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Study to Evaluate Ibudilast and TMZ Combo Treatment in Recurrent GBM

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03782415
Recruitment Status : Recruiting
First Posted : December 20, 2018
Last Update Posted : February 5, 2019
Sponsor:
Information provided by (Responsible Party):
MediciNova

Tracking Information
First Submitted Date  ICMJE December 17, 2018
First Posted Date  ICMJE December 20, 2018
Last Update Posted Date February 5, 2019
Actual Study Start Date  ICMJE December 29, 2018
Estimated Primary Completion Date December 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 19, 2018)
Determine Progression-free survival pf patients at 6 months [ Time Frame: 6 months ]
Determine proportion of patients (who take ibudilast & TMZ combination) who are progression-free at 6 months
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03782415 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: December 19, 2018)
  • Safety Evaluation (Adverse events or discontinuation due to Dose limiting toxicities) [ Time Frame: 6 months ]
    Determine the proportion of patients with
    • Treatment-emergent adverse events (TEAEs) as measured by the CTCAE v4.0 and
    • Treatment discontinuations due to TEAEs and Dose-Limiting Toxicities (DLTs)
  • Maximum tolerated dose determination [ Time Frame: 6 months ]
    Determine maximum tolerable dose of ibudilast taken in combination with TMZ
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study to Evaluate Ibudilast and TMZ Combo Treatment in Recurrent GBM
Official Title  ICMJE Phase 1b/2a 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 Glioblastoma
Brief 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Phase 1b/2a Multi-center, Open-label, Dose Escalation Study
Masking: None (Open Label)
Primary Purpose: Other
Condition  ICMJE
  • Glioblastoma
  • Recurrent Glioblastoma
  • GBM
  • Recurrent GBM
Intervention  ICMJE
  • Drug: MN-166
    MN-166 (ibudilast) is an anti-inflammatory/neuroprotective agent. MN-166 (ibudilast) distributes well to the CNS (Sanftner et al. 2009) and it is a selective inhibitor of certain cyclic nucleotide phosphodiesterases (PDE) and the pro-inflammatory cytokine, macrophage migration inhibitory factor (MIF). At clinically-relevant plasma or CNS concentrations, MN-166 (ibudilast) selectively inhibits macrophage migration inhibitory factor (MIF) (Cho et al 2010) and, secondarily, PDE3, 4 and 10 (Gibson et al 2006).
    Other Name: ibudilast
  • Drug: Temozolomide
    Temozolomide is an oral chemotherapy drug. It is an alkylating agent used as a treatment of some brain cancers; and a first-line treatment for glioblastoma multiforme.
    Other Names:
    • TMZ
    • Temodar
    • Temodal
    • Temcad
Study Arms  ICMJE
  • Experimental: MN-166 (ibudilast)
    Part 1: Open-label, single arm, dose escalation of MN-166 (ibudilast) 60 mg/day and temozolomide (TMZ) 150 mg/m² combination treatment. Part 2: Open-label, fixed-dose MN-166 (ibudilast) and temozolomide (TMZ) combination treatment for 6 cycles until disease progression, unacceptable tolerability and/or toxicity or loss of life.
    Intervention: Drug: MN-166
  • Experimental: Temozolomide

    Part 1: Temozolomide (TMZ) (150 mg/m²) will be given orally once daily without food to all subjects on Days 1-5 during a 28-day cycle.

    Part 2: If the TMZ-related toxicities are tolerated in Cycle 1, the dose of TMZ will be escalated to 200 mg/m² in combination with the fixed-dose MN-166 (ibudilast) for 6 cycles until disease progression, unacceptable tolerability and/or toxicity or loss of life.

    Intervention: Drug: Temozolomide
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 19, 2018)
50
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2020
Estimated Primary Completion Date December 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Joanna Dojillo, MSc 8583731500 ext 118 dojillo@medicinova.com
Contact: Kazuko Matsuda, MD, PhD, MPH 8583731500 matsuda@medicinova.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03782415
Other Study ID Numbers  ICMJE MN-166-GBM-1201
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party MediciNova
Study Sponsor  ICMJE MediciNova
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Patrick Wen, MD Dana-Farber Cancer Institute
PRS Account MediciNova
Verification Date February 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP