Personalized Adaptive Novel Agents for Breast Cancer

(I-SPY Trial)

Recruiting at 38 trial locations

Overseen By Julie Lang, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: QuantumLeap Healthcare Collaborative

Must not be taking: Investigational agents

Disqualifiers: Infections, Heart failure, Angina, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 12-24 weeks

5000 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new treatments for breast cancer to determine which work best for different tumor types. Researchers are testing various drug combinations, including Amcenestrant and Abemaciclib, to evaluate their performance. They also seek early success indicators through imaging and tissue analysis. The trial suits individuals with breast cancer who have not undergone chemotherapy or radiation on the affected breast and are willing to have a biopsy to guide treatment. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important findings.

Do I need to stop my current medications for the trial?

The trial information does not specify if you need to stop taking your current medications. However, you cannot use any investigational agents within 30 days of starting the study treatment.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that some treatments in the trial have promising safety records from earlier studies. For example, ARV-471 combined with abemaciclib proved safe and effective in breast cancer cells, while ARV-471 alone was well tolerated by patients with advanced breast cancer. Similarly, over 700 patients have tolerated (Z)-endoxifen well, and abemaciclib has been effective when used with other treatments for advanced breast cancer.

Datopotamab Deruxtecan has maintained a good safety record with no new concerns. Cemiplimab, when combined with drugs like sarilumab, has been studied for safety, though this combination might increase the risk of side effects.

For Zanidatamab, studies suggest it is generally manageable and well tolerated by many patients. Meanwhile, DAN-222 combined with niraparib was safe and well tolerated, showing promising results against tumors in some breast cancer patients.

These treatments are being tested in a Phase 2 trial, meaning they have passed initial safety tests and are now being studied for effectiveness and further safety in a larger group. This stage helps researchers learn more about any side effects and how well these treatments work for different types of breast cancer. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for breast cancer because they incorporate novel active ingredients and combinations that target cancer cells in new ways. For example, combinations like Amcenestrant with Abemaciclib and Letrozole offer a fresh approach by focusing on multiple hormonal pathways, potentially enhancing effectiveness against hormone receptor-positive breast cancer. Cemiplimab, an immune checkpoint inhibitor, works by unleashing the immune system to attack cancer cells, offering a promising alternative for patients who might not respond to traditional chemotherapy. Additionally, oral paclitaxel combined with Encequidar and Dostarlimab introduces a more convenient oral administration route while maintaining potent anti-cancer effects, potentially leading to improved patient adherence and outcomes. These innovative strategies represent significant advancements over standard treatments, which primarily include chemotherapy, hormone therapy, and monoclonal antibodies.

What evidence suggests that this trial's treatments could be effective for breast cancer?

Research shows that combining Amcenestrant and Abemaciclib, a treatment option in this trial, may effectively treat certain types of breast cancer. Studies have found that Abemaciclib, when used with other treatments, helps patients with advanced ER-positive, HER2-negative breast cancer live longer without disease progression. Amcenestrant blocks the effects of estrogen, which can help stop cancer growth. Together, these treatments aim to be more effective against breast cancer. Patients in these studies have reported better outcomes, making this a promising option for those with this condition. ^{1 2 5 6 7}

Who Is on the Research Team?

Laura Esserman, MD

Principal Investigator

University of California, San Francisco

Are You a Good Fit for This Trial?

This trial is for adults over 18 with invasive breast cancer, who haven't had chemotherapy or radiation for it. They must be non-pregnant, have normal organ function, and no metal implants incompatible with MRI. The cancer should be measurable in the breast and not spread far (specific stages). All hormone receptor statuses are eligible.

Inclusion Criteria

Ability to understand and willingness to sign a written informed consent document (I-SPY 2 TRIAL Consent #2)

I am fully active or can carry out light work.

My tumor's hormone and HER2 status fits the study's specific criteria.

Exclusion Criteria

I do not have any severe illnesses or social situations that would prevent me from following the study's requirements.

Use of any other investigational agents within 30 days of starting study treatment

You have had allergic reactions to similar drugs or medications in the past.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive novel investigational agents in sequence with standard chemotherapy to assess efficacy based on molecular characteristics

12-24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

Extension

Participants may continue to receive treatment with novel agents if they show a high probability of improved efficacy

What Are the Treatments Tested in This Trial?

Interventions

• Amcenestrant + Abemaciclib
• Amcenestrant + Letrozole
• Cemiplimab
• Cemiplimab plus REGN3767
• Oral Paclitaxel + Encequidar + Dostarlimab (TSR-042) + Carboplatin with or without trastuzumab
• Oral Paclitaxel + Encequidar + Dostarlimab (TSR-042) with or without trastuzumab
• Pembrolizumab - 4 cycle
• Pembrolizumab - 8 cycle
• SD-101 + Pembrolizumab

Trial Overview The study tests various new drugs against different types of breast tumors to personalize treatment. It uses MRI and tissue/blood samples before surgery to predict success. Drugs include Datopotamab deruxtecan, Durvalumab, Trilaciclib combinations, ABT-888 among others.

How Is the Trial Designed?

Group I: Zanidatamab in Block A and followed by SOC in block B Experimental Treatment 1 Intervention

Novel investigational Agent followed by SOC

Group II: VSV-IFNβ-NIS (VOYAGER V1™; VV1) + Cemiplimab in Block A and followed by SOC in block B Experimental Treatment 1 Intervention

Novel investigational Agent followed by SOC

Group III: Tucatinib Experimental Treatment 1 Intervention

Arm is closed.

Group IV: Trilaciclib with or without trastuzumab + pertuzumab Experimental Treatment 1 Intervention

Novel Investigational Agent. Arm is closed.

Group V: Talazoparib plus Irinotecan Experimental Treatment 1 Intervention

Arm is closed.

Group VI: T-DM1 and Pertuzumab Experimental Treatment 1 Intervention

Arm is closed.

Group VII: Sarilumab + Cemiplimab + Paclitaxel in Block B followed by SOC Block C Experimental Treatment 1 Intervention

Novel investigational Agent

Group VIII: SYD985 ([vic-]trastuzumab duocarmazine) Experimental Treatment 1 Intervention

Novel Investigational Agent. Arm is closed.

Group IX: SGN-LIV1A Experimental Treatment 1 Intervention

Arm is closed.

Group X: SD-101 + Pembrolizumab Experimental Treatment 1 Intervention

Arm is closed.

Group XI: Rilvegostomig + TDXd in Block A and followed by SOC in Block B Experimental Treatment 1 Intervention

Novel investigational Agent

Group XII: Pembrolizumab 8 cycle Experimental Treatment 1 Intervention

Arm is closed.

Group XIII: Pembrolizumab 4 cycle Experimental Treatment 1 Intervention

Arm is closed.

Group XIV: Patritumab with or without Trastuzumab Experimental Treatment 1 Intervention

Arm is closed.

Group XV: PLX3397 Experimental Treatment 1 Intervention

Arm is closed.

Group XVI: Oral Paclitaxel + Encequidar + Dostarlimab (TSR-042) with or without trastuzumab Experimental Treatment 1 Intervention

Novel Investigational Agent. Arm is closed.

Group XVII: Oral Paclitaxel + Encequidar + Dostarlimab (TSR-042) + Carboplatin with or without trastuzumab Experimental Treatment 1 Intervention

Novel Investigational Agent. Arm is closed.

Group XVIII: Neratinib Experimental Treatment 1 Intervention

Arm is closed.

Group XIX: MK-2206 with or without Trastuzumab Experimental Treatment 1 Intervention

Arm is closed.

Group XX: Ganetespib Experimental Treatment 1 Intervention

Arm is closed.

Group XXI: GSK 5733584 in Block A and followed by SOC in Block B Experimental Treatment 1 Intervention

Novel Investigational Agent

Group XXII: GSK 5733584 + Dostarlimab in Block A and followed by SOC in Block B Experimental Treatment 1 Intervention

Novel Investigational Agent

Group XXIII: Endocrine Optimization Pilot: Lasofoxifene Experimental Treatment 1 Intervention

Novel investigational Agent

Group XXIV: Endocrine Optimization Pilot: Amcenestrant Monotherapy Experimental Treatment 1 Intervention

Novel Investigational Agent. Arm is closed.

Group XXV: Endocrine Optimization Pilot: Amcenestrant + Letrozole Experimental Treatment 1 Intervention

Novel Investigational Agent. Arm is closed.

Group XXVI: Endocrine Optimization Pilot: Amcenestrant + Abemaciclib Experimental Treatment 1 Intervention

Novel Investigational Agent. Arm is closed.

Group XXVII: Endocrine Optimization Pilot: ARV-471 + Letrozole Experimental Treatment 1 Intervention

Novel investigational Agent

Group XXVIII: Endocrine Optimization Pilot: ARV-471 + Abemaciclib Experimental Treatment 1 Intervention

Novel investigational Agent

Group XXIX: Endocrine Optimization Pilot: ARV-471 Experimental Treatment 1 Intervention

Novel investigational Agent

Group XXX: Endocrine Optimization Pilot: (Z)-Endoxifen + Abemaciclib Experimental Treatment 1 Intervention

Novel investigational Agent

Group XXXI: Endocrine Optimization Pilot: (Z)-Endoxifen Experimental Treatment 1 Intervention

Novel investigational Agent

Group XXXII: Durvalumab plus Olaparib Experimental Treatment 1 Intervention

Arm is closed.

Group XXXIII: Datopotamab Deruxtecan in Block A and followed by SOC in block B Experimental Treatment 1 Intervention

Novel investigational Agent followed by SOC

Group XXXIV: Datopotamab Deruxtecan + Durvalumab in Block A and followed by SOC in block B Experimental Treatment 1 Intervention

Novel investigational Agent followed by SOC

Group XXXV: DAN222 + Niraparib in Block A and followed by SOC in Block B Experimental Treatment 1 Intervention

Novel investigational Agent

Group XXXVI: Cemiplimab plus REGN3767 Experimental Treatment 1 Intervention

Novel Investigational Agent. Arm is closed.

Group XXXVII: Cemiplimab Experimental Treatment 1 Intervention

Novel Investigational Agent. Arm is closed.

Group XXXVIII: ARX788 in Block A and followed by SOC in Block B Experimental Treatment 1 Intervention

Novel investigational Agent followed by SOC

Group XXXIX: ARX788 + Cemiplimab in Block A and followed by SOC in Block B Experimental Treatment 1 Intervention

Novel investigational Agent followed by SOC. Arm is closed.

Group XL: AMG 479 plus Metformin Experimental Treatment 1 Intervention

Arm is closed.

Group XLI: AMG 386 with or without Trastuzumab Experimental Treatment 2 Interventions

Arm is closed.

Group XLII: ABT-888 Experimental Treatment 1 Intervention

Arm is closed.

Group XLIII: Standard Therapy Active Control 1 Intervention

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

Group XLIV: Pertuzumab and Trastuzumab Active Control 1 Intervention

Novel Control Investigational Agent. Arm is closed.

Amcenestrant + Abemaciclib is already approved in United States, European Union for the following indications:

Approved in United States as SAR439859 + Verzenio for:

• Advanced breast cancer
• HR-positive, HER2-negative breast cancer

Approved in European Union as Amcenestrant + Abemaciclib for:

• Locally advanced or metastatic breast cancer
• HR-positive, HER2-negative breast cancer

Who Is Running the Clinical Trial?

QuantumLeap Healthcare Collaborative

Lead Sponsor

Trials

6

Recruited

7,000+

Published Research Related to This Trial

In a phase III trial, adding abemaciclib to adjuvant endocrine therapy significantly improved invasive disease-free survival and distant relapse-free survival in patients with hormone receptor-positive, HER2-negative, high-risk, early breast cancer.

This finding contrasts with results from a trial involving another CDK4/6 inhibitor, which did not show similar benefits, highlighting the variability in efficacy among different treatments in this class.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abemaciclib Reigns Over Breast Cancer in MonarchE. [2021]

Interim results from the MONARCH3 study show that abemaciclib, a CDK4/6 inhibitor, is an effective first-line treatment for advanced ER-positive, HER2-negative breast cancer.

Patients receiving abemaciclib in combination with letrozole experienced significantly improved progression-free survival compared to those receiving a placebo with endocrine therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-Line Abemaciclib Effective in ER+ Breast Cancer. [2019]

CDK 4/6 inhibitors are being used to manage endocrine resistance in ER+ HER2- breast cancer, showing promise in improving treatment outcomes in metastatic cases.

New antibody-drug conjugates and PARP inhibitors are being explored for HER2+ and triple-negative breast cancer (TNBC), particularly for patients with BRCA mutations, indicating a shift towards targeted therapies in advanced breast cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic innovations in breast cancer. Le Du, F., Perrin, C., Brunot, A., et al.[2019]

In the FLIPPER trial, the combination of palbociclib and fulvestrant significantly improved progression-free survival (PFS) in postmenopausal women with HR+/HER2- advanced breast cancer compared to placebo and fulvestrant.

Patient-reported outcomes indicated that while global health status and quality of life (QoL) were maintained during treatment with palbociclib/fulvestrant, the time to deterioration in QoL was longer with placebo/fulvestrant, suggesting that palbociclib/fulvestrant is a beneficial treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quality of life with palbociclib plus fulvestrant versus placebo plus fulvestrant in postmenopausal women with endocrine-sensitive hormone receptor-positive and HER2-negative advanced breast cancer: patient-reported outcomes from the FLIPPER trial. Tibau, A., Martínez, MT., Ramos, M., et al.[2023]

In the MONARCH 2 study, abemaciclib combined with fulvestrant significantly improved progression-free survival (PFS) and overall survival (OS) in patients with hormone receptor positive, HER2-negative advanced breast cancer, showing consistent benefits across both first-line and second-line treatment groups.

The most substantial benefits were seen in patients with primary resistance to endocrine therapy and those with visceral disease, indicating that abemaciclib may be particularly effective for these subgroups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MONARCH 2: Subgroup Analysis of Patients Receiving Abemaciclib Plus Fulvestrant as First-Line and Second-Line Therapy for HR+, HER2--Advanced Breast Cancer. Neven, P., Johnston, SRD., Toi, M., et al.[2022]

In patients with hormone receptor-positive, HER2-negative metastatic breast cancer who progressed on palbociclib, those without CDK4/6 inhibitor resistance mutations (CDKi-R[-]) had a median progression-free survival (PFS) of 7.0 months on abemaciclib, compared to just 3.5 months for those with mutations (CDKi-R[+]), indicating that the presence of these mutations significantly impacts treatment efficacy.

This study is the first to identify a genomic panel that may help predict sensitivity to abemaciclib in patients with ESR1 mutations after progression on palbociclib, suggesting that further research could refine this panel to better guide treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Gene Panel Associated With Abemaciclib Utility in ESR1-Mutated Breast Cancer After Prior Cyclin-Dependent Kinase 4/6-Inhibitor Progression. Brett, JO., Dubash, TD., Johnson, GN., et al.[2023]

Abemaciclib, a CDK4/6 inhibitor, demonstrated single-agent activity in women with metastatic HER2-negative, ER-positive breast cancer who had previously progressed on endocrine therapy and chemotherapy, showing an objective response rate of 19.7%.

Notably, 28.2% of the responses to abemaciclib lasted at least a year, indicating potential long-term efficacy for patients with this type of breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-Agent Abemaciclib Active in Breast Cancer. [2019]

Abemaciclib combined with endocrine therapy (ET) significantly improves quality-adjusted life years (QALYs) in patients with high-risk hormone receptor positive, HER2-negative early breast cancer, with an increase of 0.99 QALYs compared to ET alone.

The treatment is considered cost-effective in Italy, with an incremental cost-effectiveness ratio of €22,651 per QALY gained, and a 99% likelihood of being cost-effective at a threshold of €30,000 per QALY.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-effectiveness analysis of abemaciclib with endocrine therapy (ET) versus ET alone for HR+, HER2-, node-positive, high-risk early breast cancer in Italy. Davie, A., Traoré, S., Giovannitti, M., et al.[2023]

Oral CDK4/6 inhibitors like palbociclib, ribociclib, and abemaciclib significantly improve progression-free survival by 40-45% when combined with endocrine therapy in hormone-responsive HER2-negative advanced breast cancer, particularly in post-menopausal women.

These inhibitors have varying toxicity profiles and monitoring requirements, and ongoing clinical trials are exploring their use in other breast cancer subtypes and in combination with other therapies to overcome resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Role of CDK4/6 Inhibitors in Breast Cancer. Murphy, CG.[2020]

New combinations of endocrine therapy (ET) for hormone receptor-positive (HR+) advanced breast cancer, such as fulvestrant plus anastrozole or palbociclib plus letrozole, have shown improved progression-free survival, especially in ET-naïve patients.

While these combinations are generally safe, they carry risks of serious toxicities, necessitating careful monitoring and patient education, and the use of circulating tumor DNA as a biomarker may help tailor treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enhancing Endocrine Therapy Combination Strategies for the Treatment of Postmenopausal HR+/HER2- Advanced Breast Cancer. Pritchard, KI., Chia, SK., Simmons, C., et al.[2018]

The BYLieve trial demonstrated that alpelisib combined with fulvestrant significantly improves progression-free survival (PFS) in patients with hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer, showing a median PFS of 7.3 months compared to 3.7 months in a matched real-world cohort.

This study is the first to compare the efficacy of alpelisib with fulvestrant against standard treatments in a real-world setting, confirming that the combination therapy is more effective than standard care after prior treatment with CDK4/6 inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of Alpelisib + Fulvestrant Compared with Real-World Standard Treatment Among Patients with HR+, HER2-, PIK3CA-Mutated Breast Cancer. Turner, S., Chia, S., Kanakamedala, H., et al.[2022]

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