Patient case: 50-year-old male with cholangiocarcinoma; genetic feature: IDH1

Clinical trial: IDH1 Peptide Vaccine for Recurrent Grade II Glioma

Summary: Potential subjects with progressive Grade II primary brain tumor that have IDH1 positive testing from the primary tumor (initial diagnosis) will be offered this treatment study in order to test the safety of the PEPIDH1M vaccine in combination with standard chemotherapy (temozolomide).

Detailed description: After informed consent has been signed, subjects who have not had a tetanus booster within 10 years will undergo standard of care vaccination with 0.5 mL of Td (tetanus and diphtheria toxoids adsorbed).
  Within 2 weeks of signing consent eligible subjects will undergo a 1-2 hour leukapheresis (to pull off white blood cells) for immune monitoring and within 48 hours vaccine site pre-conditioning will be performed as a single dose of Td toxoid (in a total volume of 0.4 mLs salt water/saline) given in the intradermal space (just under the surface of the skin) 12-24 hours prior to receiving PEPIDH1M vaccine in the same manner. The peptide vaccine is administered in the upper thigh area approximately 4 inches below the groin in the intradermal space as vaccine # 1. Subsequent vaccines will be given on day 15 ±3 days (vaccine #2) and day 30 ±3 days (vaccine #3). All injections will alternate sides. These injections will occur without temozolomide (standard of care chemotherapy).
  Seven to 10 days after the 3rd vaccine, subjects will have peripheral blood work drawn for immunologic monitoring. This will be followed by surgery to remove the tumor no less than 3 days and no longer than 7 days after the immunologic monitoring blood work. Tumor samples will be evaluated for the IDH1 markers and analyzed for other cells that may have entered the tumor.
  Based on tissue obtained at surgery, subjects with stable histologic grade at recurrence will then be treated with vaccine and temozolomide. During monthly cycles of temozolomide, subjects will receive the vaccine on day 21 ±2 days for a maximum of 15 total vaccines (which includes the first 3 bi-weekly vaccines). Patients that have transitioned to a higher Grade brain tumor will not be eligible to continue and will be removed from the study. All Adverse Events will be collected from time of consent until off study. For purposes of this study, subjects will be considered off study 2 months after the last vaccine. Subjects will be followed only for survival thereafter.
  For immune monitoring, a final peripheral blood draw will be performed following 3 months of temozolomide and vaccine therapy. Peripheral blood will also be drawn for immune monitoring evaluation at progression, if possible.
  For biomarker testing, subjects will have blood and urine collected during the following times: prior to vaccine therapy (at consent or leukapheresis visit), prior to vaccine #3, prior to surgery to remove the tumor, prior to discharge from hospital following the surgery to remove the tumor, prior to each subsequent monthly vaccine administrations, and at progression (if possible).
  Subjects will be imaged with contrast-enhanced magnetic resonance imaging (MRI) according to standard of care every 2 months ±2 weeks while on temozolomide and afterward, per the treating neuro-oncologist's recommendation. Revised Assessment in Neuro-Oncology (RANO) criteria will be used for assessment of pseudoprogression and tumor progression. Subjects demonstrating definitive progression will be removed from study.
  As part of standard care for these subjects, upon tumor progression, participants may undergo biopsy or resection. As this is not a research procedure, consent will be obtained separately. Subjects that have this procedure done within the Duke University Health System will be asked to have a portion of the tumor sample, if possible, to assess immunologic cell infiltration, antigen expression, and biomarkers for immunologic response.

Eligibility: Inclusion Criteria:
  1. Age ≥ 18 years.
  2. IDH1R132H expression in primary tumor
  3. Radiographic and/or clinical progressive and resectable Grade II glioma.
  4. Signed informed consent.
  5. For females of child-bearing potential, negative serum pregnancy test 48 hours prior to first treatment with temozolomide (TMZ) or vaccine.
  6. Women of childbearing potential and male participants must agree to practice adequate contraception.
  7. Karnofsky Performance Status (KPS) of ≥ 70.
  8. Complete Blood Count (CBC)/differential with adequate bone marrow function to tolerate TMZ and surgical resection as defined below within 2 weeks of enrollment:
  -  Absolute neutrophil count, ≥ 1500 cells/mm3.
  -  Platelet count, ≥ 100,000 cells/mm3.
  -  Hemoglobin ≥ 10 g/dl. (Note: the use of transfusion or other intervention to achieve Hgb ≥ 10 g/dl is acceptable.)
  9. Adequate renal function to tolerate TMZ and surgical resection as defined below within 2 weeks of enrollment:
  -  Blood Urea Nitrogen (BUN) ≤ 25 mg/dl.
  -  Creatinine ≤ 1.7 mg/dl.
  10. Adequate hepatic function to tolerate TMZ and surgical resection as defined below within 2 weeks of enrollment:
  -  Bilirubin ≤ 2.0 mg/dl.
  -  Alanine Aminotransferase (ALT) ≤ 3 x normal range.
  -  Aspartate Aminotransferase (AST) ≤ 3 x normal range
  Exclusion Criteria:
  1. Prior invasive malignancy (except for non-melanomatous skin cancer) unless disease free for ≥ 3 years. (For example, carcinoma in situ of the breast, oral cavity, and cervix are all permissible.)
  2. Metastases detected below the tentorium or beyond the cranial vault.
  3. Severe, active co-morbidity, defined as follows:
  -  Unstable angina and/or congestive heart failure requiring hospitalization.
  -  Myocardial infarction within the last 6 months.
  -  Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition; note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because treatments involved in this protocol may be significantly immunosuppressive.
  -  Major medical illnesses or psychiatric impairments that in the investigator's opinion will prevent administration or completion of protocol therapy.
  4. Pregnant or lactating women, due to possible adverse effects on the developing fetus or infant due to study drug.
  5. Prior allergic reaction to temozolomide.
  6. Patients treated on any other therapeutic clinical protocols within 30 days prior to study entry or during participation in the study.
  7. Patients with known hypersensitivity to GM-CSF, yeast-derived products, or any component of Leukine®.
  8. Allergy or hypersensitivity to tetanus vaccine or any component of the tetanus vaccine.
  9. Unable to undergo MRI imaging.

Relevance to patient case: not relevant