Montag, 23. Dezember 2024
Navigation öffnen
Anzeige:
Wefra Programatic
 
JOURNAL ONKOLOGIE – STUDIE
PNOC023

ONC206 for Treatment of Newly Diagnosed, Recurrent Diffuse Midline Gliomas, and Other Recurrent Malignant CNS Tumors

Rekrutierend

NCT-Nummer:
NCT04732065

Studienbeginn:
August 2021

Letztes Update:
08.08.2024

Wirkstoff:
ONC206

Indikation (Clinical Trials):
Neoplasms, Glioblastoma, Glioma, Ependymoma, Nervous System Neoplasms, Central Nervous System Neoplasms, Recurrence

Geschlecht:
Alle

Altersgruppe:
Alle

Phase:
Phase 1

Sponsor:
Sabine Mueller, MD, PhD

Collaborator:
Chimerix, Mithil Prasad Foundation, Storm the Heavens Fund, The ChadTough Defeat DIPG Foundation, National Cancer Institute (NCI), Dana-Farber Cancer Institute,

Studienleiter

Sabine Mueller, MD, PhD
Study Chair
University of California, San Francisco

Kontakt

Studienlocations
(3 von 4)

University of California, San Francisco
94143 San Francisco
United StatesRekrutierend» Google-Maps
Ansprechpartner:
PNOC Operations
Phone: 415-502-1600
E-Mail: PNOC023@ucsf.edu


E-Mail: PNOC023@ucsf.edu» Ansprechpartner anzeigen
The University Children's Hospital in Zurich
8032 Zürich
SwitzerlandRekrutierend» Google-Maps
Ansprechpartner:
Nicolas Gerber, MD
Phone: +41 44 266 3117
E-Mail: glioma@kispi.uzh.ch

Stephanie Matthes, PhD
Phone: +41 44 266 3726
E-Mail: glioma@kispi.uzh.ch» Ansprechpartner anzeigen
Alle anzeigen

Studien-Informationen

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of DRD2 antagonist/ClpP agonist ONC206

(ONC206).

II. To determine the MTD of ONC206 as single agent in children and young adults with DMG,

H3K27 altered, who completed at least one line of prior therapy that included focal

radiation therapy (Arm A).

III. To determine the MTD of ONC206 in combination with focal radiation therapy in newly

diagnosed children and young adults with DMG, H3K27 altered (Arm B).

IV. To determine the MTD of ONC206 in combination with reirradiation in children and

young adults with progression of DMG, H3K27 altered (Arm C).

V. To determine the MTD of ONC206 in children and young adults with recurrent primary

malignant CNS tumors including participants with recurrent DMGs if not eligible for other

arms. (Arm D).

VI. To assess the concentration of ONC206 in tumor tissue from children and young adults

with DMG, H3K27 altered predominantly localized to the thalamus and compare to plasma

drug levels pre-surgery. (Target validation).

VII. To assess the concentration of ONC206 in tumor tissue in children and young adults

with DMG, H3K27 altered predominantly localized to the pons and compare to plasma drug

levels pre-surgery. (Target validation).

VIII. To assess the concentration of ONC206 in tumor tissue in children and young adults

with DMG, H3K27 altered in non-thalamic and non-pontine locations and compare to plasma

drug levels pre-surgery. (Target validation).

IX. To assess the concentration of ONC206 in tumor tissue in children and young adults

with recurrent primary malignant CNS tumors and compare to plasma drug levels

pre-surgery. (Target validation).

SECONDARY OBJECTIVE:

I. To characterize the pharmacokinetics (PK) of ONC206 in plasma in patients with DMG,

H3K27 altered and recurrent primary malignant CNS tumors.(Arms A and D).

EXPLORATORY OBJECTIVES:

I. To assess the clinical responses within the confines of a phase 1/expansion study.

II. To assess if amount of serum circulating tumor DNA (ctDNA) is correlated with

clinical outcome.

III. To assess if amount of cerebrospinal fluid (CSF) ctDNA is correlated with clinical

outcome.

IV. To assess if clinical outcomes are associated with anatomic location of tumor, H3K27

mutation status and other partner mutations.

V. To assess biomarkers of response.

VI. To assess the response rate to ONC206 in patients with prior ONC201 exposure.

VII. To assess pharmacodynamics (PD) of ONC206.

VIII. To assess PK-PD and identify the relationship between drug exposure and clinical

endpoints for both safety and efficacy.

IX. To characterize the PK of ONC206 in CSF in patients with DMG, H3K27 altered and

recurrent primary malignant CNS tumors.

X. To assess PD changes within tumor tissue after ONC206 administration (Target

Validation).

XI. To assess microbiome and flow cytometry studies in the context of imaging and

clinical outcomes using descriptive statistics.

XII. To assess Health Related Quality of Life (HRQOL) outcomes.

XIII. To assess patient and/or proxy satisfaction with study participation via

patient-reported outcome (PRO) measures.

XIV. To assess patient and/or proxy satisfaction with study participation via

patient-reported outcome (PRO) measures in the context of race ethnicity and other health

related social risks.

XV. To assess on therapy toxicity and survival in the context of race, ethnicity and

other health related social risks.

XVI. To assess if 18F-FET-PET can support response assessment in children treated with

ONC206.

XVII. To determine feasibility of measuring ONC206 concentrations in hair samples.

XVIII. To assess feasibility to obtain Proton (1H) MR spectroscopy (MRS) with standard

MRI.

OUTLINE: This is a dose-escalation study of ONC206. Patients are assigned to 1 of 4 arms.

ARM A (Children and young adults with DMG H3K27 altered who completed at least one line

of prior therapy) and ARM D (Participants with recurrent primary malignant CNS tumors

including participants with recurrent DMGs who failed at least one prior therapy

including radiation therapy): Patients receive ONC206 orally (PO) up to six times per

week. Cycles repeat every 28 days for up to 12 months in the absence of disease

progression or unacceptable toxicity. In case the participant receives clinical benefit

from the treatment, treatment could possibly proceed up to 24 months.

ARM B (Newly diagnosed children and young adults with DMG H3K27 altered) and ARM

C:(Children and young adults with DMG H3K27 altered who have evidence of progression but

have not been treated for this progression and are candidates for re-irradiation):

Patients undergo standard of care radiation therapy daily 5 days a week and receive

ONC206 as in Arm A.

All participants will be permitted to have an optional MRS scans. After completion of

study treatment, patients are followed up at 30 days and then every 3 months for up to 5

years.

Ein-/Ausschlusskriterien

Inclusion Criteria:

- ARM A: Children and young adults with DMG, H3K27 altered (Dose escalation: 2-21

years of age; Dose expansion: 2 years of age and above) who completed at least one

line of prior therapy. Prior treatment must have included focal radiation therapy

and patients must be within 4-14 weeks from completion of radiation therapy to

registration (patients must start treatment within 1 week from registration), have

not started any other therapies post-radiation, and have no evidence of disease

progression.

- ARM A: Tumor tissue confirmation of DMG, H3K27 altered is mandatory and pathology

must be consistent with a DMG, H3K27 altered.

- ARM A: Participants must have recovered from all acute side effects of prior

therapy.

- ARM A: From the projected start of scheduled study treatment, the following time

periods must have elapsed: 5 half-lives from any investigational agent, 4 weeks from

cytotoxic therapy (except 23 days for temozolomide and 6 weeks from nitrosoureas), 4

weeks from antibodies and must be at least 7 days since the completion of therapy

with a biologic or small molecule agent. For any biologic or small molecule agent

with known adverse events that can occur beyond 7 days after administration, the

period prior to enrollment must be beyond the time during which adverse events are

known to occur (these should be discussed with the study team)

- ARM B: Newly diagnosed children and young adults (Dose escalation: 2-21 years of

age; Dose expansion: 2 years of age and above) with a diagnosis of DMG, H3K27

altered are eligible, including spinal cord DMGs.

- ARM B: Tumor tissue confirmation of DMG is mandatory and pathology must be

consistent with a DMG, H3K27 altered.

- ARM C: Children and young adults with DMGs (Dose escalation: 2-21 years of age; Dose

expansion: 2 years of age and above) who have evidence of progression but have not

been treated for this progression and are recommended to get re-irradiation.

- ARM C: Patients must have undergone prior focal radiation therapy as part of their

initial therapy and should be at least 6 months from prior radiation therapy. If

timing is less than 6 months from prior focal radiation, these patients need to be

discussed with the study chair(s).

- ARM C: Tumor tissue confirmation is mandatory and pathology must be consistent with

a DMG, H3K27 altered.

- ARM C: Participants must have recovered from all acute side effects of prior therapy

- ARM C: From the projected start of scheduled study treatment, the following time

periods must have elapsed: 5 half-lives from any investigational agent, 4 weeks from

cytotoxic therapy (except 23 days for temozolomide and 6 weeks from nitrosoureas), 4

weeks from antibodies and must be at least 7 days since the completion of therapy

with a biologic or small molecule agent. For any biologic or small molecule agent

with known adverse events that can occur beyond 7 days after administration, the

period prior to enrollment must be beyond the time during which adverse events are

known to occur (these should be discussed with the study team)

- ARM D: Children and young adults with recurrent primary malignant CNS tumors (Dose

escalation: 2-21 years of age; Dose expansion: 2 years of age and above ) who have

evidence of progression but have not been treated for this progression .

Participants who received a surgical resection for that progression are eligible if

surgery has no curative intent. These patients need to be discussed with the study

team.

- ARM D: Prior tumor tissue confirmation is mandatory and pathology from the primary

tumor must be consistent with malignant CNS tumor (diagnosis of ependymoma is

allowed).Tissue at the time of progression is not required.

- ARM D: Participants must have recovered from all acute side effects of prior therapy

- ARM D: From the projected start of scheduled study treatment, the following time

periods must have elapsed: 5 half-lives from any investigational agent, 4 weeks from

cytotoxic therapy (except 23 days for temozolomide and 6 weeks from nitrosoureas), 4

weeks from antibodies and must be at least 7 days since the completion of therapy

with a biologic or small molecule agent. For any biologic or small molecule agent

with known adverse events that can occur beyond 7 days after administration, the

period prior to enrollment must be beyond the time during which adverse events are

known to occur (these should be discussed with the study team). Bevacizumab used for

pseudoprogression does not require a wash out period.

- TARGET VALIDATION: Newly diagnosed children and adults (2 years of age and above)

with imaging consistent with a DMG, H3K27 altered are eligible.

- TARGET VALIDATION: Children and young adults with recurrent primary malignant CNS

tumors, including recurrent DMG, (2 years of age and above) who have evidence of

progression but have not been treated for this progression.

- TARGET VALIDATION: Participants must undergo tumor tissue collection as part of

their standard of care

- Participants who are receiving steroids must be on a stable or decreasing dose for

at least 3 days prior to baseline MRI scan.

- Peripheral absolute neutrophil count (ANC) >= neutrophil 1.0 g/l.

- Platelet count >= 100 x 10^9/L (transfusion independent, defined as not receiving

platelet transfusions for at least 7 days prior to enrollment).

- Serum creatinine < 1.5 Upper Limit normal (ULN) based on age and gender.

- Total bilirubin <= 1.5 x upper limit of normal (ULN) for age; in presence of

Gilbert's syndrome, total bilirubin < 3 x ULN or direct bilirubin < 1.5 x ULN.

- Alanine aminotransferase (ALT) <= 3 x ULN.

- Aspartate aminotransferase (AST) <= 3 x ULN.

- Patients with seizure disorder may be enrolled if seizure disorder is well

controlled

- The effects of ONC206 on the developing human fetus is 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. 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. Fronzen tissue is also acceptable. Participants who previously enrolled on

PNOC022 and provided adequate tissue, may not need to submit additional tissue -

confirm with Study Chairs. Participants who do not meet this criteria may be

discussed on a case-by-case basis with the Study Chairs.

- 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:

- Arm A & B: For tumors that do not have a pontine or spinal cord epicenter the

following specific exclusion criteria apply: Thalamic DMG and cerebellar, H3K27

altered that has undergone standard radiation without concurrent therapy (other than

temozolomide).

- Arm C & D: 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.

- Participants who are currently receiving another investigational drug are not

eligible.

- Participants who are currently receiving other anti-cancer agents are not eligible.

- Participants with a known disorder that affects their immune system, such as human

immunodeficiency virus (HIV) or hepatitis B or C, or an auto-immune disorder

requiring systemic cytotoxic or immunosuppressive therapy are not eligible. Note:

Participants that are currently using inhaled, intranasal, ocular, topical or other

non-oral or non-intravenous (IV) steroids are not necessarily excluded from the

study but need to be discussed with the study chair.

- Participants with uncontrolled infection.

- 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.

- Active illicit drug use or diagnosis of alcoholism.

- History of allergic reactions attributed to compounds of similar chemical or

biologic composition to ONC206.

- Inability to follow the procedures of the study, e.g. due to language problems,

psychological disorders, dementia, etc. of the participant or family.

- Any participants with illnesses that may affect absorption of ONC206.

- Any participants on strong inhibitors or inducers of CYP3A4, 2D6, 1A2, 2C9 and 2C19

at least 14 days prior and throughout the study.

Studien-Rationale

Primary outcome:

1. Proportion of participants with dose-limiting toxicities (DLT) (Time Frame - 4 weeks after first dose):
A DLT is defined as a treatment-related adverse event (AE) or abnormal laboratory value that occurs in the first cycle of treatment (Cycle 1 for Arm A and D; Cycle 0 for Arm B and C), meets criteria for DLT as outlined below and is assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications, and is judged by the investigator to be related to ONC206 as graded by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0).

2. Maximum tolerated dose (MTD) of ONC206 (Time Frame - 4 weeks after first dose):
The Bayesian optimal interval (BOIN) design will be used to find the MTD within each arm. MTD is selected based on isotonic regression and this computation is implemented by the shiny app "BOIN" available at http://www.trialdesign.org. Specifically, select as the MTD the dose for which the isotonic estimate of the toxicity rate is closest to the target toxicity rate. If there are ties, select the higher dose level when the isotonic estimate is lower than the target toxicity rate and select the lower dose level when the isotonic estimate is greater than or equal to the target toxicity rate.

Secondary outcome:

1. Mean maximum concentration (Cmax) of ONC206 (Time Frame - Day 1 (pre-dose, 0.5, 1, 2, 4, 8 post-dose), Day 3 (pre-dose, 0.5, 1, 2, 4, 8 post-dose), (2 days in total)):
Concentration-time data will be summarized by N, Mean, Standard Deviation, Median, Min, Max and 95% Confidence Interval

2. Mean corresponding time (Tmax) of ONC206 (Time Frame - Day 1 (pre-dose, 0.5, 1, 2, 4, 8 post-dose), Day 3 (pre-dose, 0.5, 1, 2, 4, 8 post-dose), (2 days in total)):
PK parameters will be estimated using standard population PK methodologies and non-linear mixed effect modeling

3. Area under the curve (AUC) of ONC206 (Time Frame - Day 1 (pre-dose, 0.5, 1, 2, 4, 8 post-dose), Day 3 (pre-dose, 0.5, 1, 2, 4, 8 post-dose), (2 days in total)):
PK parameters will be estimated using standard population PK methodologies and non-linear mixed effect modeling

4. Elimination half-life (t1/2) of ONC206 (Time Frame - Day 1 (pre-dose, 0.5, 1, 2, 4, 8 post-dose), Day 3 (pre-dose, 0.5, 1, 2, 4, 8 post-dose), (2 days in total)):
PK parameters will be estimated using standard population PK methodologies and non-linear mixed effect modeling

5. Mean Total body clearance (CL) for ONC206 (Time Frame - Day 1 (pre-dose, 0.5, 1, 2, 4, 8 post-dose), Day 3 (pre-dose, 0.5, 1, 2, 4, 8 post-dose), (2 days in total)):
PK parameters will be estimated using standard population PK methodologies and non-linear mixed effect modeling

6. Mean Volume of Distribution (Vd) for ONC206 (Time Frame - Day 1 (pre-dose, 0.5, 1, 2, 4, 8 post-dose), Day 3 (pre-dose, 0.5, 1, 2, 4, 8 post-dose), (2 days in total)):
PK parameters will be estimated using standard population PK methodologies and non-linear mixed effect modeling

Studien-Arme

  • Experimental: Arm A: ONC206 for participants with diffuse midline gliomas + prior therapy
    Patients receive ONC206 orally (PO) up to six times per week. Cycles repeat every 28 days for up to 12 months in the absence of disease progression or unacceptable toxicity.
  • Experimental: Arm B: ONC206 + radiation therapy for newly diagnosed participants
    Patients undergo standard of care radiation therapy daily 5 days a week and receive ONC206 PO up to six times per week. Cycles repeat every 28 days for up to 12 months in the absence of disease progression or unacceptable toxicity.
  • Experimental: Arm C: ONC206 + radiation therapy, DMGs with evidence of first progression but previously untreated
    Patients undergo standard of care radiation therapy daily 5 days a week and receive ONC206 PO up to six times per week. Cycles repeat every 28 days for up to 12 months in the absence of disease progression or unacceptable toxicity.
  • Experimental: Arm D: ONC206 Therapy, Primary malignant CNS tumors with progression
    Patients receive ONC206 PO once a day (QD) up to six times per week. Cycles repeat every 28 days for up to 12 months in the absence of disease progression or unacceptable toxicity.

Geprüfte Regime

  • ONC206 (antagonist of dopamine receptor D2 (DRD2) /human mitochondrial caseinolytic protease P (ClpP)ClpP Agonist / DRD2 antagonist/ClpP agonist / ):
    Given orally (PO)
  • Standard of Care Radiation Therapy (Radiation Therapy (RT) / Cancer Radiotherapy / ):
    Undergo RT
  • Optional Proton (1H) MR spectroscopy (MRS) (MRS):
    Optional imaging procedure

Quelle: ClinicalTrials.gov


Sie können folgenden Inhalt einem Kollegen empfehlen:

"ONC206 for Treatment of Newly Diagnosed, Recurrent Diffuse Midline Gliomas, and Other Recurrent Malignant CNS Tumors"

Bitte tragen Sie auch die Absenderdaten vollständig ein, damit Sie der Empfänger erkennen kann.

Die mit (*) gekennzeichneten Angaben müssen eingetragen werden!

Die Verwendung Ihrer Daten für den Newsletter können Sie jederzeit mit Wirkung für die Zukunft gegenüber der MedtriX GmbH - Geschäftsbereich rs media widersprechen ohne dass Kosten entstehen. Nutzen Sie hierfür etwaige Abmeldelinks im Newsletter oder schreiben Sie eine E-Mail an: rgb-info[at]medtrix.group.