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

Sponsor

QuantumLeap Healthcare Collaborative (Other)

Overall Status

Recruiting

CT.gov ID

NCT01042379

Collaborator

(none)

4,000

Enrollment

Locations

Arms

261

Anticipated Duration (Months)

111.1

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Breast Neoplasms Breast Cancer Breast Tumors Angiosarcoma TNBC - Triple-Negative Breast Cancer HER2-positive Breast Cancer HER2-negative Breast Cancer Hormone Receptor Positive Tumor Hormone Receptor Negative Tumor Early-stage Breast Cancer Locally Advanced Breast Cancer	Drug: Standard Therapy Drug: AMG 386 with or without Trastuzumab Drug: AMG 479 (Ganitumab) plus Metformin Drug: MK-2206 with or without Trastuzumab Drug: AMG 386 and Trastuzumab Drug: T-DM1 and Pertuzumab Drug: Pertuzumab and Trastuzumab Drug: Ganetespib Drug: ABT-888 Drug: Neratinib Drug: PLX3397 Drug: Pembrolizumab - 4 cycle Drug: Talazoparib plus Irinotecan Drug: Patritumab and Trastuzumab Drug: Pembrolizumab - 8 cycle Drug: SGN-LIV1A Drug: Durvalumab plus Olaparib Drug: SD-101 + Pembrolizumab Drug: Tucatinib plus trastuzumab and pertuzumab Drug: Cemiplimab Drug: Cemiplimab plus REGN3767 Drug: Trilaciclib with or without trastuzumab + pertuzumab Drug: SYD985 ([vic-]trastuzumab duocarmazine) Drug: Oral Paclitaxel + Encequidar + Dostarlimab (TSR-042) + Carboplatin with or without trastuzumab Drug: Oral Paclitaxel + Encequidar + Dostarlimab (TSR-042) with or without trastuzumab Drug: Amcenestrant Drug: Amcenestrant + Abemaciclib Drug: Amcenestrant + Letrozole	Phase 2

Detailed Description

I-SPY will compare the efficacy of novel drugs in combination with standard chemotherapy with the efficacy of standard therapy alone. The goal is identify improved treatment regimens for subsets on the basis of molecular characteristics (biomarker signatures) of their disease. As described for previous adaptive trials, regimens that show a high Bayesian predictive probability of being more effective than standard therapy will graduate from the trial with their corresponding biomarker signature(s). Regimens 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

4000 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Mar 1, 2010

Anticipated Primary Completion Date :

Dec 1, 2030

Anticipated Study Completion Date :

Dec 1, 2031

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Standard Therapy Paclitaxel, Herceptin followed by Doxorubicin and Cyclophosphamide treatment depending on HR/HER-2 status.	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 Other Names: Paclitaxel (Taxol); Doxorubicin (Adriamycin)
Experimental: AMG 386 with or without Trastuzumab Arm is closed.	Drug: AMG 386 with or without Trastuzumab Arm is closed. Other Names: AMG 386 (Trebananib); (Trastuzumab) Herceptin Drug: AMG 386 and Trastuzumab Arm is closed. Other Names: AMG 386 (Trebananib); Trastuzumab (Herceptin)
Other: AMG 479 plus Metformin Arm is closed.	Drug: AMG 479 (Ganitumab) plus Metformin Arm is closed. Other Names: Ganitumab
Experimental: MK-2206 with or without Trastuzumab Arm is closed.	Drug: MK-2206 with or without Trastuzumab Arm is closed. Other Names: (Trastuzumab) Herceptin
Experimental: T-DM1 and Pertuzumab Arm is closed.	Drug: T-DM1 and Pertuzumab Arm is closed. Other Names: T-DM1 (Trastuzumab emtansine); Pertuzumab (Perjeta)
Active Comparator: Pertuzumab and Trastuzumab Novel Control Investigational Agent	Drug: Pertuzumab and Trastuzumab 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 Other Names: Pertuzumab (Perjeta); Trastuzumab (Herceptin)
Experimental: Ganetespib Arm is closed.	Drug: Ganetespib Arm is closed.
Other: ABT-888 Arm is closed.	Drug: ABT-888 Arm is closed. Other Names: Veliparib
Other: Neratinib Arm is closed.	Drug: Neratinib Arm is closed.
Experimental: PLX3397 Arm is closed.	Drug: PLX3397 Arm is closed.
Experimental: Pembrolizumab 4 cycle Arm is closed.	Drug: Pembrolizumab - 4 cycle Arm is closed.
Experimental: Talazoparib plus Irinotecan Arm is closed.	Drug: Talazoparib plus Irinotecan Arm is closed.
Experimental: Patritumab with or without Trastuzumab Arm is closed.	Drug: Patritumab and Trastuzumab Arm is closed.
Experimental: Pembrolizumab 8 cycle Arm is closed.	Drug: Pembrolizumab - 8 cycle Arm is closed.
Experimental: SGN-LIV1A Arm is closed.	Drug: SGN-LIV1A Arm is closed. SGN-LIV1A: 2.5 mg/kg IV cycles 1,4,7,10 Doxorubicin + Cyclophosphamide: Cycles 13-16
Experimental: Durvalumab plus Olaparib Arm is closed.	Drug: Durvalumab plus Olaparib Arm is closed.
Experimental: SD-101 + Pembrolizumab Arm is closed.	Drug: SD-101 + Pembrolizumab Arm is closed. SD-101: IT injection 2 mg/ml (1 ml for T2 tumors, 2 ml for >T3 tumors) weekly x 4, then every 3 weeks x 2 cycles 1,2,3,4,7,10 Pembrolizumab: 200mg IV cycles 1,4,7,10 Paclitaxel: 80 mg/m2 IV cycles 1-12 Doxorubicin + Cyclophosphamide: Cycles 13-16; Doxorubicin: 60 mg/m2 IV Every 2 or 3 weeks for 4 cycles; Cyclophosphamide: 600 mg/m2 IV Every 2 or 3 weeks for 4 cycles
Experimental: Tucatinib Arm is closed.	Drug: Tucatinib plus trastuzumab and pertuzumab Arm is closed. Tucatinib: 300 mg PO BID 12 weeks CLOSED Tucatinib: 250 mg PO BID 12 weeks CLOSED Tucatinib adaptive: 150mg BID days 1-28, 250mg BID days 29-84 Trastuzumab: 4 mg/kg IV (loading dose) cycle 1; 2 mg/kg (thereafter) cycles 2-12 Pertuzumab: 840 mg IV (loading dose) cycle 1; 420 mg (thereafter) cycles 4, 7 and 10 Paclitaxel: 80 mg/m2 IV cycles 1-12 Doxorubicin + Cyclophosphamide: Cycles 13-16; Doxorubicin: 60 mg/m2 IV Every 2 or 3 weeks for 4 cycles; Cyclophosphamide: 600 mg/m2 IV Every 2 or 3 weeks for 4 cycles
Experimental: Cemiplimab Novel Investigational Agent	Drug: Cemiplimab Cemiplimab: 350 mg q3w X 12 weeks IV cycles 1,4,7,10 Paclitaxel: 80 mg/m2 IV cycles 1-12 Doxorubicin + Cyclophosphamide: Cycles 13-16; Doxorubicin: 60 mg/m2 IV Every 2 or 3 weeks for 4 cycles; Cyclophosphamide: 600 mg/m2 IV Every 2 or 3 weeks for 4 cycles
Experimental: Cemiplimab plus REGN3767 Novel Investigational Agent	Drug: Cemiplimab plus REGN3767 Cemiplimab: 350 mg q3w X 12 weeks IV cycles 1,4,7,10 REGN 3767: 1600 mg q3W X 12 weeks IV cycles 1,4,7,10 Paclitaxel: 80 mg/m2 IV cycles 1-12 Doxorubicin + Cyclophosphamide: Cycles 13-16; Doxorubicin: 60 mg/m2 IV Every 2 or 3 weeks for 4 cycles; Cyclophosphamide: 600 mg/m2 IV Every 2 or 3 weeks for 4 cycles
Experimental: Trilaciclib with or without trastuzumab + pertuzumab Novel Investigational Agent	Drug: Trilaciclib with or without trastuzumab + pertuzumab Trilaciclib: 240 mg/m2 IV weekly cycle 1-16 Paclitaxel: 80 mg/m2 IV cycles 1-12 Doxorubicin + Cyclophosphamide: Cycles 13-16; Doxorubicin: 60 mg/m2 IV Every 2 or 3 weeks for 4 cycles; Cyclophosphamide: 600 mg/m2 IV Every 2 or 3 weeks for 4 cycles For HER2+: 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 Other Names: Trilaciclib (G1T28); Pertuzumab (Perjeta); Trastuzumab (Herceptin)
Experimental: SYD985 ([vic-]trastuzumab duocarmazine) Novel Investigational Agent	Drug: SYD985 ([vic-]trastuzumab duocarmazine) SYD985: 1.2 mg/kg IV (q3w x 12 weeks) cycles 1,4,7,10 Doxorubicin + Cyclophosphamide: Cycles 13-16; Doxorubicin: 60 mg/m2 IV Every 2 or 3 weeks for 4 cycles; Cyclophosphamide: 600 mg/m2 IV Every 2 or 3 weeks for 4 cycles
Experimental: Oral Paclitaxel + Encequidar + Dostarlimab (TSR-042) + Carboplatin with or without trastuzumab Novel Investigational Agent	Drug: Oral Paclitaxel + Encequidar + Dostarlimab (TSR-042) + Carboplatin with or without trastuzumab For HER2+ Dostarlimab (TSR-042), 500 mg, IV, q3wks for wk 1, 4, 7, 10 Trastuzumab, 4 mg/kg cycle 1, then 2 mg/kg cycles 2-12 q1wk, IV, for wk1-12 Oral paclitaxel, 205 mg/m2, oral, daily for Three (3) days in a row each week for weeks 1-12 Oral encequidar, 15 mg, oral, daily for Three (3) days in a row each week for weeks 1-12 Carboplatin, AUC 1.5, IV, q1wk from wk1-12 Followed by Doxorubicin: 60 mg/m2, IV, every 2 or 3 weeks for 4 cycles Cyclophosphamide: 600 mg/m2, IV, every 2 or 3 weeks for 4 cycle For HER2- Dostarlimab (TSR-042), 500 mg, IV, q3wks for wk 1, 4, 7, 10 Oral paclitaxel, 205 mg/m2, oral, daily for Three (3) days in a row each week for weeks 1-12 Oral encequidar, 15 mg, oral, daily for Three (3) days in a row each week for weeks 1-12 Carboplatin, AUC 1.5, IV, q1wk from wk1-12 Followed by Doxorubicin: 60 mg/m2, IV, every 2 or 3 weeks for 4 cycles Cyclophosphamide: 600 mg/m2, IV, every 2 or 3 weeks for 4 cycle Other Names: Oral Paclitaxel + Encequidar (Oraxol); Dostarlimab (TSR-042); Trastuzumab (Herceptin)
Experimental: Oral Paclitaxel + Encequidar + Dostarlimab (TSR-042) with or without trastuzumab Novel Investigational Agent	Drug: Oral Paclitaxel + Encequidar + Dostarlimab (TSR-042) with or without trastuzumab For HER2+ Dostarlimab (TSR-042), 500 mg, IV, q3wks for wk 1, 4, 7, 10 Trastuzumab, 4 mg/kg cycle 1, then 2 mg/kg cycles 2-12 q1wk, IV, for wk1-12 Oral paclitaxel, 205 mg/m2, oral, daily for Three (3) days in a row each week for weeks 1-12 Oral encequidar, 15 mg, oral, daily for Three (3) days in a row each week for weeks 1-12 Followed by Doxorubicin: 60 mg/m2, IV, every 2 or 3 weeks for 4 cycles Cyclophosphamide: 600 mg/m2, IV, every 2 or 3 weeks for 4 cycle For HER2- Dostarlimab (TSR-042), 500 mg, IV, q3wks for wk 1, 4, 7, 10 Oral paclitaxel, 205 mg/m2, oral, daily for Three (3) days in a row each week for weeks 1-12 Oral encequidar, 15 mg, oral, daily for Three (3) days in a row each week for weeks 1-12 Followed by Doxorubicin: 60 mg/m2, IV, every 2 or 3 weeks for 4 cycles Cyclophosphamide: 600 mg/m2, IV, every 2 or 3 weeks for 4 cycle Other Names: Oral Paclitaxel + Encequidar (Oraxol); Dostarlimab (TSR-042); Trastuzumab (Herceptin)
Experimental: Endocrine Optimization Pilot: Amcenestrant Monotherapy Novel Investigational Agent	Drug: Amcenestrant Amcenestrant (SAR439859), 200mg QD, p.o., for 24 weeks Other Names: SAR439859
Experimental: Endocrine Optimization Pilot: Amcenestrant + Abemaciclib Novel Investigational Agent	Drug: Amcenestrant + Abemaciclib Amcenestrant (SAR439859), 200mg QD, p.o., for 24 weeks Abemaciclib (Verzenio), 150mg BID, p.o., for 24 weeks Other Names: Amcenestrant (SAR439859), Abemaciclib (Verzenio)
Experimental: Endocrine Optimization Pilot: Amcenestrant + Letrozole Novel Investigational Agent	Drug: Amcenestrant + Letrozole Amcenestrant (SAR439859), 200mg QD, p.o., for 24 weeks Letrozole (Femara), 2.5mg QD, p.o., for 24 weeks Other Names: Amcenestrant (SAR439859), Letrozole (Femara)

Outcome Measures

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. [Post surgery based on upto 24-week treatment]

Secondary Outcome Measures

Establishing predictive and prognostic indices based on qualification and exploratory markers to predict pCR and residual cancer burden (RCB). [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. [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. [Post-Randomization, Pre-AC, Pre-Surgery, Post-Surgery upto One Year during follow-up]
MRI Volume [Four time points during the on-study phase: Baseline, Post-randomization, Pre-AC treatment and Pre-Surgery]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294
2	Mayo Clinic - Scottsdale	Scottsdale	Arizona	United States	85259
3	University of Arizona	Tucson	Arizona	United States	85724
4	City of Hope	Duarte	California	United States	91010
5	University of California San Diego	La Jolla	California	United States	92093-0698
6	University of Southern California	Los Angeles	California	United States	90033
7	HOAG Memorial Hospital Presbyterian	Newport Beach	California	United States	92663
8	University of California San Francisco (UCSF)	San Francisco	California	United States	94115
9	University of Colorado	Aurora	Colorado	United States	80045
10	Yale Cancer Center	New Haven	Connecticut	United States	06510
11	Georgetown University Medical Center	Washington	District of Columbia	United States	20007
12	Moffitt Cancer Center	Tampa	Florida	United States	33612
13	Emory University	Atlanta	Georgia	United States	30322
14	Winship Cancer Institute of Emory University	Atlanta	Georgia	United States	30322
15	University of Chicago	Chicago	Illinois	United States	60453
16	Loyola University	Maywood	Illinois	United States	60153
17	University of Kansas	Westwood	Kansas	United States	66205
18	Herbert-Herman Cancer Center, Sparrow Hospital	Lansing	Michigan	United States	48912
19	University of Minnesota	Minneapolis	Minnesota	United States	55455
20	Mayo Clinic	Rochester	Minnesota	United States	55905
21	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey	United States	08903
22	Montefiore Medical Center	Bronx	New York	United States	10467
23	Columbia University Medical Center	New York	New York	United States	10032
24	University of Rochester Wilmot Cancer Institute	Rochester	New York	United States	14642
25	Wake Forest Baptist Comprehensive Cancer Center	Winston-Salem	North Carolina	United States	27157
26	Cleveland Clinic	Cleveland	Ohio	United States	44106
27	Oregon Health & Science Institute (OHSU)	Portland	Oregon	United States	97239
28	University of Pennsylvania (U Penn)	Philadelphia	Pennsylvania	United States	19104
29	University Pittsburgh Medical Center	Pittsburgh	Pennsylvania	United States	15213
30	Sanford Clinical Research	Sioux Falls	South Dakota	United States	57104
31	Vanderbilt University Medical Center	Nashville	Tennessee	United States	27204
32	University of Texas, Southwestern Medical Center	Dallas	Texas	United States	75390-9155
33	University of Texas, M.D. Anderson Cancer Center	Houston	Texas	United States	77230-1439
34	Inova Health System	Falls Church	Virginia	United States	22042
35	Swedish Cancer Institute	Seattle	Washington	United States	98104
36	University of Washington	Seattle	Washington	United States	98115