PNOC015: MTX110 by Convection-Enhanced Delivery in Treating Participants With Newly-Diagnosed Diffuse Intrinsic Pontine Glioma

• Sponsor: Sabine Mueller, MD, PhD (Other)
• Overall Status: Completed
• CT.gov ID: NCT03566199
• Collaborator: Midatech Pharma US Inc. (Industry), Pacific Pediatric Neuro-Oncology Consortium (Other)
• Enrollment: 7
• Location: 1
• Arm: 1
• Actual Duration (Months): 34.3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This phase I/II trial studies the side effects of panobinostat nanoparticle formulation MTX110 (MTX110) in treating participants with newly-diagnosed diffuse intrinsic pontine glioma. Panobinostat nanoparticle formulation MTX110 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition or Disease	Intervention/Treatment	Phase
Diffuse Intrinsic Pontine Glioma	Drug: Panobinostat Nanoparticle Formulation MTX110; Drug: Convection-Enhanced Delivery (CED)	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To determine the safety and tolerability of repeated administration of MTX110 co-infused with gadoteridol given by intratumoral convection enhanced delivery in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG).

SECONDARY OBJECTIVES:

1. To determine the clinical efficacy of repeated administration of MTX110 given by intratumoral convection-enhanced delivery (CED) in children with newly diagnosed DIPG in the confines of a phase I and early efficacy study.

OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.

Participants receive panobinostat nanoparticle formulation MTX110 intratumorally (IT) by CED infusion on day 1 or days 1 and 2 as determined by dose level. Courses repeat every 4-8 weeks for up to 24 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment participants are followed up at 30 days and then every 2 months.

Study Design

• Study Type: Interventional
• Actual Enrollment: 7 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open Label Single Arm Phase I/II Study of MTX110 Delivered by Convection-enhanced Delivery (CED) in Patients With Diffuse Intrinsic Pontine Glioma (DIPG) Previously Treated With External Beam Radiation Therapy
• Actual Study Start Date: May 22, 2018
• Actual Primary Completion Date: Mar 31, 2021
• Actual Study Completion Date: Mar 31, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (MTX110) Participants receive panobinostat nanoparticle formulation MTX110 IT by CED infusion on day 1 or days 1 and 2 as determined by dose level. Courses repeat every 4-8 weeks for up to 24 months in the absence of disease progression or unacceptable toxicity.	Drug: Panobinostat Nanoparticle Formulation MTX110; Given IT; Other Names: MTX-110 MTX110 (CN) ; Drug: Convection-Enhanced Delivery (CED); Undergo CED; Other Names: CED

Outcome Measures

Primary Outcome Measures

1. Proportion of Participants With Grade 3 or Higher, Treatment-related, Adverse Events [Up to 12 Months]

   Adverse events and clinically significant laboratory abnormalities which meet Grade 3, 4, or 5 criteria according to Common Terminology Criteria for Adverse Events (CTCAE) classified by investigators and treating physicians as related to study treatment (probable, possible, and definite) will be summarized by maximum intensity/grade. Adverse events will be graded according to CTCAE version 4.0.

Secondary Outcome Measures

1. Overall Survival Rate (OS) at 12 Months [Up to 12 Months]

   Overall survival is defined as the percentage of participants alive from time of diagnosis up to 12 months.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Years to 21 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients with newly diagnosed DIPG by magnetic resonance imaging (MRI); defined as patients with a pontine location and diffuse involvement of at least 2/3 of the pons are eligible without histologic diagnosis. For lesions with typical imaging features, biopsy is neither encouraged nor required for eligibility. Tumors that are biopsied will be eligible if proven to be supportive of the diagnosis of a DIPG. Consensus of diagnosis by the study team must be met.

• Patients who have completed focal radiotherapy within 14 weeks from time of enrollment are eligible.

• Treatment must begin at a minimum of 4 weeks after, but no later than 14 weeks after, the date of completion of focal radiotherapy.

• Prior chemotherapy: Patients should be at least 30 days from last chemotherapy dose prior to start of CED infusion, with exception of antibody half-lives. For antibody therapies, at least 3 half-lives of the antibody after last dose of monoclonal antibody should have passed prior to CED infusion. Patients less than 30 days from last chemotherapy dose should be discussed with the study chair(s).

• Prior radiation: Patients must have received prior treatment with focal radiotherapy as part of initial treatment for DIPG and had their last dose at least 4 weeks prior to and no later than 14 weeks from the first CED treatment. Standard focal radiation therapy will include 54 to 60 Gy by external beam radiotherapy to the brainstem.

• Age ≥ 2 years of age to 21 years. Patients younger than 3 years of age may be enrolled on study at the discretion of the Study Chair(s) if supporting evidence that brainstem lesion represents a brainstem glioma.

• Karnofsky Performance Score ≥ 50 for patients > 16 years of age and Lansky Performance Score ≥ 50 for patients ≤ 16 years of age. Patients who are unable to walk because of paralysis, but who are able to mobilize using a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.

• Life expectancy of greater than 12 weeks measured from the date of completion of radiotherapy.

• Corticosteroids: Patients who are receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to registration.

• Peripheral absolute neutrophil count (ANC) ≥ 1000/mm^3.

• Hemoglobin ≥ 8g/dl.

• Platelet count ≥ 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment).

• Normal coagulation defined as normal International Normalized Ratio (INR) or per institutional guidelines.

• Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70 milliliters (mL)/minute (min)/1.73 m^2.

• A serum creatinine (mg/dL) based on age/gender as follows:

• Age: 2 to < 6 years; Male: 0.8; Female: 0.8

• Age: 6 to < 10 years; Male: 1; Female: 1

• Age: 10 to < 13 years; Male: 1.2; Female: 1.2

• Age: 13 to < 16 years; Male:1.5; Female: 1.4

• Age ≥ 16 years; Male: 1.7; Female: 1.4

• Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN) for age.

• Serum glutamate pyruvate transaminase (SGPT) [alanine aminotransferase (ALT)] ≤ 110 U/L.

• Serum albumin ≥ 2 g/dL.

• Patients with seizure disorder may be enrolled if on non-enzyme inducing anticonvulsants and well controlled.

• The effects of MTX110 on the developing human fetus are unknown. For this reason women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and 4 months after completion of MTX110 injection administration. 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.

• Able to understand, and willing to sign, a written informed consent document.

• Patients who are unable to return for follow-up visits or obtain follow-up studies required to assess toxicity to therapy.

Exclusion Criteria:

• Patients who had clinical and/or radiographic (MRI) progression of tumor following external beam radiation therapy.

• Patients with metastatic disease, including leptomeningeal or subarachnoid disseminated disease.

• Patients with tumor morphology that predicts poor coverage of the majority of the tumor including bilateral thalamic involvement, or cysts that represent > 50% of cross-sectional areas of the pons. These subjects should be discussed with the study chairs.

• Patients who are receiving any other investigational agents or other tumor-directed therapy.

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to MTX110 or gadolinium.

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

• Female patients of childbearing potential must not be pregnant or breast-feeding. Female patients of childbearing potential must have a negative serum or urine pregnancy test within 14 days of registration.

• Patients with MRI or clinical evidence of uncontrolled tumor mass effect are excluded; the assessment of mass effect should be made by the study chairs and study neurosurgeons prior to any planned CED treatment.

• Untreated symptomatic hydrocephalus determined by treating physician.

• Patients with evidence of intra-tumoral hemorrhage > 5 mm maximal diameter. These subjects should be discussed with the study chair.

• Subjects with prolonged corrected QT (QTc) (> 450 msec) will be excluded from the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, San Francisco	San Francisco	California	United States	94158

Sponsors and Collaborators

• Sabine Mueller, MD, PhD
• Midatech Pharma US Inc.
• Pacific Pediatric Neuro-Oncology Consortium

Investigators

• Principal Investigator: Sabine Mueller, M.D., University of California, San Francisco

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 20, 2019

More Information

Publications

None provided.

• Responsible Party: Sabine Mueller, MD, PhD, Assistant Professor of Clinical Neurology, University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT03566199
• Other Study ID Numbers: 170817; NCI-2018-01085; PNOC015
• First Posted: Jun 25, 2018
• Last Update Posted: Feb 25, 2022
• Last Verified: Feb 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Glioma; Diffuse Intrinsic Pontine Glioma; Panobinostat

Study Results

Participant Flow

Recruitment Details	All participants were only enrolled into Phase 1 of the clinical trial. The phase 2 expansion cohort was not activated for enrollment at behest of pharmaceutical supplier.
Pre-assignment Detail	Each participant was permitted to have a dose-escalation assigned to subsequent rounds of CED treatment upon review of safety data at each round. A dose-escalation during treatment in a previous participant, determined the starting dosage assigned to the next participant. The first three participants enrolled received escalated doses in the second or third round of CED treatment.

Arm/Group Title	Phase 1: Starting Dose Level 1 (MTX110)	Phase 1: Starting Dose Level 2 (MTX110)	Phase 1: Starting Dose Level 3 (MTX110)	Phase 1: Starting Dose Level 4 (MTX110)	Phase 1: Starting Dose Level 5 (MTX110)	Phase 1: Starting Dose Level 6 (MTX110)	Phase 1: Starting Dose Level 7 (MTX110)	Phase 2
Arm/Group Description	Participant received starting dose of single CED of 30 micrometer of MTX110 on 1 day (day 1); Total volume 3 mL. Courses repeat every 4-8 weeks for up to 24 months in the absence of disease progression or unacceptable toxicity. Panobinostat Nanoparticle Formulation MTX110: Given IT Convection-Enhanced Delivery (CED): Undergo CED	Participant received starting dose of repeated CED of 30 micrometer of MTX110 on n 2 consecutive days (days 1, 2); Total volume 6 mL (3 mL on each day). Panobinostat Nanoparticle Formulation MTX110: Given IT Convection-Enhanced Delivery (CED): Undergo CED	Participant received starting dose of repeated CED of 30 micrometer of MTX110 on n 2 consecutive days (days 1, 2); Total volume 8 mL (4 mL on each day). Panobinostat Nanoparticle Formulation MTX110: Given IT Convection-Enhanced Delivery (CED): Undergo CED	Participant received starting dose of repeated CED of 30 micrometer of MTX110 on n 2 consecutive days (days 1, 2); Total volume 10 mL (5 mL on each day). Panobinostat Nanoparticle Formulation MTX110: Given IT Convection-Enhanced Delivery (CED): Undergo CED	Participant received starting dose of repeated CED of 30 micrometer of MTX110 on n 2 consecutive days (days 1, 2); Total volume 12 mL (6 mL on each day). Panobinostat Nanoparticle Formulation MTX110: Given IT Convection-Enhanced Delivery (CED): Undergo CED	Participant received starting dose of repeated CED of 60 micrometer of MTX110 on n 2 consecutive days (days 1, 2); Total volume 12 mL (6 mL on each day). Panobinostat Nanoparticle Formulation MTX110: Given IT Convection-Enhanced Delivery (CED): Undergo CED	Participant received starting dose of repeated CED of 90 micrometer of MTX110 on n 2 consecutive days (days 1, 2); Total volume 12 mL (6 mL on each day). Panobinostat Nanoparticle Formulation MTX110: Given IT Convection-Enhanced Delivery (CED): Undergo CED	Participants will receive Recommended Phase 2 Dose (RP2D) Panobinostat Nanoparticle Formulation MTX110: Given IT Convection-Enhanced Delivery (CED): Undergo CED
Period Title: Overall Study
STARTED	1	0	1	0	1	0	4	0
COMPLETED	1	0	1	0	1	0	4	0
NOT COMPLETED	0	0	0	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	Phase 1: Treatment (MTX110) - All Participants
Arm/Group Description	Participants receive panobinostat nanoparticle formulation MTX110 IT by CED infusion on day 1 or days 1 and 2 as determined by dose level. Courses repeat every 4-8 weeks for up to 24 months in the absence of disease progression or unacceptable toxicity. Panobinostat Nanoparticle Formulation MTX110: Given IT Convection-Enhanced Delivery (CED): Undergo CED
Overall Participants	7
Age, Customized (years) [Median (Full Range) ]
Median (Full Range) [years]	8
Sex: Female, Male (Count of Participants)
Female	1 14.3%
Male	6 85.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	5 71.4%
Unknown or Not Reported	2 28.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 14.3%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	4 57.1%
More than one race	0 0%
Unknown or Not Reported	2 28.6%
Region of Enrollment (participants) [Number]
United States	7 100%

Outcome Measures

1. Primary Outcome

Title	Proportion of Participants With Grade 3 or Higher, Treatment-related, Adverse Events
Description	Adverse events and clinically significant laboratory abnormalities which meet Grade 3, 4, or 5 criteria according to Common Terminology Criteria for Adverse Events (CTCAE) classified by investigators and treating physicians as related to study treatment (probable, possible, and definite) will be summarized by maximum intensity/grade. Adverse events will be graded according to CTCAE version 4.0.
Time Frame	Up to 12 Months

Outcome Measure Data

Analysis Population Description

While individual participants were assigned to receive separate doses, participants are presented in one Arm/Group due to confidentiality concerns for this rare disease study

Arm/Group Title	Phase 1: Treatment (MTX110)
Arm/Group Description	Participants receive panobinostat nanoparticle formulation MTX110 IT by CED infusion on day 1 or days 1 and 2 as determined by dose level. Courses repeat every 4-8 weeks for up to 24 months in the absence of disease progression or unacceptable toxicity. Panobinostat Nanoparticle Formulation MTX110: Given IT Convection-Enhanced Delivery (CED): Undergo CED
Measure Participants	7
Muscle weakness right-sided (Grade 3)	0.142 2%
Stridor (Grade 3)	0.142 2%
Vagus nerve disorder (Grade 3)	0.142 2%
Gait disturbance (Grade 3)	0.142 2%
Neutrophil count decreased (Grade 3)	0.142 2%

2. Secondary Outcome

Title	Overall Survival Rate (OS) at 12 Months
Description	Overall survival is defined as the percentage of participants alive from time of diagnosis up to 12 months.
Time Frame	Up to 12 Months

Outcome Measure Data

Analysis Population Description

While individual participants were assigned to receive separate doses, participants are presented in one Arm/Group due to confidentiality concerns for this rare disease study

Arm/Group Title	Phase 1: Treatment (MTX110)
Arm/Group Description	Participants receive panobinostat nanoparticle formulation MTX110 IT by CED infusion on day 1 or days 1 and 2 as determined by dose level. Courses repeat every 4-8 weeks for up to 24 months in the absence of disease progression or unacceptable toxicity. Panobinostat Nanoparticle Formulation MTX110: Given IT Convection-Enhanced Delivery (CED): Undergo CED
Measure Participants	7
Number (95% Confidence Interval) [percentage of participants]	85.7 1224.3%

Adverse Events

Time Frame	Up to 24 months
Adverse Event Reporting Description	Additional adverse event and mortality data was collected for participants for up to 24 months following initial diagnosis. While individual participants were assigned to receive separate doses, participants are presented in one Arm/Group due to confidentiality concerns for this rare disease study.
Arm/Group Title	Phase 1: Treatment (MTX110)
Arm/Group Description	Participants receive panobinostat nanoparticle formulation MTX110 IT by CED infusion on day 1 or days 1 and 2 as determined by dose level. Courses repeat every 4-8 weeks for up to 24 months in the absence of disease progression or unacceptable toxicity. Panobinostat Nanoparticle Formulation MTX110: Given IT Convection-Enhanced Delivery (CED): Undergo CED
All Cause Mortality
	Phase 1: Treatment (MTX110)
	Affected / at Risk (%)	# Events
Total	7/7 (100%)
Serious Adverse Events
	Phase 1: Treatment (MTX110)
	Affected / at Risk (%)	# Events
Total	1/7 (14.3%)
Musculoskeletal and connective tissue disorders
Muscle weakness right-sided	1/7 (14.3%)	1
Nervous system disorders
Vagus nerve disorder	1/7 (14.3%)	1
Other (Not Including Serious) Adverse Events
	Phase 1: Treatment (MTX110)
	Affected / at Risk (%)	# Events
Total	7/7 (100%)
Blood and lymphatic system disorders
Anemia	1/7 (14.3%)	1
Cardiac disorders
Sinus bradycardia	1/7 (14.3%)	3
Sinus tachycardia	1/7 (14.3%)	1
Ear and labyrinth disorders
External ear inflammation	1/7 (14.3%)	1
External ear pain	1/7 (14.3%)	1
Hearing impaired	1/7 (14.3%)	1
Eye disorders
Blurred vision	1/7 (14.3%)	1
Corneal ulcer	1/7 (14.3%)	1
Eye disorders - Other	1/7 (14.3%)	1
Gastrointestinal disorders
Constipation	2/7 (28.6%)	2
Dysphagia	2/7 (28.6%)	3
Diarrhea	1/7 (14.3%)	1
Vomiting	1/7 (14.3%)	2
General disorders
Fatigue	4/7 (57.1%)	5
Gait disturbance	3/7 (42.9%)	5
Pain	3/7 (42.9%)	8
Irritability	1/7 (14.3%)	1
Immune system disorders
Allergic reaction	1/7 (14.3%)	1
Infections and infestations
Otitis externa	1/7 (14.3%)	1
Injury, poisoning and procedural complications
Fall	1/7 (14.3%)	2
Wound dehiscence	1/7 (14.3%)	1
Investigations
Electrocardiogram QT corrected interval prolonged	3/7 (42.9%)	4
Lymphocyte count decreased	3/7 (42.9%)	9
White blood cell decreased	3/7 (42.9%)	8
Alanine aminotransferase increased	1/7 (14.3%)	1
Aspartate aminotransferase increased	1/7 (14.3%)	1
Blood bilirubin increased	1/7 (14.3%)	1
Hemoglobin increased	1/7 (14.3%)	1
Neutrophil count decreased	1/7 (14.3%)	5
Weight loss	1/7 (14.3%)	1
Metabolism and nutrition disorders
Hypokalemia	3/7 (42.9%)	5
Hypomagnesemia	2/7 (28.6%)	2
Hyperglycemia	1/7 (14.3%)	2
Hyperkalemia	1/7 (14.3%)	1
Hypoglycemia	1/7 (14.3%)	1
Musculoskeletal and connective tissue disorders
Muscle weakness right-sided	4/7 (57.1%)	7
Muscle weakness left-sided	2/7 (28.6%)	3
Neck pain	2/7 (28.6%)	2
Nervous system disorders
Headache	5/7 (71.4%)	8
Ataxia	4/7 (57.1%)	17
Dizziness	4/7 (57.1%)	5
Abducens nerve disorder	3/7 (42.9%)	4
Dysarthria	2/7 (28.6%)	7
Facial nerve disorder	2/7 (28.6%)	2
Nervous system disorders - Other	2/7 (28.6%)	4
Paresthesia	2/7 (28.6%)	2
Trigeminal nerve disorder	2/7 (28.6%)	2
Vagus nerve disorder	2/7 (28.6%)	2
Accessory nerve disorder	1/7 (14.3%)	1
Aphonia	1/7 (14.3%)	1
Dysgeusia	1/7 (14.3%)	1
Dysphasia	1/7 (14.3%)	1
Glossopharyngeal nerve disorder	1/7 (14.3%)	1
Tremor	1/7 (14.3%)	1
Psychiatric disorders
Agitation	1/7 (14.3%)	1
Insomnia	1/7 (14.3%)	1
Psychiatric disorders - Other	1/7 (14.3%)	1
Renal and urinary disorders
Urinary incontinence	1/7 (14.3%)	1
Urinary tract pain	1/7 (14.3%)	1
Urinary urgency	1/7 (14.3%)	1
Respiratory, thoracic and mediastinal disorders
Cough	3/7 (42.9%)	6
Nasal congestion	3/7 (42.9%)	5
Epistaxis	1/7 (14.3%)	1
Hiccups	1/7 (14.3%)	1
Stridor	1/7 (14.3%)	1
Skin and subcutaneous tissue disorders
Skin ulceration	1/7 (14.3%)	2
Urticaria	1/7 (14.3%)	1
Skin and subcutaneous tissue disorders - Other	2/7 (28.6%)	3
Vascular disorders
Hematoma	1/7 (14.3%)	1
Hypertension	1/7 (14.3%)	1
Hypotension	1/7 (14.3%)	1

Limitations/Caveats

Phase 2 expansion cohort was not activated at behest of pharmaceutical supplier.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.