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Patients undergo short course RT for 5-10 fractions over 1-2 weeks on study. Patients also receive temozolomide PO on days 1-5 every 28 days during radiation therapy. Starting one month post-radiation, patients continue temozolomide on days 1-5 every 28 days for up to 5 adjuvant cycles in the absence of disease progression or unacceptable toxicity. Patients undergo PET/CT with 18-F-DOPA administered IV prior to RT on study, and undergo MRI throughout the trial. Patients may optionally undergo blood sample collection during screening and on the trial.

Patients undergo standard course RT for 15-30 fractions over 3-6 weeks on study. Patients also receive temozolomide PO QD concurrently with radiation therapy and for up to 6 adjuvant cycles in the absence of disease progression or unacceptable toxicity. Patients undergo PET/CT with 18-F-DOPA administered IV prior to RT on study, and undergo MRI throughout the trial. Patients may optionally undergo blood sample collection during screening and on the trial.

Accelerated Hypofractionated Radiation Therapy

Computed Tomography

Fluorodopa F 18

Magnetic Resonance Imaging

Positron Emission Tomography

Quality-of-Life Assessment

Questionnaire Administration

Radiation Therapy

Biospecimen Collection

Clinical Trials Referral Office

Sujay A. Vora, M.D.

Daniel M. Trifiletti, M.D.

William G. Breen, M.D.

This phase II trial compares the effect of short course radiotherapy (RT) to standard course RT for the treatment of patients diagnosed with glioblastoma (GBM). The researchers want to learn whether the shorter course treatment is non-inferior (not worse than the standard of care), for patients with GBM. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. Short course radiotherapy delivers higher doses of radiation over a shorter period of time and may kill more tumor cells and have fewer side effects.

PRIMARY OBJECTIVE:

I. To demonstrate non-inferior 12-month overall survival (OS) of patients with GBM treated with dose escalated hypofractionated radiotherapy compared to standard of care.

SECONDARY OBJECTIVES:

I. To demonstrate the safety of short-course radiotherapy via physician-reported grade (G) 3+ toxicity.

II. To explore patient-reported outcomes to demonstrate favorable quality of life with short-course radiotherapy for GBM.

III. To analyze the impact of shortening the treatment duration on treatment related lymphopenia and absolutely lymphocyte counts.

EXPLORATORY OBJECTIVES:

I. To determine the cost-effectiveness of the 5-fraction treatment regimen compared to standard of care.

II. To explore the impact on the immune system with the 5-fraction treatment regimen. Immune phenotyping will be assessed by Flow Cytometry and cytometry by flight (CyTOF).

III. To analyze series of cytokine levels over time. IV. To assess patterns of failure, specifically focusing on differences in volume delineation via Fluorodopa F 18 (FDOPA) and magnetic resonance imaging (MRI) and recurrences in-field versus (vs.) out of field.

V. To conduct a subgroup analysis for just patients =\< 65 cc. VI. To conduct a subgroup analysis for just patients with and without tumor treating fields.

VII. To analyze patient demographic data compared to historical controls to determine whether the short-course treatment regimen improves access to underserved populations.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients undergo short course RT for 5-10 fractions over 1-2 weeks on study. Patients also receive temozolomide orally (PO) on days 1-5 every 28 days during radiation therapy. Starting one month post-radiation, patients continue temozolomide on days 1-5 every 28 days for up to 5 adjuvant cycles in the absence of disease progression or unacceptable toxicity.

ARM B: Patients undergo standard course RT for 15-30 fractions over 3-6 weeks on study. Patients also receive temozolomide PO daily (QD) concurrently with radiation therapy and for up to 6 adjuvant cycles in the absence of disease progression or unacceptable toxicity.

All patients undergo positron emission tomography/computed tomography (PET/CT) with 18-F-DOPA administered intravenously (IV) prior to RT on study, and undergo MRI throughout the trial. Patients may optionally undergo blood sample collection during screening and on the trial.

After completion of study treatment, patients are followed up every 2 months for the first year, every 3 months for the second year, and every 4 months for the third year. After 3 years, clinical outcomes are monitored at least once a year until 5 years after treatment.

The MRI scan indicating progressive disease will be fused with our treatment planning scan and the region of progression will be contoured by an investigator blinded to the GTV_MRI, T2_FLAIR_NCET, GTV_PET, PTV_high, and isodose lines.

Short Course Radiotherapy for the Treatment of Patients With Glioblastoma, SAGA Study

Stereotactic Accelerated Radiotherapy in GlioblastomA (SAGA)

Comparisons between arms will be made by using a one-sided non-inferiority test of the difference in proportions with a non-inferiority limit of 10% and alpha level of .10. All patients meeting eligibility criteria who have signed a consent form, were randomized, and started treatment will be considered evaluable.

Comparisons between arms will be made by using either the Chi-square or Fisher's Exact test for each time point. All patients meeting the eligibility criteria who signed a consent form and started treatment will be in the analysis.

Changes over time from baseline will be compared between arms using the 2-sample t-test (or Wilcoxon Rank-Sum test for non-normal data). All patients meeting the eligibility criteria who have signed a consent form, started treatment, and have non-missing data on these questionnaires will be evaluable for these analyses. Changes will be measured from baseline over time of study.

Changes over time from baseline will be compared between arms using the EORTC QLQ-C30 questionnaire. All patients meeting the eligibility criteria who have signed a consent form, started treatment, and have non-missing data on these questionnaires will be evaluable for these analyses. Score is caluclated from the mean of 13 of the 15 QLQ-C30 scales.

Changes over time from baseline will be compared between arms using the EORTC-BN20 questionnaire. All patients meeting the eligibility criteria who have signed a consent form, started treatment, and have non-missing data on these questionnaires will be evaluable for these analyses on a scale of 1-4, 1 being the lesser degree and 4 being the highest degree.

Lymphocyte count at nadir will be compared between arms using the 2-sample t-test (or Wilcoxon Rank-Sum test for non-normal data). Additionally, the absolute change in lymphocyte count from pretreatment to end of RT will be compared between arms using an analysis of covariance (ANCOVA).

Mayo Clinic

Respiratory Tract (Lung and Bronchial) Diseases

Symptoms and General Pathology

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Carcinoma

Recurrence

Respiratory Tract Neoplasms

Thoracic Neoplasms

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Bronchial Neoplasms

Coagulants

Antibodies

Antibodies, Monoclonal

Durvalumab

Immunoglobulins

Immunoglobulin G

Immunoglobulins, Intravenous

Lectins

Antineoplastic Agents, Immunological

Immunologic Factors

Starting 2 weeks prior to radiation therapy, patients receive durvalumab IV over 60 minutes on day 1 of each cycle. Treatment repeats every 4 weeks for 13 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo ACRT 1 fraction per day, 5 days per week for 15 fractions. Patients also undergo brain MRI or CT scan during screening and as clinically indicated, chest CT scans on study and during follow up, and collection of blood samples during screening and on study.

Starting 2 weeks prior to radiation therapy, patients receive durvalumab IV over 60 minutes on day 1 of each cycle. Treatment repeats every 4 weeks for 13 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo conventionally fractionated radiation therapy 1 fraction per day, 5 days per week for 30 fractions. Patients also undergo brain MRI or CT scan during screening and as clinically indicated, chest CT scans on study and during follow up, and collection of blood samples during screening and on study.

Starting 2 weeks prior to radiation therapy, patients receive durvalumab IV over 60 minutes and monalizumab IV over 60 minutes on day 1 of each cycle. Treatment repeats every 4 weeks for 13 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo conventionally fractionated radiation therapy 1 fraction per day, 5 days per week for 30 fractions. Patients also undergo brain MRI or CT scan during screening and as clinically indicated, chest CT scans on study and during follow up, and collection of blood samples during screening and on study.

Starting 2 weeks prior to radiation therapy, patients receive durvalumab IV over 60 minutes on day 1 of each cycle. Patients also receive oleclumab IV over 60 minutes on days 1 and 15 of cycles 1-2, then on day 1 of cycles thereafter. Treatment repeats every 4 weeks for 13 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo conventionally fractionated radiation therapy 1 fraction per day, 5 days per week for 30 fractions. Patients also undergo brain MRI or CT scan during screening and as clinically indicated, chest CT scans on study and during follow up, and collection of blood samples during screening and on study.

160 Gy given as one 4 Gy fraction per day, 5 days per week for 15 fractions.

Administered intravenously (IV) as a 1500 mg fixed dose over 60 minutes for 13 cycles (1 cycle = 4 weeks), until disease progression or toxicity or death, whichever comes first.

Magnetic Resonance Imaging of the Brain with and without Contrast

Administered IV as a 1500 mg fixed dose over 60 minutes (+/- 10 minutes)

Monalizumab

Administered IV 3000 mg over 60 minutes (+/- 10 minutes)

Oleclumab

60 gy given as one 2 Gy fraction per day, 5 days per week for 30 fractions

Site Public Contact

William Stokes

Girindra Raval

John M. Schallenkamp

Fen Wang

Matthew J. Ferris

Brian K. Yeh

Frank A. Vicini

Pamela Samson

Timothy Dorius

Karl E. Haglund

Raid Aljumaily

Sarah W. Gordon

Steven H. Lin

Steven H Lin

This phase I trial studies the safety of adding durvalumab to accelerated hypofractionated radiation therapy (ACRT) or conventionally fractionated radiation therapy, as well as the safety of adding either monalizumab or oleclumab to durvalumab plus conventionally fractionated radiation therapy in treating patients with non-small cell lung cancer that has spread to nearby tissue or lymph nodes (locally advanced). Accelerated hypofractionated radiation therapy delivers higher doses of radiation therapy over a shorter period of time and may kill more tumor cells and have fewer side effects. Immunotherapy with monoclonal antibodies, such as durvalumab and monalizumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Oleclumab is in a class of medications called monoclonal antibodies. It binds to a protein called CD73, which is found on some types of tumor cells. Oleclumab may block CD73 and help the immune system kill tumor cells. It is not yet known whether adding durvalumab to ACRT or adding monalizumab or oleclumab to durvalumab plus conventionally fractionated radiation therapy will work better in treating patients with non-small cell lung cancer.

PRIMARY OBJECTIVES:

I. To evaluate if the addition of durvalumab to two schedules of radiation therapies (60 Gy in 30 fractions or 60 Gy in 15 fractions) is safe.

II. To evaluate if the addition of either monalizumab or oleclumab to radiation therapy (RT) (60 Gy in 30 fractions) + durvalumab is safe.

SECONDARY OBJECTIVES:

I. To examine if the addition of durvalumab to radiation therapy as well as the addition of either monalizumab or oleclumab is feasible.

II. To assess toxicities associated with the addition of durvalumab to radiation therapy as well as the addition of either monalizumab or oleclumab.

III. To obtain preliminary estimates of progression-free survival (PFS), using Response Evaluation Criteria in Solid Tumors (RECIST) guidelines, in patients who received durvalumab added to radiation, and either monalizumab or oleclumab added to RT (60 Gy in 30 fractions) + durvalumab.

EXPLORATORY OBJECTIVES:

I. To assess the impact the addition of durvalumab to RT and either monalizumab or oleclumab to RT (60 Gy in 30 fractions) + durvalumab have on progression-free survival, using Immune-Related Response Criteria (irRC) guidelines.

II. To assess the changes in circulating tumor cells (CTCs) and various immune parameters during treatment with durvalumab and radiotherapy and changes after completion of treatment.

OUTLINE: Patients are randomized to Arm I or Arm II (CLOSED TO ACCRUAL).

ARM I (CLOSED): Starting 2 weeks prior to radiation therapy, patients receive durvalumab intravenously (IV) over 60 minutes on day 1 of each cycle. Treatment repeats every 4 weeks for 13 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo accelerated hypofractionated radiation therapy (ACRT) 1 fraction per day, 5 days per week for 15 fractions. Patients also undergo brain magnetic resonance imaging (MRI) or computed tomography (CT) scan during screening and as clinically indicated, chest CT scans on study and during follow up, and collection of blood samples during screening and on study.

ARM II (CLOSED): Starting 2 weeks prior to radiation therapy, patients receive durvalumab IV over 60 minutes on day 1 of each cycle. Treatment repeats every 4 weeks for 13 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo conventionally fractionated radiation therapy 1 fraction per day, 5 days per week for 30 fractions. Patients also undergo brain MRI or CT scan during screening and as clinically indicated, chest CT scans on study and during follow up, and collection of blood samples during screening and on study.

Patients are assigned to Arm III or Arm IV.

ARM III: Starting 2 weeks prior to radiation therapy, patients receive durvalumab IV over 60 minutes and monalizumab IV over 60 minutes on day 1 of each cycle. Treatment repeats every 4 weeks for 13 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo conventionally fractionated radiation therapy 1 fraction per day, 5 days per week for 30 fractions. Patients also undergo brain MRI or CT scan during screening and as clinically indicated, chest CT scans on study and during follow up, and collection of blood samples during screening and on study.

ARM IV: Starting 2 weeks prior to radiation therapy, patients receive durvalumab IV over 60 minutes on day 1 of each cycle. Patients also receive oleclumab IV over 60 minutes on days 1 and 15 of cycles 1-2, then on day 1 of cycles thereafter. Treatment repeats every 4 weeks for 13 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo conventionally fractionated radiation therapy 1 fraction per day, 5 days per week for 30 fractions. Patients also undergo brain MRI or CT scan during screening and as clinically indicated, chest CT scans on study and during follow up, and collection of blood samples during screening and on study.

After completion of study treatment, patients are followed up every 3 months for 1 year and then every 4 months for 1 year.

Testing the Safety of Adding Either Monalizumab (IPH2201) or Oleclumab (MEDI9447) to Durvalumab (MEDI4736) Plus Standard Radiation Therapy for Locally Advanced Non-small Cell Lung Cancer (NSCLC), The ARCHON-1 Trial

Phase I Trial of Radiotherapy Combined With Durvalumab Alone Plus Either Monalizumab or Oleclumab in PD-L1 High Locally Advanced Non-Small Cell Lung Cancer (NSCLC) (ARCHON-1)

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page

Safety event is defined as one of the following:

* Grade 4-5 non-hematologic protocol-defined serious adverse event (SAE) possibly, probably, or definitely related to protocol treatment occurring within 90 days from radiation therapy (RT) start for Arm 1 or within 8 weeks from RT start for Arm 2;
* Any adverse event possibly, probably, or definitely related to protocol treatment that leads to missing at least 2 doses of durvalumab within 90 days from RT start for Arm 1 or within 8 weeks from RT start for Arm 2;
* Permanent discontinuation of durvalumab due to an adverse event possibly, probably, or definitely related to protocol treatment within the first 30 days of starting durvalumab; or
* SAEs possibly, probably, or definitely related to RT that cause either an interruption or early termination of RT.

Adverse events are graded according to the Common Terminology Criteria for Adverse Events version 5.0, which assigns a grade according to severity from 1=mild to 5=death.

Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 grades adverse event severity from 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data.

Progression is defined by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as an increase \>= 20% of the sum of longest diameters of target lesions compared with nadir (minimum 5 mm) or progression of non-target lesions or new lesion. Progression-free survival time is defined as time from registration to the date of first progression, death, or last known follow-up (censored). Progression-free survival rates are estimated using the Kaplan-Meier method.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Short Course Radiotherapy for the Treatment of Patients With Glioblastoma, SAGA Study	NCT05781321	Glioblastoma	Accelerated Hyp... Computed Tomogr... Fluorodopa F 18 Magnetic Resona... Positron Emissi... Quality-of-Life... Questionnaire A... Radiation Thera... Temozolomide Biospecimen Col...	18 Years -	Mayo Clinic
Testing the Safety of Adding Either Monalizumab (IPH2201) or Oleclumab (MEDI9447) to Durvalumab (MEDI4736) Plus Standard Radiation Therapy for Locally Advanced Non-small Cell Lung Cancer (NSCLC), The ARCHON-1 Trial	NCT03801902	Locally Advance... Locally Recurre... Stage II Lung C... Stage III Lung ... Unresectable Lu...	Accelerated Hyp... Biospecimen Col... Computed Tomogr... Durvalumab Magnetic Resona... Monalizumab Oleclumab Radiation Thera...	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for accelerated hypofractionated radiation therapy