Palliative RT & Anti-PD-1/PD-L1 Checkpoint Blockade in Metastatic Merkel Cell Carcinoma
Condition: Merkel Cell Carcinoma
MeSH terms: Carcinoma, Merkel Cell; Carcinoma
Intervention: Pembrolizumab; Radiation Therapy
Intervention description: Pembrolizumab administered at 200 mg IV every 3 weeks; 9 Gy X 3 (27 Gy in 3 fractions), or 4-6 Gy X 5 (20-30 Gy in 5 fractions).
Intervention MeSH terms: Pembrolizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 1.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      The primary objectives of this study are to assess 1) the safety and 2) efficacy of combining
      Anti-PD-1/PD-L1 blockade with palliative radiation therapy in patients with Stage IV Merkel
      Cell Carcinoma.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histologically confirmed metastatic Merkel Cell Carcinoma.

          -  Patients are eligible if they have received no more than 3 prior systemic treatments,
             inclusive of systemic adjuvant therapy. This includes previously untreated patients.

          -  Subjects with brain metastases and/or carcinomatous meningitis are eligible providing
             they are neurologically stable (if systemic steroids are required, subjects should be
             stable on the lowest clinically effective dose, as steroids may interfere with the
             activity of immunotherapy if administered at the time of the first Anti-PD-1/PD-L1
             dose.)

          -  Availability of tumor tissue (fresh or archival) for central pathology review.

          -  Must be at least 14 days since treatment with chemotherapy, biochemotherapy, surgery,
             or immunotherapy, and recovered (baseline or residual Grade 1 toxicity) from any
             clinically significant toxicity experienced during treatment before the first dose of
             pembrolizumab therapy.

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

          -  Life expectancy of ≥ 16 weeks.

          -  Subjects must have measurable disease according to RECIST v1.1, and have baseline
             (screening/baseline) radiographic images, (e.g. CT, Positron emission tomography
             (PET)/CT or MRI brain, chest, abdomen, pelvis, to be determined by the attending
             physician) within 4 weeks of confirmation of eligibility and within 6 weeks before the
             initiation of pembrolizumab therapy.

          -  Required values for initial laboratory tests:

          -  White blood cells (WBC): ≥ 2000/µL (~ 2 x 109/L)

          -  Absolute Neutrophil Count (ANC): ≥ 1000/µL (~ 1 x 109/L) Platelets: ≥ 50 x 103/µL (~
             50 x 109/L)

          -  Hemoglobin: ≥ 8 g/dL

          -  Calculated creatinine clearance greater than 30 mL/min

          -  Aspartate transaminase(AST)/alanine transaminase (ALT): Less than 2.5 x upper limit of
             normal (ULN) for subjects without liver metastasis, less than 5 times ULN for liver
             metastases

          -  Bilirubin: less than 3.0 x ULN (except for subjects with Gilbert's Syndrome, who must
             have a total bilirubin of less than 3.0 mg/dL)

          -  Non-clinically significant laboratory abnormalities such as lipase elevation would not
             be an exclusion.

          -  No known active or chronic infection with HIV, Hepatitis B, or Hepatitis C, or active
             infection requiring systemic antibiotics. Testing for the above is not required unless
             clinically suspected.

          -  At least one measurable site of disease (≥ 10 mm as per RECIST v1.1 except for lymph
             nodes that must be 15 mm or greater on the short axis) outside of the planned
             palliative radiation therapy field.

          -  Require radiation therapy for palliation of symptoms or to prevent local progression
             of disease and associated complications and/or symptoms from metastases.

          -  Women of childbearing potential (WOCBP) must be using an adequate method of
             contraception to avoid pregnancy throughout the study [and for up to 26 weeks after
             the last dose of investigational product] in such a manner that the risk of pregnancy
             is minimized.

          -  WOCBP include any female who has experienced menarche and who has not undergone
             successful surgical sterilization (hysterectomy, bilateral tubal ligation, or
             bilateral oophorectomy) or is not postmenopausal. Post-menopausal is defined as:

               -  Amenorrhea ≥ 12 consecutive months without another cause, or

               -  For women with irregular menstrual periods and on hormone replacement therapy
                  (HRT), a documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL

          -  Women who are using oral contraceptives, other hormonal contraceptives (vaginal
             products, skin patches, or implanted or injectable products), or mechanical products
             such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to
             prevent pregnancy, or are practicing abstinence or where their partner is sterile
             (e.g., vasectomy) should be considered to be of childbearing potential. WOCBP must
             have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or
             equivalent units of HCG) within 1 week prior to the start of investigational product.

          -  Men of fathering potential must be using an adequate method of contraception to avoid
             conception throughout the study [and for up to 26 weeks after the last dose of
             investigational product] in such a manner that the risk of pregnancy is minimized.

        Exclusion Criteria:

          -  WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for
             the entire study and for up to 26 weeks after the last dose of investigational
             product.

          -  Women who are pregnant or breastfeeding.

          -  Women with a positive pregnancy test on enrollment or before investigational product
             administration.

          -  Subjects on any other systemic therapy for cancer, including any other experimental
             treatment within 2 weeks of scheduled first dose of pembrolizumab.

          -  Prior treatment with an anti-PD-1/PD-L1 antibody if treatment failure was due to AEs.
             If a subject was discontinued from the prior anti-PD-1/PD-L1 treatment due to an
             Adverse events (AE) or Serious adverse events (SAE), regardless of the type of event,
             that discontinuation constitutes an exclusion criterion. If AEs were serious enough to
             require a subject's withdrawal from prior treatment, the subject should be excluded
             from this study. The exception to the above are non-clinically significant
             immune-related laboratory abnormalities - these are not automatic exclusions - e.g.
             asymptomatic elevated amylase; responsiveness to steroids. In situations above - e.g.
             non-clinically significant immune-related laboratory abnormalities, each case will be
             considered individually and a decision made by the study team.

          -  A history of AEs with prior IL-2 or Interferon will not preclude subjects from
             entering the current study.

          -  Autoimmune disease: Poorly controlled autoimmune disease is excluded. Well controlled
             autoimmune disease (e.g. well controlled RA) will be assessed by the study team and a
             decision made regarding eligibility based on the degree of immunosuppression and
             severity of symptoms.

          -  Any subject who has a life-threatening condition that requires high-dose
             immunosuppressant(s). Steroid doses greater than 20 mg/day will exclude the patient
             from participation in the trial.

          -  Presence of known hepatitis B or hepatitis C infection, regardless of control on
             antiviral therapy.

          -  Subjects who have another active, concurrent, malignant disease are not eligible, with
             the exception of subjects with adequately treated basal or squamous cell skin cancer,
             superficial bladder cancer, carcinoma in situ of the cervix, or other cancers that are
             in remission/not measurable. Patients will be excluded if they have any known
             additional malignancy that requires active treatment while on treatment for Merkel
             Cell Carcinoma.

          -  Bilirubin/total bilirubin 3 or more X ULN unless conjugated bilirubin is less than or
             equal to the ULN.

          -  Evidence of symptomatic interstitial lung disease or symptomatic active, noninfectious
             pneumonitis.

          -  Participants with impaired cardiac function or clinically significant cardiac disease
             such as unstable angina/uncompensated heart failure, uncontrolled symptomatic
             arrhythmia.

          -  Active autoimmune disease requiring systemic T-cell immunosuppression.

          -  Chronic or current active infectious disease requiring systemic antibiotics,
             antifungal, or antiviral treatment. This exclusion does not include prophylactic
             antibiotics or topical antibiotics.

          -  Known hypersensitivity to another monoclonal antibody, which cannot be controlled with
             standard measures (e.g. antihistamines and corticosteroids).

          -  Any condition that would, in the investigator's judgment, interfere with full
             participation in the study.

          -  Prior immune related AEs not meeting the conditions above.

          -  Prisoners or subjects who are involuntarily incarcerated.

          -  Subjects with acute or poorly controlled psychiatric illness or subjects who are
             compulsorily detained for physical (e.g., infectious disease) illness, with the
             exception of patients that are well supported and able to participate (e.g. paraplegia
             from a motor vehicle accident).

          -  Any underlying medical or psychiatric condition that, in the opinion of the
             investigator, could make the administration of anti-PD-1/PD-L1 hazardous or could
             obscure the interpretation of adverse events.

          -  Any live vaccine therapy for up to 4 weeks before or after any dose of immunotherapy
             on this trial.

          -  Any investigational agents within 2 weeks of scheduled first dose of pembrolizumab.