Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Carcinoma

Carcinoma, Bronchogenic

Bronchial Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Antineoplastic Agents

All Drugs and Chemicals

Immune Checkpoint Inhibitors

Definitive external beam radiation therapy will be delivered to all sites of progressive disease for all patients. The technique used to deliver radiation therapy will be determined by the treating radiation oncologist.

Second line systemic therapy is at the discretion of the treating medical oncologist.

All local consolidative radiation therapy should be delivered using hypofractionated local consolidative radiation therapy (\>2 Gy per fraction). Exceptions may be approved on a case by case basis by the trial principal investigator. Three-dimensional conformal radiotherapy (3D-CRT), intensity modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT), stereotactic body radiotherapy (SBRT), stereotactic radiosurgery (SRS), and proton beam therapy (PBT) are all acceptable.

Local consolidative radiation therapy

Standard of care palliative radiotherapy to symptomatic lesions is permissible. The dose to symptomatic lesions should not exceed 30 Gy in 10 fractions. Brain metastases will be treated with standard of care CNS therapy throughout the study. This may include (but is not limited to) stereotactic radiosurgery, neurosurgical intervention, whole brain radiotherapy

Standard of care radiation therapy

Michael Farris, MD

This is a randomized phase II study designed to evaluate the effect of local consolidative radiation therapy (LCT) to all sites of oligoprogressive disease in patients with metastatic non-small cell lung carcinoma who have progressed through first line systemic therapy containing an immune checkpoint inhibitor (ICI).

Primary Objective: To compare overall survival (OS) from the time of the time of randomization between the treatment and control groups.

Secondary Objective(s)

* To compare the extra-CNS PFS2 (EC-PFS2), defined as the time to extracranial disease progression on second line systemic therapy or death from the first day of local consolidative radiation therapy (treatment group) or from the start of second line therapy (control group).
* To evaluate time to initiation of second line systemic therapy or palliative care after completion of local consolidative therapy in the treatment group
* To compare the toxicities in the treatment and control groups;
* To compare overall progression free survival from the time of the first day of local consolidative radiation therapy for the treatment group and from the start of second line therapy for the control group
* To compare the pattern of next progression on second line therapy in the treatment group vs the control group.
* To evaluate local progression in lesions treated with local consolidative radiation therapy.

Local Consolidative Radiotherapy for Oligoprogressive in Non-small Cell Lung Carcinoma

A Randomized Phase II Study of Local Consolidative Radiotherapy Versus Standard of Care Second Line Systemic Therapy in Patients With Oligoprogressive NSCLC on Immune Checkpoint Inhibitors

In each arm overall survival will be defined as the time from randomization to death from any cause. . Patients who are alive at the last follow up at the end of the study will be censored at the date of the last follow up appointment. A comparison of overall survival between the two groups will be made first using bivariate Kaplan-Meier method and then a multivariable Cox proportional hazards model. Participants who do not die during the course of observation will be right censored. Key covariates to be included in multivariable modeling include age, ECOG status, number of progressive treated sites (1 vs 2-4), and PD-L1 status (\>=50%; 1%-49%; \< 1%).

Investigators will compare progression after second line of therapy between both arms first using the bivariate Kaplan-Meier method and then a multivariable Cox proportional hazards model age, ECOG status, number of progressive treated sites (1 vs 2-4), and PD-L1 status (\>=50%; 1%-49%; \< 1%). RECIST version 1.1 criteria will be used to assess for progression.

The time to the second line systemic therapy or palliative care will be defined as the time from the completion of local consolidation therapy to the first day of cycle 1 of a systemic therapy the patient has not yet received OR the date of hospice enrollment, whichever is sooner. Patients experiencing neither of these events will be censored at last follow up visit. Estimated median time to second line therapy (or palliative care) and corresponding 95% confidence interval as well as estimated proportion (and corresponding 95% confidence interval) of the treatment group who have started second-line therapy (or palliative care) by key time points including 6 months, 1 year, and 2 years after the end of local consolidative therapy.

Toxicities will be evaluated per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Toxicities between the two arms by comparing the proportions with grade 2 or higher, and grade 3 or higher, toxicities of any type at 3, 6, 12, 24 and 36 months following randomization using a chi-square test on the relevant 2x2 contingency table.

Progression free survival will be assessed by a modified RECIST version 1.1 criteria. If any individual target lesion meets RECIST v1.1 criteria - specifically an increase in the longest diameter (shortest diameter for lymph node lesions) of at least 20% and 5 mm absolute increase, the patient will be considered to have progression of disease. The criteria for determining pseudoprogression versus true progression and for mild progression while systemic therapy is held for the delivery of local consolidative radiation therapy in the treatment arm will be used for this outcome measure as well. Repeat oligoprogression will also be counted as progressive disease.

The pattern of next progression following local consolidation therapy (in treatment group) or second line systemic therapy (in control group) into one of three possible mutually exclusive and exhaustive categories: No progression, repeat oligoprogression or polyprogression, and will compare these patterns between the two groups using a chi-square analysis on the resulting 2x3 contingency table.

Investigators will estimate proportion of lesions treated with local consolidative radiation therapy that experienced local progression (yes/no by study end) and construct a 95% confidence interval around this estimate.

National Cancer Institute (NCI)

Wake Forest University Health Sciences

Symptoms and General Pathology

Nervous System Diseases

Rare Diseases

Recurrence

Glioblastoma

Glioma

Central Nervous System Neoplasms

Nervous System Neoplasms

Ependymoma

Disease Attributes

Astrocytoma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

Cardiotonic Agents

Dopamine

Sympathomimetics

Dopamine Agents

Neurotransmitter Agents

Protective Agents

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.

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.

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.

ONC206

Standard of Care Radiation Therapy

Optional Proton (1H) MR spectroscopy (MRS)

PNOC Operations

Sabine Mueller, MD, PhD

Carl Koschmann, MD

Andrea Franson, MD

Nicolas Gerber, MD

Stephanie Matthes, PhD

This phase I trial studies the effects and best dose of ONC206 alone or in combination with radiation therapy in treating patients with diffuse midline gliomas that is newly diagnosed or has come back (recurrent) or other recurrent primary malignant CNS tumors. ONC206 is a recently discovered compound that may stop cancer cells from growing. This drug has been shown in laboratory experiments to kill brain tumor cells by causing a so called "stress response" in tumor cells. This stress response causes cancer cells to die, but without affecting normal cells. ONC206 alone or in combination with radiation therapy may be effective in treating newly diagnosed or recurrent diffuse midline gliomas and other recurrent primary malignant CNS tumors.

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.

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

PNOC023: Open Label Phase 1 and Target Validation Study of ONC206 in Children and Young Adults With Newly Diagnosed or Recurrent Diffuse Midline Glioma (DMG), and Other Recurrent Primary Malignant Central Nervous System (CNS) Tumors

Individual participant data after de-identification.

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).

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.

Concentration-time data will be summarized by N, Mean, Standard Deviation, Median, Min, Max and 95% Confidence Interval

PK parameters will be estimated using standard population PK methodologies and non-linear mixed effect modeling

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Local Consolidative Radiotherapy for Oligoprogressive in Non-small Cell Lung Carcinoma	NCT04485026	Non Small Cell ... Oligoprogressiv...	Local consolida... Standard of car...	18 Years -	Wake Forest University Health Sciences
ONC206 for Treatment of Newly Diagnosed, Recurrent Diffuse Midline Gliomas, and Other Recurrent Malignant CNS Tumors	NCT04732065	Diffuse Midline... Glioblastoma Recurrent Epend... Recurrent Malig... Spinal Cord Gli... World Health Or... CNS Tumor Central Nervous...	ONC206 Standard of Car... Optional Proton...	2 Years - 21 Years	University of California, San Francisco

Spots Global Cancer Trial Database for standard of care radiation therapy