Study of the IDO Pathway Inhibitor, Indoximod, and Temozolomide for Pediatric Patients With Progressive Primary Malignant Brain Tumors
Study Details
Study Description
Brief Summary
This is a first-in-children phase 1 trial using indoximod, an inhibitor of the immune "checkpoint" pathway indoleamine 2,3-dioxygenase (IDO), in combination with temozolomide-based therapy to treat pediatric brain tumors. Using a preclinical glioblastoma model, it was recently shown that adding IDO-blocking drugs to temozolomide plus radiation significantly enhanced survival by driving a vigorous, tumordirected inflammatory response. This data provided the rationale for the companion adult phase 1 trial using indoximod (IND#120813) plus temozolomide to treat adults with glioblastoma, which is currently open (NCT02052648). The goal of this pediatric study is to bring IDO-based immunotherapy into the clinic for children with brain tumors. This study will provide a foundation for future pediatric trials testing indoximod combined with radiation and temozolomide in the up-front setting for patients with newly diagnosed central nervous system tumors.
Condition or Disease | Intervention/Treatment | Phase |
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Phase 1 |
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Experimental: Group 1 (CLOSED) Core Regimen: Dose-escalation of indoximod, in combination with temozolomide, for pediatric patients with progressive brain tumors. Indoximod will be administered in escalating doses. Initial dosing will be 12.8 mg/kg/dose BID with escalation planned to 22.4 mg/kg/dose BID. Temozolomide to be given at 200 mg/m^2 x 5 days |
Drug: Indoximod
Indoximod will be administered orally twice daily.
Other Names:
Drug: Temozolomide
Temozolomide will be administered on days 1-5 of every 28 day cycle.
Other Names:
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Experimental: Group 2 (CLOSED) Expansion cohorts: Indoximod therapy at the pediatric recommended phase 2 dose (RP2D) determined by Group 1, in combination with temozolomide. Indoximod will be administered at the RP2D of 19.2 mg/kg/dose BID. Temozolomide to be given at 200 mg/m^2 x 5 days |
Drug: Indoximod
Indoximod will be administered orally twice daily.
Other Names:
Drug: Temozolomide
Temozolomide will be administered on days 1-5 of every 28 day cycle.
Other Names:
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Experimental: Group 3 (CLOSED) Dose-escalation of indoximod, in combination with up-front conformal radiation therapy, for pediatric patients with progressive brain tumors. Indoximod will be administered in escalating doses. Initial dosing will be 12.8 mg/kg/dose BID with escalation planned to 22.4 mg/kg/dose BID. Temozolomide to be given at 200 mg/m^2 x 5 days |
Drug: Indoximod
Indoximod will be administered orally twice daily.
Other Names:
Drug: Temozolomide
Temozolomide will be administered on days 1-5 of every 28 day cycle.
Other Names:
Radiation: Conformal Radiation
Conformal radiation will be administered on days 3-7 of induction cycle.
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Experimental: Group 3b Indoximod, in combination with up-front conformal radiation therapy, for pediatric patients with newly diagnosed treatment-naive diffuse intrinsic pontine glioma (DIPG). Indoximod will be administered at the RP2D of 19.2 mg/kg/dose BID. Temozolomide to be given at 200 mg/m^2 x 5 days |
Drug: Indoximod
Indoximod will be administered orally twice daily.
Other Names:
Drug: Temozolomide
Temozolomide will be administered on days 1-5 of every 28 day cycle.
Other Names:
Radiation: Conformal Radiation
Conformal radiation will be administered on days 3-7 of induction cycle.
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Experimental: Group 4 Continued access to indoximod in combination with low-dose oral cyclophosphamide and etoposide for patients with progressive disease after treatment with indoximod plus temozolomide. Indoximod will be administered at 32 mg/kg/dose divided twice daily. Cyclophosphamide to be given at 2.5 mg/kg/dose daily Etoposide to be given at 50 mg/m2/dose daily |
Drug: Indoximod
Indoximod will be administered orally twice daily.
Other Names:
Drug: Cyclophosphamide
Cyclophosphamide will be administered orally daily.
Drug: Etoposide
Etoposide will be administered orally daily.
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Outcome Measures
Primary Outcome Measures
- Incidence of regimen limiting toxicities (RLTs) [First 28 days of treatment]
To estimate the RP2D of indoximod combined with temozolomide
- Objective Response Rate [Up to three years]
To assess preliminary evidence of efficacy of indoximod and temozolomide using COG brain tumor measurement criteria.
- Incidence of regimen limiting toxicities (RLTs) [First 35 days of treatment]
To estimate the RP2D of indoximod combined with conformal radiation
- Safety and tolerability assessed by development of AEs and laboratory parameters of indoximod in combination with cyclophosphamide and etoposide. [Up to three years]
In patients who initially achieve prolonged stable disease or better with Indoximod plus temozolomide but then develop progressive disease
Secondary Outcome Measures
- Pharmacokinetics: Serum concentrations (Cmax/Steady State) [First 48 hours of treatment]
Group 1
- Safety and Tolerability of Indoximod combined with Temozolomide as assessed by incidence and severity of adverse events, dose interruptions and dose reductions. [Continuous during study until 30 days after study treatment is complete.]
Group 1 and 2
- Progression Free Survival (PFS) [Up to three years]
Group 2
- Time to Progression [Start of study until disease progression follow-up, up to three years]
Group 2
- Overall Survival [Start of study until end of follow-up, up to five years]
Group 2
- Safety and Feasibility of Indoximod combined with conformal radiation as assessed by incidence and severity of adverse events, dose interruptions and dose reductions. [Continuous during study until 30 days after study treatment is complete.]
Group 3
Eligibility Criteria
Criteria
Eligibility Criteria
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Age: 3-21 years.
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Group 1 or Group 3: histologically proven initial diagnosis of primary malignant brain tumor, with no known curative treatment options.
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Group 2: histologically proven initial diagnosis of high-grade glioma (WHO grade III and IV), ependymoma, medulloblastoma, or other primary central nervous system tumor.
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Group 3b: Patients with a radiographic diagnosis or histologically proven diagnosis of diffuse intrinsic pontine glioma (DIPG).
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MRI confirmation of tumor progression or regrowth.
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Patients must be able to swallow whole capsules.
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Patients with metastatic disease are eligible for enrollment.
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Lansky or Karnofsky performance status score must be > 50%.
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Seizure disorders must be well controlled on antiepileptic medication.
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DIPG patients enrolled to Group 3b must not have been previously treated with radiation or any medical therapy.
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Patients previously treated with temozolomide, cyclophosphamide, and/or etoposide are eligible for enrollment.
Exclusion Criteria
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Prior invasive malignancy, other than the primary central nervous system tumor, unless the patient has been disease free and off therapy for that disease for a minimum of 3 years
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Patients with baseline QTc interval of more than 470 msec at study entry, and patients with congenital long QTc syndrome.
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Active autoimmune disease
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | Children's Hospital Colorado | Aurora | Colorado | United States | 80045 |
2 | Arnold Palmer Hospital for Children | Orlando | Florida | United States | 32806 |
3 | Children's Heathcare of Atlanta | Atlanta | Georgia | United States | 30342 |
4 | Augusta University | Augusta | Georgia | United States | 30912 |
5 | Children's Hospitals and Clinics of Minnesota | Minneapolis | Minnesota | United States | 55404 |
Sponsors and Collaborators
- NewLink Genetics Corporation
Investigators
- Study Director: Gene Kennedy, MD, NewLink Genetics Corporation
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- NLG2105