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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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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

Intervention / Treatment
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* 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
* Drug: ARX788
* Drug: ARX788 + Cemiplimab
* Drug: VV1 + Cemiplimab
* Drug: Datopotamab deruxtecan
* Drug: Datopotamab deruxtecan + Durvalumab
* Drug: Zanidatamab
* Drug: Lasofoxifene
* Drug: Z-endoxifen
* Drug: ARV-471
* Drug: ARV-471 + Letrozole


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard Therapy<br>Paclitaxel, Herceptin followed by Doxorubicin and Cyclophosphamide treatment depending on HR/HER-2 status. | Drug: Standard Therapy<br>* 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<br>* Other names: Paclitaxel (Taxol); Doxorubicin (Adriamycin);|
| Experimental: AMG 386 with or without Trastuzumab<br>Arm is closed. | Drug: AMG 386 with or without Trastuzumab<br>* Arm is closed.<br>* Other names: AMG 386 (Trebananib); (Trastuzumab) Herceptin;Drug: AMG 386 and Trastuzumab<br>* Arm is closed.<br>* Other names: AMG 386 (Trebananib); Trastuzumab (Herceptin);|
| Other: AMG 479 plus Metformin<br>Arm is closed. | Drug: AMG 479 (Ganitumab) plus Metformin<br>* Arm is closed.<br>* Other names: Ganitumab;|
| Experimental: MK-2206 with or without Trastuzumab<br>Arm is closed. | Drug: MK-2206 with or without Trastuzumab<br>* Arm is closed.<br>* Other names: (Trastuzumab) Herceptin;|
| Experimental: T-DM1 and Pertuzumab<br>Arm is closed. | Drug: T-DM1 and Pertuzumab<br>* Arm is closed.<br>* Other names: T-DM1 (Trastuzumab emtansine); Pertuzumab (Perjeta);|
| Active Comparator: Pertuzumab and Trastuzumab<br>Novel Control Investigational Agent. Arm is closed. | Drug: Pertuzumab and Trastuzumab<br>* 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<br>* Other names: Pertuzumab (Perjeta); Trastuzumab (Herceptin);|
| Experimental: Ganetespib<br>Arm is closed. | Drug: Ganetespib<br>* Arm is closed.<br>|
| Other: ABT-888<br>Arm is closed. | Drug: ABT-888<br>* Arm is closed.<br>* Other names: Veliparib;|
| Other: Neratinib<br>Arm is closed. | Drug: Neratinib<br>* Arm is closed.<br>|
| Experimental: PLX3397<br>Arm is closed. | Drug: PLX3397<br>* Arm is closed.<br>|
| Experimental: Pembrolizumab 4 cycle<br>Arm is closed. | Drug: Pembrolizumab - 4 cycle<br>* Arm is closed.<br>|
| Experimental: Talazoparib plus Irinotecan<br>Arm is closed. | Drug: Talazoparib plus Irinotecan<br>* Arm is closed.<br>|
| Experimental: Patritumab with or without Trastuzumab<br>Arm is closed. | Drug: Patritumab and Trastuzumab<br>* Arm is closed.<br>|
| Experimental: Pembrolizumab 8 cycle<br>Arm is closed. | Drug: Pembrolizumab - 8 cycle<br>* Arm is closed.<br>|
| Experimental: SGN-LIV1A<br>Arm is closed. | Drug: SGN-LIV1A<br>* Arm is closed. SGN-LIV1A: 2.5 mg/kg IV cycles 1,4,7,10 Doxorubicin + Cyclophosphamide: Cycles 13-16<br>|
| Experimental: Durvalumab plus Olaparib<br>Arm is closed. | Drug: Durvalumab plus Olaparib<br>* Arm is closed.<br>|
| Experimental: SD-101 + Pembrolizumab<br>Arm is closed. | Drug: SD-101 + Pembrolizumab<br>* 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<br>|
| Experimental: Tucatinib<br>Arm is closed. | Drug: Tucatinib plus trastuzumab and pertuzumab<br>* 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<br>|
| Experimental: Cemiplimab<br>Novel Investigational Agent. Arm is closed. | Drug: Cemiplimab<br>* 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<br>|
| Experimental: Cemiplimab plus REGN3767<br>Novel Investigational Agent. Arm is closed. | Drug: Cemiplimab plus REGN3767<br>* 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<br>|
| Experimental: Trilaciclib with or without trastuzumab + pertuzumab<br>Novel Investigational Agent. Arm is closed. | Drug: Trilaciclib with or without trastuzumab + pertuzumab<br>* 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<br>* Other names: Trilaciclib (G1T28); Pertuzumab (Perjeta); Trastuzumab (Herceptin);|
| Experimental: SYD985 ([vic-]trastuzumab duocarmazine)<br>Novel Investigational Agent. Arm is closed. | Drug: SYD985 ([vic-]trastuzumab duocarmazine)<br>* 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<br>|
| Experimental: Oral Paclitaxel + Encequidar + Dostarlimab (TSR-042) + Carboplatin with or without trastuzumab<br>Novel Investigational Agent. Arm is closed. | Drug: Oral Paclitaxel + Encequidar + Dostarlimab (TSR-042) + Carboplatin with or without trastuzumab<br>* 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<br>* Other names: Oral Paclitaxel + Encequidar (Oraxol); Dostarlimab (TSR-042); Trastuzumab (Herceptin);|
| Experimental: Oral Paclitaxel + Encequidar + Dostarlimab (TSR-042) with or without trastuzumab<br>Novel Investigational Agent. Arm is closed. | Drug: Oral Paclitaxel + Encequidar + Dostarlimab (TSR-042) with or without trastuzumab<br>* 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<br>* Other names: Oral Paclitaxel + Encequidar (Oraxol); Dostarlimab (TSR-042); Trastuzumab (Herceptin);|
| Experimental: Endocrine Optimization Pilot: Amcenestrant Monotherapy<br>Novel Investigational Agent. Arm is closed. | Drug: Amcenestrant<br>* Amcenestrant (SAR439859), 200mg QD, p.o., for 24 weeks<br>* Other names: SAR439859;|
| Experimental: Endocrine Optimization Pilot: Amcenestrant + Abemaciclib<br>Novel Investigational Agent. Arm is closed. | Drug: Amcenestrant + Abemaciclib<br>* Amcenestrant (SAR439859), 200mg QD, p.o., for 24 weeks Abemaciclib (Verzenio), 150mg BID, p.o., for 24 weeks<br>* Other names: Amcenestrant (SAR439859), Abemaciclib (Verzenio);|
| Experimental: Endocrine Optimization Pilot: Amcenestrant + Letrozole<br>Novel Investigational Agent. Arm is closed. | Drug: Amcenestrant + Letrozole<br>* Amcenestrant (SAR439859), 200mg QD, p.o., for 24 weeks Letrozole (Femara), 2.5mg QD, p.o., for 24 weeks<br>* Other names: Amcenestrant (SAR439859), Letrozole (Femara);|
| Experimental: ARX788 in Block A and followed by SOC in Block B<br>Novel investigational Agent followed by SOC | Drug: ARX788<br>* ARX788, 1.5 mg/kg Q3W, IV for 12 weeks<br>|
| Experimental: ARX788 + Cemiplimab in Block A and followed by SOC in Block B<br>Novel investigational Agent followed by SOC. Arm is closed. | Drug: ARX788 + Cemiplimab<br>* ARX788, 1.5 mg/kg Q3W, IV for 12 weeks Cemiplimab, 350 mg Q3W, IV for 12 weeks<br>|
| Experimental: VSV-IFNβ-NIS (VOYAGER V1™; VV1) + Cemiplimab in Block A and followed by SOC in block B<br>Novel investigational Agent followed by SOC | Drug: VV1 + Cemiplimab<br>* VV1, 3x10^9 TCID50 once (day-8), Intra-tumoral injection Cemiplimab, 350 mg Q3W, IV for 12 weeks<br>* Other names: VSV-IFNβ-NIS;|
| Experimental: Datopotamab Deruxtecan in Block A and followed by SOC in block B<br>Novel investigational Agent followed by SOC | Drug: Datopotamab deruxtecan<br>* Dato-DXd, 6 mg/kg Q3W, IV for 12 weeks<br>* Other names: Dato-DXd;|
| Experimental: Datopotamab Deruxtecan + Durvalumab in Block A and followed by SOC in block B<br>Novel investigational Agent followed by SOC | Drug: Datopotamab deruxtecan + Durvalumab<br>* Dato-DXd, 6 mg/kg Q3W, IV for 12 weeks Durvalumab, 1120 mg Q3W, IV for 12 weeks<br>* Other names: Dato-DXd;|
| Experimental: Zanidatamab in Block A and followed by SOC in block B<br>Novel investigational Agent followed by SOC | Drug: Zanidatamab<br>* Zanidatamab: Flat dose of 1,200mg Q2W for 12 weeks<br>|
| Experimental: Endocrine Optimization Pilot: Lasofoxifene<br>Novel investigational Agent | Drug: Lasofoxifene<br>* Lasofoxifene: 5.0 mg QD, p.o., for 24 weeks<br>|
| Experimental: Endocrine Optimization Pilot: (Z)-Endoxifen<br>Novel investigational Agent | Drug: Z-endoxifen<br>* Z-endoxifen: 10 mg QD, p.o., for 24 weeks<br>|
| Experimental: Endocrine Optimization Pilot: ARV-471<br>Novel investigational Agent | Drug: ARV-471<br>* ARV-471: 200 mg QD, p.o, for 24 weeks<br>|
| Experimental: Endocrine Optimization Pilot: ARV-471 + Letrozole<br>Novel investigational Agent | Drug: ARV-471 + Letrozole<br>* ARV-471: 200 mg QD, p.o, for 24 weeks Letrozole: 2.5 mg QD, p.o, for 24 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 36-week treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neoplasm, pCR, Neoadjuvant, Breast, Cancer, Adaptive, Pathologic Complete Response, Biomarkers signature, MRI Volume, Endocrine Therapy, Chemotherapy, Immunotherapy