Pembrolizumab in High-risk Ductal Carcinoma in Situ (DCIS)

• ClinicalTrials.gov Identifier: NCT02872025
• Recruitment Status: Recruiting
• First Posted: August 18, 2016
• Last Update Posted: October 25, 2022
• Sponsor: Laura Esserman
• Collaborators: Merck Sharp & Dohme LLC; ModernaTX, Inc.
• Information provided by (Responsible Party): Laura Esserman, University of California, San Francisco

Tracking Information

• First Submitted Date: August 10, 2016
• First Posted Date: August 18, 2016
• Last Update Posted Date: October 25, 2022
• Actual Study Start Date: December 12, 2016
• Estimated Primary Completion Date: March 31, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 26, 2021)

• Maximum tolerated dose (MTD) [ Time Frame: 18 months ]
  To determine the maximum tolerated dose (MTD), and recommended dose for subsequent expansion cohort, of intralesionally administered pembrolizumab in patients with ductal carcinoma in situ (DCIS) of the breast.
• Number of participants with Dose-limiting toxicities (DLTs) [ Time Frame: 18 months ]
  To define the dose-limiting toxicities (DLTs), tolerability, and feasibility of intralesional administration of pembrolizumab in patients with DCIS.
• Percentage of patients who demonstrate an increase (baseline vs. post intralesional injection) in intralesional CD8+ T cells [ Time Frame: post intralesional injection ]
  To determine the response rate to intralesional pembrolizumab in patients with DCIS, as measured by an increase (baseline vs. post treatment) in intralesional CD8+ T cells, compared to untreated controls.

Original Primary Outcome Measures (submitted: August 15, 2016)

• Maximum tolerated dose (MTD) [ Time Frame: 18 months ]
  To determine the maximum tolerated dose (MTD), and recommended dose for subsequent expansion cohort, of intralesionally administered pembrolizumab in patients with ductal carcinoma in situ (DCIS) of the breast.
• Dose-limiting toxicities (DLTs) [ Time Frame: 18 months ]
  To define the dose-limiting toxicities (DLTs), tolerability, and feasibility of intralesional administration of pembrolizumab in patients with DCIS.
• Percentage of patients who demonstrate an increase (baseline vs. post intralesional injection) in intralesional CD8+ T cells (treated vs. untreated participants) as measured using multiplex immunofluorescence on FFPE tissue sections [ Time Frame: baseline ]
  To determine the response rate to intralesional pembrolizumab in patients with DCIS, as measured by an increase (baseline vs. post treatment) in intralesional CD8+ T cells, compared to untreated controls.

• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided

Current Other Pre-specified Outcome Measures (submitted: January 26, 2021)

• Changes in Mean Tumor volume [ Time Frame: 18 months ]
  To determine whether intralesional pembrolizumab with or without mRNA 2752 decreases tumor volume on MRI imaging
• Exploratory immunological responses to pembrolizumab before and after intralesional injection as measured using multiplex immunofluorescence on formalin-fixed paraffin-embedded (FFPE) tissue sections [ Time Frame: 18 months ]
  To characterize changes in the immune landscape of DCIS following intralesional administration of pembrolizumab with or without mRNA 2752.

Original Other Pre-specified Outcome Measures (submitted: August 15, 2016)

• Tumor volume [ Time Frame: 18 months ]
  To determine whether intralesional pembrolizumab decreases tumor volume on MRI imaging.
• Exploratory immunological responses to pembrolizumab before and after intralesional injection as measured using multiplex immunofluorescence on FFPE tissue sections [ Time Frame: 18 months ]
  To characterize changes in the immune landscape of DCIS following intralesional administration of pembrolizumab.

Descriptive Information

• Brief Title: Pembrolizumab in High-risk Ductal Carcinoma in Situ (DCIS)
• Official Title: Testing the Ability of Pembrolizumab and mRNA 2752 to Alter the Tumor Immune MicroEnvionment (TIME) of High Risk DCIS
• Brief Summary: This is a pilot study to investigate the change in the immune microenvironment of high risk ductal carcinoma in situ (DCIS) after short term exposure to pembrolizumab.

Detailed Description

This study will include 3 dose cohorts using a 3+3 cohort dose escalation design followed by a 4th cohort (the dose expansion phase) at the maximum tolerated dose. Unless a dose limiting toxicity (DLT), defined any grade 3 or 4 toxicity, is observed requiring expansion of a cohort or a subject withdraws, 3 subjects will be enrolled into each cohort in the dose escalation phase. Subjects, 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 subject will then undergo the surgical treatment as determined by the surgeon and the subject (partial mastectomy or mastectomy). The primary objective of this phase of the study will be safety and feasibility of intralesional injection of pembrolizumab.

The maximum tolerated dose will be used in the expansion phase. The expansion cohort will have a target enrollment of 30 subjects enrolled to either the control group or the treatment group. The treatment group will consist of 20 subjects who agree to receive the treatment. The control group will consist of 10 eligible subjects who decline treatment and agree to tissue collection and to the use of tissue for research purposes. The control group will proceed to surgery alone within a 4 month timeframe following the diagnosis of high risk DCIS. The treatment group will receive 4 doses of intralesional pembrolizumab monotherapy 3 weeks apart (+/- 1 week) prior to surgery (first 5 patients enrolled) but will now receive 2 doses of intralesional pembrolizumab and intralesional mRNA 2752 3 weeks apart (+/- 1 week) prior to surgery. All subjects in the expansion cohort will also undergo a baseline MRI at diagnosis and undergo a 2nd MRI prior to surgery. Baseline and pre-surgical MRI images will be evaluated for changes in tumor volume.

Note: The last patient finished the escalation phase on 08/14/2018, and the study is currently in the expansion phase.

• Study Type: Interventional
• Study Phase: Early Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Carcinoma, Intraductal, Noninfiltrating

Intervention

• Drug: Pembrolizumab
  Injected intralesionally
  Other Names:

  • Keytruda
  • MK-3475
• Biological: Intralesional mRNA 2752
  Injected intralesionally
  Other Name: mRNA 2752

Study Arms

• Experimental: Pembrolizumab intralesionally (IL) x 2 doses (Escalation Phase)
  Subjects, 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 subject will then undergo the surgical treatment as determined by the surgeon and the subject (partial mastectomy or mastectomy).
  Intervention: Drug: Pembrolizumab
• Experimental: Pembrolizumab intralesionally (IL) x 4 doses (Expansion Phase)
  Subjects, 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 subject will then undergo the surgical treatment as determined by the surgeon and the subject (partial mastectomy or mastectomy).
  Intervention: Drug: Pembrolizumab
• Experimental: Pembrolizumab intralesional (IL) x 2 doses + intralesional mRNA 2752 x 2-4 doses (Expansion Phase)
  Subjects, 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 subject will then undergo the surgical treatment as determined by the surgeon and the subject (partial mastectomy or mastectomy).
  Interventions:

  • Drug: Pembrolizumab
  • Biological: Intralesional mRNA 2752
• No Intervention: No active treatment
  The control group will proceed to surgery alone within a 4 month timeframe following the diagnosis of high risk DCIS.

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: August 15, 2016): 48
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: March 31, 2024
• Estimated Primary Completion Date: March 31, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Plan on having surgical treatment to remove the lesion
2. Have at least 2 of the following high risk features associated with her DCIS - high-grade (grade II-III), palpable mass, hormone receptor negative (less than 1%), Her2 positive, young age (less than 45 years old), and large size (greater than 5 cm)
3. Patients with a history of tamoxifen and/or aromatase inhibitor use for treatment or prevention are eligible but should discontinue these medications at least 2 weeks prior to starting this trial
4. Be willing and able to provide written informed consent/assent for the trial.
5. Be >=18 years of age on day of signing informed consent.
6. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1

7. Demonstrate adequate organ function:

   • All screening labs should be performed within 10 days of treatment initiation.
   • 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)
   • Renal Serum creatinine <=1.5 X upper limit of normal (ULN) OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) >=60 mL/min for subject with creatinine levels > 1.5 X institutional ULN
   • Hepatic Serum total bilirubin <=1.5 x ULN OR Direct bilirubin <= ULN for subjects with total bilirubin levels > 1.5 ULN aspartate aminotransferase (AST) / serum glutamic-oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT) / serum glutamic-pyruvic transaminase (SGPT) <= 2.5 X ULN Albumin >=2.5mg/dL
   • Coagulation International Normalized Ratio (INR) or Prothrombin Time (PT) <=1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants Activated Partial Thromboplastin Time (aPTT) <=1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
   • Female subjects of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
   • Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication (Reference Section 5.7.2). Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.

8. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:

   1. Not a woman of childbearing potential (WOCBP) OR
   2. A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 90 days corresponding to time needed to eliminate any study treatment plus 30 days (a menstruation cycle) after the last dose of study treatment.
9. A male participant must agree to use a contraception during the treatment period and for at least 90 days corresponding to time needed to eliminate any study treatment plus an additional 120 days (a spermatogenesis cycle) after the last dose of study treatment and refrain from donating sperm during this period.

Exclusion Criteria:

1. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
3. Is not interested in surgical treatment of her DCIS
4. Has invasive breast cancer. This does not include DCIS with <10% invasive component and a clinically node negative disease.
5. Has a known history of active Bacillus Tuberculosis (TB)
6. Hypersensitivity to pembrolizumab or any of its excipients.
7. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
8. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g.,, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
9. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
10. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
11. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
12. 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.
13. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
14. 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.
15. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Laura Esserman, MD; 877-827-3222; cancertrials@ucsf.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02872025
• Other Study ID Numbers: 16704; NCI-2017-01320 ( Registry Identifier: NCI Clinical Trials Reporting Program (CTRP) )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Laura Esserman, University of California, San Francisco
• Original Responsible Party: Same as current
• Current Study Sponsor: Laura Esserman
• Original Study Sponsor: Same as current

Collaborators

• Merck Sharp & Dohme LLC
• ModernaTX, Inc.

Investigators

• Principal Investigator: Laura Esserman, MD; University of California, San Francisco

• PRS Account: University of California, San Francisco
• Verification Date: October 2022