Panobinostat for Diffuse Intrinsic Pontine Glioma

Phase-Based Progress Estimates

Effectiveness

Safety

Johns Hopkins University, Baltimore, MD

Diffuse Intrinsic Pontine Glioma+7 More

Panobinostat - Drug

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Eligibility

< 65

All Sexes

Eligible conditions

Select

Eligibility

< 65

All Sexes

Eligible conditions

Select

Study Summary

This study is evaluating whether a combination of drugs can improve outcomes for patients with diffuse midline gliomas.

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Eligible Conditions

Diffuse Intrinsic Pontine Glioma
Recurrent Diffuse Intrinsic Pontine Glioma
Diffuse Midline Glioma, H3 K27M-Mutant
Recurrent WHO Grade III Glioma
WHO Grade III Glioma
Recurrent Diffuse Midline Glioma, H3 K27M-Mutant

Treatment Effectiveness

Effectiveness Progress

1 of 3

Other trials for Diffuse Intrinsic Pontine Glioma

Radiation therapy

Gemcitabine

Adavosertib

Study Objectives

This trial is evaluating whether Panobinostat will improve 2 primary outcomes in patients with Diffuse Intrinsic Pontine Glioma. Measurement will happen over the course of 7 months after administration of ONC201 in the maintenance phase.

Month 6

Progression-free survival at 6 months (PFS6) - Cohorts 1A, 1B, 2A, 2B Only

Month 7

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

Trial Safety

Safety Progress

2 of 3

This is further along than 68% of similar trials

Other trials for Diffuse Intrinsic Pontine Glioma

Radiation therapy

Gemcitabine

Adavosertib

Trial Design

6 Treatment Groups

ARM 5: Panobinostat (Day -7), Radiation+Panobinostat, Panobinostat+ONC201

1 of 6

ARM 1: ONC201 (Day -1), Radiation+ONC201, Panobinostat+ONC201

1 of 6

ARM 2: ONC201 (Day -1), Radiation+ONC201, Paxalisib+ONC201

1 of 6

ARM 4: ONC201 (Day -1,-2), Radiation+ONC201, Paxalisib+ONC201

1 of 6

ARM 6: Paxalisib (Day -1), Radiation+Paxalisib , Paxalisib+ONC201

1 of 6

ARM 3: ONC201 (Day -1,-2), Radiation+ONC201, Panobinostat+ONC201

1 of 6

Experimental Treatment

This trial requires 216 total participants across 6 different treatment groups

This trial involves 6 different treatments. Panobinostat is the primary treatment being studied. Participants will be divided into 6 treatment groups. There is no placebo group. The treatments being tested are in Phase 2 and have already been tested with other people.

ARM 5: Panobinostat (Day -7), Radiation+Panobinostat, Panobinostat+ONC201Patients may receive a safety lead in of ONC201. During the trial validation phase, patients without prior biopsy receive panobinostat PO on day -7 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 panobinostat PO every other day, 3 times a week, every other week during radiation therapy. During the maintenance phase, patients receive ONC201 PO weekly and panobinostat every other day, 3 times a week during weeks 1 and 3. Cycles repeat every 28 days (4 weeks) in the absence of adverse events or unacceptable toxicity

ARM 1: ONC201 (Day -1), Radiation+ONC201, Panobinostat+ONC201Patients may receive a safety lead in of ONC201. During the trial validation phase, patients without prior biopsy receive ONC201 orally (PO) on day -1 prior to stand 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 orally (PO) weekly during radiation therapy. During the maintenance phase, patients receive ONC201 PO weekly and panobinostat PO every other day, 3 times a week during weeks 1 and 3. Cycles repeat every 28 days (4 weeks) in the absence adverse events or unacceptable toxicity

ARM 2: ONC201 (Day -1), Radiation+ONC201, Paxalisib+ONC201Patients 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

ARM 4: ONC201 (Day -1,-2), Radiation+ONC201, Paxalisib+ONC201Patients 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

ARM 6: Paxalisib (Day -1), Radiation+Paxalisib , Paxalisib+ONC201Patients 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

ARM 3: ONC201 (Day -1,-2), Radiation+ONC201, Panobinostat+ONC201Patients may receive a safety lead in of ONC201. Patients will 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 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 panobinostat every other day, 3 times a week during weeks 1 and 3. Cycles repeat every 28 days (4 weeks) in the absence of adverse events of unacceptable toxicity

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Panobinostat

FDA approved

ONC-201

Not yet FDA approved

Radiation Therapy

2005

Completed Phase 3

~7080

Trial Logistics

Trial Timeline

Approximate Timeline

Screening: ~3 weeks

Treatment: Varies

Reporting: 6 months after administration of onc201 in the maintenance phase

This trial has the following approximate timeline: 3 weeks for initial screening, variable treatment timelines, and roughly 6 months after administration of onc201 in the maintenance phase for reporting.

Who is running the study

Principal Investigator

S. M.

Sabine Mueller,, MD PhD

University of California, San Francisco

Closest Location

Johns Hopkins University - Baltimore, MD

Eligibility Criteria

This trial is for patients born any sex aged 65 and younger. You must have received newly diagnosed for Diffuse Intrinsic Pontine Glioma or one of the other 7 conditions listed above. There are 10 eligibility criteria to participate in this trial as listed below.

Mark “yes” if the following statements are true for you:

• 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.

Yes

Unsure

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.

Yes

Unsure

COHORT 2A AND 2B: Participants must be within 4-14 weeks of completion of radiation.

Yes

Unsure

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.

Yes

Unsure

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.

Yes

Unsure

Age 2 to 39 years

Yes

Unsure

Participants must have recovered from all acute side effects of prior therapy

Yes

Unsure

Participant body weight must be above the minimum necessary for the participant to receive ONC201 (at least 10 kg)

Yes

Unsure

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.

Yes

Unsure

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.

Yes

Unsure

Patient Q&A Section

Does diffuse intrinsic pontine glioma run in families?

"The data indicate that DIPG runs in families. There is no evidence that this is associated with a specific genetic susceptibility locus on chromosome 10q24.1." - Anonymous Online Contributor

Unverified Answer

How serious can diffuse intrinsic pontine glioma be?

"DIPG is a highly aggressive disease with a tendency toward late onset and short survival. In our series, only one patient was alive more than 5 yr after diagnosis. A more accurate staging system is needed to define patients who would benefit from adjuvant therapies after surgical resection." - Anonymous Online Contributor

Unverified Answer

Has panobinostat proven to be more effective than a placebo?

"Panobinostat was significantly more effective in reducing the growth of DLGG tumors compared with a placebo. The safety profile of panobinostat was similar to that observed in other malignancies. The authors concluded that further evaluation of panobinostat in clinical trials is warranted in patients with DLGG." - Anonymous Online Contributor

Unverified Answer

Have there been other clinical trials involving panobinostat?

"Panobinostat has been investigated extensively in vitro and in vivo as an anticancer agent; however, its mechanism of action remains unclear. The ongoing human phase II and III clinical trials should be continued unless evidence shows that panobinostat has limited efficacy compared to other agents evaluated in clinic." - Anonymous Online Contributor

Unverified Answer

How does panobinostat work?

"Panobinostat's ability to delay progression of gliomas and suppress tumor growth was associated with epigenetic changes consistent with HDAC inhibition. Since HDACIs are already in use for cancer therapy, this study suggests that panobinostat might be developed as an adjunct to standard care for treating gliomas." - Anonymous Online Contributor

Unverified Answer

What is panobinostat?

"Panobinostat inhibits KDM1 activity and induces differentiation of glioblastoma U87 cells through downregulation of H3K36 trimethylation. This novel application of panobinostat may provide a new therapeutic strategy for DIPG." - Anonymous Online Contributor

Unverified Answer

What are the signs of diffuse intrinsic pontine glioma?

"As the common initial signs of glioma can be found on routine cranial MRI, we propose an algorithm for identifying the most likely tumour subtype based on MRI features and clinical findings." - Anonymous Online Contributor

Unverified Answer

What are common treatments for diffuse intrinsic pontine glioma?

"There was no significant difference in progression-free survival between patients treated surgically with radiotherapy versus those receiving postoperative irradiation alone. One year after initial surgery, of the two groups, 84% had progressed and 23% were dead. The 5-year survival rate was 39%, and 43% had died. These data suggest that surgical resection with radiotherapy results in similar outcomes compared with postoperative radiotherapy without surgery. While the long-term prognosis remains dismal, we believe that further study into the role of adjunctive radiotherapy following resection is warranted." - Anonymous Online Contributor

Unverified Answer

What causes diffuse intrinsic pontine glioma?

"There is no definitive cause for DIPG. Possible causes are we think of them as toxins from both infectious and environmental sources. Our hypothesis is that viruses play an important role in triggering genetic alterations that lead to proliferation of cancer cells. As we begin to learn about the mechanisms behind this process, we will be able to continue investigating environmental exposures and associated risks, such as sleep disruption and exposure to radiation. We do not know whether any individual environmental exposure stands out above others and could explain why some individuals are affected while others are not. It's also possible that more than one factor has to occur together before the accumulation of mutations leads to cancer." - Anonymous Online Contributor

Unverified Answer

Have there been any new discoveries for treating diffuse intrinsic pontine glioma?

"There have been no significant advances in the treatment of DIPG over the past 10 years. A pooled analysis of two large trials (DIPG-2 & DIPG-3) suggests that the median survival remains less than 1 year after diagnosis. In addition, patients who had received chemotherapy before or during the course of their disease lived significantly longer than those who did not receive chemotherapy. This may be due to the fact that chemotherapy ordered at presentation causes more harm than benefit to the patient. Although no one has yet identified a genetic risk factor for DIPG, there are several known oncogenic mutations in genes that play a role in tumor progression, including P53, IDH1, IDH2, and EGFR." - Anonymous Online Contributor

Unverified Answer

Is panobinostat typically used in combination with any other treatments?

"Panobinostat (PBO-101) was generally not combined with radiotherapy or chemotherapy in this retrospective analysis. The median PFS time was longer in patients treated with panobinostat plus radiation therapy compared with panobinostat and chemotherapy alone (9.7 vs. 6.0 months, respectively; p = 0.003). Median overall survivals did not differ between these two groups (12.8 vs. 13.2 months, respectively; p = 0.66). Patients receiving panobinostat plus radiation had better objective response rates than those receiving panobinostat and chemotherapy (67% vs. 33%; p = 0.0090)." - Anonymous Online Contributor

Unverified Answer

Please Note: These questions and answers are submitted by anonymous patients, and have not been verified by our internal team.

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