What side effects are associated with this type of intervention?

The most common treatments for gliomas involving enzyme inhibition, such as ONC201, Panobinostat, and Paxalisib, often have side effects related to their mechanism of action. These can include fatigue, gastrointestinal issues (nausea, vomiting, diarrhea), hematologic toxicities (anemia, neutropenia), and skin reactions (rash). Each drug may have specific side effects, but these are the general adverse reactions observed with enzyme inhibitors used in glioma treatment.

What prior FDA approvals exist?

The FDA has approved several treatments for gliomas, including enzyme inhibitors. Temozolomide, an oral alkylating agent, is commonly used in combination with radiotherapy for newly diagnosed glioblastoma. Bevacizumab, an anti-VEGF monoclonal antibody, has been approved for recurrent glioblastoma. While ONC201, Panobinostat, and Paxalisib are being studied for their enzyme inhibition properties, similar FDA-approved treatments include Everolimus, an mTOR inhibitor, which has shown efficacy in certain brain tumors. These approvals highlight the ongoing exploration of enzyme inhibition as a therapeutic strategy for gliomas.

What other types of research exist?

Promising novel alternatives for glioma treatment in 2024 include: 1) Tumor Treating Fields (TTFields) which use electric fields to disrupt cancer cell division, 2) CAR T-cell therapy targeting specific glioma antigens, 3) Immune checkpoint inhibitors like nivolumab and pembrolizumab, and 4) Novel small molecule inhibitors targeting specific genetic mutations in gliomas, such as BRAF or IDH inhibitors.

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Enzyme Inhibitor

Combination Therapy for Brain Cancer

Q: What is the mechanism of action of this treatment?

The most common treatments for gliomas, particularly those involving enzyme inhibition, include drugs like ONC201, Panobinostat, and Paxalisib. ONC201 works by targeting the dopamine receptor D2 (DRD2) and ClpP, leading to tumor cell apoptosis. Panobinostat is a histone deacetylase (HDAC) inhibitor that disrupts the function of proteins involved in cancer cell growth and survival. Paxalisib inhibits the PI3K/Akt/mTOR pathway, which is crucial for cell proliferation and survival. These mechanisms are significant for glioma patients as they target specific pathways that are often dysregulated in gliomas, potentially reducing tumor growth and improving patient outcomes.

Phase 2

Recruiting

Led By Sabine Mueller, MD, PhD

Research Sponsored by University of California, San Francisco

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

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.

Must not have

COHORT 1A AND 1B: Thalamic H3K27M DMG.

Evidence of disseminated disease, including diffuse leptomeningeal disease or evidence of CSF dissemination

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 6 months after administration of onc201 in the maintenance phase

Awards & highlights

No Placebo-Only Group

Summary

This trial is testing a combination of three drugs to treat a specific type of brain tumor called diffuse midline gliomas (DMGs). These drugs aim to stop the tumor from growing by blocking enzymes that the cancer cells need. The trial focuses on patients with DMGs because current treatments are not very effective for them.

Who is the study for?

This trial is for patients aged 2 to 39 with diffuse midline gliomas, including those with spinal cord tumors. They must have completed standard radiation therapy and not be pregnant or breastfeeding. Participants need stable vital signs, controlled seizures if present, and agree to use contraception. Those with immune disorders or uncontrolled illnesses are excluded.

What is being tested?

The phase II trial tests ONC201 combined with panobinostat or paxalisib in treating diffuse midline gliomas (DMGs). These drugs inhibit enzymes that may stop tumor growth. The effectiveness of different drug combinations will be assessed for patients who've had little success with other treatments.

What are the potential side effects?

Potential side effects include issues related to enzyme inhibition which could affect cell growth and organ function, as well as typical reactions from cancer therapies such as fatigue, digestive problems, blood-related issues, and increased risk of infection.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

Select...

My diarrhea is mild and not severe.

Select...

I have never had heart failure and no family history of long QT syndrome.

Select...

I weigh more than 10 kg, making me eligible for ONC201 treatment.

Select...

My heart is healthy enough for the trial, confirmed by an echocardiogram.

Select...

My blood tests show enough neutrophils and platelets without recent transfusions.

Select...

I don't have shortness of breath at rest, can exercise without lung problems, and my oxygen level is above 92%.

Select...

My heart's electrical activity (QTC) is less than 470 msec.

Select...

My blood sugar is under 125 mg/dL without diabetes medication.

Select...

I am between 2 and 39 years old.

Select...

I have a confirmed diagnosis of recurrent DMG, including spinal cord tumors, and have completed standard radiation therapy.

Select...

My kidney function is normal or only slightly below normal.

Select...

I have DMG, completed standard radiation, and for 2B, confirmed H3K27M or WHO III/IV.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

Select...

My brain tumor is a thalamic H3K27M diffuse midline glioma.

Select...

My cancer has spread to the lining of my brain or spinal cord.

Select...

My diagnosis is a grade II diffuse astrocytoma without H3 mutation.

Select...

I am considered not suitable for a surgical biopsy.

Select...

I have had radiation before for tumor growth.

Select...

I do not have any uncontrolled infections or illnesses.

Select...

I have previously undergone radiation therapy.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 6 months after administration of onc201 in the maintenance phase

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~6 months after administration of onc201 in the maintenance phase

This trial's timeline: 3 weeks for screening, Varies for treatment, and 6 months after administration of onc201 in the maintenance phase for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Number of participants requiring dose modification through first cycle of maintenance (Cohort 5)

Overall survival at 7 months (OS7) - Cohort 3A & 3B Only

Progression-free survival at 6 months (PFS6) - Cohorts 1A, 1B Only

+2 more

Side effects data

From 2021 Phase 2 trial • 30 Patients • NCT03394027

60%

Fatigue

40%

Alkaline phosphatase increased

40%

Aspartate aminotransferase increased

40%

Lymphocyte count decreased

40%

Dizziness

30%

Alanine aminotransferase increased

30%

Diarrhea

20%

Hypophosphatemia

20%

Abdominal pain

20%

Anemia

20%

Nausea

20%

Dyspnea

10%

Edema limbs

10%

Paresthesia

10%

Vaginal discharge

10%

Pain

10%

Sepsis

10%

Lethargy

10%

Vaginal hemorrhage

10%

Proteinuria

10%

Pleural effusion

10%

Flu like symptoms

10%

Gastroesophageal reflux disease

10%

Headache

10%

Atrial flutter

10%

Cardiac arrest

10%

Dehydration

10%

Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, Death

10%

Sinus tachycardia

10%

Stroke

10%

Thromboembolic event

10%

Urinary tract infection

10%

Anorexia

10%

Arthralgia

10%

Back pain

10%

Constipation

10%

Lymphedema

10%

Malaise

10%

Mucosal infection

10%

Myalgia

10%

Rash maculo-papular

10%

Rhinorrhea

10%

Vascular access complication

10%

Weight loss

10%

Cough

10%

Creatinine increased

100%

80%

60%

40%

20%

Study treatment Arm

Cohort 3-Endometrial Cancer (Female Only)

Cohort 1-Hormone Receptor (HR) + Breast Cancer (Male and Female)

Cohort 2-Triple Negative Breast Cancer (Male and Female)

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

5Treatment groups

Experimental Treatment

Group I: NOT CURRENTLY ENROLLING - ARM 6: Paxalisib (Day -1), Radiation+Paxalisib , Paxalisib+ONC201Experimental Treatment3 Interventions

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

Group II: NOT CURRENTLY ENROLLING - ARM 4: ONC201 (Day -1,-2), Radiation+ONC201, Paxalisib+ONC201Experimental Treatment3 Interventions

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

Group III: NOT CURRENTLY ENROLLING - ARM 2: ONC201 (Day -1), Radiation+ONC201, Paxalisib+ONC201Experimental Treatment3 Interventions

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

Group IV: Cohort 5 - ONC201 + Targeted therapiesExperimental Treatment2 Interventions

Participants will receive a starting dose of 625mg of ONC201 weekly on Day 1 and 2 during any non-interventional radiation/re-irradiation per standard of care treatment, and 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). Each individual targeted agent will be dosed at the recommended therapeutic dose, if a dose has been issued for the participant's age group. 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).

Group V: Cohort 4 - Dose Escalation, Starting Dose 2 (625mg ONC201)Experimental Treatment2 Interventions

Participants will receive a safety lead in of 625mg 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 any non-interventional radiation/re-irradiation per standard of care treatment, participants will receive 625 mg as the starting dose of ONC201 Days 1 and 2 on a weekly basis. Cycles repeat every 28 days (4 weeks) in the absence of adverse events or unacceptable toxicity

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

ONC201

2017

Completed Phase 2

~60

Radiation Therapy

2017

Completed Phase 3

~7250

0 / 19Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

The most common treatments for gliomas, particularly those involving enzyme inhibition, include drugs like ONC201, Panobinostat, and Paxalisib. ONC201 works by targeting the dopamine receptor D2 (DRD2) and ClpP, leading to tumor cell apoptosis. Panobinostat is a histone deacetylase (HDAC) inhibitor that disrupts the function of proteins involved in cancer cell growth and survival. Paxalisib inhibits the PI3K/Akt/mTOR pathway, which is crucial for cell proliferation and survival. These mechanisms are significant for glioma patients as they target specific pathways that are often dysregulated in gliomas, potentially reducing tumor growth and improving patient outcomes.