Patient case: 50-year-old male with glioblastoma; genetic feature: IDH1 (R132H)

Clinical trial: Study to Evaluate Ibudilast and TMZ Combo Treatment in Recurrent GBM

Summary: Part 1 is an open-label, single-arm, dose escalation study of MN-166 (ibudilast) and temozolomide (TMZ) combination treatment. Evaluate safety and tolerability of ibudilast (MN-166) and TMZ combination treatment for 1 cycle (28 days); determine dosage in dose-finding study. Part 2 will evaluate efficacy of fixed-dose MN-166 (ibudilast) and TMZ combination treatment for 6 cycles (~6 months) until disease progression, unacceptable tolerability and/or toxicity or loss of life.

Detailed description: This is a multi-center open-label, dose escalation study to evaluate the safety, tolerability and efficacy of MN-166 (ibudilast) and Temozolomide combination treatment in patients with recurrent glioblastomas. To be eligible, subjects are histologically confirmed GBM (glioblastoma), WHO Grade IV, must have a Karnofsky Performance Status (KPS) ≥ 70 or Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
  This is divided into a dose-escalation phase (Part 1) followed by a fixed-dose phase (Part 2).
  Part 1 will evaluate the safety and tolerability of MN-166 (ibudilast) when given in combination with TMZ, and determine the dose of MN-166 (ibudilast) to be used in Part 2 of the study. A total of 15-18 adult subjects are planned to be enrolled in Part 1.
  Part 2 will evaluate the efficacy of MN-166 (ibudilast) and temozolomide combination treatment in patients with recurrent GBM as measured by the proportion of patients who are progression-free at 6 months. Other outcome measures include the evaluation of overall survival, response rate, and median six-month progression-free survival and approximately 32 subjects are planned to be enrolled in Part 2.

Eligibility: Inclusion Criteria:
  1. Age 18 or above
  2. Ability and willingness to signed informed consent form
  3. Histologically confirmed GBM (glioblastoma), WHO Grade IV
  4. Patients must have a Karnofsky Performance Status (KPS) ≥ 70 or Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (see Appendix 7)
  5. Previously received standard front-line GBM treatment including maximal surgical resection followed by external beam radiation therapy and TMZ therapy. Prior use of NovoTTF (Optune) and Gliadel wafers is allowed.
  6. Patients must be in first relapse.
  1. Relapse is defined as progression following initial therapy (i.e., radiation and/or chemotherapy). The intent therefore is that patients had no more than 1 prior therapy (i.e., initial treatment). If the patient had a surgical resection for relapsed disease and no anti-cancer therapy was instituted for up to 12 weeks, and the patient undergoes another surgical resection, this is considered to constitute one (1) relapse.
  2. Documented recurrence or progression by brain MRI imaging ≤ 14 days before study registration.
  3. Measurable disease by RANO criteria (≥ 10 mm x 10 mm) (Appendix 6)
  7. If patient is receiving corticosteroid, dose must be stable or decreasing for at least 5 days prior to the scan. If steroids are added or the steroid dose is increased between the date of the pre-treatment MRI and the start of study, a new baseline MRI or CT is required.
  8. Patients who tolerated prior TMZ therapy; (No grade 3 or greater hematologic toxicity or grade 3 or greater nausea and vomiting despite maximal medical therapy and completed at least 80% of prior TMZ administered concomitantly with radiation therapy = at least 34 of 42 days of treatment).
  9. A period Patient has a period of at least 3 months should have lapsed stability since the patient has he or she received last TMZ and radiotherapy treatment.
  10. Patients who suffered clinically significant toxic effects on prior therapy must have recovered to grade 0 or 1 or pre-treatment baseline value (including but not limited to exceptions of alopecia, laboratory values listed per inclusion criteria, and lymphopenia which is common after therapy with TMZ).
  11. Patients having undergone recent resection or open biopsy or stereotactic biopsy of recurrent or progressive tumor will be eligible as long as the following conditions apply:
  1. They have recovered from the effects of surgery.
  2. To best assess the extent of residual disease post-operatively, an MRI or CT scan should ideally have been performed no later than 96 hours following surgery, or at least 28 days post-operatively, but scans performed outside of this window are considered acceptable if no alternative is available. In either case, the baseline/screening MRI must be performed within 14 days prior to registration. If the patient is taking corticosteroids, the dose must be stable or decreasing for at least 5 days prior to the scan. If steroids are added or the steroid dose is increased between the date of the screening MRI or CT scan and the start of treatment, a new baseline MRI or CT is required.
  12. Confirmation of availability of sufficient tissue from a prior surgery for correlative studies (ten formalin fixed paraffin embedded [FFPE] slides).
  Exclusion Criteria:
  1. History of Grade 2 (CTCAE v4.0) or greater intracranial or intratumoral hemorrhage confirmed by either MRI or CT scan;
  2. Any significant laboratory abnormality which, in the opinion of the Investigator, may put the patient at risk and with the following laboratory abnormalities at screening:
  -  Inadequate Bone Marrow function WBCs < 3,000 mm3 Lymphocytes < 500 mm3Neutrophils < 1500 mm3 Platelets < 100,000 mm3
  -  Inadequate Liver function ALT, AST, T.bil > 2x UNL
  -  Inadequate Renal function Serum Creatinine > 1.5 mg/dL or calculated Creatinine Clearance > 50 mL/min;
  3. Current use of anticoagulant treatment with coumadin (low-molecular-weight heparin and factor Xa inhibitors are permitted);
  4. Any systemic illness or unstable medical condition that might pose additional risk, including: cardiac, unstable metabolic or endocrine disturbances, renal or liver disease;
  5. Patients with a history of a different malignancy except the following circumstances:
  a) They have been disease-free for at least 2 years prior to starting study drug and are deemed by the investigator to be at low risk for recurrence of that malignancy. Patients with the following cancers are eligible if diagnosed and treated within the past 2 years:
  • Cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin;
  6. Active drug or alcohol dependence or any other factors that, in the opinion of the site investigators would interfere with adherence to study requirements;
  7. Patients who have not recovered to ≤ Grade 1 toxicity by NCI CTCAE v4.0 from the toxic effects of previous therapy with exception of lymphopenia, alopecia and fatigue;
  8. Pregnant or breastfeeding;
  1. Women of childbearing potential must agree to use a medically approved contraceptive method during the treatment period and for 3 months following the last dose of ibudilast and TMZ. Men must agree to use a reliable method of birth control and to not donate sperm during the study and for at least 3 months following the last dose of ibudilast and TMZ. Contraceptive methods may include an intrauterine device (IUD) or barrier method. If condoms are used as a barrier method, a spermicidal agent should be added as a double barrier protection;
  2. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to first dose of ibudilast and TMZ;
  3. Women are considered post-menopausal and not of childbearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL and estradiol < 20 pg/mL or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks prior to screening. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of childbearing potential;
  9. For use of other investigational drug or other anti-tumor treatment, the following time periods must have elapsed from the projected start of scheduled study treatment:
  1. 4 weeks or 5 half-lives (whichever is shorter) from any investigational agent;
  2. 4 weeks from cytotoxic therapy (except 23 days for TMZ; 6 weeks from nitrosoureas);
  3. 6 weeks from antibodies treatment (i.e., anti-VEGF antibody);
  4. 4 weeks or 5 half-lives (whichever is shorter) from other anti-tumor therapies;
  5. 2 days from NOVO-TTF (Optune®);
  10. ECG finding of resting pulse < 50 bpm, SA or AV block, QTc prolongation > 450 ms for males and > 470 ms for females at screening.

Relevance to patient case: not relevant