This study has been transitioned to CTIS with ID 2023-507598-16-00 check the CTIS register for the current data. Primary objectives:Cohorts 1 and 2Maintenance Arm(s) Combinations:-To assess efficacy of combination therapy with ONC201 and novel agent…
ID
Source
Brief title
Condition
- Nervous system neoplasms malignant and unspecified NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Cohort 1 and 2: progression-free survival at 6 months
Cohort 3: overall survival at 7 months
Secondary outcome
Exploratory objectives:
-Cohort 1_radiation therapy: toxicity of weekly ONC201 given on day 1; ONC201
given on Day 1, 2; or a novel agent in combination with up-front radiation
therapy. Participants who receive at least 1 dose of the protocol therapy will
be evaluable for toxicity. Safety of protocol therapy will be assessed by
monitoring for adverse events, scheduled laboratory assessments, vital sign
measurements, and physical examinations for participants who receive at least 1
dose per protocol therapy.
-Cohorts 1, 2, and 3_Target Validation: Penetration of drug into tumor will be
measured and reported as a continuous variable based on the absolute
value of total intra-tumor drug concentration.
-Cohorts 1 and 2_Maintenance Combinations: overall survival at 12 months (OS12)
of the combination of backbone, ONC201, with a novel agent, given in the
maintenance phase of therapy. Toxicity of each combination therapy in the
maintenance phase of the study. Participants who receive at least 1 dose of the
protocol therapy will be evaluable for toxicity. Safety of each protocol
therapy will be assessed by monitoring for adverse events, scheduled laboratory
assessments, vital sign measurements, and physical examinations for
participants who receive at least 1 dose of the protocol therapy.
-Cohort 3: toxicity of weekly ONC201 given on day 1 or a novel agent in
combination with re-irradiation. Participants who receive at least 1 dose of the
protocol therapy will be evaluable for toxicity. Safety of protocol therapy
will be assessed by monitoring for adverse events, scheduled laboratory
assessments, vital sign measurements, and physical examinations for
participants who receive at least 1 dose per protocol therapy.
All cohorts:
-Intratumoral drug concentration of study drugs in the context of clinical
outcome - Degree of intratumoral drug concentration will be correlated with
clinical outcome across each arm/cohort using descriptive statistics.
-Intratumoral drug concentrations in irradiated versus non irradiated tumor
tissue - Comparison of intratumoral drug concentrations between irradiated and
non- irradiated tumor tissue will be assessed between cohorts 1 and 2 using
descriptive statistics.
-Tumor tissue biomarkers in the context of clinical outcomes - Tumor tissue
biomarker analysis will be done across each arm/cohort using descriptive
statistics.
- CSF biomarkers in the context of clinical outcomes - CSF biomarker analysis
will be done across each arm/cohort using descriptive statistics.
-Levels of circulating tumor DNA in the context of imaging response criteria
and clinical outcomes - Levels of ctDNA will be correlated with imaging
response and clinical outcomes using descriptive statistics, mixed models,
regression models, and categorical tables.
-Single cell RNA sequencing in the context of clinical outcomes - Single cell
RNA sequencing across each arm/cohort will be detailed using descriptive
statistics.
-Microbiome and flow cytometry studies in the context of imaging and clinical
outcomes using descriptive statistics.
-Health-Related Quality of Life (HRQOL) and cognitive measures - HRQOL
assessments and cognitive measures will be collected for descriptive purposes.
No formal hypothesis will be performed on the HRQOL tests. Results will
potentially be used as reference for future clinical trials.
-DMG-ACT Patient-Reported Outcome (PRO) Questionnaire - This questionnaire will
be collected for descriptive purposes. No formal hypothesis testing will be
performed. The results will potentially be used as reference data for future
clinical trials.
Background summary
Despite years of research and much knowledge gained about the underlying
biology of diffuse midline gliomas (DMGs) - especially those with H3K27M
mutations - little to no progress has been made to improve outcomes for these
patients. The reasons for the ongoing failures are multi-factorial but include
(a) limited preclinical data from a variety of model systems and validation in
multiple laboratories, (b) limited knowledge about the blood brain barrier
(BBB) penetration and (c) lack of multi-agent therapy plans. Within this
clinical trial, we aim to address these key issues by working with several
laboratories around the world to select the most promising combination therapy
strategies, leveraging a target validation design to confirm BBB penetration
and by offering each participants combination therapy approach. Given the
limited treatment options for participants with DMGs, we also aim to offer
trial enrollment at different disease stages - newly-diagnosed, after
completion of radiation therapy, and at time of progression.
Rationale for Selected ONC201 Backbone:
ONC201 will be used as a backbone and will be combined with novel agents that
have been shown in preclinical studies to be additive or synergistic in
combination. ONC201 is an impiridone, a novel therapeutic class that
antagonizes dopamine receptor D2 (DRD2), and has also shown to activate the
mitochondrial protease ClpP, stimulate degradation of mitochondrial proteins,
impair mitochondrial energy production, and evoke an intrinsic cell death
program. ONC201 is currently being tested in a phase 1 trial for pediatric
participants with histone H3 K27M-mutated glioma (NCT03416530), with this study
nearing completion. The drug has demonstrated BBB penetration and initial
studies are reporting promising response rates in both adult and pediatric
participants with H3K27M mutant tumors. However, biomarkers of response remain
unknown as wildtype H3 DMGs also respond to ONC201 in preclinical models.
Rationale for the Overall Study Design:
This trial will utilize an adaptive platform design in that the different
treatment arms for each cohort will be opened and closed based on ongoing
preclinical investigation as well as evolving outcome data from the trial, such
as BBB penetration and/or efficacy signals. The intent of this design is to
overcome some of the key challenges faced when conducting clinical trials for
patients with DMGs. We aim to understand the effects in DMG tumor tissue (tumor
drug concentration and PD assessment) for each incorporated therapy and offer
combination therapies at different stages of disease. Further, such a facile
trial design will allow for rapid incorporation of new agents based on our and
others* preclinical investigations.
Paxalisib (GDC-0084) is a novel, CNS penetrant small molecule inhibitor of the
class I PI3K/mTOR kinase. Activating mutations in the PI3K/mTOR pathway have
been previously described in a variety of cancers, including pediatric DMGs.
Specifically, over half of DMG tumors demonstrate alterations in the PI3K/mTOR
pathway, including AKT gain/mutations, PIK3CA mutations and PTEN loss.
PI3K/mTOR pathway is also activated as a response to accumulated mitochondrial
reactive oxygen species (ROS), as demonstrated by our protein profiling in CSF
samples collected from participants with DMG and similar to what has been seen
with ONC201. Our data have also demonstrated that paxalisib shows combinatorial
efficacy with ONC201 in DMGs and a first in human phase 1 study in recurrent,
adult glioblastoma (GBM) participants found paxalisib penetrates that
blood-brain-barrier and shows signs of clinical activity based on FDG-PET
imaging. A recently completed, phase 1 study at St. Jude Children*s Research
Hospital assessed paxalisib after completion of radiation therapy in children
with newly diagnosed DIPG. This study identified the RP2D for the agent. Our
data supporting the potential clinical impact of paxalisib combined with human
experience provide rationale for combining paxalisib with ONC201 in the
proposed clinical trial.
Study objective
This study has been transitioned to CTIS with ID 2023-507598-16-00 check the CTIS register for the current data.
Primary objectives:
Cohorts 1 and 2
Maintenance Arm(s) Combinations:
-To assess efficacy of combination therapy with ONC201 and novel agent in
participants with DMG based on median progression-free survival at 6 months
(PFS6)
Cohort 3
-To assess efficacy of combination therapy with ONC201 and novel agent in
participants with recurrent DMG based on overall survival at 7 months (OS7)
Secondary objectives
All Cohorts
Target Validation Phase:
-To confirm BBB penetration of ONC201 in DMGs by measuring the concentration of
ONC201 in tumor tissue
-To confirm BBB penetration of novel agents in DMGs by measuring the
concentration of drug (or metabolite) in tumor tissue
-To assess changes in immune cell infiltration in DMG tumor tissue after 1 or 2
doses of ONC201
-To assess correlation of intratumoral concentration of ONC201 with clinical
outcome
-To assess correlation of intratumoral drug concentration of novel agents with
clinical outcome
-To assess if intratumoral ONC201 concentrations differ in irradiated versus
nonirradiated tumor tissue
-To assess if intratumoral concentrations of novel agents differ in irradiated
versus nonirradiated tumor tissue
-To assess tumor tissue biomarkers in the context of clinical outcome, such as
PFS6 and/or OS12
Maintenance Combinations:
-To assess efficacy of combination therapy ONC201 and novel agent based on
overall survival at 12 months (OS12)
-To assess toxicity of combination therapy ONC201 and novel agents
Cohort 1
Radiation Therapy Phase:
-To assess the toxicity of weekly ONC201 in combination with up-front radiation
therapy
-To assess the toxicity of twice weekly ONC201 in combination with up-front
radiation therapy
-To assess the toxicity of novel agents in combination with up-front radiation
therapy
Cohort 3
-To assess the toxicity of weekly ONC201 in combination with re-irradiation
after progression
-To assess the toxicity of twice weekly ONC201 in combination with
re-irradiation therapy after progression
-To assess the toxicity of novels agents in combination with re-irradiation
after progression
-To assess the toxicity of ONC201 in combination with novel agents in
participants after re-irradiation after progression
All Cohorts/Phases
-To assess CSF biomarkers in the context of clinical outcome, such as PFS6
and/or OS12
-To assess levels of circulating tumor DNA (ctDNA) in the context of imaging
response criteria and clinical outcome, such as PFS6 and/or OS12
-To assess single cell RNA sequencing in the context of clinical outcome, such
as PFS6 and/or OS12
-To assess microbiome and flow cytometry studies in the context of imaging and
clinical outcomes using descriptive statistics.
-To assess Health-Related Quality of Life (HRQOL) and cognitive measures
-To assess patient and/or proxy satisfaction with study participation via
patient-reported outcome (PRO) measures
Study design
This is a multi-arm/cohort, multi-institutional, open-label trial for children
and young adults with DMGs. The study is divided into three cohorts based on
stage of disease (newly-diagnosed, postradiation therapy without disease
progression, and at disease progression). Participants will be
randomized at study entry within each cohort to various combination therapy
arms in the maintenance phase of therapy.
Intervention
ONC201 will be used as a backbone and will be combined with novel agents that
have been shown in preclinical studies to be additive or
synergistic in combination. At this moment only paxalisib is used as a second
novel agent.
ONC201 is taken weekly (based on weight, equivalent of 625 mg adult dose) and
paxalisib daily (27 mg/m2). All patients will receive this combination therapy.
Study burden and risks
The patient does not need to come to the examination site more often. However,
extra tests are done and extra blood or CSF is taken (see section E). The
patient may experience side effects of the study drugs.
Heidelberglaan 25
Utrecht 3584 CS
NL
Heidelberglaan 25
Utrecht 3584 CS
NL
Listed location countries
Age
Inclusion criteria
Cohort 1A and 1B (participants with newly diagnosed DMG prior to radiation
therapy)
-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; WHO Grade 3 and 4 H3 wildtype gliomas.
Cohort 2A and 2B (participants with DMG who have completed radiation therapy)
-Diagnosis of DMG with imaging and/or pathology consistent with a DMG,
including spinal cord tumors, who have completed 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 3 and 4 H3 wildtype gliomas.
-Participants must be within 4-14 weeks of completion of radiation.
Cohort 3A and 3B (participants with DMG at progression)
-Diagnosis of recurrent DMG with imaging and/or pathology consistent with a
DMG, including spinal cord tumors, who have completed 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 3 and 4 H3 wildtype gliomas.
-Participants must have evidence of progression and not have received any
treatment for this progression and have not previously received re-irradiation.
All Cohorts
-Age 2 to 39 years.
-Participants must have recovered from all acute side effects of prior therapy.
-Participant body weight must be above the minimum necessary for the
participant to receive ONC201 (at least 10 kg).
-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 (21 days for bevacizumab when used for tumordirected
therapy, guidance on use for pseudoprogression is below), or 4 weeks (or 5
halflives, whichever is shorter) from other anti-tumor therapies.
o 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.
o The use of bevacizumab to control radiation therapy-induced edema is allowed
(if used for tumor-directed therapy, please see required time period above).
* Dosing limitations are as follows: Bevacizumab (or equivalent) for up to a
maximum of 5 doses, dosing per institutional standard. There is no required
washout period.
* Prior use of temozolomide during radiation at maximum of the standard
pediatric dosing (defined as 90 mg/m2 /dose continuously during radiation
therapy for 42 days) or dexamethasone is allowed. Corticosteroids: Participants
who are receiving dexamethasone must be on a stable or decreasing dose for at
least 3 days prior to baseline MRI scan.
-The participant must have adequate organ function (see protocol for details;
protocol v3.0 dd 26JAN2023)
-The effects of the study drugs on the developing human fetus are unknown. For
this reason, females of child-bearing potential and males must agree to use
adequate contraception. Adequate methods include: hormonal or barrier method of
birth control; or abstinence prior to study entry and for the duration of study
participation. 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. Males treated or enrolled on this protocol must
also agree to use adequate contraception prior to the study and for the
duration of study participation.
-Karnofsky >= 50 for Participants>= 16 years of age and Lansky >= 50 for
participants <=16 years of age (See Appendix A). Participants who are unable to
walk because of paralysis, but who are up in a wheelchair, will be considered
ambulatory for the purpose of assessing the performance score.
-Participants must be willing to provide adequate tissue. A minimum of 10-20
paraffin embedded unstained slides OR 1 block with tumor content of 40% or
greater is required. Participants who do not meet this criteria must be
discussed with Study Chair(s).
-A legal parent/guardian or participant must be able to understand, and willing
to sign, a written informed consent and assent document, as appropriate.
Exclusion criteria
Cohort 1A and 1B (participants with newly diagnosed DMG prior to radiation
therapy)
-Prior exposure to radiation therapy.
-Thalamic H3K27M DMG*
Cohort 2A and 2B
-For tumors that do not have a pontine or spinal cord epicenter the following
specific exclusion criteria apply:
--Thalamic H3K27M DMG that has undergone standard radiation without concurrent
therapy (other than temozolomide)*
Cohort 1A and 2A (participants with newly diagnosed DMG prior to radiation
therapy and who have not previously undergone tumor tissue collection prior to
study entry)
-Deemed not appropriate for tissue resection/biopsy.
Cohort 3A and 3B (participants with DMG at progression)
-Prior exposure to re-irradiation for tumor progression.
-Patients who participated in trials investigating ONC201 in the upfront
setting will not be eligible. Prior ONC201 exposure as part of PNOC022 or
expanded access programs will be allowed.*
All Cohorts
-Diagnosis of a histone H3 wildtype Grade 2 diffuse astrocytoma
-Investigational Drugs
o Participants who are currently receiving another investigational drug.
Investigational imaging agents or agents used to enhance tumor visibility on
imaging or during tumor biopsy/resection should be discussed with the study
chairs.
-Anti-cancer Agents
o Participants who are currently receiving other anti-cancer agents.
-Participants with a known disorder that affects their immune system, such as
HIV or Hepatitis B or C, or an auto-immune disorder requiring systemic
cytotoxic or immunosuppressive therapy. Note: Participants that are currently
using inhaled, intranasal, ocular, topical or other non-oral or non-IV steroids
are not necessarily excluded from the study but need to be discussed with the
study chair.
-Participants with uncontrolled infection or other uncontrolled systemic
illness.
-Female participants of childbearing potential must not be pregnant or
breast-feeding. Female participants of childbearing potential must have a
negative serum or urine pregnancy test prior to the start of therapy (as
clinically indicated).
-Active illicit drug use or diagnosis of alcoholism.
-History of allergic reactions attributed to compounds of similar chemical or
biologic composition as the agents used in study.
-Evidence of disseminated disease, including multi-focal disease, diffuse
leptomeningeal disease or evidence of CSF dissemination.
-Known additional malignancy that is progressing or requires active treatment
within 3 years of start of study drug.
-Concomitant use of potent CYP3A4/5 inhibitors during the treatment phase of
the study and within 72 hours prior to starting study drug administration.
-Concomitant use of potent CYP3A4/5 inducers, which include enzyme inducing
antiepileptic drugs (EIAEDs; see Appendix I), during the treatment phase of the
study and within 2 weeks prior to starting treatment. Concurrent
corticosteroids is allowed.
*Exclusion criteria do not apply to patient of <=18 years old who have thalamic
disease; these patients can still be included in the PNOC022 trial at the
Prinses Máxima Center. Exclusion criteria do apply to patients over the age of
18 years old who have thalamic disease. These patients can be enrolled in the
ACTION trial.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2023-507598-16-00 |
| EudraCT | EUCTR2022-000636-40-NL |
| ClinicalTrials.gov | NCT05009992 |
| CCMO | NL81136.041.22 |