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

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.

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.

Arms & interventions

• DrugStandard 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

• DrugAMG 386 with or without Trastuzumab

  Arm is closed.

• DrugAMG 479 (Ganitumab) plus Metformin

  Arm is closed.

• DrugMK-2206 with or without Trastuzumab

  Arm is closed.

• DrugAMG 386 and Trastuzumab

  Arm is closed.

• DrugT-DM1 and Pertuzumab

  Arm is closed.

• DrugPertuzumab 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

• DrugGanetespib

  Arm is closed.

• DrugABT-888

  Arm is closed.

• DrugNeratinib

  Arm is closed.

• DrugPLX3397

  Arm is closed.

• DrugPembrolizumab - 4 cycle

  Arm is closed.

• DrugTalazoparib plus Irinotecan

  Arm is closed.

• DrugPatritumab and Trastuzumab

  Arm is closed.

• DrugPembrolizumab - 8 cycle

  Arm is closed.

• DrugSGN-LIV1A

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

• DrugDurvalumab plus Olaparib

  Arm is closed.

• DrugSD-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

• DrugTucatinib 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

• DrugCemiplimab

  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

• DrugCemiplimab plus REGN3767

  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

• DrugTrilaciclib with or without trastuzumab + pertuzumab

  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

• DrugSYD985 ([vic-]trastuzumab duocarmazine)

  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

• DrugOral Paclitaxel + Encequidar + Dostarlimab (TSR-042) + Carboplatin with or without trastuzumab

  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

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

  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

• DrugAmcenestrant

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

• DrugAmcenestrant + Abemaciclib

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

• DrugAmcenestrant + Letrozole

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

• DrugARX788

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

• DrugARX788 + Cemiplimab

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

• DrugVV1 + Cemiplimab

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

• DrugDatopotamab deruxtecan

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

• DrugDatopotamab deruxtecan + Durvalumab

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

• DrugZanidatamab

  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.

• DrugLasofoxifene

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

• DrugZ-endoxifen

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

• DrugARV-471

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

• DrugARV-471 + Letrozole

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

• DrugARV-471 + Abemaciclib

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

• DrugEndoxifen + Abemaciclib

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

• DrugRilvegostomig + TDXd

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

• DrugDan222 + Niraparib

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

• DrugSarilumab + Cemiplimab + Paclitaxel

  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

• DrugGSK 5733584

  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.

• DrugGSK 5733584 + Dostarlimab

  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.

• DrugIvonescimab (20mg/kg Q3W)

  Strengths to be used in trial: 1. 20 mg/kg IV Q3W monotherapy 2. 20 mg/kg IV Q3W with paclitaxel 3. 20 mg/kg IV Q3W with carboplatin and paclitaxel. Standard Regimen: 20 mg/kg IV Q3W. Patients in Block A will receive a minimum of 6 weeks a maximum of 12 weeks of Ivonescimab monotherapy in Block A. Patients that have completed Block A, may receive ivonescimab plus paclitaxel or ivonescimab plus paclitaxel plus carboplatin in Block B (depending on subtype).

Outcome measures

Eligibility criteria