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

42 Participants Needed

Trial Summary

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.

What data supports the idea that Immunotherapy for Intraductal Carcinoma is an effective treatment?

The available research does not provide specific data supporting the effectiveness of immunotherapy for Intraductal Carcinoma. Instead, it discusses the use of pembrolizumab, a drug used in immunotherapy, for other types of cancer. For example, pembrolizumab showed minimal benefit for most patients with pancreatic cancer, but there was a case where a patient with a specific type of pancreatic cancer had a prolonged response to the drug. Additionally, pembrolizumab was tested in lung and ovarian cancers, but the results focused on safety and tolerability rather than effectiveness. Therefore, there is no direct evidence from the provided research that supports the effectiveness of this treatment for Intraductal Carcinoma. ^{1 2 3 4 5}

What data supports the effectiveness of the drug Pembrolizumab in treating cancer?

Pembrolizumab has shown effectiveness in treating certain types of cancer, such as non-small cell lung cancer and ovarian cancer, by helping the immune system attack cancer cells. However, its benefits can vary depending on the type of cancer, as seen in a case where a patient with a specific type of pancreatic cancer had a prolonged response to the drug. ^{1 2 3 4 5}

What safety data is available for the immunotherapy treatment involving Pembrolizumab and related therapies?

Pembrolizumab (Keytruda) is associated with immune-related adverse events (irAEs), including type 1 diabetes mellitus in 0.2% of cases, pneumonitis in 1%-5% of patients, and other immune-mediated reactions like colitis, hepatitis, and thyroid disorders. Common adverse reactions include fatigue, cough, nausea, rash, and diarrhea. Despite these risks, the benefits in treating life-threatening diseases like metastatic melanoma and non-muscle invasive bladder cancer have been considered to outweigh the risks. ^{5 6 7 8 9}

Is the immunotherapy treatment generally safe for humans?

Pembrolizumab, a part of the immunotherapy treatment, has been associated with some side effects like fatigue, cough, and nausea, and more serious immune-related effects like pneumonitis (lung inflammation) and type 1 diabetes in rare cases. While these side effects exist, the benefits in treating certain cancers have been considered to outweigh the risks. ^{5 6 7 8 9}

Is the drug Pembrolizumab a promising treatment for Intraductal Carcinoma?

Pembrolizumab is a promising drug because it helps the immune system fight cancer by targeting a specific pathway (PD-1/PD-L1) that tumors use to hide from immune cells. It has shown effectiveness in treating various cancers, like lung cancer and melanoma, and is approved for use in several types of tumors. Its ability to work in different cancers suggests it could be promising for Intraductal Carcinoma as well. ^{1 2 5 9 10}

What makes the drug pembrolizumab unique for treating intraductal carcinoma?

Pembrolizumab is unique because it is an immunotherapy drug that works by blocking the PD-1 receptor, helping the immune system attack cancer cells. Unlike traditional chemotherapy, it specifically targets the immune system to fight cancer, which can be beneficial for tumors that express PD-L1, although it may cause immune-related side effects. ^{1 2 5 9 10}

What is the purpose of this trial?

This is a study to investigate the change in the immune microenvironment of high risk ductal carcinoma in situ (DCIS) after short term exposure to immunotherapy.

Research Team

Laura Esserman, MD

Principal Investigator

University of California, San Francisco

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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, 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]

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]

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 (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]

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]

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]

References

1. Germany 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. [2023]

2. Ireland pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. [2022]

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

Pembrolizumab in patients with programmed death ligand 1-positive advanced ovarian cancer: Analysis of KEYNOTE-028. [2019]

4. Switzerland pubmed.ncbi.nlm.nih.gov

A Patient with Metastatic Microsatellite Instability-High Pancreatic Ductal Adenocarcinoma with a Prolonged Response to Single-Agent Pembrolizumab. [2021]

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

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. [2022]

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

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. [2023]

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

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

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

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. [2017]

10. New Zealand 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. [2023]