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

Phase 2RecruitingNCT01042379

QuantumLeap Healthcare Collaborative5,000 enrolled

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

5,000

Conditions

Breast Neoplasms Breast Cancer

Interventions

Standard TherapyDRUG

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

AMG 386 with or without TrastuzumabDRUG

Arm is closed.

AMG 479 (Ganitumab) plus MetforminDRUG

Arm is closed.

MK-2206 with or without TrastuzumabDRUG

Arm is closed.

AMG 386 and TrastuzumabDRUG

Arm is closed.

T-DM1 and PertuzumabDRUG

Arm is closed.

Pertuzumab and TrastuzumabDRUG

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

GanetespibDRUG

Arm is closed.

ABT-888DRUG

Arm is closed.

NeratinibDRUG

Arm is closed.

PLX3397DRUG

Arm is closed.

Pembrolizumab - 4 cycleDRUG

Arm is closed.

Talazoparib plus IrinotecanDRUG

Arm is closed.

Patritumab and TrastuzumabDRUG

Arm is closed.

Pembrolizumab - 8 cycleDRUG

Arm is closed.

SGN-LIV1ADRUG

Arm is closed. SGN-LIV1A: 2.5 mg/kg IV cycles 1,4,7,10 Doxorubicin + Cyclophosphamide: Cycles 13-16

Durvalumab plus OlaparibDRUG

Arm is closed.

SD-101 + PembrolizumabDRUG

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

Tucatinib plus trastuzumab and pertuzumabDRUG

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

CemiplimabDRUG

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

Cemiplimab plus REGN3767DRUG

Arm is closed. 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

Trilaciclib with or without trastuzumab + pertuzumabDRUG

Arm closed for accrual. 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

SYD985 ([vic-]trastuzumab duocarmazine)DRUG

Arm is closed. 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

Oral Paclitaxel + Encequidar + Dostarlimab (TSR-042) + Carboplatin with or without trastuzumabDRUG

Arm is closed. 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

Oral Paclitaxel + Encequidar + Dostarlimab (TSR-042) with or without trastuzumabDRUG

Arm is closed. 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

AmcenestrantDRUG

Arm is closed. Amcenestrant (SAR439859), 200mg QD, p.o., for 24 weeks.

Amcenestrant + AbemaciclibDRUG

Arm is closed. Amcenestrant (SAR439859), 200mg QD, p.o., for 24 weeks Abemaciclib (Verzenio), 150mg BID, p.o., for 24 weeks

Amcenestrant + LetrozoleDRUG

Arm is closed. Amcenestrant (SAR439859), 200mg QD, p.o., for 24 weeks Letrozole (Femara), 2.5mg QD, p.o., for 24 weeks

ARX788DRUG

Arm is closed. ARX788, 1.5 mg/kg Q3W, IV for 12 weeks

ARX788 + CemiplimabDRUG

Arm is closed. ARX788, 1.5 mg/kg Q3W, IV for 12 weeks Cemiplimab, 350 mg Q3W, IV for 12 weeks

VV1 + CemiplimabDRUG

Arm is closed. VV1, 3x10\^9 TCID50 once (day-8), Intra-tumoral injection Cemiplimab, 350 mg Q3W, IV for 12 weeks

Datopotamab deruxtecanDRUG

Arm is closed. Dato-DXd, 6 mg/kg Q3W, IV for 12 weeks

Datopotamab deruxtecan + DurvalumabDRUG

Arm is closed. Dato-DXd, 6 mg/kg Q3W, IV for 12 weeks Durvalumab, 1120 mg Q3W, IV for 12 weeks

ZanidatamabDRUG

Zanidatamab: IV Infusion at a 2-tiered flat dose. 1,800mg (\<70 kg) and 2400mg (≥70 kg). Neoadjuvant doing of zanidatamab: The initial dose will be administered on Cycle 1 Day 1, with Cycle 2 Day 1 occurring 14 days thereafter, followed by subsequent dosing every 3 weeks (Q3W) for a total of up to 5 doses in block A, up to 4 doses Block B, up to 5 doses Block C. Adjuvant dosing of zanidatamab: Administered every 3 weeks (Q3W) for a total of 1 year of HER2 based therapy. The total number of adjuvant weeks will be dependent on the number of weeks of exposure of zanidatamab in Blocks A, B, and C.

LasofoxifeneDRUG

Arm is closed. Lasofoxifene: 5.0 mg QD, p.o., for 24 weeks

Z-endoxifenDRUG

Arm is closed. Z-endoxifen: 10 mg QD, p.o., for 24 weeks

ARV-471DRUG

Arm is closed. ARV-471: 200 mg QD, p.o, for 24 weeks.

ARV-471 + LetrozoleDRUG

Arm is closed. ARV-471: 200 mg QD, p.o, for 24 weeks Letrozole: 2.5 mg QD, p.o, for 24 weeks

ARV-471 + AbemaciclibDRUG

Arm is closed. ARV-471: 200 mg QD, p.o, for 24 weeks Abemaciclib: 150 mg BID, p.o, for 24 weeks

Endoxifen + AbemaciclibDRUG

Z-endoxifen: 80 mg QD, p.o., for 24 weeks Abemaciclib: 150 mg BID, p.o, for 20 weeks

Rilvegostomig + TDXdDRUG

Arm closed to accrual Rilvegostomig: 750mg IV Q3W for 12 weeks TDXd: 5.4 mg/kg IV Q3W for 12 weeks

Dan222 + NiraparibDRUG

Arm is closed. DAN222: 8mg/m2 IV QW for 12 weeks Niraparib: 200mg QD p.p., 12 weeks

Sarilumab + Cemiplimab + PaclitaxelDRUG

Arm is closed to accrual. Sarilumab: 200mg Subcutaneous injection Q2W for 12 weeks Cemiplimab: 350mg IV Q3W for 12 weeks Paclitaxel: 80 mg/m2 IV QW for 12 weeks

GSK 5733584DRUG

Arm is open for accrual. Route: Intravenous infusion Dosage Form: 4.8 mg/kg intravenous Q3W for injection. Will receive a max of 12 weeks.

GSK 5733584 + DostarlimabDRUG

Arm is open for accrual. GSK 5733584 Route: Intravenous Infusion Dosage Form: 4.8 mg/kg intravenous Q3W for injection x 12 weeks max. Dostarlimab Route: Intravenous Infusion Dosage Form: 500 mg fixed dose intravenous Q3W for infusion x 12 weeks max.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (42)

University of Alabama at Birmingham

Birmingham, Alabama, United States

RECRUITING

Mayo Clinic - Scottsdale

Scottsdale, Arizona, United States

NOT_YET_RECRUITING

University of Arizona

Tucson, Arizona, United States

ACTIVE_NOT_RECRUITING

University of California - Davis, Comprehensive Cancer Center

Davis, California, United States

Outcomes

Primary Outcomes

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 Outcomes

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

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

Overview

Conditions

Interventions

Eligibility

Locations (42)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts