Phase I Study of Marizomib + Panobinostat for Children With DIPG

NCT04341311 | Terminated Phase 1 DMC FDA Drug

• 1 other identifier: 19-654
• Study Type: interventional
• Target: 4
• Locations: 1 country
• Sites: 2

Brief Summary

This research study is evaluating the safety, tolerability and preliminary efficacy of the drugs marizomib and panobinostat in pediatric patients with diffuse intrinsic pontine glioma (DIPG). The names of the study drugs involved in this study are:

• Marizomib
• Panobinostat

Conditions

Diffuse Intrinsic Pontine Glioma; Pediatric Brainstem Glioma; Pediatric Brainstem Gliosarcoma, Recurrent; Pediatric Cancer; Pediatric Brain Tumor; Diffuse Glioma

Keywords

Diffuse Intrinsic Pontine Glioma; Pediatric Brainstem Glioma; Pediatric Cancer; Pediatric Brain Tumor; Diffuse Glioma; Progressive Diffuse Intrinsic Pontine Glioma

Outcome Measures

Primary Outcomes (9)

• Dose-limiting toxicity (DLT) of marizomib as a single agent

  To determine the toxicity profile and any dose-limiting toxicity (DLT) of marizomib as a single agent at doses up to 0.8 mg/m2 , in children with DIPG

  28 Days

• Dose-limiting toxicity (DLT) of marizomib in combination with panobinostat

  To determine the toxicity profile and any DLT of marizomib at doses up to 0.8 mg/m2 when administered in combination with panobinostat to children with DIPG

  28 days

• Maximum Tolerated Dose of Marizomib (single agent)

  To estimate the maximum-tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of marizomib when administered as a single agent in children with DIPG

  28 Days

• Maximum Tolerated Dose of Marizomib in combination with panobinostat

  To estimate the MTD or RP2D of marizomib when administered in combination with panobinostat in children with DIPG

  28 Days

• Pharmacokinetic parameters-volume of the central compartment (Vc/F)

  Estimated using compartmental methods. Plasma drug concentrations and pharmacokinetic parameters will be presented in tabular and graphical form

  Day 1 Course A1

• Pharmacokinetic parameters-elimination rate constant (Ke),

  Estimated using compartmental methods. Plasma drug concentrations and pharmacokinetic parameters will be presented in tabular and graphical form

  Course A1, Day 1

• Pharmacokinetic parameters half-life (t1/2)

  Estimated using compartmental methods. Plasma drug concentrations and pharmacokinetic parameters will be presented in tabular and graphical form

  Course A1, Day 1

• Pharmacokinetic parameters-apparent clearance (CL/F)

  Estimated using compartmental methods Plasma drug concentrations and pharmacokinetic parameters will be presented in tabular and graphical form

  Course A1, Day 1

• Area under the plasma concentration time curve (AUC)

  Estimated using compartmental methods Plasma drug concentrations and pharmacokinetic parameters will be presented in tabular and graphical form

  Course A1, Day 1

Secondary Outcomes (3)

• Radiographic progression-free survival (rPFS)

  rPFS will be measured from the time of treatment initiation until the time of progressive disease or death from any cause in patients with an event up to 60 Months.

• Overall survival (OS)

  time from enrollment until death due to any cause up to 60 Months

• Clinical Benefit Score

  Baseline, Day 1 of every Cycle up to 2 years. One cycle is 28 days. Higher scores may indicate more clinical benefit.

Study Arms (2)

Marizomib

EXPERIMENTAL

All patients will initially receive marizomib (MRZ) alone (Course A1) The dose escalation and de-escalation for single agent and combination will be guided using the Bayesian optimal interval (BOIN) design -Intravenously initially given every other week over a 28 day course but may go to weekly x 3 and weekly x 4 as the dose levels increase. Up to 26 courses.

Drug: Marizomib

Marizomib + Panobinostat

EXPERIMENTAL

If tolerated,combination of Marizomib: and panobinostat on subsequent cycles. The dose escalation and de-escalation for single agent and combination will be guided using the Bayesian optimal interval (BOIN) design. * Intravenously initially given every other week over a 28 day course but may go to weekly x 3 and weekly x 4 as the dose levels increase. Up to 26 courses. * Panobinostat: Oral dosage is given 3 times weekly, every other week over a 28 day course

Drug: Marizomib; Drug: Panobinostat

Interventions

Marizomib DRUG

\- Intravenously initially given every other week over a 28 day course but will go to weekly x 3 and weekly x 4 as the dose levels increase Up to 26 courses.

Also known as: salinosporamide A, salinosporin A

Marizomib; Marizomib + Panobinostat

Panobinostat DRUG

\- Panobinostat: Oral dosage is given 3 times weekly, every other week over a 28 day course

Also known as: Farydak

Marizomib + Panobinostat

Eligibility Criteria

• Age: Up to 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Patients must have DIPG, as defined below, to be eligible for this protocol. Given the poor prognosis of all patients with DIPG, patients may enroll at any point in their disease course provided they have received standard radiation therapy (also defined below) and meet all other eligibility requirements.
• DIPG is defined, for this study, as a diffusely infiltrative lesion with the epicenter in the pons, involving at least 2/3 of the pons as assessed by T2 or FLAIR imaging, and with no major or primary exophytic component, OR a pontine-based lesion that is biopsy proven non-pilocytic, WHO II-IV glioma. H3K27M status will be assessed in patients when tissue is available, but patients are eligible regardless of H3K27M status. (Biopsy will NOT be performed as part of this study).
• Standard radiation therapy is defined, for this study, as 54-60 Gy standard focal (photon or proton) radiation therapy, administered over 6 weeks (+/- 10 days). Patients who receive standard radiation therapy with concurrent chemotherapy may be eligible as long as other criteria are met.
• Patients must be \< 22 years of age at the time of enrollment.
• Patient must be able to swallow capsules whole.
• Karnofsky Performance Scale (KPS, for ≥ 16 years of age) or Lansky Performance Scale (LPS, for \< 16 years of age) assessed within 7 days prior to treatment initiation must be ≥ 50%. Patients who are unable to walk because of neurologic deficits, but who are up and awake in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• Patients must have recovered (defined as \< Grade 1 or baseline to meet otherwise defined eligibility criteria) from acute treatment-related toxicities of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
• Patients must have received their last fraction of radiation therapy at least 2 weeks prior to treatment initiation.
• Patients must have received their last dose of known myelosuppressive chemotherapy at least 21 days prior to enrollment (42 days if prior nitrosourea).
• Investigational/Biologic Agent/Immunotherapy (for agents that fit more than one category, i.e. biologic and immunotherapy, use the longest time-point indicated since last therapy to assess eligibility; contact PI or Study Chair if any questions):
• Patient must have recovered (\< Grade 1) from any acute toxicity potentially related to the agent and received their last dose of the investigational or biologic agent ≥ 7 days prior to study enrollment.
• For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur and discussed with the principal investigator.
• Monoclonal antibody treatment and agents with known prolonged half-lives: At least three half-lives must have elapsed prior to enrollment due to the potential risk of pseudoprogression.
• Checkpoint inhibitors, vaccine, or CAR T cell therapy: At least 3 months must have elapsed from last treatment prior to enrollment due to the risk of pseudo-progression.
• Convection Enhanced Delivery (CED)

You may not qualify if:

• Patients who have received \> 60 Gy total radiation to the pons (e.g. patients who have received re-irradiation) due to potential increased risk of intratumoral hemorrhage
• Patients who have had prior bone marrow transplant or received marrow ablative therapy
• Patients with implanted CED catheters (e.g. Renshaw) due to inability to fully evaluate disease status
• Patients with a history of spinal radiation or those with an indication for acute spine radiation (e.g. significant cord compression) (Patients with leptomeningeal disease may be eligible but should be reviewed with study PI prior to enrollment).
• Patients with a history of disorientation, hallucinations or episodes of confusion (unless associated with a clear etiology, e.g. sedation, and fully resolved with no episodes in the 2 weeks prior to enrollment) since diagnosis of DIPG
• Patients with current or prior history of posterior reversible encephalopathy syndrome (PRES)
• Patients with significant (i.e. requiring active/ongoing treatment) GI dysfunction or GI disease, e.g. inflammatory bowel disease.
• Patients with chronic diarrhea or current diarrhea (≥ 4 stools/day).
• Patients with any clinically significant unrelated systemic illness (e.g. serious infections, mental illness, or significant cardiac, pulmonary, hepatic or other organ dysfunction), that, in the opinion of the investigator, would compromise the ability of the patient to tolerate protocol therapy or put them at additional risk for toxicity or would interfere with the study procedures, ability to assign attribution, or results.
• Any ventricular arrhythmias with the exception of benign premature ventricular contractions
• Patients known to be refractory to red blood cell or platelet transfusions. Patients who are receiving any other anticancer or investigational drug therapy
• Patients who are required to receive any medication listed in Appendix B or is otherwise known to significantly prolong the QTc interval. (Note: Loperamide use is acceptable at doses no higher than listed in this protocol).
• Patients who are taking cannabinoids, cannabinoid oils, any psychoactive supplement, narcotics, or any agent that can potentially cause hallucinations, disorientation, confusion or dizziness
• Patients/parents/caregivers must disclose all supplements and/or alternative therapies being administered to the patient. If unwilling or unable, patient is not eligible.
• Patients receiving enzyme-inducing antiepileptic drugs and/or valproic acid. Patients are eligible if they discontinue enzyme-inducing antiepileptic drugs and/or valproic acid prior to enrollment and have a washout period of least 5 half-lives.

Sponsors & Collaborators

• Dana-Farber Cancer Institute: lead
• Celgene: collaborator
• Secura Bio, Inc.: collaborator

Study Sites (2)

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

MeSH Terms

Conditions

Diffuse Intrinsic Pontine Glioma; Recurrence; Neoplasms

Interventions

marizomib; Panobinostat

Condition Hierarchy (Ancestors)

Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; 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; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Hydroxamic Acids; Hydroxylamines; Amines; Organic Chemicals; Hydroxy Acids; Carboxylic Acids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Katherine Warren, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: March 5, 2020
• First Posted: April 10, 2020
• Study Start: August 10, 2020
• Primary Completion: February 14, 2024
• Study Completion: February 14, 2024
• Last Updated: February 15, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu

Locations

US (2)