Patient case: 54-year-old male with malignant hyperthermia; genetic feature: RYR1

Clinical trial: A Study of Pembrolizumab Monotherapy or in Combination With Other Agents in Patients With Previously Treated Advanced Gastroesophageal Adenocarcinoma

Summary: The goal of this clinical research study is to learn if pembrolizumab can help to control advanced gastroesophageal adenocarcinoma. The safety of this drug will also be studied.
  This is an investigational study. Pembrolizumab is FDA approved and commercially available for the treatment of several types of cancer, but not gastroesophageal adenocarcinoma. It is investigational to use pembrolizumab alone to treat gastroesophageal adenocarcinoma.
  The study doctor can explain how the study drug is designed to work.
  Up to 30 participants will be enrolled in this study. All will take part at MD Anderson.

Detailed description: Study Drug Administration:
  If you are found to be eligible to take part in this study, you will receive pembrolizumab by vein over about 30 minutes on Day 1 of each 21-day cycle.
  Length of Study:
  You may receive the study drug(s) for up to about 1 year (17 cycles).
  You will no longer be able to receive the study drug(s) if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.
  Study Visits (for all participants):
  On Day 1 of each cycle:
  -  You will have a physical exam.
  -  Blood (about 1 tablespoon) will be drawn for routine tests, to check the status of the disease, and for tumor marker testing. If you can become pregnant, part of this sample will be used for a pregnancy test.
  -  Urine will be collected for routine tests (Cycles 1, 2, and every even-numbered cycle after that [Cycles 4, 6, 8 and so on]).
  On Day 8 of Cycle 1:
  -  You will have a physical exam.
  -  Blood (about 1 tablespoon) will be drawn for routine tests, to check the status of the disease, and for tumor marker testing.
  -  Urine will be collected for routine tests.
  At Week 6, you will have a core biopsy and blood (about 3 tablespoons) will be drawn for biomarker testing.
  During the first 6 months, you will have an MRI or CT scan every 6 weeks. After that, this will be done every 12 weeks.
  At any time that the study doctor thinks it is needed, you will have an EKG.
  If you had a brain scan at screening and the disease appears to completely go away, you will have another brain scan to confirm this.
  If at any time the disease appears to respond to the study drug, blood (about 3 tablespoons) will be drawn for biomarker testing.
  End-of-Treatment Visit:
  As soon as possible after your last dose of study drug(s):
  vYou will have a physical exam.
  -  Blood (about 3 tablespoons) will be drawn for routine tests and biomarker testing.
  -  You will have a CT scan or MRI.
  Follow-Up:
  About 30 days after the End-of-Treatment Visit:
  -  Urine will be collected for routine tests.
  -  Blood (about 1 tablespoon) will be drawn for routine tests and to check the status of the disease. If you can become pregnant, part of this sample will be used for a pregnancy test.
  If you stop receiving the study drug(s) for reasons other than the disease getting worse, you will move into follow-up and be checked on every 12 weeks. At these visits:
  -  Your vital signs will be measured, including your weight and height.
  -  You will have a CT scan or MRI until you start a new anti-cancer treatment, the disease gets worse, or the study ends.
  Long-Term Follow-Up:
  You will be called every 12 weeks and asked about how you are doing. Each call should last about 5-10 minutes.

Eligibility: Inclusion Criteria:
  1. The subject (or legally acceptable representative if applicable) provides written informed consent for the trial. The subject may also provide consent for Future Biomedical Research. However the subject may participate in the main trial without participating in Future Biomedical Research.
  2. Be willing and able to provide written informed consent/assent for the trial.
  3. Male and female subjects who are at least 18 years of age on day of signing informed consent with histologically and cytologically documented diagnosis as gastroesophageal adenocarcinoma.
  4. Histologically and cytologically documented diagnosis as gastroesophageal adenocarcinoma.
  5. Have a documented advanced (metastatic and/or unresectable) gastroesophageal adenocarcinoma that is incurable and for which prior first-line or later-line SOC treatments have failed. There is no limit to the number of prior treatment regimens. Prior neoadjuvant or adjuvant therapy included in initial treatment may not be considered first- or later-line SOC treatment unless such treatments were completed less than 12 months prior to the current tumor recurrence.
  6. Have submitted an evaluable tissue sample for biomarker analysis from a newly obtained core, incisional, or excisional biopsy of a tumor lesion not previously irradiated. The tumor tissue submitted for analysis must be from a single tumor tissue specimen and of sufficient quantity and quality to allow biomarker study. A newly obtained tumor specimen, defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on Day 1, for biomarker characterization will be required for enrollment of all subjects. Tissue from tumor progressing at a site of prior radiation may be allowed for biomarker characterization upon agreement from Merck. 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 Merck
  7. Have measurable disease based on RECIST 1.1 as assessed by the Investigator. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
  8. Have a performance status of 0 or 1 on the ECOG Performance Scale.
  9. Life expectancy of greater than 3 months per the judgment of the investigators.
  10. Have adequate organ function. Specimens must be collected within 5 days prior to the start of study treatment. 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(GFR can also be used in place of creatinine or CrCl) </= 1.5 X upper limit of normal (ULN) OR >/= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN; 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
  11. Inclusion #9 Cont'd: 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. Creatinine clearance should be calculated per institutional standard.
  12. 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.
  13. Male and female subjects of childbearing potential must be willing to use an adequate method of contraception as outlined in Section 5.7.2, for the course of the study through 120 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
  Exclusion Criteria:
  1. Is currently participating in or has participated in a study of an investigational agent or used an investigational device within 4 weeks prior to the first dose of study treatment. Note: Subjects who have entered the follow-up phase of an investigational trial may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
  2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (in dosing 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.
  3. Has severe hypersensitivity (>/=Grade 3) to pembrolizumab or any of its excipients.
  4. 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.
  5. 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.1) Note: Subjects with </= Grade 2 neuropathy or alopecia are an exception to this criterion. 2) Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention as determined by the investigators prior to starting therapy.
  6. Has a known additional malignancy that is progressing or requires active treatment. Note: Subjects with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
  7. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are radiological stable (i.e., without evidence of progression for at least 4 weeks 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 the first dose of trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
  8. Has an 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. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
  9. Has a history of (non-infectious) pneumonitis that required treatment with steroids or has current pneumonitis.
  10. Has an active infection requiring systemic therapy.
  11. 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.
  12. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  13. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the visit through 120 days after the last dose of trial treatment.
  14. 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 TCR (e.g., CTLA-4, OX 40, CD137).
  15. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). No HIV testing is required unless mandated by local health authority.
  16. Had a solid organ or hematologic transplant
  17. Has a known history of hepatitis B virus (HBV; hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (HCV; HCV RNA [qualitative] is detected) infection. No testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
  18. Has received a live vaccine within 30 days prior to the first dose of the trial drug. 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.

Relevance to patient case: not relevant