Patient case: 48-year-old female with melanoma; genetic feature: tumor cells with >50% membranous PD-L1 expression

Clinical trial: Study of Oral Azacitidine (CC-486) in Combination With Pembrolizumab (MK-3475) in Patients With Metastatic Melanoma

Summary: The goal of this clinical research study is to learn if oral azacitidine (CC-486) and pembrolizumab (MK-3475) can help to control melanoma. The safety of this drug combination will also be studied.

Detailed description: Study Drug Administration:
  Each study cycle is 3 weeks.
  Participant will take azacitidine by mouth 1 time each day on Days 1-15 of each cycle.
  Participant will receive pembrolizumab by vein over about 30 minutes on Day 1 of each cycle.
  Study Visits:
  On Day 1 of Cycles 1-3:
  -  Participant will have a physical exam.
  -  Blood (about 2½ teaspoons) will be drawn for routine tests.
  -  During Cycle 1 only (if it was not done at screening), blood (about 1 teaspoon) will be drawn to learn if the study drugs have affected the disease.
  -  During Cycle 3 only, participant will have 4 core needle tumor biopsies.
  -  If participant can become pregnant, part of the above routine blood sample or urine will be collected for a pregnancy test.
  On Day 1 of Cycle 4:
  -  Participant will have a physical exam.
  -  Participant will have an MRI or CT scan.
  -  Blood (about 4 teaspoons) will be drawn for routine tests and to learn if the study drugs have affected the disease.
  -  If participant can become pregnant, part of the above routine blood sample or urine will be collected for a pregnancy test.
  On Day 1 of Cycle 5:
  -  Participant will have a physical exam.
  -  Blood (about 2½ teaspoons) will be drawn for routine tests.
  -  Participant will have 4 core needle tumor biopsies.
  -  If participant can become pregnant, part of the above routine blood sample or urine will be collected for a pregnancy test.
  On Day 1 of Cycles 6 and beyond:
  -  Participant will have a physical exam.
  -  Blood (up to 3½ teaspoons) will be drawn for routine tests. During Cycle 7, this blood will be used to learn if the study drugs have affected the disease.
  -  During Cycle 7 only, if participant can become pregnant, part of the above routine blood sample or urine will be collected for a pregnancy test.
  On Day 1 of Cycle 8 and then every 4 cycles after that (Cycles 12, 16, 20, and so on), participant will have an MRI or CT scan.
  Length of Study:
  Participant may continue taking the study drugs for as long as the doctor thinks it is in participant's best interest. Participant will no longer be able to take the study drugs if the disease gets worse, if intolerable side effects occur, or if participant is unable to follow study directions.
  End-of-Treatment Visit:
  -  Blood (about 4 teaspoons) will be drawn for routine testing and to learn how the study drug has affected the disease.
  -  Participant will have an MRI or CT scan.
  -  If participant stops treatment because the disease got worse, participant may have 4 core needle tumor biopsies.
  -  If participant can become pregnant, part of the above routine blood sample or urine will be collected for a pregnancy test.
  Follow-Up:
  If participant stopped taking the study drug for any reason other than the disease getting worse, participant will have an MRI or CT scan every 6 weeks. After 1 year, participant will have these scans every 9 weeks.
  If the disease appears to get worse during this time, participant may be eligible to be re-treated with pembrolizumab for an additional year (described below).
  Re-Treatment:
  If the disease got worse during follow-up and participant is still eligible, participant may be able to receive up to 1 year of additional treatment with pembrolizumab. If participant continues to receive pembrolizumab, participant will receive it at the same dose and schedule as described above. Participant will also continue to have study visits as described above.
  Safety Follow-Up Visit:
  About 30 days after participant's last dose of study drugs or before participant starts a new anti-cancer treatment (whichever happens first), participant will have a safety follow-up visit. At this visit, participant will have a physical exam and participant will have an MRI or CT scan.
  This may mean that participant has 2 safety follow-up visits if participant receives an additional year of pembrolizumab.
  Long-Term Follow-Up:
  After follow-up, participant will be called every 12 weeks by a member of the study staff to learn how participant is doing. This call should last about 5 minutes.
  This is an investigational study. Azacitidine is FDA approved and commercially available for the treatment of myelodysplastic syndrome (MDS) and acute myeloid leukemia. Pembrolizumab is FDA approved and commercially available for the treatment of melanoma. It is considered investigational to use this drug combination to treat melanoma.
  The study doctor will explain how the study drugs are designed to work.
  Up to 71 participants will be enrolled in this study. All will take part at MD Anderson.

Eligibility: Inclusion Criteria:
  1. Patients who have unresectable Stage III through stage IV metastatic melanoma that have not received prior PD-1 directed therapy (Arm A) or that have progressed despite prior PD-1 directed therapy (Arm B).
  2. No more than two prior systemic therapeutic regimens for unresectable stage III or stage IV melanoma. This includes chemotherapy, biologic therapy, biochemotherapy, or investigational treatment. This does not include any therapies given in the adjuvant setting.
  3. Be willing and able to provide written informed consent/assent for the trial.
  4. Be >/= 18 years of age on day of signing informed consent.
  5. Have measurable or evaluable disease based on RECIST 1.1.
  6. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on Day 1. Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the Sponsor.
  7. Have a performance status of 0 or 1 on the ECOG Performance Scale.
  8. Demonstrate adequate organ function, 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 OR Measured or calculated creatinine clearance </=1.5 X upper limit of normal (ULN) OR Direct bilirubin </= 9 ULN for subjects with total bilirubin levels > 1.5 ULN. 9 AST (SGOT) and ALT (SGPT) 9 </= 2.5 X ULN OR </= 5 X ULN for subjects with liver metastases.
  9. contd from #8. Albumin >/= 2.5 mg/dL. Coagulation: International Normalized Ratio (INR) or Prothrombin Time (PT) 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 </= 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
  10. 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.
  11. 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.
  12. 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:
  1. 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.
  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, azacitidine, mannitol, or any of their excipients.
  5. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 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. Has known history of, or any evidence of active, non-infectious pneumonitis.
  11. Significant active cardiac disease within the previous 6 months including: - NYHA class 4 CHF - Unstable angina - Myocardial infarction
  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-PD-1, anti-PD-L1, or anti-PD-L2 agent [for Arm A only].
  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.

Relevance to patient case: not relevant