PEP-CMV + Nivolumab for Newly Diagnosed Diffuse Midline Glioma/High-grade Glioma and Recurrent Diffuse Midline Glioma/High-grade Glioma, Medulloblastoma, and Ependymoma
Phase 1
Not yet recruiting
- Conditions
- Interventions
- Registration Number
- NCT06639607
- Lead Sponsor
- Washington University School of Medicine
- Brief Summary
This is a multisite, phase I/II clinical trial in children and young adults with newly-diagnosed high-grade glioma (HGG), diffuse midline glioma (DMG) and recurrent HGG/DMG, Medulloblastoma (MB), or ependymoma (EPN) to determine the safety, immunogenicity, and efficacy of a CMV-directed peptide vaccine plus checkpoint blockade.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 68
Inclusion Criteria
Not provided
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Exclusion Criteria
- Pregnant or breast-feeding women will not be entered on this study due to known or unknown risks of fetal and teratogenic adverse events as seen in animal/human studies. Pregnancy tests must be obtained in girls and women who are post-menarchal at least 7 days prior to study enrollment. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method, which includes abstinence.
- Active infection requiring treatment.
- Patients with malignancy related to HIV or solid organ transplant: known history of HIV, HBV surface antigen positivity or positive HCV antibody are not eligible. Viral testing is not required unless clinically indicated in patients without a known history
- Known immunosuppressive disease.
- Patients with active unrelated systemic illness including but not limited to renal, hepatic cardiac (congestive cardiac failure, myocardial infarction, myocarditis), or moderate to severe pulmonary problems generally defined by need for medical intervention (e.g., oxygen, medications) and/or limiting activities of daily living (generally CTCAE Grade 2 or higher) or shortness of breath with limited exertion are not eligible. Pulmonary conditions include (but are not limited to) COPD, asthma, and hemi-pneumectomy
- Patients receiving concomitant immunosuppressive agents for medical conditions; inhaled corticosteroids for asthma are allowed.
- Patients receiving concomitant tumor-directed therapy.
- Patients receiving any other investigational drug therapy.
- Previous enrollment and treatment on an interventional clinical trial (Stratum 1 only).
- Patients on dexamethasone > 0.1 mg/Kg/day up to maximum dose of 4 mg/day or equivalent.
- Patients with inability to return for follow-up visits or obtain follow-up studies required to assess toxicity to therapy.
- Patients at high risk for imminent neurologic decline due to extensive bulk disease, midline shift, or herniation on MRI. These patients should be discussed with the study chairs.
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Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Phase I Stratum I: Temozolomide + Nivolumab + PEP-CMV vaccine + Td booster Temozolomide Patients with newly-diagnosed high-grade glioma or DMG may be enrolled any time within 42 days after completing radiation. Cycle 1 (Induction cycle) is 77±2 days. Will receive 1 course of temozolomide 200 mg/m\^2/day x 5 days on Days 1-5 of cycle 1 \& receive PEP-CMV vaccine at dose level 1 (250 μg/m\^2) on Days 21, 35 ±2 days, and 49 ±2 days. After the induction cycle, each subsequent cycle is 28 days. Starting in cycle 2, PEP-CMV vaccine is administered every 28 days on day 1 of each course. Patient can continue to receive PEP-CMV every 28 days until recurrence/progression. Patients will receive a tetanus (Td) booster at the time of enrollment. Immunotherapy begins with a Td pre-conditioning vaccine delivered 6-24 hours prior to the first vaccine on day 21. Patients will also receive nivolumab 3 mg/kg IV on day 14±1 day then every 14 days ±2 days thereafter. Phase I Stratum II: Temozolomide + Nivolumab + PEP-CMV vaccine + Td booster PEP-CMV vaccine Patients with recurrent/progressive HGG or DMG with measurable disease can be enrolled at any point following recurrence regardless of any prior therapy. Cycle 1 (Induction cycle) is 77±2 days. Will receive 1 course of temozolomide 200 mg/m\^2/day x 5 days on Days 1-5 of cycle 1 \& receive PEP-CMV vaccine at dose level 1 (250 μg/m\^2) on Days 21, 35 ±2 days, and 49 ±2 days. After the induction cycle, each subsequent cycle is 28 days. Starting in cycle 2, PEP-CMV vaccine is administered every 28 days on day 1 of each course. Patient can continue to receive PEP-CMV every 28 days until recurrence/progression. Patients will receive a tetanus (Td) booster at the time of enrollment. Immunotherapy begins with a Td pre-conditioning vaccine delivered 6-24 hours prior to the first vaccine on day 21. Patients will also receive nivolumab 3 mg/kg IV on day 14±1 day then every 14 days ±2 days thereafter. Phase I Stratum II: Temozolomide + Nivolumab + PEP-CMV vaccine + Td booster Tetanus booster Patients with recurrent/progressive HGG or DMG with measurable disease can be enrolled at any point following recurrence regardless of any prior therapy. Cycle 1 (Induction cycle) is 77±2 days. Will receive 1 course of temozolomide 200 mg/m\^2/day x 5 days on Days 1-5 of cycle 1 \& receive PEP-CMV vaccine at dose level 1 (250 μg/m\^2) on Days 21, 35 ±2 days, and 49 ±2 days. After the induction cycle, each subsequent cycle is 28 days. Starting in cycle 2, PEP-CMV vaccine is administered every 28 days on day 1 of each course. Patient can continue to receive PEP-CMV every 28 days until recurrence/progression. Patients will receive a tetanus (Td) booster at the time of enrollment. Immunotherapy begins with a Td pre-conditioning vaccine delivered 6-24 hours prior to the first vaccine on day 21. Patients will also receive nivolumab 3 mg/kg IV on day 14±1 day then every 14 days ±2 days thereafter. Phase I Stratum I: Temozolomide + Nivolumab + PEP-CMV vaccine + Td booster Nivolumab Patients with newly-diagnosed high-grade glioma or DMG may be enrolled any time within 42 days after completing radiation. Cycle 1 (Induction cycle) is 77±2 days. Will receive 1 course of temozolomide 200 mg/m\^2/day x 5 days on Days 1-5 of cycle 1 \& receive PEP-CMV vaccine at dose level 1 (250 μg/m\^2) on Days 21, 35 ±2 days, and 49 ±2 days. After the induction cycle, each subsequent cycle is 28 days. Starting in cycle 2, PEP-CMV vaccine is administered every 28 days on day 1 of each course. Patient can continue to receive PEP-CMV every 28 days until recurrence/progression. Patients will receive a tetanus (Td) booster at the time of enrollment. Immunotherapy begins with a Td pre-conditioning vaccine delivered 6-24 hours prior to the first vaccine on day 21. Patients will also receive nivolumab 3 mg/kg IV on day 14±1 day then every 14 days ±2 days thereafter. Phase I Stratum I: Temozolomide + Nivolumab + PEP-CMV vaccine + Td booster PEP-CMV vaccine Patients with newly-diagnosed high-grade glioma or DMG may be enrolled any time within 42 days after completing radiation. Cycle 1 (Induction cycle) is 77±2 days. Will receive 1 course of temozolomide 200 mg/m\^2/day x 5 days on Days 1-5 of cycle 1 \& receive PEP-CMV vaccine at dose level 1 (250 μg/m\^2) on Days 21, 35 ±2 days, and 49 ±2 days. After the induction cycle, each subsequent cycle is 28 days. Starting in cycle 2, PEP-CMV vaccine is administered every 28 days on day 1 of each course. Patient can continue to receive PEP-CMV every 28 days until recurrence/progression. Patients will receive a tetanus (Td) booster at the time of enrollment. Immunotherapy begins with a Td pre-conditioning vaccine delivered 6-24 hours prior to the first vaccine on day 21. Patients will also receive nivolumab 3 mg/kg IV on day 14±1 day then every 14 days ±2 days thereafter. Phase I Stratum I: Temozolomide + Nivolumab + PEP-CMV vaccine + Td booster Tetanus booster Patients with newly-diagnosed high-grade glioma or DMG may be enrolled any time within 42 days after completing radiation. Cycle 1 (Induction cycle) is 77±2 days. Will receive 1 course of temozolomide 200 mg/m\^2/day x 5 days on Days 1-5 of cycle 1 \& receive PEP-CMV vaccine at dose level 1 (250 μg/m\^2) on Days 21, 35 ±2 days, and 49 ±2 days. After the induction cycle, each subsequent cycle is 28 days. Starting in cycle 2, PEP-CMV vaccine is administered every 28 days on day 1 of each course. Patient can continue to receive PEP-CMV every 28 days until recurrence/progression. Patients will receive a tetanus (Td) booster at the time of enrollment. Immunotherapy begins with a Td pre-conditioning vaccine delivered 6-24 hours prior to the first vaccine on day 21. Patients will also receive nivolumab 3 mg/kg IV on day 14±1 day then every 14 days ±2 days thereafter. Phase I Stratum II: Temozolomide + Nivolumab + PEP-CMV vaccine + Td booster Nivolumab Patients with recurrent/progressive HGG or DMG with measurable disease can be enrolled at any point following recurrence regardless of any prior therapy. Cycle 1 (Induction cycle) is 77±2 days. Will receive 1 course of temozolomide 200 mg/m\^2/day x 5 days on Days 1-5 of cycle 1 \& receive PEP-CMV vaccine at dose level 1 (250 μg/m\^2) on Days 21, 35 ±2 days, and 49 ±2 days. After the induction cycle, each subsequent cycle is 28 days. Starting in cycle 2, PEP-CMV vaccine is administered every 28 days on day 1 of each course. Patient can continue to receive PEP-CMV every 28 days until recurrence/progression. Patients will receive a tetanus (Td) booster at the time of enrollment. Immunotherapy begins with a Td pre-conditioning vaccine delivered 6-24 hours prior to the first vaccine on day 21. Patients will also receive nivolumab 3 mg/kg IV on day 14±1 day then every 14 days ±2 days thereafter. Phase I Stratum II: Temozolomide + Nivolumab + PEP-CMV vaccine + Td booster Temozolomide Patients with recurrent/progressive HGG or DMG with measurable disease can be enrolled at any point following recurrence regardless of any prior therapy. Cycle 1 (Induction cycle) is 77±2 days. Will receive 1 course of temozolomide 200 mg/m\^2/day x 5 days on Days 1-5 of cycle 1 \& receive PEP-CMV vaccine at dose level 1 (250 μg/m\^2) on Days 21, 35 ±2 days, and 49 ±2 days. After the induction cycle, each subsequent cycle is 28 days. Starting in cycle 2, PEP-CMV vaccine is administered every 28 days on day 1 of each course. Patient can continue to receive PEP-CMV every 28 days until recurrence/progression. Patients will receive a tetanus (Td) booster at the time of enrollment. Immunotherapy begins with a Td pre-conditioning vaccine delivered 6-24 hours prior to the first vaccine on day 21. Patients will also receive nivolumab 3 mg/kg IV on day 14±1 day then every 14 days ±2 days thereafter. Phase I Stratum III: Temozolomide + Nivolumab + PEP-CMV vaccine + Td booster PEP-CMV vaccine Patients with recurrent/progressive MB or EPN with measurable disease can be enrolled at any point following recurrence regardless of any prior therapy. Cycle 1 (Induction cycle) is 77±2 days. Will receive 1 course of temozolomide 200 mg/m\^2/day x 5 days on Days 1-5 of cycle 1 \& receive PEP-CMV vaccine at dose level 1 (250 μg/m\^2) on Days 21, 35 ±2 days, and 49 ±2 days. After the induction cycle, each subsequent cycle is 28 days. Starting in cycle 2, PEP-CMV vaccine is administered every 28 days on day 1 of each course. Patient can continue to receive PEP-CMV every 28 days until recurrence/progression. Patients will receive a tetanus (Td) booster at the time of enrollment. Immunotherapy begins with a Td pre-conditioning vaccine delivered 6-24 hours prior to the first vaccine on day 21. Patients will also receive nivolumab 3 mg/kg IV on day 14±1 day then every 14 days ±2 days thereafter. Phase I Stratum III: Temozolomide + Nivolumab + PEP-CMV vaccine + Td booster Tetanus booster Patients with recurrent/progressive MB or EPN with measurable disease can be enrolled at any point following recurrence regardless of any prior therapy. Cycle 1 (Induction cycle) is 77±2 days. Will receive 1 course of temozolomide 200 mg/m\^2/day x 5 days on Days 1-5 of cycle 1 \& receive PEP-CMV vaccine at dose level 1 (250 μg/m\^2) on Days 21, 35 ±2 days, and 49 ±2 days. After the induction cycle, each subsequent cycle is 28 days. Starting in cycle 2, PEP-CMV vaccine is administered every 28 days on day 1 of each course. Patient can continue to receive PEP-CMV every 28 days until recurrence/progression. Patients will receive a tetanus (Td) booster at the time of enrollment. Immunotherapy begins with a Td pre-conditioning vaccine delivered 6-24 hours prior to the first vaccine on day 21. Patients will also receive nivolumab 3 mg/kg IV on day 14±1 day then every 14 days ±2 days thereafter. Phase I Stratum III: Temozolomide + Nivolumab + PEP-CMV vaccine + Td booster Nivolumab Patients with recurrent/progressive MB or EPN with measurable disease can be enrolled at any point following recurrence regardless of any prior therapy. Cycle 1 (Induction cycle) is 77±2 days. Will receive 1 course of temozolomide 200 mg/m\^2/day x 5 days on Days 1-5 of cycle 1 \& receive PEP-CMV vaccine at dose level 1 (250 μg/m\^2) on Days 21, 35 ±2 days, and 49 ±2 days. After the induction cycle, each subsequent cycle is 28 days. Starting in cycle 2, PEP-CMV vaccine is administered every 28 days on day 1 of each course. Patient can continue to receive PEP-CMV every 28 days until recurrence/progression. Patients will receive a tetanus (Td) booster at the time of enrollment. Immunotherapy begins with a Td pre-conditioning vaccine delivered 6-24 hours prior to the first vaccine on day 21. Patients will also receive nivolumab 3 mg/kg IV on day 14±1 day then every 14 days ±2 days thereafter. Phase I Stratum III: Temozolomide + Nivolumab + PEP-CMV vaccine + Td booster Temozolomide Patients with recurrent/progressive MB or EPN with measurable disease can be enrolled at any point following recurrence regardless of any prior therapy. Cycle 1 (Induction cycle) is 77±2 days. Will receive 1 course of temozolomide 200 mg/m\^2/day x 5 days on Days 1-5 of cycle 1 \& receive PEP-CMV vaccine at dose level 1 (250 μg/m\^2) on Days 21, 35 ±2 days, and 49 ±2 days. After the induction cycle, each subsequent cycle is 28 days. Starting in cycle 2, PEP-CMV vaccine is administered every 28 days on day 1 of each course. Patient can continue to receive PEP-CMV every 28 days until recurrence/progression. Patients will receive a tetanus (Td) booster at the time of enrollment. Immunotherapy begins with a Td pre-conditioning vaccine delivered 6-24 hours prior to the first vaccine on day 21. Patients will also receive nivolumab 3 mg/kg IV on day 14±1 day then every 14 days ±2 days thereafter. Phase II: Temozolomide + Nivolumab + PEP-CMV vaccine + Td booster PEP-CMV vaccine Cycle 1 (Induction cycle) is 77±2 days. Will receive 1 course of temozolomide 200 mg/m\^2/day x 5 days on Days 1-5 of cycle 1 \& receive PEP-CMV vaccine at dose level 1 (250 μg/m\^2) on Days 21, 35 ±2 days, and 49 ±2 days. After the induction cycle, each subsequent cycle is 28 days. Starting in cycle 2, PEP-CMV vaccine is administered every 28 days on day 1 of each course. Patient can continue to receive PEP-CMV every 28 days until recurrence/progression. Patients will receive a tetanus (Td) booster at the time of enrollment. Immunotherapy begins with a Td pre-conditioning vaccine delivered 6-24 hours prior to the first vaccine on day 21. Patients will also receive nivolumab 3 mg/kg IV on day 14±1 day then every 14 days ±2 days thereafter. Phase II: Temozolomide + Nivolumab + PEP-CMV vaccine + Td booster Tetanus booster Cycle 1 (Induction cycle) is 77±2 days. Will receive 1 course of temozolomide 200 mg/m\^2/day x 5 days on Days 1-5 of cycle 1 \& receive PEP-CMV vaccine at dose level 1 (250 μg/m\^2) on Days 21, 35 ±2 days, and 49 ±2 days. After the induction cycle, each subsequent cycle is 28 days. Starting in cycle 2, PEP-CMV vaccine is administered every 28 days on day 1 of each course. Patient can continue to receive PEP-CMV every 28 days until recurrence/progression. Patients will receive a tetanus (Td) booster at the time of enrollment. Immunotherapy begins with a Td pre-conditioning vaccine delivered 6-24 hours prior to the first vaccine on day 21. Patients will also receive nivolumab 3 mg/kg IV on day 14±1 day then every 14 days ±2 days thereafter. Phase II: Temozolomide + Nivolumab + PEP-CMV vaccine + Td booster Nivolumab Cycle 1 (Induction cycle) is 77±2 days. Will receive 1 course of temozolomide 200 mg/m\^2/day x 5 days on Days 1-5 of cycle 1 \& receive PEP-CMV vaccine at dose level 1 (250 μg/m\^2) on Days 21, 35 ±2 days, and 49 ±2 days. After the induction cycle, each subsequent cycle is 28 days. Starting in cycle 2, PEP-CMV vaccine is administered every 28 days on day 1 of each course. Patient can continue to receive PEP-CMV every 28 days until recurrence/progression. Patients will receive a tetanus (Td) booster at the time of enrollment. Immunotherapy begins with a Td pre-conditioning vaccine delivered 6-24 hours prior to the first vaccine on day 21. Patients will also receive nivolumab 3 mg/kg IV on day 14±1 day then every 14 days ±2 days thereafter. Phase II: Temozolomide + Nivolumab + PEP-CMV vaccine + Td booster Temozolomide Cycle 1 (Induction cycle) is 77±2 days. Will receive 1 course of temozolomide 200 mg/m\^2/day x 5 days on Days 1-5 of cycle 1 \& receive PEP-CMV vaccine at dose level 1 (250 μg/m\^2) on Days 21, 35 ±2 days, and 49 ±2 days. After the induction cycle, each subsequent cycle is 28 days. Starting in cycle 2, PEP-CMV vaccine is administered every 28 days on day 1 of each course. Patient can continue to receive PEP-CMV every 28 days until recurrence/progression. Patients will receive a tetanus (Td) booster at the time of enrollment. Immunotherapy begins with a Td pre-conditioning vaccine delivered 6-24 hours prior to the first vaccine on day 21. Patients will also receive nivolumab 3 mg/kg IV on day 14±1 day then every 14 days ±2 days thereafter.
- Primary Outcome Measures
Name Time Method Proportion of patients with unacceptable toxicity From the first vaccine (day 21) through 2 weeks after the third vaccine (day 49) (estimated to be 42 days) An unacceptable toxicity will be defined as any life-threatening toxicity ≥ Grade 3 that is possibly, probably, or definitely related to the PEP CMV vaccine. There are exceptions listed in the protocol
- Secondary Outcome Measures
Name Time Method Mean change in immune response as measured by ELISPOT (IFN-γ) (Phase I only) Before vaccine #1 (day 21), before vaccine #4 (cycle 2 day 1, each cycle is 28 days), every 2 cycles (each cycle is 28 days), and upon removal from therapy (up to 10 years) For this analysis, the newly diagnosed patients (n=10) will be analyzed separately from the recurrent patients (n=20)
Median change in immune response as measured by ELISPOT (IFN-γ) (Phase I only) Before vaccine #1 (day 21), before vaccine #4 (cycle 2 day 1, each cycle is 28 days), every 2 cycles (each cycle is 28 days), and upon removal from therapy (up to 10 years) For this analysis, the newly diagnosed patients (n=10) will be analyzed separately from the recurrent patients (n=20)
Overall survival (OS) Through completion of follow-up (estimated to be 12 years) OS is defined as time between the start of TMZ Day 1 and death.
Progression-free survival (PFS) Through completion of follow-up (estimated to be 12 years) PFS is defined as the time between the start of TMZ on Day 1 and first documentation of death or disease progression/recurrence. Patients remaining alive without disease progression will have PFS censored at their last follow-up.
Trial Locations
- Locations (3)
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
MD Anderson Cancer Center
🇺🇸Houston, Texas, United States