Personalized Adaptive Novel Agents for Breast Cancer

(I-SPY Trial)

Recruiting at 36 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

Trial Summary

What is the purpose of this trial?

This trial is testing new medicines along with regular cancer treatment to find the best combinations for breast cancer patients. It focuses on identifying which treatments work best based on specific cancer characteristics. Early signs of success are monitored using MRI scans and tests on blood and tissue samples.

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.

What data supports the effectiveness of the drug combination Amcenestrant + Abemaciclib for breast cancer?

Research from the MONARCH3 and MonarchE studies shows that abemaciclib, when added to endocrine therapy, significantly improves progression-free survival and disease-free survival in patients with hormone receptor-positive, HER2-negative breast cancer. ^{1 2 3 4 5}

Is the combination of abemaciclib with endocrine therapy safe for breast cancer treatment?

Abemaciclib, when combined with endocrine therapy, has been shown to improve outcomes in hormone receptor-positive, HER2-negative breast cancer, but it has different toxicity profiles that require careful monitoring. The safety profiles of these combinations are generally predictable and manageable, though there is an increased risk of potentially serious toxicities. ^{1 6 7 8 9}

What makes the drug combination of Amcenestrant and Abemaciclib unique for breast cancer treatment?

The combination of Amcenestrant and Abemaciclib is unique because it targets hormone receptor-positive, HER2-negative breast cancer by combining a selective estrogen receptor degrader (Amcenestrant) with a CDK4/6 inhibitor (Abemaciclib), which has shown effectiveness in improving progression-free survival in advanced cases. ^{1 2 3 10 11}

Research Team

Laura Esserman, MD

Principal Investigator

University of California, San Francisco

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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: Endocrine Optimization Pilot: Lasofoxifene Experimental Treatment 1 Intervention

Novel investigational Agent

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

Novel Investigational Agent. Arm is closed.

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

Novel Investigational Agent. Arm is closed.

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

Novel Investigational Agent. Arm is closed.

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

Novel investigational Agent

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

Novel investigational Agent

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

Novel investigational Agent

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

Novel investigational Agent

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

Novel investigational Agent

Group XXX: Durvalumab plus Olaparib Experimental Treatment 1 Intervention

Arm is closed.

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

Novel investigational Agent followed by SOC

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

Novel investigational Agent followed by SOC

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

Novel investigational Agent

Group XXXIV: Cemiplimab plus REGN3767 Experimental Treatment 1 Intervention

Novel Investigational Agent. Arm is closed.

Group XXXV: Cemiplimab Experimental Treatment 1 Intervention

Novel Investigational Agent. Arm is closed.

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

Novel investigational Agent followed by SOC

Group XXXVII: 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 XXXVIII: AMG 479 plus Metformin Experimental Treatment 1 Intervention

Arm is closed.

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

Arm is closed.

Group XL: ABT-888 Experimental Treatment 1 Intervention

Arm is closed.

Group XLI: Standard Therapy Active Control 1 Intervention

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

Group XLII: 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+

Findings from Research

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]

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 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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Abemaciclib Reigns Over Breast Cancer in MonarchE. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

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

3. England 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. [2023]

4. United States 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. [2022]

5. United States 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. [2023]

6. Italy 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. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

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

8. England pubmed.ncbi.nlm.nih.gov

Enhancing Endocrine Therapy Combination Strategies for the Treatment of Postmenopausal HR+/HER2- Advanced Breast Cancer. [2018]

9. England pubmed.ncbi.nlm.nih.gov

Effectiveness of Alpelisib + Fulvestrant Compared with Real-World Standard Treatment Among Patients with HR+, HER2-, PIK3CA-Mutated Breast Cancer. [2022]

10. France pubmed.ncbi.nlm.nih.gov

Therapeutic innovations in breast cancer. [2019]

11. United States pubmed.ncbi.nlm.nih.gov

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