Immunotherapy for Intraductal Carcinoma

Overseen By Laura Esserman, MD

Age: 18+

Sex: Female

Trial Phase: Phase < 1

Sponsor: Laura Esserman

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Immunodeficiency, Active autoimmune, HIV, others

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

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 9-15 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how immunotherapy affects the immune environment in high-risk ductal carcinoma in situ (DCIS), a non-invasive breast cancer. Participants will receive different combinations of pembrolizumab (an immunotherapy drug) and mRNA-2752 injections, followed by surgery to remove the lesion. The trial seeks individuals diagnosed with high-risk DCIS who plan to undergo surgery and have certain features, such as a palpable mass or hormone receptor-negative status. The goal is to observe changes in the body’s immune response to this treatment before surgery. As an Early Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking cancer research.

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

If you are using tamoxifen or aromatase inhibitors, you must stop taking them at least 2 weeks before starting the trial. The protocol does not specify about other medications.

Will I have to stop taking my current medications?

If you are currently taking tamoxifen or aromatase inhibitors, you will need to stop these medications at least 2 weeks before starting the trial. For other medications, the trial protocol does not specify, so it's best to discuss with the trial team.

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

Research has shown that pembrolizumab, a treatment that aids the immune system, is generally safe for people with various types of cancer. Large studies have found that many patients used pembrolizumab without serious issues. Most side effects are mild, such as fatigue or skin rash, while serious side effects are less common.

For mRNA-2752, studies suggest it is also safe when injected directly into tumors. Patients have responded well, and side effects are usually not severe, with some experiencing minor issues like pain at the injection site.

Both treatments aim to help the body's immune system fight cancer. While early studies indicate they are safe, researchers continue to investigate any possible long-term effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Most treatments for intraductal carcinoma, like surgery and radiation, focus on removing or targeting the tumor directly. But pembrolizumab, an immunotherapy drug, works differently by boosting the body's immune system to recognize and fight cancer cells more effectively. Additionally, mRNA-2752 offers a novel approach by using messenger RNA to instruct cells to produce proteins that help the immune system attack the cancer. These treatments are exciting because they aim to harness the body's own defenses, potentially offering more targeted and less invasive options compared to traditional treatments. Researchers hope these innovative therapies could improve outcomes and reduce the need for extensive surgeries.

What evidence suggests that this trial's treatments could be effective for high risk DCIS?

Research has shown that injecting pembrolizumab directly into tumors holds promise for treating ductal carcinoma in situ (DCIS). In earlier studies, about 80% of patients responded positively, and in 30% of cases, the cancer completely disappeared. Almost all patients experienced an increase in immune cells attacking the cancer. In this trial, some participants will receive pembrolizumab alone, while others will receive it in combination with mRNA-2752.

For mRNA-2752, studies suggest it is safe and may help the immune system fight DCIS effectively. This treatment can quickly shrink tumors. In this trial, some participants will receive mRNA-2752 alone, while others will receive it in combination with pembrolizumab. Combining mRNA-2752 with pembrolizumab might enhance these effects, leading to a strong immune response against cancer cells. ^{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 with high-risk ductal carcinoma in situ (DCIS) who plan to have surgery, are not pregnant or breastfeeding, and agree to use contraception. Eligible participants must have certain high-risk features like a palpable mass or hormone receptor negative status, be in good physical condition (ECOG 0-1), and demonstrate adequate organ function.

Inclusion Criteria

Be willing and able to provide written informed consent/assent for the trial

Hematological Absolute Neutrophil Count (ANC) >=1,500/microliter (mcL) Platelets >=100,000/mcL Hemoglobin >=9 g/dL or >=5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment)

My cancer is mostly non-invasive, with less than 10% being invasive.

Exclusion Criteria

Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial

Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment

Has a known history of Hepatitis B (defined as Hepatitis B surface antigen (HBsAg) reactive) or known active Hepatitis C virus (HCV) (defined as HCV RNA [qualitative] is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive intralesional injections of mRNA-2752 and/or pembrolizumab, with doses administered 3 weeks apart, followed by surgery or biopsy

9-15 weeks

3-5 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

18 months

What Are the Treatments Tested in This Trial?

Interventions

• Intralesional mRNA 2752
• Pembrolizumab

Trial Overview The study tests the effects of short-term immunotherapy on DCIS using Pembrolizumab and Intralesional mRNA 2752 before surgical removal. It aims to understand how these treatments alter the immune environment within the breast tissue affected by cancer.

How Is the Trial Designed?

Group I: mRNA-2752 x 2-4 doses with or without immune checkpoint inhibitor (Expansion Cohort) Experimental Treatment 1 Intervention

Participants will be will be offered injections of mRNA-2752 given on up to 4 occasions, 3 weeks apart (+/- 1 week) or a combination mRNA-2752 and immune checkpoint inhibitor will be given up to 4 occasions, 3 weeks apart (+/- 1 week). The participants will proceed to biopsy, either image guided or excisional or partial mastectomy.

Group II: mRNA-2752 Monotherapy x 2-4 doses (Escalation Cohort) Experimental Treatment 1 Intervention

Participants will be offered up to 4 doses of mRNA-2752 injected intralesionally (IL) 3 weeks apart (+/- 1) week) with surgery or core biopsy 3 weeks (+/-1 week). The participants will proceed to biopsy, either image guided or excisional or partial mastectomy

Group III: CLOSED:Pembrolizumab intralesionally (IL) x 2 doses (Escalation Phase) Experimental Treatment 1 Intervention

Participants, upon diagnosis with high risk DCIS, will be offered 2 doses of pembrolizumab injected intralesionally (IL) 3 weeks apart (+/- 1 week) with surgery 3 weeks (+/- 2 weeks) after the 2nd dose. The participant will then undergo the surgical treatment as determined by the surgeon and the participant (partial mastectomy or mastectomy).

Group IV: CLOSED:Pembrolizumab IL x 4 doses (Expansion Phase) Experimental Treatment 1 Intervention

Participants, upon diagnosis with high risk DCIS, will be offered 4 doses of pembrolizumab injected intralesionally (IL) 3 weeks apart (+/- 1 week) with surgery 3 weeks (+/- 2 weeks) after the 4th dose. The participant will then undergo the surgical treatment as determined by the surgeon and the participant (partial mastectomy or mastectomy).

Group V: CLOSED:Pembrolizumab IL x 2 doses + mRNA 2752 IL x 2-4 doses (Expansion Phase) Experimental Treatment 2 Interventions

Participants, upon diagnosis with high risk DCIS, will be offered 2 doses of pembrolizumab and intralesional mRNA 2752 injected intralesionally (IL) 3 weeks apart (+/- 1 week) with surgery 3 weeks (+/- 2 weeks) after the 2nd dose. The participant will then undergo the surgical treatment as determined by the surgeon and the participant (partial mastectomy or mastectomy).

Group VI: No active treatment Active Control 1 Intervention

The control group will proceed to surgery alone within a 4 month timeframe following the diagnosis of high risk DCIS.

Pembrolizumab is already approved in United States, European Union, United Kingdom for the following indications:

Approved in United States as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in European Union as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in United Kingdom as KEYTRUDA for:

• Untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1

Who Is Running the Clinical Trial?

Laura Esserman

Lead Sponsor

Trials

1

Recruited

40+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

ModernaTX, Inc.

Industry Sponsor

Trials

127

Recruited

66,790,000+

Dr. Stephen Hoge

ModernaTX, Inc.

Chief Medical Officer

MD from Harvard Medical School

Stéphane Bancel

ModernaTX, Inc.

Chief Executive Officer since 2011

MBA from Harvard Business School, MSc in Engineering from École Centrale Paris

Published Research Related to This Trial

Pembrolizumab, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating advanced melanoma, showing an overall response rate of 24% in a trial of 89 patients, with 86% of responses lasting at least 6 months.

While there are potential immune-mediated side effects, the benefits of prolonged tumor response durations were deemed to outweigh these risks, marking an improvement over existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. Chuk, MK., Chang, JT., Theoret, MR., et al.[2021]

In a study of 41 pancreas cancer patients treated with pembrolizumab, the median overall survival was 7.2 months, which is considered favorable compared to the benchmark of over 4 months.

Patients with specific genetic markers (dMMR, MSI-H, TMB-H, or Lynch syndrome) had a significantly lower risk of death, indicating that these biomarkers may help identify patients who could benefit more from pembrolizumab treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab near the end of life in patients with metastatic pancreatic cancer: a multi-site consecutive series to examine survival and patient treatment burden. Storandt, MH., Tran, N., Martin, N., et al.[2023]

Pembrolizumab is an effective monoclonal antibody that targets the PD-1 immune checkpoint, helping to restore T cell anti-tumor responses, and is administered at a dose of 200 mg every 3 weeks until disease progression or for up to 24 months.

It has received approval for treating various cancers, including melanomas and non-small cell lung cancers, particularly in tumors that are hypermutated or express PD-L1, but ongoing research aims to expand its use to less immunogenic tumor types through combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical utility of pembrolizumab in the management of advanced solid tumors: an evidence-based review on the emerging new data. du Rusquec, P., de Calbiac, O., Robert, M., et al.[2023]

Pembrolizumab, an immune checkpoint inhibitor, can cause pneumonitis in 1%-5% of patients, and this case report highlights an atypical presentation of this side effect in a patient with metastatic squamous cell carcinoma.

The patient was successfully treated with steroid therapy after ruling out other potential causes, leading to complete resolution of the pneumonitis, emphasizing the importance of recognizing and managing atypical cases of checkpoint inhibitor-pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. Jeon, WJ., Nguyen, J., Castillo, DR., et al.[2023]

Pembrolizumab, a PD-1 inhibitor used in cancer treatment, can lead to rare but serious immune-related adverse events, including type 1 diabetes mellitus, occurring in about 0.2% of cases.

A review of 42 cases revealed that patients may develop diabetic ketoacidosis during treatment, highlighting the need for blood glucose monitoring and awareness of this potential side effect among clinicians.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. Clotman, K., Janssens, K., Specenier, P., et al.[2022]

A patient with metastatic pancreatic ductal adenocarcinoma (PDAC) that is microsatellite instability-high showed a remarkable response to the immunotherapy drug pembrolizumab, lasting nearly 3 years.

This case highlights the potential for immunotherapy to be effective in certain subtypes of PDAC, which typically do not respond well to such treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Patient with Metastatic Microsatellite Instability-High Pancreatic Ductal Adenocarcinoma with a Prolonged Response to Single-Agent Pembrolizumab. Guedikian, AA., Randall, ME., Sharko, A., et al.[2021]

Pembrolizumab (Keytruda) has been approved by the FDA for treating high-risk, non-muscle invasive bladder cancer (NMIBC) in patients who are unresponsive to BCG therapy and are either ineligible for or have opted not to undergo cystectomy.

This approval specifically targets patients with carcinoma in situ (CIS) with or without papillary tumors, highlighting its role as a treatment option for those with limited surgical options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approves Pembrolizumab for BCG-Unresponsive NMIBC. Wright, KM.[2021]

In a phase Ib trial involving 26 patients with advanced PD-L1-positive ovarian cancer, pembrolizumab demonstrated a confirmed objective response rate of 11.5%, indicating some level of antitumor activity, with 1 complete response and 2 partial responses observed.

The treatment was generally well-tolerated, with 73.1% of patients experiencing treatment-related adverse events, but no deaths or treatment discontinuations due to these events, suggesting that pembrolizumab has a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in patients with programmed death ligand 1-positive advanced ovarian cancer: Analysis of KEYNOTE-028. Varga, A., Piha-Paul, S., Ott, PA., et al.[2019]

Citations

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Intratumoral Injection of mRNA-2752 and Pembrolizumab ... The results suggest that intratumoral injections of pembrolizumab and mRNA-2752 are safe and may induce rapid regression of high-risk DCIS with high immune ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT02872025

Immunotherapy in High-risk Ductal Carcinoma in Situ (DCIS) To determine the efficacy of intralesional mRNA-2752 monotherapy in participants with ductal carcinoma in situ (DCIS) of the breast as measured by the ...

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OX40L/IL-23/IL-36γ (Triplet) (mRNA-2752) Key Objectives. ▫. Evaluate safety and tolerability of. mRNA-2752 administered alone and in combination with PD-L1 inhibitor.

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Intratumoral Injection of mRNA-2752 and Pembrolizumab ... Effective mRNA vaccine design for in vivo function requires consideration of many factors, including effective vaccine targets, mRNA structures, ...

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Intratumoral Injection of mRNA-2752 and Pembrolizumab ... The results suggest that intratumoral injections of pembrolizumab and mRNA-2752 are safe and may induce rapid regression of high-risk DCIS with high immune ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12272796/

Breaking new ground in ductal carcinoma in situ ... mRNA-2752 encodes three key immune stimulators, including two immune stimulatory cytokines, involving danger signals with interleukin (IL)-23 ...

7. s29.q4cdn.com s29.q4cdn.com/435878511/files/doc_presentations/2022/Oct/14/sitc-2022-poster-final-14oct2022-72.pdf

Safety and Preliminary Efficacy of mRNA-2752, a Lipid ... On-treatment core biopsies of injected and satellite lesions showed no residual carcinoma. PR ongoing for 6+ months. Pre-treatment. C1D15. C2D1. C3D1. mRNA-2752 ...