A Combination Therapy Trial Using an Adaptive Platform Design for Children and Young Adults With Diffuse Midline Gliomas (DMGs) Including Diffuse Intrinsic Pontine Gliomas (DIPGs) at Initial Diagnosis, Post-Radiation Therapy and at Time of Progression
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 360
- 试验地点
- 62
- 主要终点
- Progression-free survival at 6 months (PFS6) - Cohorts 1A, 1B Only
研究概览
简要总结
This phase II trial determines if the combination of ONC201 with different drugs is effective for treating participants with diffuse midline gliomas (DMGs). Despite years of research, little to no progress has been made to improve outcomes for participants with DMGs, and there are few treatment options. This trial will utilize an adaptive platform design in that the different treatment arms for each cohort will be opened and closed based on ongoing preclinical investigation as well as evolving outcome data from the trial.
Novel agents will be continuously added to this study as pre-clinical data emerge to suggest additive or synergistic activity when combined ONC201. Should a novel agent not have an RP2D at the time of incorporation into this study, a phase 1 lead-in will be performed prior to initiation of combination therapy (via study amendment).
详细描述
OUTLINE:
This is a multi-arm/cohort, multi-institutional, open-label trial. The study is divided into cohorts based on stage of disease (newly-diagnosed, post-radiation therapy without disease progression, and at disease progression).
---THIS STUDY IS NOT ENROLLING ON COHORTS 1, 2, 3, and 4 --
COHORT DESCRIPTIONS:
--ENROLLING-- COHORT 5: Includes participants whose tumor demonstrates specific molecular alterations of interest considered targetable by an approved/available agent(s) and recommended by the PNOC022 tumor board. Participants are also allowed to receive ONC201 monotherapy with radiation or re-irradiation therapy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 2 Years 至 39 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •--COHORTS 1, 2, AND 3 CLOSED---
- •INCLUSION CRITERIA:
- •COHORT 1A AND 1B:
- •* New diagnosis of DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors. In cohort 1B, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG including diffuse midline glioma Histone 3 lysine 27 - mutant (H3K27M); World Health Organization (WHO) grade III and IV H3 wildtype gliomas.
- •* Must be within 6 weeks of diagnosis to begin standard of care radiation therapy on study.
- •COHORT 2A AND 2B:
- •* Diagnosis of DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors, who have complete standard-of-care radiation therapy. In Cohort 2B, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG including diffuse midline glioma H3K27M mutant; WHO grade III and IV H3 wildtype gliomas.
- •* Participants must be within 4-14 weeks of completion of radiation. Radiation should have started within 6 weeks of diagnosis.
- •COHORT 3A AND 3B:
- •* Diagnosis of recurrent DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors, who have complete standard-of-care radiation therapy. In cohort 3B, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG including diffuse midline glioma H3K27M mutant; WHO grade III and IV H3 wildtype gliomas.
- •* Participants must have evidence of progression and not have received any treatment for this progression and have not previously received re-irradiation.
- •COHORT 4A AND 4B:
- •* Diagnosis of DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors. In cohort 4B\^1, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG diffuse midline glioma H3K27-altered.
- •* Not currently eligible for any other clinical trials that include administration of ONC201.
- •Cohort 4A\^1 and 4B\^1 (participants with newly diagnosed DMG prior to radiation): Must be able to begin standard of care radiation therapy on study within 6 weeks of diagnosis.
- •Cohort 4A\^2 and 4B\^2 (participants with newly diagnosed DMG who have completed radiation): Participants must be within 4-14 weeks of completion of radiation and not have received additional therapy beyond completion of radiation therapy. Radiation should have started within 6 weeks of diagnosis.
- •Cohort 4A\^3 and 4B\^3 (participants with DMG at progression): Participants must have evidence of progression and not have received any treatment for this progression and have not previously received re-irradiation.
- •* Diagnosis of DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors. In cohort 5\^1, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG diffuse midline glioma H3K27-altered.
- •* Not currently eligible for any other clinical trials that include administration of ONC201.
- •* Multifocal and leptomeningeal disease will be eligible for Cohort 5.
- •* Participant's tumor must demonstrate one of the following molecular alterations considered targetable by an approved agent:
- •* BRAFV600E
- •* PDGFRA (DNA point mutation or amplification with \>=5 copy numbers)
- •* FGFR1 (DNA point mutation, gene fusions, or amplification with \>=5 copy numbers)
- •Cohort 5\^1 (participants pre-radiation): Must be able to begin standard of care radiation therapy on study within 6 weeks of diagnosis.
- •Cohort 5\^2 (participants post-radiation): Participants must be within 4-14 weeks of completion of radiation and not have received additional therapy beyond completion of radiation therapy. Radiation should have started within 6 weeks of diagnosis.
- •Cohort 5\^3 (participants with progression): Participants must have evidence of progression and not have received any treatment for this progression and have not previously received re-irradiation.
- •All Cohorts (except Cohort 6):
- •* Age 2 to 39 years
- •* Participants must have recovered from all acute side effects of prior therapy and be beyond the window for expected ongoing acute toxicities. Any number of prior therapies are allowed.
- •* Prior ONC201 exposure is allowed, except in participants who have participated in Chimerix trials investigating ONC201 in the upfront setting. Participants who participated in trials investigating ONC201 in the upfront setting will not be eligible at any time, with the exception if participants received ONC201 as part of PNOC022 or other expanded access programs such as German sources of ONC201.
- •* Participant body weight must be above the minimum necessary for the participant to receive ONC201 (at least 10 kilograms (kg))
- •* From the projected start of scheduled study treatment, the following time periods must have elapsed: At least 7 days after last dose of a biologic agent or beyond time during which adverse events are known to occur for a biologic agent, 5 half-lives from any investigational agent, 4 weeks from cytotoxic therapy (except 23 days for temozolomide and 6 weeks from nitrosoureas), 6 weeks from antibodies (21 days for bevacizumab when used for tumor-directed therapy, guidance on use for pseudo-progression is below), or, or 4 weeks (or 5 half-lives, whichever is shorter) from other anti-tumor therapies.
- •o The use of bevacizumab to control radiation therapy-induced edema is allowed (if used for tumor-directed therapy, please see required time period above).
- •* Dosing limitations are as follows:
- •* \* Bevacizumab (or equivalent) for up to a maximum of 5 doses, dosing per institutional standard. There is no required washout period.
- •* Prior use of temozolomide during radiation at maximum of the standard pediatric dosing (defined as 90 mg/m2 /dose continuously during radiation therapy for 42 days) or dexamethasone is allowed. Any other agent given throughout radiation therapy must be discussed with the study chairs prior to beginning the agent.
- •* Corticosteroids: Participants who are receiving dexamethasone must be on a stable or decreasing dose for at least 3 days prior to baseline magnetic resonance imaging (MRI) scan.
- •* The participant must have adequate organ function defined as:
- •* Peripheral absolute neutrophil count (ANC) \>= 750/mm\^3 (1.0g/l) AND
- •* Platelet count \>= 75,000/mm\^3 (100x10\^9/l) (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment).
- •* Creatinine clearance or radioisotope glomerular filtration rate (GFR) \>= 70 mL/min/1.73 m\^2 OR
- •* A serum creatinine within the normal limits for age
- •* Bilirubin (sum of conjugated + unconjugated) =\< 1.5 x upper limit of normal (ULN) for age AND
- •* Serum glutamate pyruvate transaminase (SGPT)(alanine aminotransferase (ALT)) =\< 3 x ULN AND
- •* Serum albumin \>= 2 g/Dl
- •* No evidence of dyspnea at rest, no exercise intolerance due to pulmonary insufficiency, and a pulse oximetry of \> 92% while breathing room air.
- •* Diarrhea \< grade 2 by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0
- •* No history of congestive heart failure or family history of long QT syndrome.
- •* ECG must be obtained to verify the Corrected QT Interval (QTc). If an abnormal reading is obtained, the ECG should be repeated in triplicate. QTC \< 470 msec.
- 另有 25 项未显示
排除标准
- •COHORT 1A AND 1B:
- •Prior exposure to radiation therapy.
- •Thalamic and Cerebellar H3K27M DMG.
- •COHORT 2A AND 2B:
- •For tumors that do not have a pontine or spinal cord epicenter the following specific exclusion criteria apply:
- •Thalamic and Cerebellar H3K27M DMG that has undergone standard radiation without concurrent therapy (other than temozolomide).
- •COHORT 1A AND 2A:
- •Deemed not appropriate for tissue resection/biopsy.
- •COHORT 3A AND 3B:
- •Prior exposure to re-irradiation for tumor progression.
- •Thalamic and cerebellar H3K27M mutant DMG.
- •COHORT 4A AND 4B:
- •Cohort 4A^1and 4B^1: Prior exposure to radiation therapy Cohort 4A^3 and 4B^3: Prior exposure to re-irradiation for tumor progression
- •Thalamic and cerebellar H3K27M mutant DMG, except those who received ONC201/ONC026 from alternative source prior to 2024 or US patients enrolled while the accelerated approval new drug application for dordaviprone to treat recurrent H3 K27M-mutant diffuse glioma is under review by US FDA.
- •Cohort 4A^1and 4B^1: Prior exposure to radiation therapy
- •Cohort 4A^3 and 4B^3: Prior exposure to re-irradiation for tumor progression
- •Thalamic and cerebellar H3K27M mutant DMG, except those who received ONC201/ONC026 from alternative source prior to 2024 or US patients enrolled while the accelerated approval new drug application for dordaviprone to treat recurrent H3 K27M-mutant diffuse glioma is under review by US FDA.
- •Cohort 5^1: Prior exposure to radiation therapy
- •Cohort 5^3: Prior exposure to re-irradiation for tumor progression
- •All Cohorts (except Cohort 6):
- •Diagnosis of a histone H3 wildtype grade II diffuse astrocytoma.
- •Participants who are currently receiving another investigational drug. Investigational imaging agents or agents used to enhance tumor visibility on imaging or during tumor biopsy/resection should be discussed with the study chairs.
- •Participants who are currently receiving other anti-cancer agents.
- •Participants with a known disorder that affects their immune system, such as human immunodeficiency virus (HIV) or hepatitis B or C, or an auto-immune disorder requiring systemic cytotoxic or immunosuppressive therapy. Note: Participants that are currently using inhaled, intranasal, ocular, topical or other non-oral or non-intravenous (IV) steroids are not necessarily excluded from the study but need to be discussed with the study chair.
- •Participants with uncontrolled infection or other uncontrolled systemic illness.
- •Female participants of childbearing potential must not be pregnant or breast-feeding. Female participants of childbearing potential must have a negative serum or urine pregnancy test prior to the start of therapy (as clinically indicated).
- •Active illicit drug use or diagnosis of alcoholism.
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition as the agents used in study.
- •Evidence of disseminated disease, including diffuse leptomeningeal disease or evidence of CSF dissemination, with the exception of Cohort
- •Known additional malignancy that is progressing or requires active treatment within 3 years of start of study drug.
- •Concomitant use of potent CYP3A4/5 inhibitors during the treatment phase of the study and within 72 hours prior to starting study drug administration.
- •Concomitant use of potent CYP3A4/5 inducers, which include enzyme inducing antiepileptic drugs (EIAEDs), during the treatment phase of the study and within 2 weeks prior to starting treatment. Concurrent corticosteroids is allowed.
- •COHORT 6 Exclusion Criteria:
- •• DMGs located outside the thalamus and pons including bilateral thalamic tumors.
- •Unacceptable anesthesia or surgery risk, as determined by the anesthesiologist or the neurosurgeon.
- •Evidence of significant mass effect
- •Evidence of herniation on imaging.
- •Participants with a known history coagulopathy that increases risk of bleeding or a history of clinically significant hemorrhage within 12 months of registration.
- •Participants must not require systemic anti-coagulation that cannot be halted for each intraoperative and perioperative biopsy time-period.
- •Participants with active viral infection or who are currently receiving antiviral treatment.
- •Participants with active, known, or suspected immunosuppressive disorders, such as acquired or congenital immune deficiency syndromes and autoimmune diseases.
- •This virus infects cells with a deficit in the RB gene. Therefore, participants with Li-Fraumeni Syndrome or a known germ line deficit in the retinoblastoma gene or its related pathway are excluded.
- •Participants must not have live or live-attenuated vaccinations within 30 days prior to DNX-2401 administration and while participating in the study. Killed vaccines are permitted.
- •Participants who are currently receiving another investigational drug. Investigational imaging agents or agents used to enhance tumor visibility on imaging or during tumor biopsy/resection should be discussed with the study chairs.
- •Participants with a known disorder that affects their immune system, such as HIV or Hepatitis B or C, or an auto-immune disorder requiring systemic cytotoxic or immunosuppressive therapy. Note: Participants who are currently using inhaled, intranasal, ocular, topical or other non-oral or non-IV steroids are not necessarily excluded from the study but need to be discussed with the study chair(s).
- •Participants with uncontrolled infection or other uncontrolled systemic illness.
- •Female participants of childbearing potential must not be pregnant or breast-feeding. Female participants of childbearing potential must have a negative serum or urine pregnancy test prior to the start of therapy (as clinically indicated).
- •Active illicit drug use or diagnosis of alcoholism.
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition as the agents used in the study.
- •Evidence of disseminated disease, including multi-focal disease, diffuse leptomeningeal disease or CSF dissemination.
研究组 & 干预措施
NOT CURRENTLY ENROLLING - ARM 6: Paxalisib (Day -1), Radiation+Paxalisib , Paxalisib+ONC201
Participants may receive a safety lead in of ONC201. During trial validation phase, participants without prior biopsy receive paxalisib PO on day -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, participants without prior radiation therapy or have disease progression after radiation therapy undergo weekly radiation therapy and receive paxalisib PO daily during radiation therapy. During the maintenance phase, participants receive ONC201 PO weekly and paxalisib PO QD. Cycles repeat every 28 days (4 weeks) in the absence of adverse events of unacceptable toxicity
干预措施: Paxalisib (Drug)
Cohort 5 - ONC201 + Targeted therapies
Participants will receive a starting dose of 625mg (or weight-adjusted adult equivalent RP2D for pediatrics) of ONC201 on Day 1 and 2 of each week in combination with targeted agents to be selected from approved/available agents based on a rational therapy approach guided by molecular data from the tumor tissue or cerebral spinal fluid (CSF). For participants receiving non-interventional radiation/re-irradiation per standard of care treatment, prior to starting the combination therapy, participants will receive 625 mg as the starting dose of ONC201 Days 1 and 2 on a weekly basis during radiation. Observations and schedule of events will be issued based on the chosen agent determined to best fit the molecular profile (e.g. BRAFV600E, PDGFRA, FGFR1, NF1).
干预措施: Radiation Therapy (Radiation)
NOT CURRENTLY ENROLLING - ARM 2: ONC201 (Day -1), Radiation+ONC201, Paxalisib+ONC201
Participants may receive a safety lead in of ONC201. During the trial validation phase, participants without prior biopsy receive ONC201 PO on day -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, participants without prior radiation therapy or have disease progression after radiation therapy undergo weekly radiation therapy and receive ONC201 PO weekly during radiation therapy. During the maintenance phase, participants receive ONC201 PO weekly and paxalisib PO daily (QD). Cycles repeat every 28 days (4 weeks) in the absence of adverse events of unacceptable toxicity
干预措施: ONC201 (Drug)
NOT CURRENTLY ENROLLING - ARM 2: ONC201 (Day -1), Radiation+ONC201, Paxalisib+ONC201
Participants may receive a safety lead in of ONC201. During the trial validation phase, participants without prior biopsy receive ONC201 PO on day -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, participants without prior radiation therapy or have disease progression after radiation therapy undergo weekly radiation therapy and receive ONC201 PO weekly during radiation therapy. During the maintenance phase, participants receive ONC201 PO weekly and paxalisib PO daily (QD). Cycles repeat every 28 days (4 weeks) in the absence of adverse events of unacceptable toxicity
干预措施: Radiation Therapy (Radiation)
NOT CURRENTLY ENROLLING - ARM 4: ONC201 (Day -1,-2), Radiation+ONC201, Paxalisib+ONC201
Participants may receive a safety lead in of ONC201. During the trial validation phase, participants without prior biopsy receive ONC201 PO on days -2 and -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, participants may receive ONC201 PO weekly during radiation therapy. During the maintenance phase, participants receive ONC201 PO weekly and paxalisib PO QD. Cycles repeat every 28 days (4 weeks) in the absence of adverse events or unacceptable toxicity
干预措施: Radiation Therapy (Radiation)
NOT CURRENTLY ENROLLING - ARM 6: Paxalisib (Day -1), Radiation+Paxalisib , Paxalisib+ONC201
Participants may receive a safety lead in of ONC201. During trial validation phase, participants without prior biopsy receive paxalisib PO on day -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, participants without prior radiation therapy or have disease progression after radiation therapy undergo weekly radiation therapy and receive paxalisib PO daily during radiation therapy. During the maintenance phase, participants receive ONC201 PO weekly and paxalisib PO QD. Cycles repeat every 28 days (4 weeks) in the absence of adverse events of unacceptable toxicity
干预措施: ONC201 (Drug)
NOT CURRENTLY ENROLLING - ARM 6: Paxalisib (Day -1), Radiation+Paxalisib , Paxalisib+ONC201
Participants may receive a safety lead in of ONC201. During trial validation phase, participants without prior biopsy receive paxalisib PO on day -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, participants without prior radiation therapy or have disease progression after radiation therapy undergo weekly radiation therapy and receive paxalisib PO daily during radiation therapy. During the maintenance phase, participants receive ONC201 PO weekly and paxalisib PO QD. Cycles repeat every 28 days (4 weeks) in the absence of adverse events of unacceptable toxicity
干预措施: Radiation Therapy (Radiation)
Cohort 5 - ONC201 + Targeted therapies
Participants will receive a starting dose of 625mg (or weight-adjusted adult equivalent RP2D for pediatrics) of ONC201 on Day 1 and 2 of each week in combination with targeted agents to be selected from approved/available agents based on a rational therapy approach guided by molecular data from the tumor tissue or cerebral spinal fluid (CSF). For participants receiving non-interventional radiation/re-irradiation per standard of care treatment, prior to starting the combination therapy, participants will receive 625 mg as the starting dose of ONC201 Days 1 and 2 on a weekly basis during radiation. Observations and schedule of events will be issued based on the chosen agent determined to best fit the molecular profile (e.g. BRAFV600E, PDGFRA, FGFR1, NF1).
干预措施: ONC201 (Drug)
NOT CURRENTLY ENROLLING - ARM 2: ONC201 (Day -1), Radiation+ONC201, Paxalisib+ONC201
Participants may receive a safety lead in of ONC201. During the trial validation phase, participants without prior biopsy receive ONC201 PO on day -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, participants without prior radiation therapy or have disease progression after radiation therapy undergo weekly radiation therapy and receive ONC201 PO weekly during radiation therapy. During the maintenance phase, participants receive ONC201 PO weekly and paxalisib PO daily (QD). Cycles repeat every 28 days (4 weeks) in the absence of adverse events of unacceptable toxicity
干预措施: Paxalisib (Drug)
NOT CURRENTLY ENROLLING - ARM 4: ONC201 (Day -1,-2), Radiation+ONC201, Paxalisib+ONC201
Participants may receive a safety lead in of ONC201. During the trial validation phase, participants without prior biopsy receive ONC201 PO on days -2 and -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, participants may receive ONC201 PO weekly during radiation therapy. During the maintenance phase, participants receive ONC201 PO weekly and paxalisib PO QD. Cycles repeat every 28 days (4 weeks) in the absence of adverse events or unacceptable toxicity
干预措施: ONC201 (Drug)
NOT CURRENTLY ENROLLING - ARM 4: ONC201 (Day -1,-2), Radiation+ONC201, Paxalisib+ONC201
Participants may receive a safety lead in of ONC201. During the trial validation phase, participants without prior biopsy receive ONC201 PO on days -2 and -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, participants may receive ONC201 PO weekly during radiation therapy. During the maintenance phase, participants receive ONC201 PO weekly and paxalisib PO QD. Cycles repeat every 28 days (4 weeks) in the absence of adverse events or unacceptable toxicity
干预措施: Paxalisib (Drug)
Cohort 6 - DNX-2401 Repeated Intratumoral Administration
Participants will receive repeated DNX-2401 intratumoral infusions every 30 days, for a maximum of six injections. During Infusion 1 and Infusion 3, participants will have a biopsy for tumor tissue collection.
干预措施: DNX-2401 (Drug)
结局指标
主要结局
Progression-free survival at 6 months (PFS6) - Cohorts 1A, 1B Only
时间窗: 6 months after diagnosis
Percentage of participants alive and free from progression at 6 months after the diagnosis. The primary analysis for PFS6 is based on the intention to treat (ITT) population, according to treatment arm assignment. PFS6 is estimated using the Kaplan-Meier method with exact confidence intervals for each cohort and arm. Participants with unknown progression status at 6 months are considered failures (i.e., progressed) for the PFS6 analysis.
Progression-free survival at 6 months (PFS6) - Cohorts 2A, 2B Only
时间窗: 6 months after diagnosis
Percentage of participants alive and free from progression at 6 months after diagnosis. The primary analysis for PFS6 is based on the intention to treat (ITT) population, according to treatment arm assignment. PFS6 is estimated using the Kaplan-Meier method with exact confidence intervals for each cohort and arm. Participants with unknown progression status at 6 months are considered failures (i.e., progressed) for the PFS6 analysis.
Overall survival at 7 months (OS7) - Cohort 3A & 3B Only
时间窗: 7 months after administration of ONC201 in the maintenance phase
OS7 is defined as the percentage of participants alive at 7 months after the initiation of the combination of the backbone (i.e., ONC201) with a novel agent given in the maintenance phase of therapy. The primary analysis for OS7 is based on the ITT population, according to treatment arm assignment. OS7 is estimated using the Kaplan-Meier method with exact confidence intervals for each cohort and arm. Participants with unknown survival status at 7 months are considered failures (i.e., dead) for the OS7 analysis.
Proportion of participants reporting dose-limiting toxicities (DLTs) (Cohort 4)
时间窗: Up through the first cycle of maintenance therapy, approximately 8 months
The safety and tolerability of ONC201 at a previously untested dose will be measured by the proportion of participants reporting a DLT within the first cycle of treatment.
Number of participants requiring dose modification through first cycle of maintenance (Cohort 5)
时间窗: Up through the first cycle of maintenance therapy, approximately 8 months
The safety and tolerability of ONC201 in combination with targeted therapies will be measured by the number of participants reporting dose modification during first cycle.
Progression-free survival at 6 months (PFS6) - Cohorts 1A, 1B Only
时间窗: 6 months after diagnosis
Percentage of participants alive and free from progression at 6 months after the diagnosis. The primary analysis for PFS6 is based on the intention to treat (ITT) population, according to treatment arm assignment. PFS6 is estimated using the Kaplan-Meier method with exact confidence intervals for each cohort and arm. Participants with unknown progression status at 6 months are considered failures (i.e., progressed) for the PFS6 analysis.
Progression-free survival at 6 months (PFS6) - Cohorts 2A, 2B Only
时间窗: 6 months after diagnosis
Percentage of participants alive and free from progression at 6 months after diagnosis. The primary analysis for PFS6 is based on the intention to treat (ITT) population, according to treatment arm assignment. PFS6 is estimated using the Kaplan-Meier method with exact confidence intervals for each cohort and arm. Participants with unknown progression status at 6 months are considered failures (i.e., progressed) for the PFS6 analysis.
Overall survival at 7 months (OS7) - Cohort 3A & 3B Only
时间窗: 7 months after administration of ONC201 in the maintenance phase
OS7 is defined as the percentage of participants alive at 7 months after the initiation of the combination of the backbone (i.e., ONC201) with a novel agent given in the maintenance phase of therapy. The primary analysis for OS7 is based on the ITT population, according to treatment arm assignment. OS7 is estimated using the Kaplan-Meier method with exact confidence intervals for each cohort and arm. Participants with unknown survival status at 7 months are considered failures (i.e., dead) for the OS7 analysis.
Proportion of participants reporting dose-limiting toxicities (DLTs) (Cohort 4)
时间窗: Up through the first cycle of maintenance therapy, approximately 8 months
The safety and tolerability of ONC201 at a previously untested dose will be measured by the proportion of participants reporting a DLT within the first cycle of treatment.
Number of participants requiring dose modification through first cycle of maintenance (Cohort 5)
时间窗: Up through the first cycle of maintenance therapy, approximately 8 months
The safety and tolerability of ONC201 in combination with targeted therapies will be measured by the number of participants reporting dose modification during first cycle.
Maximum tolerated number of intratumor infusions of DNX-2401, with a maximum of 6, in participants with thalamic or pontine DMG who have completed radiotherapy (Cohort 6)
时间窗: A maximum of 6 infusions will be administered every 30 days - approximately 8 months
The safety and tolerability of DNX-2401 at Dose Level 1 (5 × 10\^10 viral particles) will be measured by the proportion of participants reporting a DLT.
次要结局
未报告次要终点
研究者
Sabine Mueller, MD, PhD
Principal Investigator
University of California, San Francisco