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

Phase 1b/2a Single-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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Glioblastoma; GBM; Recurrent Glioblastoma; Newly Diagnosed Glioblastoma
• Intervention / Treatment: Drug: MN-166; Drug: Temozolomide

Detailed Description

This is a single-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. To be eligible, subjects are histologically confirmed glioblastoma or gliosarcoma, or astrocytomas with molecular features of glioblastoma, WHO Grade 4. Recurrent glioblastoma patients must have a Karnofsky Performance Status (KPS) ≥70 or Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Patients having newly diagnosed glioblastoma, gliosarcoma, or astrocytomas with molecular features of glioblastoma 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 when given in combination with temozolomide, and determine the dose of MN-166 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 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 up to 2 years and up to 50 subjects are planned to be enrolled in Part 2.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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®).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: MN-166 and temozolomide; Part 1: Combination treatment of MN-166 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 and temozolomide combination treatment for 6 cycles until disease progression, unacceptable tolerability and/or toxicity or loss of life.

Drug: MN-166; MN-166 is an anti-inflammatory/neuroprotective agent. MN-166 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 selectively inhibits macrophage migration inhibitory factor (MIF) (Cho et al 2010) and, secondarily, PDE3, 4 and 10 (Gibson et al 2006).; Other Names: 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: Temodar; Temodal; Temcad; TMZ

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluate safety and tolerability of ibudilast and temozolomide combination treatment	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).	1-6 months
Evaluate efficacy of ibudilast and TMZ combination treatment	Proportion of patients who are progression free at 6 months (PFS6) using the RANO criteria.	1-6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluate Tmax	Time from start of dosing at which the maximum concentration is observed)	1-6 months
Cmax	Maximum observed concentration)	1-6 months
AUC	Area under the concentration versus time curve from the start of dose administration to the last quantifiable point within the dosing interval.	1-6 months
Terminal rate constant	Calculated from the terminal slope of the log-linear regression of concentration with time.	1-6 months
Terminal half-life	Time required for the plasma concentration of a drug to decrease 50% in the final stage of its elimination	1-6 months
Maximum tolerated dose determination	Determine maximum tolerable dose of ibudilast taken in combination with TMZ	1-6 months
Evaluate the safety of fixed-dose ibudilast in combination with TMZ	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).	1-6 months
Evaluate overall survival, response rate, and median 6-month progression-free survival (PFS6)	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.	1-6 months

Collaborators and Investigators

• Sponsor: MediciNova
• Investigators: Study Director: Kazuko Matsuda, MD PhD MPH, MediciNova, Inc.

Publications and helpful links

General Publications

• Gibson LC, Hastings SF, McPhee I, Clayton RA, Darroch CE, Mackenzie A, Mackenzie FL, Nagasawa M, Stevens PA, Mackenzie SJ. The inhibitory profile of Ibudilast against the human phosphodiesterase enzyme family. Eur J Pharmacol. 2006 May 24;538(1-3):39-42. doi: 10.1016/j.ejphar.2006.02.053. Epub 2006 Mar 13.
• Sanftner LM, Gibbons JA, Gross MI, Suzuki BM, Gaeta FC, Johnson KW. Cross-species comparisons of the pharmacokinetics of ibudilast. Xenobiotica. 2009 Dec;39(12):964-77. doi: 10.3109/00498250903254340.
• Cho Y, Crichlow GV, Vermeire JJ, Leng L, Du X, Hodsdon ME, Bucala R, Cappello M, Gross M, Gaeta F, Johnson K, Lolis EJ. Allosteric inhibition of macrophage migration inhibitory factor revealed by ibudilast. Proc Natl Acad Sci U S A. 2010 Jun 22;107(25):11313-8. doi: 10.1073/pnas.1002716107. Epub 2010 Jun 8.

Study record dates

Study Major Dates

• Study Start (Actual): December 29, 2018
• Primary Completion (Actual): December 31, 2023
• Study Completion (Estimated): June 30, 2024

Study Registration Dates

• First Submitted: December 17, 2018
• First Submitted That Met QC Criteria: December 19, 2018
• First Posted (Actual): December 20, 2018

Study Record Updates

• Last Update Posted (Actual): March 15, 2024
• Last Update Submitted That Met QC Criteria: March 14, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: GBM; glioblastoma; newly diagnosed glioblastoma; temozolomide; recurrent GBM; MN-166
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Disease Attributes; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Recurrence; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Platelet Aggregation Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Phosphodiesterase Inhibitors; Temozolomide; Ibudilast
• Other Study ID Numbers: MN-166-GBM-1201

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No