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


i-SPY 2 TRiaL is a neoadjuvant trial making use of adaptive design to identify successful treatment regimens for Stage ii/iii breast cancer. Patients will also undergo a pretreatment MRi for determination of maximum tumor dimension. experimental agents will be given in 12 weekly intervals or at other intervals over a 12-week period. after a patient completes three weekly cycles of paclitaxel, she will undergo a repeat MRi, core biopsy of the tumor, and blood draw. She will continue treatment for nine more weekly cycles (or nine weeks for a total of 12), and undergo a third MRi and blood draw. She will then receive four cycles of doxorubicin and cyclophosphamide at three-week intervals prior to surgery. The patient will have an MRi and blood draw prior to surgery and tumor tissue will be collected at surgery.
Peripheral blood samples will be collected pre-treatment, early in paclitaxel treatment (end of week 3), inter-regimen, and pre-surgery. Tissue samples will be collected from core biopsies done pre-treatment and early in paclitaxel treatment (end of week 3), and surgical tissue will be collected at the time of surgery. These molecular characteristics (biomarkers/pathways) will be used to correlate with pathologic, imaging, or RCB response measures in the neoadjuvant setting with the investigational therapeutic agents. Tissue and blood will be used for exploratory research and to generate molecular data on next-generation technology platforms. Finally, patients will be followed post-surgery for five years.
Drugs will be assigned to all signatures where they might be effective. The control arm will apply to all profiles. Randomization probabilities are determined based on the accumulating data about all agents in the trial. The trial is designed to study over time which profiles predict response to each agent. each agent's probability of being successful in a phase 3 confirmatory trial will be calculated:
* agents will be graduated at an interim point should one or more of these probabilities reach a sufficient level.
* agents will be dropped from the trial for futility when probabilities drop sufficiently low.
* if the maximum sample size of 120 patients assigned to a regimen (over all biomarker types) is reached, assignments to the regimen will end.
if an investigational agent reaches a threshold for graduation, the Data Safety Monitoring Board (DSMB) will review the findings and make a recommendation to Study Principal investigators (Pis) for final approval. if an agent is found not to reach a specified threshold of improvement in response, it may be dropped for futility.
if the maximum sample size of 120 patients is reached and an agent is dropped from the trial, and patients are presently on that agent, the option to continue or drop the agent will be at the discretion of the patient and her treating physician. Patients who do not continue on the agent will continue on-study but will revert to the standard/control regimen; their outcomes will remain part of the arm to which they were randomized.
if an investigational agent is removed from the trial due to serious side effects from the agent, use of that agent for all patients will be stopped. Patients will continue on-study but will revert to the standard/control regimen and their outcomes will remain part of the arm to which they were randomized.
Trial data will also be used to test, qualify, and validate biomarkers as predictors of response to specific therapeutic agents. This trial is an opportunity to integrate information from emerging biomarkers and thereby accelerate identification of optimal therapies for women at highest risk of progression.
Randomization will be adaptive to maximize information about better-performing therapies and minimize the time it takes to identify optimal biomarker profiles. using MRi results as a biomarker during various stages of treatment, our design will build a longitudinal model of tumor response.

Participant Eligibility

Eligibility Criteria for Initial Screening Phase of I-SPY 2 TRIAL
1. Histologically confirmed invasive cancer of the breast. Histologic confirmation can be obtained by fine-needle aspiration (FNA), core needle biopsy, or excisional biopsy. Metaplastic and inflammatory carcinomas are eligible, and synchronous bilateral primaries are eligible if the more advanced tumor meets staging criteria. Patients who have an FNA for diagnosis must have histological documentation of invasive carcinoma by the start of chemotherapy.
2. Clinically or radiologically measureable disease in the breast after diagnostic biopsy, defined as longest diameter greater than or equal to 25 mm (2.5 cm). Measurable disease is defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as > 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.
3. Prior therapy: No prior cytotoxic regimens are allowed for this malignancy. Patients may not have had prior chemotherapy, other targeted anticancer therapies, or prior radiation therapy to the ipsilateral breast for this malignancy. Prior bis-phosphonate therapy is allowed.
4. Age >= 18 years: Because no dosing or AE data are currently available on use of experimental trial agents for patients < 18 years of age, children are excluded from this study.
5. Performance status: ECOG performance status 0[?]1.
6. Core biopsy: Willing and able to undergo core biopsy of the primary breast lesion to assess baseline biomarkers to determine eligibility for treatment phase of I-SPY 2 TRIAL.
7. Non-pregnant and non-lactating: Effects on a developing human fetus of phase 2 agents under study at the recommended therapeutic dose are unknown. For this reason and because these agents may be teratogenic, women of child-bearing potential must agree to use adequate contraception (double barrier methods of birth control or abstinence) prior to study entry and for the duration of study treatment phase. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately.
If a patient is of child-bearing potential (women are considered not of childbearing potential if they are at least one year postmenopausal and/or surgically sterile), she must have documented negative serum or negative urine pregnancy tests within 14 days of entry to screening phase.
8. No ferromagnetic prostheses: Patients who have metallic surgical implants that are not compatible with an MRI machine are not eligible. Otherwise eligible patients should be asked if they have any heart valves, aneurysm clips, orthopedic prosthesis, or any metallic fragments anywhere in their body prior to enrolling in the study.
9. Ability to understand and willingness to sign a written informed consent document (I-SPY 2 TRIAL Screening Consent).
10. Female patients of all ethnic and racial groups.

Criteria for Inclusion of Subjects for Treatment Phase of I-SPY 2 TRIAL:
Patients successfully enrolled on the screening phase of I-SPY 2 TRIAL will be evaluated for eligibility for the treatment phase of I-SPY 2 based on the results of several tumor biomarker assays. In addition to the eligibility criteria outlined in section 4.2 of the protocol, patients who have completed the Initial Screening phase must meet the following eligibility criteria:

1. Eligible breast tumors must also meet one of the following criteria:

* Stage II or III

* T4, any N, M0, including clinical or pathologic inflammatory cancer

* Regional Stage IV, where supraclavicular lymph nodes are the only sites of metastasis.
2. Breast Hormone status: Any tumor ER/PgR status, any HER-2/neu status as measured by local hospital pathology laboratory and meets any tumor assay profile described in 4.1.2 F of the protocol.
3. Normal organ and marrow function as defined below (test results can be used if done within 30 days of entry to screening phase):

* Leukocytes >= 3000/[MICRO-SYMBOL]L

* Absolute neutrophil count >=1500/[MICRO-SYMBOL]L

* Platelets >=100,000/[MICRO-SYMBOL]L

* Total bilirubin within normal institutional limits, unless patient has Gilbert[?]s disease, for which bilirubin must be <= 2.0 x ULN

* Aspartate aminotransferase (AST) (SGOT)/alanine transaminase (ALT) (SGPT) <= 1.5 x institutional ULN

* Creatinine < 1.5 x institutional ULN

* For agent-specific inclusion criteria, refer to the appendices
4. No uncontrolled or severe cardiac disease. [history of diagnosis of unstable angina, myocardial infarction, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia (including atrial flutter/fibrillation), requirement for inotropic support or use of devices for cardiac conditions (pacemaker/defibrillators)]. Baseline ejection fraction (by nuclear imaging or echocardiography) must be >=50%.
5. No clinical or imaging evidence of distant metastases by CT with or without PET, PA and lateral CXR, radionuclide bone scan, and/or LFTs including total bilirubin, ALT, AST within ranges defined in section 4.1.2 C of the protocol.
6. Breast Tumor assay profile must include one of the following:

* MammaPrint High, any ER status, any HER2 status

* MammaPrint Low, ERx (< 5%), any HER2 status

* MammaPrint Low, ER+, HER2/neu positive by any one of the three methods used (IHC, FISH, TargetPrint). See Section 3, Table of Eligibility in the protocol.
7. Ability to understand and willingness to sign a written informed consent document (I-SPY 2 TRIAL Treatment Consent)
8. HgbA1c less than or equal to 8%. Patients with diabetes who meet the HbgA1C criteria are eligible. Patients currently on metformin or another oral hypglycemic drug as their medication to manage their insulin resistance are eligible and should stay on their current medication. Insulin-dependent diabetics are eligible for study participation.
8. See drug-specific appendices for additional criteria, as applicable.