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:

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: 201911047
  • 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 1-15 (every 2 weeks for the first 2 treatments, then every 3 weeks until week 15) Topical imiquimod will be applied 5 days per week (5 days on, 2 days off from weeks 1-15) Pembrolizumab will be given every 3 weeks for a minimum of 4 cycles starting at Week 3 until disease progression or unacceptable toxicity. Intra-lesional GM-CSF 250 mcg every 2 weeks x 2 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
             (any ER, PR, HER2) with biopsy-proven cutaneous metastasis

          -  Disease progression in skin and/or systemic lesions after one or more lines of therapy
             as follows:

               -  HER2 positive patients must have been previously treated with Pertuzumab,
                  Trastuzumab, and T-DM1, with at least one of them in the metastatic setting

               -  ER positive patients must have had at least one prior line of endocrine therapy
                  in the metastatic setting.

               -  Prior treatment could include:

                    -  Chemotherapy

                    -  Endocrine therapy for patients with ER+ disease (including aromatase
                       inhibitors, selective estrogen receptor degraders/modulators, mTOR
                       inhibitors, CDK 4/6 inhibitors)

                    -  HER2-targeted therapies for HER2+ disease (including monoclonal antibodies,
                       antibody drug conjugates, tyrosine kinase inhibitors) Note: there is no
                       limit to the number of prior therapy lines for unresectable or metastatic
                       breast cancer.

          -  Concurrent treatment is allowed as follows:

               -  Patients with stable systemic disease may continue on concurrent maintenance
                  therapy provided there is no anticipated need to change therapy during the study
                  period.

        Note: for these patients, the cutaneous lesions must either be progressing or stable for at
        least 2 months (i.e. not responding to current therapy).

          -  Patients changing to a new systemic therapy must start treatment at least 2 weeks
             before the planned start of study treatment.

             -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.

          -  Patients with non-measurable or measurable systemic disease are eligible.

               -  Be willing to provide serial tumor and blood specimens (baseline, weeks 3, 9, 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 14 days prior to the anticipated treatment
                  start date.

               -  Demonstrate adequate organ function (within 14 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:

          -  Not a woman of childbearing potential (WOCBP) OR

          -  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.

          -  All WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25
             IU/L or equivalent units of beta-human chorionic gonadotropin [β-hCG]) within 14 days
             of anticipated start of study treatment. Pregnancy test will be repeated on day 1
             prior to initiation 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.

          -  Prior treatment with the following:

               -  Any 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).

               -  Radiotherapy within 2 weeks of start of study treatment. A 1-week washout is
                  permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-CNS
                  disease.

               -  Investigational agents or devices within 4 weeks prior to anticipated study
                  treatment start date Note: Participants must have recovered from all AEs due to a
                  previous therapies to ≤ grade 1 or baseline. Subjects with ≤ Grade 2 neuropathy
                  are eligible if per treating physician the neuropathy symptoms are stable.
                  Patients must have completed any corticosteroids for treatment-related
                  toxicities. Patients who developed radiation pneumonitis are not eligible.

        Note: If subject had recent surgery, they must have recovered adequately from the toxicity
        and/or complications from the intervention in the opinion of the treating investigator
        prior to starting therapy

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

          -  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 for at least 4 weeks and without requirement of steroid
                  treatment for at least 14 days prior to first dose of study treatment.

        Note: Patients with stable brain metastases must have stable brain imaging within 28 days
        prior to first dose of study treatment

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

          -  Has known history of Hepatitis B or known active Hepatitis C infection. Note: testing
             for Hepatitis B and Hepatitis C is required unless mandated by local health authority.

          -  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 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 3 in the number of tumor infiltrating lymphocytes after epicutaneous cryoimmunotherapy
Time Frame:Baseline and week 3
Safety Issue:
Description:
Measure:Change from baseline to week 9 in the number of tumor infiltrating lymphocytes after epicutaenous cryoimmunotherapy plus pemrolizumab
Time Frame:Baseline and week 9
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 skin 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:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Washington University School of Medicine

Last Updated

September 16, 2020