17

4.1 Inclusion Criteria Overview 17

4.1.1. Eligibility Criteria for Initial Screening Phase of I-SPY 2 TRIAL 18

4.1.2 Inclusion Criteria for Treatment Phase of I-SPY 2 TRIAL 19

4.2 Exclusion Criteria 20

4.3 Inclusion of Women and Minorities 20

4.4 Recruitment and Retention Plan 20

5. AGENT ADMINISTRATION (See Appendices A−E) 21

6. PHARMACEUTICAL INFORMATION (See Appendices A−E) 21

7. BIOMARKERS FOR ELIGIBILITY, STRATIFICATION AND RESPONSE MONITORING 21

7.1 Tissue and Blood Specimens for Biomarker Assessment 21

7.2 Incorporation of Established Biomarkers 22

7.3 Incorporation of Qualifying Biomarkers 22

7.4 Incorporation of Exploratory Biomarkers 24

7.5 Repository for Storing, Analyzing, and Comparing Assay Results 24

8. CLINICAL EVALUATIONS AND PROCEDURES 25

8.1 Schedule of Events 25

8.2 Baseline Testing/Pre-Treatment Evaluation 25

8.3 Evaluations During Neoadjuvant Chemotherapy Treatment 26

8.4 Evaluations at Completion of Neoadjuvant Chemotherapy Treatment 26

8.5 Post Surgery Follow-up 26

9. CRITERIA FOR EVALUATION AND ENDPOINT DEFINITION 27

9.1 Primary Endpoint 27

9.2 Secondary Endpoints 27

9.3 Off-Agent Criteria 28

9.4 Off-Study Criteria 28

9.5 Study Termination 28

10. SPECIMEN MANAGEMENT 28

10.1 Central Laboratories 29

10.2 Specimen Collection, Handling, and Shipping Procedures 29

10.3 Ancillary Laboratories 30

10.3.1 Agendia 30

10.3.2 Theranostics Health 30

10.3.3 UCSF CLIA Laboratory 31

10.3.4 UCSF CLIA GWAS 31

10.3.5 Additional Samples 31

11. REPORTING ADVERSE EVENTS 31

11.1 Adverse Events 31

11.1.1 Reportable AEs 31

11.1.2 AE Data Elements 32

11.1.3 Severity of AEs 32

11.1.4 Assessment of relationship of AE to treatment 33

11.1.5 Follow-up of AEs 33

11.2 Serious Adverse Events 34

11.2.1 SAE Definition 34

11.2.2 Reporting Serious Adverse Events to FNIH 34

12. STUDY OVERSIGHT AND MONITORING 35

12.1 Data Management 36

12.2 Case Report Forms 37

12.3 Source Documents 38

12.4 Data and Safety Monitoring Plan 38

12.5 FNIH or FDA Monitoring 39

12.7 Clinical Trials Agreement 39

13. I-SPY 2 STATISTICAL CONSIDERATIONS 39

13.1 Trial Design Overview/Endpoints 39

13.2 Sample Size/Accrual Rate 40

13.3 Randomization and Stratification Using Biomarker Signatures 40

13. 4 Primary Endpoint and Probability of Success by Biomarker Signature 42

13.5 Design Algorithm Overview 43

13.6 Assessing Operating Characteristics of the Design via Simulation 44

14. ETHICAL AND REGULATORY CONSIDERATIONS 57

14.1 Form FDA 1572 57

14.2 Other Required Documents 58

14.3 IRB Approval 58

14.4 Informed Consent 58

14.5 Submission of Regulatory Documents 59

14.6 Other 59

15. FINANCING, EXPENSES, AND/OR INSURANCE 59

REFERENCES 60

Informed Consent Template and Instructions 63

LIST OF ABBREVIATIONS

AC Doxorubicin /cyclophosphamide

ACRIN American College of Radiology Imaging Network

AE Adverse event

caBIG cancer Biomedical Informatics Grid

CALGB Cancer and Leukemia Group B

CBIIT Center for Biomedical Informatics and Information Technology

CDE Common Data Element

cCR Clinical complete response

cDNA complementary DNA

CGH comparative genomic hybridization

CI Confidence interval

CLIA Clinical Laboratory Improvement Amendment

CRADA Cooperative Research and Development Agreement

CRF Case report form

CT Computed tomography

CTA Clinical Trials Agreement

DCC Data Coordinating Center

DFS Disease-free survival

DSMB Data Safety Monitoring Board

E Experimental Agent

EBCTCG Early Breast Cancer Trialists Collaborative Group

ECOG Eastern Cooperative Oncology Group

ER Estrogen receptor

FDA Food and Drug Administration

FISH Fluorescence in situ hybridization

FNA Fine-needle aspiration

FNIH Foundation for the National Institutes of Health

GWAS Genome-wide association study

HIPAA Health Insurance Portability and Accountability Act

HER2 Human epidermal growth factor receptor

HR Hormone receptor (ER + PgR)

IDE Investigational Device Exemption

IGF Insulin-like growth factor

IGFR Insulin-like growth factor receptor

IHC Immunohistochemistry

IL Interleukin

IND Investigational New Drug

IRB Institutional Review Board

I-SPY TRIAL Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis

FISH Fluorescence in-situ hybridization

LABC Locally advanced breast cancer

MP MammaPrint

MR Magnetic resonance

MRI Magnetic resonance imaging

MUGA Multi Gated Acquisition Scan

NCI National Cancer Institute

NDA New Drug Application

NIH National Institutes of Health

NKI 70 Netherlands Cancer Institute 70-gene signature

NSABP National Surgical Adjuvant Breast and Bowel Project

OHRP Office of Human Research Protections

OIVD Office of In Vitro Diagnostics

OS Overall survival

pCR Pathologic complete response

PgR Progesterone receptor

PE Percent enhancement

PET Positron emission tomography

PgR Progesterone receptor

pHER2 Phosphorylated HER2

PI3K Phosphatidylinositol-3-kinase

RCB Residual cancer burden

RFS Relapse free survival

RPMA Reverse phase protein microarray

ROR Risk of recurrence

ROR-S Retinoid-related orphan receptors

SAE Serious adverse event

SER Signal enhancement ratio

SNP Single-nucleotide polymorphism

SPORE Specialized Programs of Research Excellence

T4 Tumor growing into the chest wall or skin, including inflammatory bc.

TFAC Paclitaxel (Taxol®), doxorubicin (Adriamycin™) and cyclophosphamide

TRANSCEND TRANslational Informatics System to Coordinate Emerging Biomarkers, Novel Agents and Clinical Data

TP HER2 TargetPrint HER2

UCSC University of California, Santa Cruz

UCSF University of California, San Francisco

1. OBJECTIVES

1.1 Primary Objective

To determine whether adding experimental agents to standard neoadjuvant paclitaxel, doxorubicin, and cyclophosphamide increases the probability of pathologic complete response (pCR) over standard neoadjuvant chemotherapy for each biomarker signature established at trial entry, and to determine for each experimental agent used, the predictive probability of success in a subsequent phase III trial for each possible biomarker signature.

1.2 Secondary Objectives

1.2.1 Predictive and Prognostic Indices

To build predictive and prognostic indices based on qualification and exploratory markers to predict pCR and residual cancer burden (RCB).

1.2.2 Biological Specimen Resource and Imaging Data Base

To initiate the creation of a Biological Specimen Repository , consisting of tumor tissue, RNA, DNA, serum and cells, as well as corresponding magnetic resonance (MR) and pathology images of these specimens for ongoing translational studies in genomics, proteomics, and imaging, for establishing their relationship to overall survival. .

1.2.3 Relapse-Free Survival

To determine three- and five-year relapse-free survival and overall survival among the treatment arms.

2. BACKGROUND

2.1 Breast Cancer

Breast cancer is diagnosed in almost 200,000 women annually in the United States alone, and 45,000 women still die annually of this disease. Although many women now present with Stage I and II mammographically-detected cancers and have excellent outcomes, 10–20 % of newly diagnosed breast cancers present as locally advanced breast cancer (LABC) in which the risk of recurrence and death is significantly higher [1]. The absolute numbers of these cancers has not decreased over time [2] and successful treatment options remain limited. Women with LABC are distinct from those with screen-detected cancers. Up to 26% of LABCs present in women under the age of 40, prior to the age when screening is recommended [3]. In women who are being screened, the majority of women with LABC today (84%) present as “interval” cancers, where a palpable mass develops within one–two years of a normal screening mammogram[3]. Women with LABC represent a disproportionately large fraction of those who die from their disease. Since standard of care for these women increasingly includes neoadjuvant therapy prior to surgical resection, this population and setting represent a unique opportunity to learn how to tailor treatment for high-risk breast cancers.

The last decade of cancer research has shown breast cancer to be a heterogeneous disease, suggesting that directing drugs to molecular pathways that characterize the disease in subsets of patients will improve treatment efficacy. Today, however, new breast cancer drugs are first tested in phase II and III trials in the metastatic setting, followed by randomized phase III registration trials in the adjuvant setting. For the most part, these trials do not consider the specific molecular characteristics of the patient’s disease. Moreover, adjuvant trials require long follow-up and many thousands of patients [4]. This process can typically take 15−20 years before marketing approval is gained for successful drugs, and a substantial investment in time and resources is often put into drugs that ultimately fail. The development and use of biomarkers for early measures of therapeutic response would facilitate the efficient evaluation of new agents in focused early clinical trials [5] and enable the development of more informed, smaller phase III trials. Although the use of biomarkers (molecular profiles, protein pathways, imaging, etc.) holds promise to enable the tailoring of agents to specific patient populations, developing translational approaches in clinical trials to predict drug response presents a major challenge.

2.1.1 Neoadjuvant Therapy for Breast Cancer

Development of multi-agent adjuvant chemotherapy regimens over the last two decades has substantially improved both disease-specific and overall survival (OS) outcomes for women with breast cancer [6]. The most effective adjuvant combination regimens include anthracyclines, such as doxorubicin or epirubicin (topoisomerase II inhibitors), the alkylating agent cyclophosphamide, and taxanes (currently docetaxel or paclitaxel), which are microtubule stabilizers. These different mechanisms of action often produce synergistic tumor shrinkage and avoid the development of resistance to single-agent treatment [7]. In the case of HER2-positive patients, a HER2 targeted monoclonal antibody, trastuzumab, has been shown to significantly improve survival when combined with a taxane-containing regimen [8]. Despite the gains in disease-free (DFS) and overall survival from these combination regimens, especially in hormone receptor (HR) negative patients [6], a substantial fraction of patients still relapse and die of breast cancer.

Although adjuvant therapy remains the mainstay of treatment for breast cancer, neoadjuvant (preoperative) chemotherapy is increasingly being used in women with large or locally advanced breast cancers. Several large trials have assessed the efficacy of neoadjuvant therapy when compared to standard adjuvant chemotherapy. A meta-analysis of 11 neoadjuvant trials was performed by the Early Breast Cancer Trialists Collaborative Group (EBCTCG) [9]. Preliminary results from this meta-analysis were presented at the National Cancer Institute (NCI) neoadjuvant conference. Eleven randomized trials performed between 1981–1993, encompassing 4675 women, were included in the analysis. Preoperative therapy was associated with 18% fewer mastectomies and no significant difference in any breast cancer recurrence, breast cancer mortality or death within 10 years of follow-up.

Two of these large randomized trials were undertaken by the National Surgical Adjuvant Breast and Bowel Project (NSABP) and provide the largest randomized data to date comparing preoperative to standard adjuvant chemotherapy. The NSABP B18 trial randomized 1523 women to either preoperative or postoperative doxorubicin/cyclophosphamide for a total of four cycles [10]. Breast tumor size was reduced in 80% of patients after preoperative therapy; 36% had a clinical complete response (cCR). The absolute pCR rate was 13%. Tumor size and clinical nodal status were independent predictors of cCR. Twenty-six percent of women with a cCR had a pCR. Clinical nodal response occurred in 89% of node-positive patients: 73% had a cCR and 44% of those had a pCR. There was a 37% increase in the incidence of pathologically negative nodes. Before randomization, lumpectomy was proposed for 86% of women with tumors ≤ 2 cm, 70% with tumors 2.1–5.0 cm, and 3% with tumors ≥ 5.1 cm. Clinical tumor size and nodal status influenced the physician's decision. Overall, 12% more lumpectomies were performed in the preoperative therapy group; in women with tumors ≥ 5.1 cm, there was a 175% increase. The NSABP-B27 trial was designed to determine the effects of adding docetaxel to preoperative doxorubicin and cyclophosphamide on breast cancer response rates and OS [11]. Women with operable breast cancer (n = 2411) were randomly assigned to receive preoperative doxorubicin and cyclophosphamide followed by surgery, doxorubicin and cyclophosphamide followed by docetaxel and surgery, or doxorubicin and cyclophosphamide followed by surgery and then docetaxel. Tamoxifen was initiated concurrently with chemotherapy. Median time on study for 2404 patients with follow-up was 77.9 months. Addition of docetaxel to doxorubicin and cyclophosphamide did not significantly impact DFS or OS. There were trends toward improved DFS with addition of docetaxel, which reduced the incidence of local recurrences as first events (p = 0.0034). Preoperative, but not postoperative, docetaxel significantly improved DFS in patients who had a clinical partial response after doxorubicin and cyclophosphamide (hazard ratio = 0.71; 95% confidence interval (CI), 0.55–0.91; p = 0.007). Thus, the primary benefit of neoadjuvant chemotherapy is to downstage tumors, thereby improving optimal surgical resection and increasing the probability of breast conservation [12].

However, an additional important finding in these studies was that the achievement of a pCR (i.e., elimination of tumor in breast and axillary lymph nodes, as assessed at surgery) is a useful surrogate for prognosis in breast cancer patients overall, suggesting that chemotherapy sensitivity, in and of itself, is an independent predictor of DFS and OS. pCR, which occurred in 27% of patients in NSABP B-27, was doubled by addition of preoperative docetaxel, and was a significant predictor of OS regardless of treatment (hazard ratio = 0.33; 95% CI, 0.23–0.47; p  20 mm (2 cm) with conventional techniques (positron emission tomography (PET), computed tomography (CT), MRI, x-ray) or as > 10 mm (1 cm) with spiral CT scan. All tumor measurements must be recorded in metric notation.

Prior therapy: No prior cytotoxic regimens are allowed for this malignancy. Patients may not have had prior chemotherapy or prior radiation therapy to the ipsilateral breast for this malignancy. Bis-phosphonate therapy is allowed.

Age ≥ 18 years: Because no dosing or adverse event (AE) data are currently available on the use of experimental agents in this trial for patients ................
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