Symptoms and General Pathology

All Conditions

Neoplasms

Rare Diseases

Recurrence

Glioblastoma

Astrocytoma

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

All Drugs and Chemicals

Antineoplastic Agents

Immunomodulating Agents

Immune Checkpoint Inhibitors

Antineoplastic Agents, Immunological

Subjects in this arm (N=16) receive a single priming dose of both INCMGA00012 (500mg) and INCAGN01876 (300mg) prior to stereotactic radiosurgery (SRS), then undergo SRS (8 Gy x 3 fractions). Following SRS, INCMGA00012 (500mg IV every 4 weeks) and INCAGN01876 (300mg IV every 2 weeks) are resumed and continued until disease progression, unacceptable toxicity, or for 2 years, whichever occurs first.

Subjects in this arm (N=8) receive neoadjuvant immunotherapy INCMGA00012 (500mg) + INCAGN01876 (300mg) + SRS. Subjects then undergo surgery. Postoperatively, the immunotherapy combination of INCMGA00012 (500 mg IV every 4 weeks) and INCAGN01876 (300mg IV every 2 weeks) is resumed and continued until disease progression, unacceptable toxicity, or for 2 years, whichever occurs first.

Subjects in this arm (N=8) receive neoadjuvant immunotherapy INCMGA00012 + INCAGN01876 (without SRS). Subjects then undergo surgery. Postoperatively, the immunotherapy combination of INCMGA00012 (IV every 4 weeks) and INCAGN01876 (IV every 2 weeks) is resumed and continued until disease progression, unacceptable toxicity, or for 2 years, whichever occurs first.

500mg IV neoadjuvant treatment; 500 mg adjuvant treatment

INCMGA00012

300mg IV neoadjuvant treatment; 300 mg adjuvant treatment

INCAGN01876

administered over the course of 3 consecutive business days (8 Gy x 3 fractions, one fraction per day, total dose 24 Gy).

maximal safe surgical resection of the tumor.

Brain surgery

Stephen Bagley, MD, MSCE

This is a phase II study of the combination of the GITR agonist monoclonal antibody INCAGN01876, the anti-PD1 monoclonal antibody INCMGA00012, and stereotactic radiosurgery (SRS) for recurrent Glioblastoma (GBM). The investigators hypothesize that the proposed regimen will be safe and stimulate a robust anti-tumor immune response and result in improved tumor responses.

The study has 2 arms:

Arm A (Cohort A) is a nonsurgical arm (N=16) that will serve as the primary study cohort and evaluated for the primary study endpoint. Subjects in this arm receive a single priming dose of both INCMGA00012 and INCAGN01876 prior to stereotactic radiosurgery (SRS), then undergo SRS (8 Gy x 3 fractions). Following SRS, INCMGA00012 (IV every 4 weeks) and INCAGN01876 (IV every 2 weeks) are resumed and continued until disease progression, unacceptable toxicity, or for 2 years, whichever occurs first.

Arm B (Cohort B) is a surgical arm (N=16) that will allow for evaluation of the effects on the tumor immune microenvironment of INCMGA00012, INCAGN01876, and SRS. In order to be enrolled on this arm, subjects must have a clinical indication for surgical resection of the recurrent GBM tumor. Prior to planned surgical resection, subjects receive neoadjuvant immunotherapy (one of two possible combinations, as outlined below). Subjects then undergo surgery. Postoperatively, the immunotherapy combination of INCMGA00012 (IV every 4 weeks) and INCAGN01876 (IV every 2 weeks) is resumed and continued until disease progression, unacceptable toxicity, or for 2 years, whichever occurs first. Subjects in the surgical arm with a focus of contrast-enhancing tumor that is amenable to SRS will be assigned to surgical sub-arm #1 of Cohort B (N=8). These subjects will receive neoadjuvant INCMGA00012 + INCAGN01876 + SRS. All other subjects enrolled on Cohort B (N=8) are treated with neoadjvuant INCMGA00012 + INCAGN01876 (without SRS).

The overall study population will be broken down into two cohorts: Cohort A (N=16) and Cohort B (N=16). Subjects for whom surgical resection is not clinically indicated at the time of study screening will be enrolled into Cohort A (non-surgical cohort). Subjects for whom surgical resection is clinically indicated at the time of study screening will be enrolled into Cohort B (surgical cohort).

Anti-GITR/Anti-PD1/Stereotactic Radiosurgery, in Recurrent Glioblastoma

A Phase II Study of the Anti-GITR Agonist INCAGN1876 and the PD-1 Inhibitor INCMGA00012 in Combination With Stereotactic Radiosurgery in Recurrent Glioblastoma

Per modified response assessment in neuro-oncology (RANO) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=50% decrease in the sum of the products of the perpendicular diameters of target lesions; Overall Response (OR) = CR + PR.

Adverse events will be evaluated by monitoring frequency, duration, and severity of adverse events (AEs) per NCI CTCAE v 5.0

OS, defined as the time from date of enrollment until death from any cause

PFS, defined as the time from date of enrollment until the earliest date of disease progression (as determined by modified RANO criteria) or death due to any cause

Incyte Corporation

University of Pennsylvania

All subjects who sign informed consent will be included in safety analyses and in calculation of the rate of AEs, regardless of whether and how much study drug was received. Subjects who were determined to be ineligible for treatment or who withdrew consent and did not receive treatment are included in the safety analyses, in the "Ineligible or Withdrew Consent" cohort.

Subjects in this arm (N=18) signed the consent form and received a single priming dose of both INCMGA00012 (500mg) and INCAGN01876 (300mg) prior to stereotactic radiosurgery (SRS), then undergo SRS (8 Gy x 3 fractions). Following SRS, INCMGA00012 (500mg IV every 4 weeks) and INCAGN01876 (300mg IV every 2 weeks) are resumed and continued until disease progression, unacceptable toxicity, or for 2 years, whichever occurs first.

INCMGA00012: 500mg IV neoadjuvant treatment; 500 mg adjuvant treatment

INCAGN01876: 300mg IV neoadjuvant treatment; 300 mg adjuvant treatment

SRS: administered over the course of 3 consecutive business days (8 Gy x 3 fractions, one fraction per day, total dose 24 Gy).

Cohort A

Subjects in this arm (N=8) signed the consent form and received neoadjuvant immunotherapy INCMGA00012 (500mg) + INCAGN01876 (300mg) + SRS. Subjects then undergo surgery. Postoperatively, the immunotherapy combination of INCMGA00012 (500 mg IV every 4 weeks) and INCAGN01876 (300mg IV every 2 weeks) is resumed and continued until disease progression, unacceptable toxicity, or for 2 years, whichever occurs first.

INCMGA00012: 500mg IV neoadjuvant treatment; 500 mg adjuvant treatment

INCAGN01876: 300mg IV neoadjuvant treatment; 300 mg adjuvant treatment

SRS: administered over the course of 3 consecutive business days (8 Gy x 3 fractions, one fraction per day, total dose 24 Gy).

Brain surgery: maximal safe surgical resection of the tumor.

Cohort B Sub-arm #1

Subjects in this arm (N=8) signed the consent form and received neoadjuvant immunotherapy INCMGA00012 + INCAGN01876 (without SRS). Subjects then undergo surgery. Postoperatively, the immunotherapy combination of INCMGA00012 (IV every 4 weeks) and INCAGN01876 (IV every 2 weeks) is resumed and continued until disease progression, unacceptable toxicity, or for 2 years, whichever occurs first.

INCMGA00012: 500mg IV neoadjuvant treatment; 500 mg adjuvant treatment

INCAGN01876: 300mg IV neoadjuvant treatment; 300 mg adjuvant treatment

Brain surgery: maximal safe surgical resection of the tumor.

Cohort B Sub-arm #2

Subjects in this arm (N=5) signed the consent form but were either ineligible for the study or withdrew consent and were never treated.

Ineligible or Withdrew Consent

Subjects in this arm (N=18) receive a single priming dose of both INCMGA00012 (500mg) and INCAGN01876 (300mg) prior to stereotactic radiosurgery (SRS), then undergo SRS (8 Gy x 3 fractions). Following SRS, INCMGA00012 (500mg IV every 4 weeks) and INCAGN01876 (300mg IV every 2 weeks) are resumed and continued until disease progression, unacceptable toxicity, or for 2 years, whichever occurs first. Because of a protocol deviation, two subjects' data is not analyzed for efficacy.

INCMGA00012: 500mg IV neoadjuvant treatment; 500 mg adjuvant treatment

INCAGN01876: 300mg IV neoadjuvant treatment; 300 mg adjuvant treatment

SRS: administered over the course of 3 consecutive business days (8 Gy x 3 fractions, one fraction per day, total dose 24 Gy).

GITR + PD1, SRS (Cohort A)

Subjects in this arm (N=8) receive neoadjuvant immunotherapy INCMGA00012 (500mg) + INCAGN01876 (300mg) + SRS. Subjects then undergo surgery. Postoperatively, the immunotherapy combination of INCMGA00012 (500 mg IV every 4 weeks) and INCAGN01876 (300mg IV every 2 weeks) is resumed and continued until disease progression, unacceptable toxicity, or for 2 years, whichever occurs first.

INCMGA00012: 500mg IV neoadjuvant treatment; 500 mg adjuvant treatment

INCAGN01876: 300mg IV neoadjuvant treatment; 300 mg adjuvant treatment

SRS: administered over the course of 3 consecutive business days (8 Gy x 3 fractions, one fraction per day, total dose 24 Gy).

Brain surgery: maximal safe surgical resection of the tumor.

GITR + PD1, SRS, Surgery (Cohort B Sub-arm #1)

Subjects in this arm (N=8) receive neoadjuvant immunotherapy INCMGA00012 + INCAGN01876 (without SRS). Subjects then undergo surgery. Postoperatively, the immunotherapy combination of INCMGA00012 (IV every 4 weeks) and INCAGN01876 (IV every 2 weeks) is resumed and continued until disease progression, unacceptable toxicity, or for 2 years, whichever occurs first.

INCMGA00012: 500mg IV neoadjuvant treatment; 500 mg adjuvant treatment

INCAGN01876: 300mg IV neoadjuvant treatment; 300 mg adjuvant treatment

Brain surgery: maximal safe surgical resection of the tumor.

GITR + PD1, Surgery (Cohort B Sub-arm #2)

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

United States

Region of Enrollment

Regulatory Lead

Per protocol, it was pre-specified to only include subjects in Cohort A and the subject must have received at least one dose of BOTH study drugs AND has received at least one fraction of SRS. Because of a protocol deviation, the data of 2 subjects is not included for efficacy analysis.

Objective Radiographic Response (ORR)

Incidence of Treatment-Emergent Adverse Events as Assessed by NCI CTCAE v 5.0

Overall Survival

Progression Free Survival

Subjects in this arm (N=5) signed the consent form but were either ineligible for the study or withdrew consent and were never treated

Overall Study

Nervous System Diseases

Wounds and Injuries

Heart and Blood Diseases

Hemorrhage

Brain Neoplasms

Stroke

Ischemic Stroke

Ischemia

Headache

Intracranial Hemorrhages

Craniocerebral Trauma

Cerebrovascular Disorders

Brain Diseases

Central Nervous System Diseases

Vascular Diseases

Pain

Neurologic Manifestations

Trauma, Nervous System

patients suffering from ischemic stroke diagnosed by clinical examination and CT-scan

patients diagnosed with a brain tumor diagnosed by clinical examination and CT-scan or MRI

patients that have undergone brain surgery

patients with intracranial hemorrhage diagnosed by clinical examination and CT-scan

patients with headache complaints and a normal CT-scan of the brain

patients with head trauma and a normal CT-scan of the brain

bilateral measurement cerebral blood flow with near infrared spectroscopy using the Infrascanner on the frontal, temporal, parietal and occipital region of the head.

Infrascanner

Pascal Vanelderen, MD, PhD

The investigators prospectively want to use the Infrascanner in patients with ischemic stroke, patients with brain surgery, patients with brain tumors, patients with intracranial hemorrhage and patients with a normal CT scan of the brain as part of a diagnostic work-up after head trauma or headache to determine to positive and negative predictive value of the Infrascanner in these different settings.

Infrascanner is a portable device initially designed to detect intracranial hemorrhage in battlefield traumas. Infrascanner uses near infrared spectroscopy to measure cerebral blood flow non-invasively. This is achieved by putting the device against the scalp in 4 different areas (frontal, temporal, parietal, occipital) on the left and right side and by comparing both sides.This allows for the detection of intracranial hemorrhages with a volume upwards of 3.5ml and to a depth of 2.5cm. However, little is known about the influence of other intracranial conditions that could confound the measurements of the Infrascanner (e.g. ischemic stroke, brain surgery, brain tumors,...).

Therefore, the investigators prospectively want to use the Infrascanner in patients with ischemic stroke, patients with brain surgery, patients with brain tumors, patients with intracranial hemorrhage and patients with a normal CT scan of the brain as part of a diagnostic work-up after head trauma or headache to determine the positive and negative predictive value of the Infrascanner in these different settings.

Confounding Factors in the Detection of Intracranial Hemorrhage With the Infrascanner

A Prospective Study to Determine Confounding Factors in the Detection of Intracranial Hemorrhage With the Infrascanner

Ziekenhuis Oost-Limburg

Prof. Dr.

Neoplasm Metastasis

Neoplastic Processes

Central Nervous System Neoplasms

Nervous System Neoplasms

Intraoperative Radiotherapy (IORT) administered during surgery

If biopsy is positive, local treatment with IORT will be performed. After IORT (15,40 Gray at 2 mm dept), the applicator will be removed and surgery will be continued in a standard fashion.

Intraoperative Radiotherapy (IORT)

Surgery should be performed according to the local standard of care, preferentially as image-(neuronavigation) guided surgery. To establish the diagnosis of a metastasis and to exclude primary CNS tumors, lymphomas, SCLCs or germinomas it will be performed a peroperative biopsy

Miquel Macià, MD

Anna Lucas, MD

To evaluate the feasibility and efficacy of the Intraoperative Radiation Therapy (IORT) after the resection of a brain metastases to reduce the incidence of local relapse

IORT After Surgical Resection of Brain Metastases

IORT After Surgical Resection of Brain Metastases: Feasibility and Efficacy Phase II Trial

Time span (in months) between surgery and recurrence within a 0,5 cm margin around the resection cavity, evaluated through Response Assessment in Neuro-Oncology (RANO) criteria for brain metastasis obtained from serial Magnetic resonance imaging (MRI) scans.

The time (in months) from surgery to any progression outside of the 0,5 cm margin around the resection cavity, evaluated through Response Assessment in Neuro-Oncology (RANO) criteria for brain metastasis obtained from serial Magnetic resonance imaging (MRI) scans.

Time (in months) from surgery to any intra- and extracranial tumor progression evaluated through Response Assessment in Neuro-Oncology (RANO) criteria for brain metastasis obtained from serial Magnetic resonance imaging (MRI) scans.

Time (in days) from surgery to the day of initiation of any systemic anti-tumor therapy (e.g., chemotherapy)

Time (in months) from surgery of brain metastases to death by any cause

Assessed by minimal mental scale examination

Assessed by number repetition test (forward and backward)

Assessed by controlled oral word association test

Assessed by European Organization for Research and Treatment (EORTC)- Quality of Life Questionnaires (QLQ C30/BN20)

Assessed by regular neurological examinations combined by serial MRI scans

Institut Català d'Oncologia

Disease Attributes

Patients undergo surgery as indicated clinically when applicable.

Brain Surgery

Clinical Trials Referral Office

Terry C. Burns, M.D., Ph.D.

Terry C Burns, M.D., Ph.D.

This clinical trial evaluates the side effects and possible benefits of operating on brain tumors prior to the tumor coming back (recurrence). Understanding when surgery is most useful to patients with brain tumors is important. Some patients may undergo chemotherapy or radiation but still have visible tumor remaining after treatment. The purpose of this research is to compare outcomes of those who have surgery after chemotherapy or radiation, but prior to tumor recurrence, to those who have surgery at a different time, or no surgery at all.

PRIMARY OBJECTIVE:

I. To evaluate the safety and feasibility of surgical resection for pre-recurrent brain tumors.

SECONDARY OBJECTIVES:

I. To determine whether there are differences in overall survival for patients who receive radiation therapy (RT) prior to surgery as compared to patients who receive RT after surgery or patients undergoing no further surgery.

II. To determine for patients having pre-recurrent surgery whether there is a longer interval to local/regional progression, any central nervous system (CNS) progression or need for subsequent intracranial treatment compared to patients receiving post-operative RT, time to each will be separately documented.

III. To determine for patients with pre-operative as compared to post-operative fractionated radiation for brain metastases (mets) whether there is a decreased rate of local recurrence.

IV. To determine for patients with pre-operative as compared to post-operative fractionated radiation for brain mets whether there is a decreased rate of leptomeningeal disease.

CORRELATIVE RESEARCH OBJECTIVES:

I. To determine the genetic and molecular alterations occurring in radiated brain and radiated tumor tissue compared to nonradiated tissue specimens (subjects will be matched to Mayo Clinic Cancer Center Neuro-Oncology Program Registry for the study of Nervous System Tumors 12-003458).

II. To investigate the relative sensitivity of radiated human CNS tumors to senolytic or other therapies in ex vivo assays targeting radiation-induced biology to promote synthetic lethality using cryopreserved or fresh tissue.

III. To investigate the availability and utility of candidate biomarkers reflective of tumor burden and therapeutic susceptibility, from tissue, cerebrospinal fluid (CSF) and peripheral blood.

IV. Patients self-reported outcomes may be obtained through the Neurosurgery Registry program. As available, these data may be referenced as a screening tool for any impact on quality of life (QOL) associated with trial participation as compared to matched controls.

OUTLINE:

Patients undergo surgery as indicated clinically when applicable.

After completion of surgery, patients are followed up at 3 and 6 months, and then every 6 months thereafter.

Surgical Resection of Latent Brain Tumors Prior to Recurrence

Feasibility will be evaluated by meeting enrollment criteria.

Safety will be evaluated by recording adverse events utilizing proper reporting measures.

Median time of survival along with 95% confidence interval will be estimated using the Kaplan-Meier method.

Median time of progress-free survival along with the 95% confidence interval will be estimated using the Kaplan Meier method.

Postoperative complications such as wound infection and neurologic deficits will be logged. Additional metrics including hospital stay and readmission rates will also be logged. Standard descriptive statistics will be used to summarize the outcomes.

Median time to subsequent treatment along with the 95% confidence interval will be estimated using standard descriptive statistics.

Will be logged as a categorical value and continuous data - endpoint is diagnosis of local recurrent disease. The presence and time to local recurrent disease will be logged and standard descriptive statistics will be used to summarize the outcomes.

Will be logged as both a categorical value and continuous data - endpoint is diagnosis of leptomeningeal disease. The presence and time to occurrence of leptomeningeal disease will be logged and standard descriptive statistics will be used to summarize the outcomes.

Mayo Clinic

Principal Investigator

Surgical Resection followed by SRS within 3 weeks of surgery date.

SRS followed by surgery within 1 week of radiotherapy end date.

SRS uses many focused radiation beams to treat tumors within the brain

Stereotactic Radiosurgery

Muhammad Faruqi, MD

Huhammad Faruqi, MD

The purpose of this study is to determine if performing radiotherapy (SRS) prior to surgery results in better treatment outcomes than performing surgery before radiotherapy for patients with brain metastases.

Brain metastases occur when cancer cells from a primary cancer (e.g. lung, breast, colon) travel through the bloodstream and spread (metastasize) to the brain. As these new tumors grow they apply pressure and change how healthy brain tissue works. This can lead to a loss of brain function and worsening quality of life. Treatments for patients whose cancer has spread to the brain is often surgery, radiation therapy (radiotherapy) or a combination of both.

Surgery is one the main treatments for brain tumors. To remove the tumor, a neurosurgeon makes an opening in the skull and attempts to the remove the entire tumor. If the tumor is too close to important brain tissue, the surgeon may attempt to remove part of the tumor. Removal of the tumor from the brain tissue is called resection. The complete or partial removal of tumor helps to relieve symptoms by reducing pressure on healthy tissues and reduces the amount of tumor that needs to be treated by radiotherapy.

One type of radiotherapy used to treat brain metastases is stereotactic radiosurgery (SRS). SRS uses many focused radiation beams to treat tumors within the brain. Unlike surgery, there is no incision or cut being made. Instead, SRS uses an accurate map of your brain to deliver a precise beam of radiation to the tumors. The radiation damages the tumor cells forcing them to shrink and die off. The focused radiation beams also limit damage to healthy brain tissue minimizing side effects.

Surgery followed by radiotherapy is a standard treatment for brain metastases. However, there are still risks associated with the combination of treatments. This study plans to investigate whether performing surgery prior to SRS results in improved quality of life and decreased side effects.

Pre- Versus Post-operative SRS for Resectable Brain Metastases

A Randomized Controlled Trial of Pre-operative Versus Post-operative Stereotactic Radiosurgery for Patients With Surgically Resectable Brain Metastases

To compare local control (in months) of pre-operative versus post-operative SRS

To compare Distant Brain Recurrence Rate (%) of pre-operative versus post-operative SRS

To compare the Leptomeningeal Recurrence Rate (%) of pre-operative versus post-operative SRS

Overall survival will be compared between both treatment arms

Participants are scored using a points based system on Total Recall, Delayed Recall, Retention (% retained), and a Recognition Discrimination Index.

Participants are scored on their ability to generate words starting with a specific letter in a one minute timeframe.

Participants are scored on their ability to complete the test within a certain timeframe.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Anti-GITR/Anti-PD1/Stereotactic Radiosurgery, in Recurrent Glioblastoma	NCT04225039	Glioblastoma	INCMGA00012 INCAGN01876 SRS Brain surgery	18 Years -	University of Pennsylvania
Confounding Factors in the Detection of Intracranial Hemorrhage With the Infrascanner	NCT02809651	Ischemic Stroke Brain Tumor Brain Surgery Intracranial He... Headache Head Trauma	Infrascanner	-	Ziekenhuis Oost-Limburg
IORT After Surgical Resection of Brain Metastases	NCT05084092	Brain Neoplasms	Intraoperative ... Brain surgery	18 Years -	Institut Català d'Oncologia
Surgical Resection of Latent Brain Tumors Prior to Recurrence	NCT04810871	Brain Neoplasm	Brain Surgery	18 Years -	Mayo Clinic
Pre- Versus Post-operative SRS for Resectable Brain Metastases	NCT04474925	Brain Metastase...	Brain Surgery Stereotactic Ra...	18 Years - 100 Years	AHS Cancer Control Alberta
Anti-GITR/Anti-PD1/Stereotactic Radiosurgery, in Recurrent Glioblastoma	NCT04225039	Glioblastoma	INCMGA00012 INCAGN01876 SRS Brain surgery	18 Years -	University of Pennsylvania
Pre- Versus Post-operative SRS for Resectable Brain Metastases	NCT04474925	Brain Metastase...	Brain Surgery Stereotactic Ra...	18 Years - 100 Years	AHS Cancer Control Alberta
Anti-GITR/Anti-PD1/Stereotactic Radiosurgery, in Recurrent Glioblastoma	NCT04225039	Glioblastoma	INCMGA00012 INCAGN01876 SRS Brain surgery	18 Years -	University of Pennsylvania
IORT After Surgical Resection of Brain Metastases	NCT05084092	Brain Neoplasms	Intraoperative ... Brain surgery	18 Years -	Institut Català d'Oncologia

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