Patient case: 84-year-old male with glioblastoma; genetic feature: CDK6

Clinical trial: Autologous Cytomegalovirus (CMV)-Specific Cytotoxic T Cells for Glioblastoma (GBM) Patients

Summary: The goal of Phase I of this clinical research study is to find the highest tolerable dose of cytomegalovirus cytotoxic T lymphocytes (CMV CTLs) that can be given in combination with temozolomide to patients with glioblastoma.
  The goal of Phase II of this study is to learn if CMV CTLs combined with temozolomide can help to control glioblastoma. The safety of this combination will also be studied.

Detailed description: Study Groups:
  If you are found to be eligible to take part in this study, you will be assigned to a study phase based on when you join this study.
  If you are enrolled in the Phase I Dose Escalation part (Group 1), up to 4 dose levels of CMV CTLs will be studied in this Phase I part. Up to 6 participants will be enrolled at each dose level. The first 3-6 of participants will receive the lowest dose level. Each 3-6 new participants will receive a higher dose of the study drugs than the participants before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of CMV CTLs is found.
  If you are enrolled in the Phase II Dose Expansion part, you will receive CMV CTLs at the highest dose that was tolerated in Phase 1. You will be assigned to 1 of 2 study groups (Groups 2 and 3) based on the status of the disease and the treatment you received previously.
  -  If the disease has come back after treatment and you will be having surgery as part of routine care, you will be in Group 2.
  -  If you have completed chemotherapy and radiation therapy with no tumor growth, you will be in Group 3.
  Study Drug/Cell Administration:
  There are 42 days in each cycle during Cycles 1-4. If you are in Group 1 or 2, Cycles 5 and beyond will also have 42 days. If you are in Group 3, Cycles 5 and beyond will have 28 days.
  On Day 0, the day you enroll in the study, you will have leukapheresis performed over 2-3 hours to collect white blood cells, including a type called T cells. Leukapheresis uses a machine to remove white cells from the blood.
  These white blood cells will be used to make CMV CTLs for your treatment later, starting on Day 22 of Cycle 1. For the leukapheresis procedure, you will lie on a bed or lean back in a chair, with a tube in a vein in each arm. One tube removes blood and passes it into a machine that removes white blood cells, including T cells. The rest of your blood will go back into your body through the tube in your other arm.
  After leukapheresis, you will start receiving temozolomide and CMV CTLs.
  You will take temozolomide capsules by mouth 1 time a day on Days 1-21 of Cycles 1-4.
  If you are in Group 1 or 2, you will continue taking temozolomide on Days 1-21 of Cycles 5 and beyond.
  If you are in Group 3, you will take temozolomide on Days 1-5 of Cycles 5 and beyond.
  You should take temozolomide at bedtime at about the same time each day. Temozolomide should be taken on an empty stomach (at least 2 hours before or after eating) with 1 cup (about 8 ounces) of water. You should swallow the temozolomide capsules whole, one right after the other, without chewing them. If you vomit the study drug, do not make up the dose. You should take the next scheduled dose at the usual time.
  The capsules of temozolomide should not be opened. If a capsule is damaged or broken, you should avoid letting the capsule contents have contact with your skin or mucous membranes. Spills of powder from temozolomide capsules should be cleaned up carefully. If you come in contact with the powder, you should wash your hands very well. If the spill is on a surface, the area must be washed at least 3 times with rubbing alcohol, followed by water.
  You will receive CMV CTLs by vein over 1-5 minutes on Day 22 of Cycles 1-4. After the infusions, you will need to stay in the clinic for up to 1 hour so the study staff can check on you.
  Before you receive CMV CTLs, you will be given standard drugs to help decrease the risk of side effects. You may ask the study staff for information about how the drugs are given and their risks.
  If you are in Group 2, on Day 30 of Cycle 1, you will have surgery to remove the tumor as part of routine care. You will sign a separate consent form that describes the procedure and risks. Leftover tumor tissue from surgery will be collected and used for biomarker testing. After recovering from surgery (which may take about 14 days), you will start receiving temozolomide on Day 1 of Cycle 2.
  Study Visits for All Groups:
  On Day 1 of every cycle:
  -  You will have a physical exam, including a neurological exam.
  -  Blood (about 2 teaspoons) will be drawn for routine tests. This blood draw will also include a pregnancy test if you can become pregnant (starting in Cycle 2).
  -  If you can become pregnant, urine will be collected for a pregnancy test. (Cycle 1 only).
  On Days 8, 15, 22, 29, and 36 of Cycle 1, and then on Days 22 and 29 of Cycles 2-4, blood (about 1 teaspoon) will be drawn for routine tests.
  If the disease gets worse during study treatment and you will be having surgery as part of standard care, leftover tumor tissue from surgery will be collected for biomarker testing.
  Study Visits for Group 1:
  On Days 15 and 29 of Cycles 5 and beyond, blood (about 1 teaspoon) will be drawn for routine tests.
  Every 6 weeks, you will have an MRI of the brain.
  On Days 22 and 30 of Cycles 1-4, on Day 1 of Cycles 2-5 and on Day 34 of Cycle 8, blood (about 4 tablespoons) will be drawn for biomarker testing.
  Study Visits for Group 2:
  On Days 15 and 29 of Cycles 5 and beyond, blood (about 1 teaspoon) will be drawn for routine tests.
  Every 6 weeks starting in Cycle 3, you will have an MRI of the brain.
  Within 48 hours before surgery, blood (about 4 tablespoons) will be drawn for biomarker testing.
  Within 24 hours before surgery, you will have an MRI of the brain.
  On Day 30 of Cycle 1, you will have surgery to remove the tumor as part of routine care. Blood (about 4 tablespoons) will be drawn for biomarker testing.
  Within 2 days after surgery, you will have an MRI of the brain. After you have recovered from surgery, you will start back up with your study visits.
  Blood (about 4 tablespoons) will be drawn for biomarker testing on the following schedule:
  -  Day 1 of Cycles 2-5
  -  Day 38 of Cycle 1
  -  Day 16 of Cycle 2
  -  Days 22 and 30 of Cycles 2-4
  -  Day 34 of Cycle 8
  Study Visits for Group 3:
  Every 6 weeks for Cycles 2-4, then every 8 weeks, you will have an MRI of the brain.
  On Days 22 and 30 of Cycles 1-4, on Day 1 of Cycles 2-5 and on Day 20 of Cycle 10, blood (about 4 tablespoons) will be drawn for biomarker testing.
  At any time during the study, if the doctor thinks it is needed, you may have 1 or more of the above tests repeated for your safety.
  Length of Treatment:
  You will receive the CMV CTLs for up to 4 cycles and temozolomide for up to 12 cycles. You will no longer be able to take the study drug/cells if the disease gets worse, if you have intolerable side effects, or if you are unable to follow study directions. You will need to stop receiving CMV CTLs early if not enough CTLs are available.
  Follow-Up:
  The study staff will call and ask how you are feeling on the following schedule:
  -  about 30 days after your last study drug/cell dose
  -  every 8 weeks, if you stop the study drug/cells because of intolerable side effects (if the disease gets worse or you start a new cancer treatment, the schedule will change to every 3 months)
  -  every 3 months, if you stop the study drug/cells because the disease gets worse
  These calls should take about 5-10 minutes each time.
  This is an investigational study. CMV CTLs are not FDA approved or commercially available. They are currently being used for research purposes only. Temozolomide is FDA approved and commercially available for the treatment of some brain tumors, including glioblastoma. The use of this combination to treat glioblastoma is investigational. The study doctor can explain how the study drug/cells are designed to work.
  Up to 54 participants will be enrolled in this study. All will take part at MD Anderson.

Eligibility: Inclusion Criteria:
  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 histologically confirmed World Health Organization Grade IV glioma (glioblastoma or gliosarcoma). Participants will also be eligible if the original histology was lower grade glioma and there is suspected transformation to glioblastoma based on imaging findings. If the final pathology report after resection fails to confirm recurrent glioblastoma or gliosarcoma, the subject will be followed for AEs and survival, but excluded for other primary and secondary objective analysis. The subject will be replaced. (Phase II Dose Expansion in Recurrent GBM undergoing resection)
  4. Have histologically confirmed World Health Organization Grade IV glioma (glioblastoma or gliosarcoma). (Phase II Dose Expansion in Newly diagnosed GBM)
  5. Be at first relapse. Note: Relapse is defined as progression following initial therapy (i.e., radiation, chemotherapy, or radiation+chemotherapy). If the participant had a surgical resection for relapsed disease and no antitumor therapy instituted for up to 12 weeks, this is considered one relapse. For participants who had prior therapy for a lower grade glioma, the surgical diagnosis of glioblastoma or gliosarcoma will be considered first relapse. (Phase II Dose Expansion in Recurrent GBM undergoing resection)
  6. Patients must have completed standard radiation therapy with concurrent TMZ within 5 wks of enrollment and must not have evidence of progressive disease on post treatment imaging.Progression can only be defined using diagnostic imaging if there is new enhancement outside of the radiation field (beyond the high-dose region or 80% isodose line) or if there is unequivocal evidence of viable tumor on histopathologic sampling(e.g.,solid tumor areas[i.e,>70% tumor cell nuclei in areas],high or progressive increase in MIB-1 proliferation index compared with prior biopsy,or evidence for histologic progression or increased anaplasia in tumor).Note:Given the difficulty of differentiating true progression from pseudoprogression,clinical decline alone,in the absence of radiographic or histologic confirmation of progression,will not be sufficient for definition of progressive disease in the first 12 weeks after completion of concurrent chemoradiotherapy.(Ph II Dose Expansion in Newly diagnosed GBM)
  7. Have measurable disease consisting of a minimal volume of 1 cm3. (Phase II Dose Expansion in Recurrent GBM undergoing resection)
  8. CMV seropositive.
  9. Be willing to provide tissue from an archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion. (Phase I and Phase II Dose Expansion in Recurrent GBM undergoing resection)
  10. Be willing to provide tissue from an archival tissue sample. (Phase II Dose Expansion in Newly diagnosed GBM)
  11. Have a performance status of >/= 60 on the KPS.
  12. If patient is on steroids, patient must be on a stable or decreasing dose of steroids for 5 days, no more than 2 mg dexamethasone (or equivalent) total per day at the time of screening and consent. If on steroids at the time of screening, the dose will need to be tapered and discontinued at least 5 days prior to CMV T cell infusion.
  13. Demonstrate adequate organ function as defined in Inclusion 14.
  14. all screening labs should be performed within 14 days (+3 working days) of treatment initiation. 1) Hematological: Absolute neutrophil count (ANC), >/=1,500 /mcL; Platelets, >/=100,000 / mcL Hemoglobin, >/= 9 g/dL or >/= 5.6 mmol/L. 2) 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. 3) 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. 4) Coagulation International Normalized Ratio (INR) or Prothrombin Time (PT), Activated Partial Thromboplastin Time (aPTT), </=1.5 X ULN. *Creatinine clearance should be calculated per institutional standard.
  15. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours of study enrollment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
  16. Female subjects of childbearing potential should be willing to use 2 methods of birth control during the study and for 30 days after the last dose of the study drug or be surgically sterile. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
  17. Male subjects should agree to use an adequate method of contraception during the course of the study and for 30 days after the last dose of the study drug.
  18. Have histologically confirmed World Health Organization Grade IV glioma (glioblastoma or gliosarcoma). Participants will be eligible if the original histology was low-grade glioma and a subsequent histological diagnosis of glioblastoma or variants is made. (Phase I)
  19. A baseline brain MRI must be obtained no more than 14 days (+ 3 working days) prior to study enrollment. The patient must either be on no steroids or a stable dose of dexamethasone no greater than 2 mg a day for at least 5 days prior to entrance onto the study. Patients having undergone recent surgery are eligible as long as they are at least 3 weeks from resection or 1 week from stereotactic biopsy, and recovering from any operative or perioperative complications. No measurable disease post resection will be required. (Phase I)
  20. Patients having undergone recent surgery are eligible as long as they are at least 3 weeks from resection or 1 week from stereotactic biopsy, and recovering from any operative or perioperative complications. No measurable disease post resection will be required. (Phase I)
  21. Any number of prior relapses. (Phase I)
  22. A baseline brain MRI must be obtained no more than 14 days (+ 3 working days) prior to study enrollment. The patient must either be on no steroids or a stable dose of dexamethasone no greater than 2 mg a day for at least 5 days prior to entrance onto the study. (Phase II Dose Expansion in Recurrent GBM undergoing resection)
  23. A baseline brain MRI obtained no more than 14 days (+ 3 working days) prior to study enrollment on a stable dose of steroids no greater than 2 mg a day of dexamethasone for at least 5 days, is required prior to entrance of a patient onto the study. Patients must be registered on the study within 5 weeks of completion of concurrent chemoradiation. (Phase II Dose Expansion in Newly diagnosed GBM)
  Exclusion Criteria:
  1. Has been treated previously with bevacizumab.
  2. Has tumor localized primarily to the posterior fossa, spinal cord, or an unresectable location. (Phase II Dose Expansion in Recurrent GBM undergoing resection)
  3. Has received prior interstitial brachytherapy, implanted chemotherapy, or therapeutics delivered by local injection or convection enhanced delivery. Prior treatment with Gliadel® wafers will be excluded.
  4. Is </= 12 weeks from completing external beam radiotherapy. (Phase I and Phase II Dose Expansion in Recurrent GBM undergoing resection)
  5. Is currently participating in a study of an investigational agent or using an investigational device for therapeutic purposes. Concurrent use of Optune® device is not allowed. (Phase I and Phase II Dose Expansion in Recurrent GBM undergoing resection)
  6. Is currently participating or has participated in any other newly diagnosed therapeutic trial before or after chemoradiation. (Phase II Dose Expansion in Newly diagnosed GBM)
  7. CMV seronegative.
  8. Has a known history of Human Immunodeficiency Virus (HIV) (positive HIV 1/2 antibodies); HTLV1 and/or HTLV2; active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected). Patients with prior HBV vaccination (anti-HBs positive, HBsAg negative, anti-HBc negative) will NOT be excluded.
  9. Has a diagnosis of immunodeficiency or is receiving systemic immunosuppressive therapy within 7 days of study entrance.
  10. Has had prior chemotherapy, or targeted small molecule 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. 12) Has known gliomatous meningitis, subependymal spread, extracranial disease, or multifocal disease. (Phase II Dose Expansion in Recurrent GBM undergoing resection)
  11. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.
  12. Has known gliomatous meningitis, subependymal spread, extracranial disease, or multifocal disease. (Recurrent glioblastoma cohort)
  13. Has known gliomatous meningitis, extracranial disease, or multifocal disease. (Phase II Dose Expansion in Newly diagnosed GBM)
  14. Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjogren's syndrome will not be excluded from the study.
  15. Has evidence of interstitial lung disease or active, non-infectious pneumonitis.
  16. Has an active infection requiring systemic therapy.
  17. 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.
  18. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  19. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit.
  20. Has received prior therapy with any antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways. (Phase II Dose Expansion in Recurrent GBM undergoing resection and in newly diagnosed GBM)
  21. Has received a live vaccine within 30 days prior to the first dose of trial treatment.
  22. Contraindication for undergoing MRIs.
  23. Evidence of bleeding diathesis or use of anticoagulant medication or any medication that may increase the risk of bleeding that cannot be stopped prior to surgery. ( Phase II Dose Expansion in Recurrent GBM undergoing resection)
  24. Tumor localized primarily to the posterior fossa or spinal cord. (Phase I)
  25. Has known gliomatous meningitis, subependymal spread, or extracranial disease. (Phase I)

Relevance to patient case: not relevant