Clinical Trials /

Epicutaneous Cryoimmunotherapy Combined With Pembrolizumab for Cutaneous Metastatic Breast Cancer

NCT03982004

Description:

The purpose of this research study is to look at the safety and side effects of combining the drug pembrolizumab with imiquimod, GM-CSF, and cryotherapy to treat breast cancer that includes skin lesions.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Epicutaneous Cryoimmunotherapy Combined With Pembrolizumab for Cutaneous Metastatic Breast Cancer
  • Official Title: Phase IB Pilot Study of Epicutaneous Cryoimmunotherapy Combined With Pembrolizumab for Cutaneous Metastatic Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: 19-x150
  • NCT ID: NCT03982004

Conditions

  • Metastatic Breast Cancer

Interventions

DrugSynonymsArms
Topical imiquimodEpicutaneous cryoimmunotherapy+imiquimod+pembrolizumab+GM-CSF
PembrolizumabKeytrudaEpicutaneous cryoimmunotherapy+imiquimod+pembrolizumab+GM-CSF
Intra-lesional GM-CSFEpicutaneous cryoimmunotherapy+imiquimod+pembrolizumab+GM-CSF

Purpose

The purpose of this research study is to look at the safety and side effects of combining the drug pembrolizumab with imiquimod, GM-CSF, and cryotherapy to treat breast cancer that includes skin lesions.

Trial Arms

NameTypeDescriptionInterventions
Epicutaneous cryoimmunotherapy+imiquimod+pembrolizumab+GM-CSFExperimentalEpicutaneous cryoimmunotherapy treatments (6 total) during weeks 1-14 (every 2 weeks for 5 weeks, then every 3 weeks until week 14) Topical imiquimod will be applied 5 days per week (Weeks 1-12) Pembrolizumab will be given every 3 weeks starting at Week 5 until disease progression or unacceptable toxicity. Intra-lesional GM-CSF 250 mcg every 2 weeks x 3 doses then every 3 weeks for 3 doses
  • Topical imiquimod
  • Pembrolizumab
  • Intra-lesional GM-CSF

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically confirmed locally advanced unresectable or metastatic breast cancer
             with cutaneous metastasis with progression after one or more therapies including
             endocrine therapies for estrogen receptor positive breast cancer.

          -  Failed at least 1 prior therapies

          -  Patients can have concurrent maintenance therapy (including endocrine therapy,
             pertuzumab, or trastuzumab) if they have had stable or progressive cutaneous disease
             for 2 months prior to study entry and there is no anticipated change in maintenance
             therapy drug during the study period.

          -  Patients that are starting a new systemic therapy must receive the new systemic
             therapy for at least 2 weeks before enrolling in this study.

          -  Have measurable disease based on RECIST 1.1. Lesions situated in a previously
             irradiated area are considered measurable if progression has been demonstrated in such
             lesions.

          -  Be willing to provide serial tumor and blood specimens (week 0, 2, 5, 10, and 18).
             Baseline biopsy should be performed within 2 weeks of 1st treatment.

          -  At least 18 years of age on the day of signing informed consent.

          -  Have a performance status of 0 or 1 on the ECOG Performance Scale. Evaluation of ECOG
             PS is to be performed within 7 days prior to the date of allocation.

          -  Demonstrate adequate organ function (performed within 10 days of treatment
             initiation), defined as:

               -  Absolute neutrophil count (ANC) ≥1,500 /mcL

               -  Platelets ≥100,000 / mcL

               -  Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/L without erythropoietin dependency and without
                  packed red blood cell transfusion within the last 2 weeks

               -  Creatinine ≤1.5 X upper limit of normal (ULN) OR

               -  Measured or calculateda creatinine clearance (GFR can also be used in place of
                  creatinine or CrCl) ≥30 mL/min for subject with creatinine levels > 1.5 X
                  institutional ULN

               -  Total bilirubin ≤ 1.5 X ULN OR

               -  Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN

               -  AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN (≤ 5 X ULN for subjects with liver
                  metastases)

               -  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

          -  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 12 days after the last dose of study treatment.

          -  A male participant must agree to use contraception during the treatment period and for
             at least 120 days after the last dose of study treatment and refrain from donating
             sperm during this period.

          -  Ability to understand and willingness to sign an IRB approved written informed consent
             document.

        Exclusion Criteria:

          -  Has large, ulcerated, bulky tumors (defined as total volume greater than 4 x 4 x 4
             cm^3 with > 50% ulceration).

          -  Has life expectancy of < 6 months.

          -  Is currently participating in or has participated in a study of an investigational
             agent or has used an investigational device within 4 weeks of the first dose of
             treatment. Note: Participants who have entered the follow-up phase of an
             investigational study may participate as long as it has been 4 weeks after the last
             dose of the previous investigational agent.

          -  Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (in doses
             exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive
             therapy within 7 days prior to the first dose of trial treatment.

          -  Has a known history of active TB (Bacillus Tuberculosis)

          -  Has severe hypersensitivity (≥ grade 3) to pembrolizumab or any of its excipients.

          -  Patients that have received prior systemic anti-cancer therapy including
             investigational agents within 2 weeks prior to study Day 1. or who.

               -  Note: Participants must have recovered from all AEs due to a previous therapies
                  to ≤ grade 1 or baseline. Subjects with ≤ Grade 2 neuropathy may be eligible.

               -  Note: If subject received major surgery, they must have recovered adequately from
                  the toxicity and/or complications from the intervention prior to starting
                  therapy.

          -  Has received prior radiotherapy within 2 weeks of start of study treatment.
             Participants must have recovered from all radiation-related toxicities, not require
             corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted
             for palliative radiation (≤ 2 weeks of radiotherapy) to non-CNS disease.

          -  Has a known additional malignancy that is progressing or requires active treatment
             within the past 3 years. Note: participants with basal cell carcinoma of the skin,
             squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma,
             cervical cancer) that have undergone potentially curative therapy are not excluded.

          -  Has known active central nervous system (CNS) metastases and/or carcinomatous
             meningitis. Subjects with previously treated brain metastases may participate provided
             they are radiologically stable i.e. without evidence of progression by imaging for at
             least four weeks prior by repeat imaging (note that the repeat imaging should be
             performed during study screening), clinically stable and without requirement of
             steroid treatment for at least 14 days prior to first dose of study treatment.

          -  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., thyroxin, 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 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. A WOCBP who has a positive
             urine pregnancy test within 72 hours prior to allocation. If the urine test is
             positive or cannot be confirmed as negative, a serum pregnancy test will be required.

          -  Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with
             an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g.
             CTLA-4, OX-40, CD137).

          -  Has a known history of Human Immunodeficiency Virus (HIV).

          -  Has known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg]
             reactive) or known active Hepatitis C (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.

          -  Has received a live vaccine within 30 days of planned start of study therapy. 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety and tolerability as measured by rate of treatment emergent grade 3 or higher toxicities
Time Frame:From beginning of treatment through 90 days following completion of treatment or 30 days following completion of treatment if the participant initiates new therapy (whichever is earlier)
Safety Issue:
Description:-NCI Common terminology criteria for adverse events (CTCAE v5.0) will be used to grade toxicities

Secondary Outcome Measures

Measure:Objective response rate (ORR) as measured by RECIST 1.1
Time Frame:Baseline and 18 weeks
Safety Issue:
Description:For patients who present with discrete measurable lesions ORR = number of patients who achieve CR or PR divided by the total number response-evaluable patients Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Measure:Progression-free survival (PFS)
Time Frame:2 years
Safety Issue:
Description:Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). PFS is defined from date on treatment to the earliest date of progression, death, or last follow-up and progression or death are events of interest for PFS.
Measure:Change from baseline to week 5 in the number of tumor infiltrating lymphocytes after epicutaneous cryoimmunotherapy
Time Frame:Baseline and week 5
Safety Issue:
Description:
Measure:Change from week 6 to week 10 in the number of tumor infiltrating lymphocytes after epicutaenous cryoimmunotherapy plus 2 cycles of pemrolizumab
Time Frame:Week 6 and week 10
Safety Issue:
Description:
Measure:Change from baseline to 18 weeks in the number of tumor cells
Time Frame:Baseline and 18 weeks
Safety Issue:
Description:
Measure:Change in quality of life as measured by the Dermatologic Quality of Life Index
Time Frame:Baseline and 18 weeks
Safety Issue:
Description:10 questions about how much skin problems has affected the participant's life over the past week The scoring of each question is as follows: very much = 3, a lot = 2, a little = 1, not at all = 0, not relevant = 0, and question #7 'prevented work or studying' = 3 The DLQI is calculated by summing the score of each question resulting in a max of 30 and min of 0. The higher the score, the more quality of life is impaired.
Measure:Change in quality of life as measured by the Functional Assessment of Cancer Therapy (FACT)
Time Frame:Baseline and 18 weeks
Safety Issue:
Description:
Measure:Objective response rate as measured by measurement of 2 sentinel lesions
Time Frame:Baseline and 18 weeks
Safety Issue:
Description:-Largest diameter in 2 dimensions
Measure:Objective response rate as measured by photography-based estimates of body surface area
Time Frame:Baseline and 18 weeks
Safety Issue:
Description:
Measure:Objective response rate as measured by five point overall severity scale
Time Frame:Baseline and 18 weeks
Safety Issue:
Description:-None, minimal, mild, moderate, severe
Measure:Objective response rate as measured by minutes spent per week for wound care
Time Frame:Baseline and 18 weeks
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Washington University School of Medicine

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