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Study to Evaluate Ibudilast and TMZ Combo Treatment in Newly Diagnosed and Recurrent Glioblastoma

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 : May 27, 2020
Sponsor:
Information provided by (Responsible Party):
MediciNova

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.

Condition or disease Intervention/treatment Phase
Glioblastoma Recurrent Glioblastoma GBM Recurrent GBM Drug: MN-166 Drug: Temozolomide Phase 1 Phase 2

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 newly diagnosed or recurrent glioblastomas. To be eligible, subjects are histologically confirmed GBM (glioblastoma) or gliosarcoma, or astrocytomas with molecular features of GBM, WHO Grade 4. Recurrent GBM patients must have a Karnofsky Performance Status (KPS) ≥70 or Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Newly diagnosed glioblastoma GBM, gliosarcoma, or astrocytomas with molecular features of GBM must have a KPS ≥60 and ECOG score 0-1.

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. Up to 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 as measured by the proportion of subjects 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 up to 32 subjects are planned to be enrolled in Part 2.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Phase 1b/2a Multi-center, Open-label, Dose Escalation Study
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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 Newly Diagnosed or Recurrent Glioblastoma
Actual Study Start Date : December 29, 2018
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : December 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: MN-166 (ibudilast) and temozolomide
Part 1: Combination treatment of MN-166 (ibudilast) 60 mg/day (30 mg twice a day) for 28 days and temozolomide 150 mg/m² on Days 1-5 of 28-day cycle. Part 2: Open-label, fixed-dose MN-166 (ibudilast) and temozolomide combination treatment for 6 cycles until disease progression, unacceptable tolerability and/or toxicity or loss of life.
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




Primary Outcome Measures :
  1. Evaluate safety and tolerability of ibudilast and temozolomide combination treatment [ Time Frame: 1-6 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).

  2. Evaluate efficacy of ibudilast and TMZ combination treatment [ Time Frame: 1-6 months ]
    Proportion of patients who are progression free at 6 months (PFS6) using the RANO criteria.


Secondary Outcome Measures :
  1. Evaluate Tmax [ Time Frame: 1-6 months ]
    Time from start of dosing at which the maximum concentration is observed)

  2. Cmax [ Time Frame: 1-6 months ]
    Maximum observed concentration)

  3. AUC [ Time Frame: 1-6 months ]
    Area under the concentration versus time curve from the start of dose administration to the last quantifiable point within the dosing interval.

  4. Terminal rate constant [ Time Frame: 1-6 months ]
    Calculated from the terminal slope of the log-linear regression of concentration with time.

  5. Terminal half-life [ Time Frame: 1-6 months ]
    Time required for the plasma concentration of a drug to decrease 50% in the final stage of its elimination

  6. Maximum tolerated dose determination [ Time Frame: 1-6 months ]
    Determine maximum tolerable dose of ibudilast taken in combination with TMZ

  7. Evaluate the safety of fixed-dose ibudilast in combination with TMZ [ Time Frame: 1-6 months ]

    Reporting of treatment-emergent adverse events

    • Treatment-emergent adverse events (TEAEs) as measured by the CTCAE v4.0 and
    • Treatment discontinuations due to TEAEs and Dose-Limiting Toxicities (DLTs).

  8. Evaluate overall survival, response rate, and median 6-month progression-free survival (PFS6) [ Time Frame: 1-6 months ]
    Overall survival will be measured for each subject with time origin at the date of Study Day 1 until recorded date or death or last follow-up visit.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Major Inclusion Criteria for Recurrent GBM Patients:

  1. Age 18 or older;
  2. Histologically confirmed GBM (glioblastoma), WHO Grade 4;
  3. Patients must have a Karnofsky Performance Status (KPS) ≥70 or Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (see Appendix 7);
  4. 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;
  5. 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).

Major Inclusion criteria for newly diagnosed patients:

  1. Ages 18 or older;
  2. Newly diagnosed glioblastoma or gliosarcoma (WHO Grade 4) confirmed by histology or astrocytomas with molecular features of gliobastoma;
  3. Starting maintenance therapy with temozolomide (150 mg/m^2 on Days 1-5 every 28 days) within 4 weeks prior to screening phase;
  4. 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 pretreatment MRI and the start of study, a new baseline MRI or CT scan is required;
  5. Karnofsky Performance Status ≥60 at time of screening;
  6. ECOG score of 0 or 1 at time of screening;
  7. Life expectancy of at least 3 months.

Exclusion Criteria (applied to all patients):

  1. History of Grade 2 (CTCAE v4.0) or greater intracranial or intratumoral hemorrhage confirmed by either MRI or CT scan;
  2. Current use of anticoagulant treatment with coumadin (low-molecular-weight heparin and factor Xa inhibitors are permitted);
  3. Any systemic illness or unstable medical condition that might pose additional risk, including: cardiac, unstable metabolic or endocrine disturbances, renal or liver disease;
  4. Patients with a history of a different malignancy except the following circumstances:

    1. 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: i. Cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin;

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; 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®).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03782415


Contacts
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Contact: Joanna Dojillo, MSc 8583731500 ext 118 dojillo@medicinova.com
Contact: Kazuko Matsuda, MD, PhD, MPH 8583731500 matsuda@medicinova.com

Locations
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United States, Massachusetts
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Amanda Spearman    877-442-3324    Amanda_Spearman@DFCI.HARVARD.EDU   
Contact: Brenda Acevedo    8774423324    Brenda_Acevedo@DFCI.HARVARD.EDU   
Sponsors and Collaborators
MediciNova
Investigators
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Principal Investigator: Patrick Wen, MD Dana-Farber Cancer Institute
Publications:
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Responsible Party: MediciNova
ClinicalTrials.gov Identifier: NCT03782415    
Other Study ID Numbers: MN-166-GBM-1201
First Posted: December 20, 2018    Key Record Dates
Last Update Posted: May 27, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by MediciNova:
ibudilast
MN-166
GBM
glioblastoma
recurrent GBM
temozolomide
Additional relevant MeSH terms:
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Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Temozolomide
Ibudilast
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Platelet Aggregation Inhibitors
Vasodilator Agents