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Combination Therapy for the Treatment of Diffuse Midline Gliomas

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: NCT05009992
Recruitment Status : Recruiting
First Posted : August 18, 2021
Last Update Posted : December 6, 2022
Sponsor:
Collaborators:
The Chad-Tough Defeat DIPG Foundation
Mithil Prasad Foundation
Storm the Heavens Fund
National Institute of Neurological Disorders and Stroke (NINDS)
Information provided by (Responsible Party):
Sabine Mueller, MD, PhD, University of California, San Francisco

Brief Summary:
This phase II trial determines if the combination of ONC201 with different drugs, panobinostat or paxalisib, is effective for treating patients with diffuse midline gliomas (DMGs). Despite years of research, little to no progress has been made to improve outcomes for patients with DMGs, and there are few treatment options. ONC201, panobinostat, and paxalisib are all enzyme inhibitors that may stop the growth of tumor cells by clocking some of the enzymes needed for cell growth. This phase II trial assesses different combinations of these drugs for the treatment of DMGs.

Condition or disease Intervention/treatment Phase
Diffuse Intrinsic Pontine Glioma Diffuse Midline Glioma, H3 K27M-Mutant Recurrent Diffuse Intrinsic Pontine Glioma Recurrent Diffuse Midline Glioma, H3 K27M-Mutant Recurrent WHO Grade III Glioma WHO Grade III Glioma Drug: ONC201 Radiation: Radiation Therapy Drug: Paxalisib Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 216 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : October 20, 2021
Estimated Primary Completion Date : December 31, 2025
Estimated Study Completion Date : June 30, 2027


Arm Intervention/treatment
Experimental: ARM 2: ONC201 (Day -1), Radiation+ONC201, Paxalisib+ONC201
Patients may receive a safety lead in of ONC201. During the trial validation phase, patients without prior biopsy receive ONC201 PO on day -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, patients 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, patients 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
Drug: ONC201
Given orally (PO)
Other Names:
  • TIC10
  • Antagonist of dopamine receptor D2 (DRD2) and caseinolytic protease proteolytic subunit (ClpP)

Radiation: Radiation Therapy
Undergo radiation therapy
Other Name: Radiotherapy

Drug: Paxalisib
Given PO
Other Names:
  • Inhibitor of the PI3K/AKT/mTOR pathway
  • GDC-0084
  • GDC0084
  • PI3K Inhibitor GDC-0084

Experimental: ARM 4: ONC201 (Day -1,-2), Radiation+ONC201, Paxalisib+ONC201
Patients may receive a safety lead in of ONC201. During the trial validation phase, patients without prior biopsy receive ONC201 PO on days -2 and -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, patients may receive ONC201 PO weekly during radiation therapy. During the maintenance phase, patients receive ONC201 PO weekly and paxalisib PO QD. Cycles repeat every 28 days (4 weeks) in the absence of adverse events or unacceptable toxicity
Drug: ONC201
Given orally (PO)
Other Names:
  • TIC10
  • Antagonist of dopamine receptor D2 (DRD2) and caseinolytic protease proteolytic subunit (ClpP)

Radiation: Radiation Therapy
Undergo radiation therapy
Other Name: Radiotherapy

Drug: Paxalisib
Given PO
Other Names:
  • Inhibitor of the PI3K/AKT/mTOR pathway
  • GDC-0084
  • GDC0084
  • PI3K Inhibitor GDC-0084

Experimental: ARM 6: Paxalisib (Day -1), Radiation+Paxalisib , Paxalisib+ONC201
Patients may receive a safety lead in of ONC201. During trial validation phase, patients without prior biopsy receive paxalisib PO on day -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, patients 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, patients receive ONC201 PO weekly and paxalisib PO QD. Cycles repeat every 28 days (4 weeks) in the absence of adverse events of unacceptable toxicity
Drug: ONC201
Given orally (PO)
Other Names:
  • TIC10
  • Antagonist of dopamine receptor D2 (DRD2) and caseinolytic protease proteolytic subunit (ClpP)

Radiation: Radiation Therapy
Undergo radiation therapy
Other Name: Radiotherapy

Drug: Paxalisib
Given PO
Other Names:
  • Inhibitor of the PI3K/AKT/mTOR pathway
  • GDC-0084
  • GDC0084
  • PI3K Inhibitor GDC-0084




Primary Outcome Measures :
  1. Progression-free survival at 6 months (PFS6) - Cohorts 1A, 1B, 2A, 2B Only [ Time Frame: 6 months after administration of ONC201 in the maintenance phase ]
    Percentage of participants alive and free from progression at 6 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 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.

  2. Overall survival at 7 months (OS7) - Cohort 3A & 3B Only [ Time Frame: 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   2 Years to 39 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 H3K27M mutant; World Health Organization (WHO) grade III and IV H3 wildtype gliomas.

    • 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.
    • COHORT 2A AND 2B: Participants must be within 4-14 weeks of completion of radiation.
    • 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.
    • COHORT 3A AND 3B: Participants must have evidence of progression and not have received any treatment for this progression and have not previously received re-irradiation.
    • Age 2 to 39 years
    • Participants must have recovered from all acute side effects of prior therapy
    • Participant body weight must be above the minimum necessary for the participant to receive ONC201 (at least 10 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, or 4 weeks (or 5 half-lives, whichever is shorter) from other anti-tumor therapies.

      • For participants who have received radiotherapy, participants in Cohort 2 must be between 4 and 14 weeks from the completion of local up-front radiotherapy and not have received additional therapy beyond completion of radiation therapy.
      • 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.
    • 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.
    • Peripheral absolute neutrophil count (ANC) >= 1000/mm^3 (1.0g/l) AND
    • Platelet count >= 100,000/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)) =< 2 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
    • Non-fasting glucose < 125 mg/dL without the use of antihyperglycemic agents
    • If non-fasting glucose > 125 mg/dL, a fasting glucose should be done. If fasting glucose =< 160 mg/dL without the use of antihyperglycemic agents, participants will meet adequate metabolic function criteria
    • Triglycerides of < 300 mg/dl and total cholesterol of < 300 mg/dl - can be on lipid lowering medications as needed to achieve.
    • No history of congestive heart failure or family history of long QT syndrome.
    • ECG must be obtained to verify the QTC. If an abnormal reading is obtained, the ECG should be repeated in triplicate. QTC < 470 msec.
    • Participants with history of congestive heart failure, at risk of having or have underlying cardiovascular disease, or with history of exposure to cardiotoxic drugs must have adequate cardiac function as determined by echocardiogram. Shortening fraction of >= 27%.
    • Participants with seizure disorder may be enrolled if seizure disorder is well controlled
    • The effects of the study drugs on the developing human fetus are unknown. For this reason, females of child-bearing potential and males must agree to use adequate contraception. Adequate methods include: hormonal or barrier method of birth control; or abstinence prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Males treated or enrolled on this protocol must also agree to use adequate contraception prior to the study and for the duration of study participation.
    • Karnofsky >= 50 for participants > 16 years of age and Lansky >= 50 for participants =< 16 years of age. Participants who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
    • Participants must be willing to provide adequate tissue. A minimum of 10-20 paraffin embedded unstained slides OR 1 block with tumor content of 40% or greater is required. Participants who do not meet this criteria must be discussed with Study Chair(s).
    • A legal parent/guardian or participant must be able to understand, and willing to sign, a written informed consent and assent document, as appropriate.

Exclusion Criteria:

  • COHORT 1A AND 1B: Prior exposure to radiation therapy.
  • COHORT 1A AND 2A: Deemed not appropriate for tissue resection/biopsy.
  • COHORT 3A AND 3B: Prior exposure to re-irradiation for tumor progression.
  • 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
  • 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.

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): NCT05009992


Contacts
Layout table for location contacts
Contact: Kelly Hitchner (415) 502-1600 PNOC022@ucsf.edu

Locations
Show Show 18 study locations
Sponsors and Collaborators
University of California, San Francisco
The Chad-Tough Defeat DIPG Foundation
Mithil Prasad Foundation
Storm the Heavens Fund
National Institute of Neurological Disorders and Stroke (NINDS)
Investigators
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Principal Investigator: Sabine Mueller, MD, PhD University of California, San Francisco
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Sabine Mueller, MD, PhD, Principal Investigator, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT05009992    
Other Study ID Numbers: 200821
NCI-2021-08386 ( Registry Identifier: NCI Clinical Trials Reporting Program (CTRP) )
1R01NS124607-01 ( U.S. NIH Grant/Contract )
First Posted: August 18, 2021    Key Record Dates
Last Update Posted: December 6, 2022
Last Verified: December 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Individual participant data after de-identification.
Supporting Materials: Study Protocol

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Glioma
Diffuse Intrinsic Pontine Glioma
Recurrence
Disease Attributes
Pathologic Processes
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Brain Stem Neoplasms
Infratentorial Neoplasms
Brain Neoplasms
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
TIC10 compound
Dopamine
GDC-0084
Cardiotonic Agents
Sympathomimetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Dopamine Agents