I-SPY TRIAL: Neoadjuvant and Personalized Adaptive Novel Agents to Treat Breast Cancer

Official title

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

Overview

The purpose of this study is to further advance the ability to practice personalized medicine by learning which new drug agents are most effective with which types of breast cancer tumors and by learning more about which early indicators of response (tumor analysis prior to surgery via magnetic resonance imaging (MRI) images along with tissue and blood samples) are predictors of treatment success.

Detailed description

I-SPY2 will assess the efficacy of novel drugs in sequence with standard chemotherapy. The goal is identify treatment strategies for subsets on the basis of molecular characteristics (biomarker signatures) of their disease with high estimated pCR rate. As described for previous adaptive trials, novel regimens with sufficiently high activities alone and contribute to treatment strategies that show a high Bayesian predictive probability of being more effective than the dynamic control will graduate from the trial with their corresponding biomarker signature(s). Treatment strategies will be dropped if they show a low probability of improved efficacy with any biomarker signature. New drugs will enter as those that have undergone testing complete their evaluation.

Interventions

• Drug Standard Therapy
  Paclitaxel: 80 mg/m2 IV during the 12 weekly treatment cycles post randomization; Doxorubicin: 60 mg/m2 IV after completion of the 12 weekly treatment cycles and prior to surgery for weeks 13-16; Cyclophosphamide: 600 mg/m2 IV after completion of the 12 weekly treatment cycles and prior to surgery for weeks 13-16
• Drug AMG 386 with or without Trastuzumab
  Arm is closed.
• Drug AMG 479 (Ganitumab) plus Metformin
  Arm is closed.
• Drug MK-2206 with or without Trastuzumab
  Arm is closed.
• Drug AMG 386 and Trastuzumab
  Arm is closed.
• Drug T-DM1 and Pertuzumab
  Arm is closed.
• Drug Pertuzumab and Trastuzumab
  Arm is closed for Accrual. Pertuzumab: 840 mg IV (loading dose) week 1 and 420 mg every 3 weeks (weeks 4, 7, 10) post-randomization; Trastuzumab: 4 mg/kg (loading dose) week 1 and 2 mg/kg weekly (weeks 2-12) post-randomization
• Drug Ganetespib
  Arm is closed.
• Drug ABT-888
  Arm is closed.
• Drug Neratinib
  Arm is closed.

Primary outcome measures

• Determine whether adding experimental agents to standard neoadjuvant medications increases the probability of pathologic complete response (pCR) over standard neoadjuvant chemotherapy for each biomarker signature established at trial entry. [Time frame: Post surgery based on upto 36-week treatment]

Secondary outcome measures (4)

• Establishing predictive and prognostic indices based on qualification and exploratory markers to predict pCR and residual cancer burden (RCB). [Time frame: Blood and Tissue Collection: Baseline, Post-Randomization, Pre-AC, Pre- and Post-Surgery]
• To determine three- and five-year relapse-free survival (RFS) and OS among the treatment arms. [Time frame: Three- and Five-Year Post-surgery Follow-up]
• To determine incidence of adverse events (AEs), serious adverse events (SAEs), and laboratory abnormalities of each investigational agent tested. [Time frame: Post-Randomization, Pre-AC, Pre-Surgery, Post-Surgery upto One Year during follow-up]
• MRI Volume [Time frame: Four time points during the on-study phase: Baseline, Post-randomization, Pre-AC treatment and Pre-Surgery]

Eligibility criteria

Inclusion criteria

• Histologically confirmed invasive cancer of the breast
• Clinically or radiologically measureable disease in the breast after diagnostic biopsy, defined as longest diameter greater than or equal to 25 mm (2.5cm)
• 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. Prior bis-phosphonate therapy is allowed
• Age ≥18 years
• ECOG performance status 0-1
• Willing to undergo core biopsy of the primary breast lesion to assess baseline biomarkers
• Non-pregnant and non-lactating
• No ferromagnetic prostheses. Patients who have metallic surgical implants that are not compatible with an MRI machine are not eligible.
• Ability to understand and willingness to sign a written informed consent (I-SPY TRIAL Screening Consent)
• Eligible tumors must meet one of the following criteria: Stage II or III, or T4, any N, M0, including clinical or pathologic inflammatory cancer or Regional Stage IV, where supraclavicular lymph nodes are the only sites metastasis
• 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 protocol section 4.1.2F
• Normal organ and marrow function: Leukocytes ≥ 3000/μL, Absolute neutrophil count ≥ 1500/μL, Platelets ≥ 100,000/μL, Total bilirubin within normal institutional limits, unless patient has Gilbert's disease, for which bilirubin must be ≤ 2.0 x ULN, AST(SGOT)/ALT (SGPT) ≤ 1.5 x institutional ULN, creatinine < 1.5 x institutional ULN
• No uncontrolled or severe cardiac disease. Baseline ejection fraction (by nuclear imaging or echocardiography) must by ≥ 50%
• No clinical or imaging evidence of distant metastases by PA and Lateral CXR, Radionuclide Bone scan, and LFTs including total bilirubin, ALT, AST, and alkaline phosphatase
• Tumor assay profile must include on of the following: MammaPrint High, any ER status, any HER2 status, or MammaPrint Low, ER negative (<5%), any HER2 status, or MammaPrint Low, ER positive, HER2/neu positive by any one of the three methods used (IHC, FISH, TargetPrint™)
• Ability to understand and willingness to sign a written informed consent document (I-SPY 2 TRIAL Consent #2)

Exclusion criteria

• Use of any other investigational agents within 30 days of starting study treatment
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to the study agent or accompanying supportive medications.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 42 centers

• University of Alabama at Birmingham — Birmingham
• Mayo Clinic - Scottsdale — Scottsdale
• University of Arizona — Tucson
• University of California - Davis, Comprehensive Cancer Center — Davis
• City of Hope — Duarte
• University of California San Diego — La Jolla
• University of Southern California — Los Angeles
• HOAG Memorial Hospital Presbyterian — Newport Beach
• … and 34 more centers

Publications

• Barker AD, Sigman CC, Kelloff GJ, Hylton NM, Berry DA, Esserman LJ. I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy. Clin Pharmacol Ther. 2009 Jul;86(1):97-100. doi: 10.1038/clpt.2009.68. Epub 2009 May 13. PMID 19440188
• Esserman LJ, Woodcock J. Accelerating identification and regulatory approval of investigational cancer drugs. JAMA. 2011 Dec 21;306(23):2608-9. doi: 10.1001/jama.2011.1837. No abstract available. PMID 22187281
• Esserman LJ, Berry DA, DeMichele A, Carey L, Davis SE, Buxton M, Hudis C, Gray JW, Perou C, Yau C, Livasy C, Krontiras H, Montgomery L, Tripathy D, Lehman C, Liu MC, Olopade OI, Rugo HS, Carpenter JT, Dressler L, Chhieng D, Singh B, Mies C, Rabban J, Chen YY, Giri D, van 't Veer L, Hylton N. Pathologic complete response predicts recurrence-free survival more effectively by cancer subset: results f PMID 22649152
• Hylton NM, Blume JD, Bernreuter WK, Pisano ED, Rosen MA, Morris EA, Weatherall PT, Lehman CD, Newstead GM, Polin S, Marques HS, Esserman LJ, Schnall MD; ACRIN 6657 Trial Team and I-SPY 1 TRIAL Investigators. Locally advanced breast cancer: MR imaging for prediction of response to neoadjuvant chemotherapy--results from ACRIN 6657/I-SPY TRIAL. Radiology. 2012 Jun;263(3):663-72. doi: 10.1148/radiol.1 PMID 22623692
• Lin C, Buxton MB, Moore D, Krontiras H, Carey L, DeMichele A, Montgomery L, Tripathy D, Lehman C, Liu M, Olapade O, Yau C, Berry D, Esserman LJ; I-SPY TRIAL Investigators. Locally advanced breast cancers are more likely to present as Interval Cancers: results from the I-SPY 1 TRIAL (CALGB 150007/150012, ACRIN 6657, InterSPORE Trial). Breast Cancer Res Treat. 2012 Apr;132(3):871-9. doi: 10.1007/s10 PMID 21796368
• Esserman LJ, Berry DA, Cheang MC, Yau C, Perou CM, Carey L, DeMichele A, Gray JW, Conway-Dorsey K, Lenburg ME, Buxton MB, Davis SE, van't Veer LJ, Hudis C, Chin K, Wolf D, Krontiras H, Montgomery L, Tripathy D, Lehman C, Liu MC, Olopade OI, Rugo HS, Carpenter JT, Livasy C, Dressler L, Chhieng D, Singh B, Mies C, Rabban J, Chen YY, Giri D, Au A, Hylton N; I-SPY 1 TRIAL Investigators. Chemotherapy r PMID 22198468
• Tseng J, Dimitroff K, Sauder CAM, Chien AJ, Ahmed KA, Allen LF, Arciero CA, Burke EE, Chandler JM, Jordan JE, Golshan M, Gutnik LA, Jaskowiak NT, Hewitt KC, Howard-McNatt M, Ito F, Kang IM, Kesmodel SB, Kuerer HM, Lee MC, Moran MC, Postlewait LM, Prionas ND, Rao R, Reyna CR, Schwer A, Taunk NK, Tchou J, Wallace AM, Li TJ, Perlmutter J, DeMichele AM, Yee D, Hylton NM, Veer LJV, Rugo HS, Symmans WF, PMID 42545411
• Isaacs C, Nanda R, Yau C, Chien AJ, Hershman DL, Stringer-Reasor EM, Wallace AM, Thomas A, Vaklavas C, Clark AS, Kennedy LC, Sanford A, Boughey JC, Albain KS, Pusztai L, Kalinsky KM, Beckwith H, Williams NO, Han HS, Falkson C, Arora M, Elias AD, Pohlmann PR, Rozenblit M, Marshall N, Chen YY, Trivedi MS, McGuinness JE, Howard FM, Chen N, Khoury K, Lancaster RB, Yeung KT, Douglas E, Wei M, Mainor C, PMID 42530945

Identifiers

NCT: NCT01042379 · 097517

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗