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

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ClinicalTrials.gov Identifier: NCT02872025
Recruitment Status : Recruiting
First Posted : August 18, 2016
Last Update Posted : October 26, 2017
Sponsor:
Information provided by (Responsible Party):
Laura Esserman, University of California, San Francisco

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.

Condition or disease Intervention/treatment Phase
Carcinoma, Intraductal, Noninfiltrating Drug: Pembrolizumab Early Phase 1

Detailed Description:
This study will include 3 dose cohorts using a 3+3 cohort dose escalation design (see figure 1) followed by a 4th cohort 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 randomized to either the control group or the treatment group. 10 subjects will be randomized to the control group and 20 subjects will be randomized to the treatment group. The control group will proceed to surgery alone following the diagnosis of high risk DCIS. The treatment group will receive 2 doses of intralesional pembrolizumab 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.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Testing the Ability of Pembrolizumab to Alter the Tumor Immune MicroEnvironment (TIME) of High Risk DCIS
Actual Study Start Date : December 12, 2016
Estimated Primary Completion Date : March 2018
Estimated Study Completion Date : September 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Pembrolizumab intralesionally (IL) x 2 doses
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).
Drug: Pembrolizumab
Other Names:
  • Keytruda
  • MK-3475

No Intervention: No active treatment
The control group will proceed to surgery alone following the diagnosis of high risk DCIS.



Primary Outcome Measures :
  1. 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.

  2. 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.

  3. 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: 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.


Other Outcome Measures:
  1. Tumor volume [ Time Frame: 18 months ]
    To determine whether intralesional pembrolizumab decreases tumor volume on MRI imaging.

  2. 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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Plan on having surgical treatment to remove the lesion
  • 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)
  • 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
  • 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 a performance status of 0 or 1 on the ECOG Performance Scale.
  • Demonstrate adequate organ function as defined in Table 1 Adequate Organ Function Laboratory Values
  • All screening labs should be performed within 10 days of treatment initiation.
  • Hematological Absolute Neutrophil Count (ANC) >=1,500/mcL Platelets >=100,000/mcL Hemoglobin >=9 g/dL or >=5.6 mmol/L without transfusion or 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 xULN OR Direct bilirubin <= ULN for subjects with total bilirubin levels > 1.5 ULN AST (SGOT) and ALT (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.

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.
  • Is not interested in surgical treatment of her DCIS
  • Has invasive breast cancer
  • Has a known history of active TB (Bacillus Tuberculosis)
  • Hypersensitivity to pembrolizumab 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 history of/active pneumonitis that required/is requiring steroid treatment or had history of/active interstitial lung disease. Has an active infection requiring systemic therapy.
  • 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.
  • 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 received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
  • Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
  • Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
  • Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02872025


Contacts
Contact: Katherine Forster 415-885-7691 katherine.forster@ucsf.edu

Locations
United States, California
University of California, San Francisco Recruiting
San Francisco, California, United States, 94115
Sponsors and Collaborators
Laura Esserman

Responsible Party: Laura Esserman, Professor, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT02872025     History of Changes
Other Study ID Numbers: 16704
First Posted: August 18, 2016    Key Record Dates
Last Update Posted: October 26, 2017
Last Verified: October 2017

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Intraductal, Noninfiltrating
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Breast Carcinoma In Situ
Carcinoma in Situ
Neoplasms, Ductal, Lobular, and Medullary
Pembrolizumab
Antineoplastic Agents