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Paclitaxel, Herceptin followed by Doxorubicin and Cyclophosphamide treatment depending on HR/HER-2 status.

Novel Control Investigational Agent. Arm is closed.

Novel Investigational Agent. Arm is closed.

Novel investigational Agent followed by SOC

Novel investigational Agent followed by SOC. Arm is closed.

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

Standard Therapy

AMG 386 with or without Trastuzumab

AMG 479 (Ganitumab) plus Metformin

MK-2206 with or without Trastuzumab

AMG 386 and Trastuzumab

T-DM1 and Pertuzumab

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

Pertuzumab and Trastuzumab

Ganetespib

ABT-888

PLX3397

Pembrolizumab - 4 cycle

Talazoparib plus Irinotecan

Patritumab and Trastuzumab

Pembrolizumab - 8 cycle

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

Durvalumab plus Olaparib

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

SD-101 + Pembrolizumab

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

Tucatinib plus trastuzumab and pertuzumab

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: 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

Cemiplimab plus REGN3767

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

Trilaciclib with or without trastuzumab + pertuzumab

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

SYD985 ([vic-]trastuzumab duocarmazine)

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) + 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 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

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

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

Amcenestrant

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

Amcenestrant + Abemaciclib

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

Amcenestrant + Letrozole

ARX788

ARX788, 1.5 mg/kg Q3W, IV for 12 weeks Cemiplimab, 350 mg Q3W, IV for 12 weeks

ARX788 + Cemiplimab

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

VV1 + Cemiplimab

Datopotamab deruxtecan

Dato-DXd, 6 mg/kg Q3W, IV for 12 weeks Durvalumab, 1120 mg Q3W, IV for 12 weeks

Datopotamab deruxtecan + Durvalumab

Zanidatamab: Flat dose of 1,200mg Q2W for 12 weeks

Zanidatamab

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

Lasofoxifene

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

Z-endoxifen

ARV-471

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

ARV-471 + Letrozole

Won Chang

Maria Pitsiouni, PhD

Erica Stringer-Reasor, MD

Donald Northfelt, MD

Jennifer Tseng, MD

Anne Wallace, MD

Kristy Watkins, RN

Evanthia Roussos Torres, MD

Chaitali Nangia, MD

Amy Jo Chien, MD

Anthony Elias, MD

Trisha Burello, MS

Tara Snaft, MD

Lajos Pusztai, MD

Marlya Rozenblit, MD

Minetta Liu, MD

Claudine Isaacs, MD

Heather Han, MD

Kevin Kalinsky, MD

Rita Nanda, MD

Kathy S Albain, MD

Brittani Thomas, DO

Douglas Yee, MD

Judy C Boughey, MD

Coral Omene, MD, PhD

Jesus D Anampa

Yannis Karamitas

Nancy Chan, MD

Meghana Trivedi, MD

Carla Folksm, MD

Angela Howell, MD

Alexandra Thomas, MD

Taylor Knapp

Alexandra Zimmer, MD

Amy Clark, MD

Amy Sanford, MD

Laura Esserman, MD, MBA

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.

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

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

QuantumLeap Healthcare Collaborative

Spots Global Cancer Trial Database for amcenestrant + letrozole