Pembrolizumab and Ipilimumab After Prior Immunotherapy for Melanoma
Condition: Melanoma
MeSH terms: Melanoma
Intervention: Pembrolizumab; Ipilimumab
Intervention description: Pembrolizumab given every 3 weeks (200 mg) by IV infusion.; Ipilimumab given every 3 weeks (200 mg) by IV infusion for total of 4 doses.
Intervention MeSH terms: Pembrolizumab; Ipilimumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 70.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Melanoma; Pembrolizumab; Ipilimumab

Summary:

      Phase II study evaluating the benefit of the combination of anti-PD1 (pembrolizumab) and
      anti-CTLA4 (ipilimumab) antibodies in advanced melanoma. The study will determine the
      response rate of the combination and evaluate other clinical parameters such as
      progression-free survival and safety of the combination following anti-PD1/L1 antibody. The
      study will also provide the opportunity to investigate blood or tumor based factors that may
      predict response to anti-PD1 antibody in combination with anti-CTLA4.
    

Eligibility criteria:

        Inclusion Criteria:

        In order to be eligible for participation in this trial, the subject must:

          1. Be willing and able to provide written informed consent for the trial.

          2. Be 18 years of age on day of signing informed consent.

          3. Have experienced disease progression or stable disease lasting at least 24 weeks
             during treatment with an anti-PD1/L1 antibody as the treatment regimen immediately
             prior to accrual to this study or disease progression within 6 months of adjuvant
             anti-PD1 antibody.

          4. Have measurable disease based on irRECIST 1.1.

          5. Have a performance status of 0 or 1 on the ECOG Performance Scale.

          6. Demonstrate adequate organ function as defined below, 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 ≥8 g/dL or ≥4.96 mmol/L

             Renal Serum creatinine OR Measured or calculated creatinine clearance ≤1.5 X upper
             limit of normal (ULN) OR ≥60 mL/min for subject with creatinine levels > 1.5 X
             institutional ULN (GFR can also be used in place of creatinine or CrCl)

             Hepatic Serum 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 OR ≤ 5 X ULN
             for subjects with liver metastases Albumin >2.5 mg/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

          7. Female subject 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.

          8. 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. Subjects of
             childbearing potential are those who have not been surgically sterilized or have not
             been free from menses for > 1 year.

          9. Male subjects should agree to use an adequate method of contraception starting with
             the first dose of study therapy through 120 days after the last dose of study therapy.

        Exclusion Criteria:

        The subject must be excluded from participating in the trial if the subject:

          1. Has received study therapy (including investigational device) as part of a clinical
             trial within 4 weeks of the first dose of treatment, with the exclusion of an
             anti-PD1/L1 antibody given as either a single agent or non-CTLA-4 antibody containing
             combination.

          2. 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.

          3. Has a known history of active TB (Bacillus Tuberculosis)

          4. Hypersensitivity to pembrolizumab or any of its excipients.

          5. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
             Day 1 (excluding commercial or investigational anti-PD1 or anti-PD-L1 antibodies as
             single agents) or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse
             events due to agents administered more than 4 weeks earlier.

          6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
             within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at
             baseline) from adverse events due to a previously administered agent.

               -  Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and
                  may qualify for the study.

               -  Note: If subject received major surgery, they must have recovered adequately from
                  the toxicity and/or complications from the intervention prior to starting
                  therapy.

          7. 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.

          8. Has known active central nervous system (CNS) metastases and/or carcinomatous
             meningitis. Subjects with previously treated brain metastases may participate provided
             they are stable (without evidence of progression by imaging for at least four weeks
             prior to the first dose of trial treatment and any neurologic symptoms have returned
             to baseline), have no evidence of new or enlarging brain metastases, and are not using
             steroids for at least 7 days prior to trial treatment. This exception does not include
             carcinomatous meningitis which is excluded regardless of clinical stability.

          9. 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 (eg., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment.

         10. Patients with uveal/ocular melanoma are excluded.

         11. Has known history of, or any evidence of active, non-infectious pneumonitis.

         12. Has an active infection requiring systemic therapy.

         13. 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.

         14. Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

         15. 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.

         16. Has received prior therapy with an anti-CTLA4 agent.

         17. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

         18. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
             [qualitative] is detected).

         19. 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 are live attenuated vaccines, and are
        not allowed.