NORTH: A Study of Panobinostat in Pediatric Patients With Solid Tumors Including MRT/ATRT

Sponsor

Australian & New Zealand Children's Haematology/Oncology Group (Other)

Overall Status

Terminated

CT.gov ID

NCT04897880

Collaborator

National Health and Medical Research Council, Australia (Other), Secura Bio, Inc. (Industry)

Enrollment

Locations

Arms

35.5

Actual Duration (Months)

2.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This trial is evaluating the anti-tumor activity and side effects of panobinostat in treating patients with osteosarcoma, malignant rhabdoid tumor/atypical teratoid rhabdoid tumor (MRT/ATRT), and neuroblastoma.

Condition or Disease	Intervention/Treatment	Phase
Rhabdoid Tumor Atypical Teratoid/Rhabdoid Tumor Malignant Rhabdoid Tumor Recurrent Brain Tumor, Childhood	Drug: Panobinostat	Phase 2

Detailed Description

This is an open label, phase II, multi-centre study evaluating the anti-tumor activity of continuous, low dose of panobinostat in patients with recurrent or refractory solid tumors stratified by primary histology into osteosarcoma, malignant rhabdoid tumor/atypical teratoid rhabdoid tumor (MRT/ATRT), and neuroblastoma.

Patients will be stratified at study entry by tumor type into three strata: osteosarcoma, MRT/ATRT and neuroblastoma [osteosarcoma and neuroblastoma arms are closed to enrolment]. Patients will be enrolled onto the study following completion of their conventional therapy including chemotherapy and/or radiation treatment and completion of a three-week wash out period.

Panobinostat will then be administered as a continuous oral dose (starting at a de-escalated dose of 8mg/m2 per day), for up to 12 courses, a total of 48 weeks. The minimum dose is 2mg/m2 per day. Dosing will follow a dose de-escalation or escalation scheme for each stratum which will be determined by biological effect of the drug (measured in patient peripheral blood samples) and levels of toxicity (measured by dose limiting toxicity and adverse events observed). Dose levels for subsequent enrolments in each strata will be based on the de-escalated or escalated dose in each cohort. The final dose per strata will be that which achieves significant biological effect with acceptable toxicity that is maintained for a 4 week period.

Patients or their parents/guardians will be required to maintain a drug diary to monitor drug usage throughout the trial. Patients will be followed for up to 2 years from completion of study therapy.

Study Design

Study Type:

Interventional

Actual Enrollment :

25 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase II Study of Panobinostat in Pediatric, Adolescent and Young Adult Patients With Solid Tumors Including Osteosarcoma, Malignant Rhabdoid Tumor/Atypical Teratoid Rhabdoid Tumors and Neuroblastoma

Actual Study Start Date :

Jan 9, 2019

Actual Primary Completion Date :

Dec 24, 2021

Actual Study Completion Date :

Dec 24, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Osteosarcoma [arm closed]	Drug: Panobinostat Panobinostat capsules, 10mg, starting at a de-escalated dose of 8mg/m2 per day Other Names: Farydak®
Experimental: Malignant Rhabdoid Tumor/Atypical Teratoid Rhabdoid Tumor	Drug: Panobinostat Panobinostat capsules, 10mg, starting at a de-escalated dose of 8mg/m2 per day Other Names: Farydak®
Experimental: Neuroblastoma [arm closed]	Drug: Panobinostat Panobinostat capsules, 10mg, starting at a de-escalated dose of 8mg/m2 per day Other Names: Farydak®

Arm

Intervention/Treatment

Experimental: Osteosarcoma [arm closed]

Drug: Panobinostat

Panobinostat capsules, 10mg, starting at a de-escalated dose of 8mg/m2 per day

Other Names:

Farydak®

Experimental: Malignant Rhabdoid Tumor/Atypical Teratoid Rhabdoid Tumor

Drug: Panobinostat

Panobinostat capsules, 10mg, starting at a de-escalated dose of 8mg/m2 per day

Other Names:

Farydak®

Experimental: Neuroblastoma [arm closed]

Drug: Panobinostat

Panobinostat capsules, 10mg, starting at a de-escalated dose of 8mg/m2 per day

Other Names:

Farydak®

Outcome Measures

Primary Outcome Measures

Efficacy as measured by Clinical Benefit Rate (percentage of patients with stable disease or better using MRI/CT imaging) [4 months after intervention commencement]
Safety, as assessed by incidence of adverse events graded according to the NCI-CTCAE, version 4.0 [1 week to 12 months after intervention commencement]

Secondary Outcome Measures

Clinical Benefit Rate: Percentage of patients with stable disease or better using functional imaging (MIBG or FDG-PET). [Every 2 months for 12 months after treatment commencement]
Time to progression calculated as the time from registration to date of event defined as the first documented progression or death resulting from underlying cancer. [2 years after completion of treatment]
Overall Survival calculated as the time from registration to date of death [2 years after completion of treatment]

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 39 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients must be < 40 years of age.
Patient must have been histologically diagnosed with osteosarcoma, neuroblastoma or MRT/ATRT at time of diagnosis or relapse. [osteosarcoma and neuroblastoma arms are closed to recruitment].
Patient disease is refractory to conventional therapy, in the case of osteosarcoma, neuroblastoma and MRT/ATRT or there is an absence of effective conventional therapy available in the case of ATRT. Patients must have stable disease (SD) or better following treatment with salvage therapy.
Karnofsky performance level greater than or equal to 60% for patients 16 years of age and greater, OR Lansky performance levels greater than or equal to 60% for patients less than 16 years of age.
Life expectancy of greater than 8 weeks.
Fully recovered from acute toxic effects of all prior chemotherapy, immunotherapy or radiotherapy prior to entering study.
Patients with CNS tumours who are receiving dexamethasone are on a stable/decreasing dose for at least 1 week.
Adequate BM function
Adequate renal function
Adequate liver function
Adequate cardiac function
Adequate pulmonary function
Adequate CNS function - seizure free for at least 2 months
Adequate serum calcium, magnesium and potassium concentrations
If female and post-menarchal, pregnancy test must be negative.
If of reproductive potential, have agreed to use effective contraceptive method.
If female and lactating, have agreed not to breastfeed.
Patient and/or their legal guardian have signed a written informed consent form.

Exclusion Criteria:

Have received myelosuppressive chemotherapy and/or biologic therapy within 3 weeks (4 weeks if prior nitrosourea).
Have received local palliative radiotherapy within 2 weeks.
Have received craniospinal radiotherapy within 3 weeks.
Have received greater than or equal to 50% radiation of the pelvis within 6 weeks.
Have received other substantial BM radiation within 6 weeks.
Have received growth factor(s) within 1 week.
Are receiving enzyme inducing anticonvulsant therapy.
Are receiving medications associated with prolongation of QTc interval
Are receiving hydrochlorothiazide.
Are receiving metronidazole and/or disulfiram
Have uncontrolled sepsis.
Have previously received panobinostat.
Have symptoms of congestive heart failure, uncontrolled cardiac rhythm disturbance, or a QTc greater than or equal to 450msec.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center	Durham	North Carolina	United States	27710
2	John Hunter Children's Hospital	New Lambton	New South Wales	Australia	2305
3	Sydney Children's Hospital	Randwick	New South Wales	Australia	2031
4	The Children's Hospital at Westmead	Westmead	New South Wales	Australia	2145
5	Women's and Children's Hospital	North Adelaide	South Australia	Australia	5006
6	Royal Hobart Hospital	Hobart	Tasmania	Australia	7000
7	Monash Children's Hospital	Clayton	Victoria	Australia	3168
8	The Royal Children's Hospital	Parkville	Victoria	Australia	3052
9	Perth Children's Hospital	Nedlands	Western Australia	Australia	6009
10	Starship Children's Hospital	Grafton	Auckland	New Zealand	1023
11	Christchurch Hospital	Christchurch		New Zealand	8011