Testing the Ability of Immunotherapy to Alter the Tumor Immune MicroEnvionment (TIME) and Reduce or Eradicate High Risk DCIS
Overview
- Phase
- Early Phase 1
- Intervention
- Pembrolizumab
- Conditions
- Carcinoma, Intraductal, Noninfiltrating
- Sponsor
- Laura Esserman
- Enrollment
- 42
- Locations
- 1
- Primary Endpoint
- Percentage of patients who demonstrate an increase (baseline vs. post intralesional injection) in intralesional CD8+ T cells
- Status
- Active, not recruiting
- Last Updated
- last year
Overview
Brief Summary
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.
Detailed Description
PRIMARY OBJECTIVES: DOSE ESCALATION (Monotherapy Messenger RNA-2725 (mRNA-2752): I. To determine the efficacy of intralesional mRNA-2752 monotherapy in participants with ductal carcinoma in situ (DCIS) of the breast as measured by the change in the MRI tumor size/volume/enhancement. Absence of tumor on biopsy and increase in immune infiltrates as measured by immune multiplex assays. II. To characterize the safety of mRNA-2752 and feasibility of intralesional administration of mRNA-2752 in patients with high-risk DCIS. DOSE EXPANSION (mRNA-2752 with or without an immune checkpoint inhibitor): I. To determine the Magnetic resonance imaging (MRI) response rate and complete pathologic response rate with either mRNA-2752 monotherapy or combined therapy in high risk DCIS. ENROLLMENT IN THE PREVIOUS COHORTS HAS BEEN COMPLETED.
Investigators
Laura Esserman
Professor
University of California, San Francisco
Eligibility Criteria
Inclusion Criteria
- •Plan on having surgical treatment to remove the lesion
- •Have at least 2 of the following high-risk features associated with 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) and abundant T cell infiltration.
- •Participants with extensive DCIS and a small component of invasive disease are eligible as long as the extent of invasive disease is 10% or less of the total burden of disease.
- •Participants 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
- •Be willing and able to provide written informed consent/assent for the trial.
- •Be \>=18 years of age on day of signing informed consent.
- •Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
- •Demonstrate adequate organ function (all screening labs should be performed within 3 months of treatment initiation):
- •Absolute Neutrophil Count (ANC) \>=1,500/microliter (mcL).
- •Platelets \>=100,000/mcL.
Exclusion Criteria
- •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.
- •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.
- •Has hormone positive DCIS (HR+) that is not Her2+.
- •Has invasive breast cancer. This does not include DCIS with \<10% invasive component and a clinically node negative disease.
- •Has a known history of active Bacillus Tuberculosis (TB)
- •Hypersensitivity to mRNA-2752 for mRNA-2752 monotherapy and combination therapy and hypersensitivity to immune check point inhibitor for the combination therapy or any of its excipients.
- •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.
- •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.
- •Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
- •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.
Arms & Interventions
CLOSED:Pembrolizumab intralesionally (IL) x 2 doses (Escalation Phase)
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).
Intervention: Pembrolizumab
CLOSED:Pembrolizumab IL x 4 doses (Expansion Phase)
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).
Intervention: Pembrolizumab
CLOSED:Pembrolizumab IL x 2 doses + mRNA 2752 IL x 2-4 doses (Expansion Phase)
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).
Intervention: Pembrolizumab
CLOSED:Pembrolizumab IL x 2 doses + mRNA 2752 IL x 2-4 doses (Expansion Phase)
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).
Intervention: Intralesional mRNA 2752
mRNA-2752 Monotherapy x 2-4 doses (Escalation Cohort)
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
Intervention: Intralesional mRNA 2752
mRNA-2752 x 2-4 doses with or without immune checkpoint inhibitor (Expansion Cohort)
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.
Intervention: Intralesional mRNA 2752
Outcomes
Primary Outcomes
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.
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.