Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Symptoms and General Pathology

Nervous System Diseases

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Neoplasm Metastasis

Brain Neoplasms

Neoplastic Processes

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Radiation Therapy: Radiosurgical (SRS) technique via Gamma Knife Perfexion radiosurgical system

whole-brain radiation therapy 30 Gy in 10 fractions. Treatment will be delivered once daily, 5 fractions per week, over 2 to 2.5 weeks

Stereotactic radiosurgery (SRS)

External beam whole-brain radiation therapy 30 Gy in 10 fractions. Treatment will be delivered once daily, 5 fractions per week, over 2 to 2.5 weeks

Whole brain radiation therapy (WBRT)

Igor J Barani, MD

This is randomized study of neurocognitive outcomes in patients with five or more brain metastases treated with stereotactic radiosurgery (SRS), specifically the Gamma Knife (GK) system, or whole-brain radiation therapy (WBRT). The primary aim of this study is to compare the change in neurocognitive function outcome between baseline and 6 months in WBRT versus SRS treatment groups.

This is randomized controlled study of neurocognitive outcomes in patients with five or more brain metastases treated with stereotactic radiosurgery (SRS), specifically the Gamma Knife (GK) system, or whole-brain radiation therapy (WBRT). The goal of the study is to enroll 120 patients with at least five (≥5) newly-diagnosed brain metastases from non-melanoma, except melanoma patients with BRAF V600E B-Raf protein mutation, primary cancers with the largest intracranial tumor volume ≤10 cc, ≤15 cc total tumor volume, absence of leptomeningeal disease on MRI, and Karnofsky performance status (KPS) score ≥70 (unless due to intracranial disease), and KPS expected to improve to ≥70 with treatment.

All study participants will undergo standard, pre-treatment clinical evaluations that include: complete clinical/neurologic exam, performance status assessment, systemic staging, and diagnostic MRI of the brain. The baseline neurocognitive function (NCF) will be assessed by a short (20-30 minute) online test battery that can be completed by patients at home. All study participants will be randomized to receive radiosurgical or whole-brain radiation treatment for their brain metastases. All patients will have treatment response assessments every 10-12 weeks consisting of a clinical/neurologic exam, performance status evaluation, disease re-staging (if indicated), and diagnostic MRI of the brain. If progressive disease is identified (radiographic progression of treated lesions or new brain lesions), the patients will be considered for "salvage" therapy which will primarily consist of SRS, WBRT, surgery±brachytherapy or best supportive care (e.g. steroids only). The preferred salvage therapy will be SRS provided that the re-treatment criteria are met. The NCF follow-up will start 2 weeks after completion of the initial SRS treatment and will repeat at 2-week intervals, irrespective of any salvage therapy that may be indicated. All study participants will be followed until death or withdrawal from the study.

The primary aim of this study is to compare the change in neurocognitive outcome between baseline and 6 months for surviving patients in upfront WBRT versus SRS treatment groups. The primary study endpoint is neurocognitive function as measured by a significant change in online neurocognitive function (oNCF) z-score from baseline to 6 months. The outcomes will be compared after initial treatment and then repeatedly in follow-up, and will include the impact of salvage SRS treatments. This approach will allow us to assess the relative impact on neurocognitive outcomes of repeat SRS treatments to sites of new brain metastases.

Since SRS and WBRT are two very different forms of treatment (single high-dose treatment vs. multiple low-dose treatments) with markedly different target volumes, it is expected that local control rates will also be markedly different. This, in turn, will impact salvage therapies and associated costs. This study will evaluate local control rates and overall intracranial disease control at 3, 6, 9, and 12 months as a function of initial treatment cohort (SRS vs. WBRT). We also expect significant differences between the treatment groups in patient and caregiver reported quality of life (QoL) measures.

It is also expected that the SRS cohort will require multiple SRS treatments over the course of the study since, unlike WBRT, the treatments target only gross brain metastases and do not address microscopic (clinically undetectable) disease. Conversely, WBRT is expected to result in inferior control rates of gross metastatic disease, increasing the likelihood of subsequent SRS or other salvage therapy. For these reasons, we will track the actual costs of treatments over the course of the study, including the need for supportive care and the ability of patients to continue to work in their previous occupation.

The structure of the current study provides a unique opportunity to explore various dosimetric SRS parameters in the setting of multiple brain metastases. Dose-volume criteria for SRS have been established in a prospective RTOG 90-05 dose-finding study and subsequently validated in RTOG 95-08, a randomized controlled trial of WBRT±SRS in patients with 1-3 brain metastases. Several single-institution series as well as multi-institutional retrospective analyses support the use of single-dose SRS for treatment of brain metastases; however, the dose-volume criteria and prescription guidelines are not known in the setting of ≥5 brain metastases where dose interaction among different lesion targets are much more likely. These interactions can potentially lead to increased rates of radiation necrosis, and if the SRS doses are arbitrarily reduced because of such concerns, then to a potentially decreased local control rates. These parameters will be closely tracked in this study with the aim of establishing an evidence-based dosimetric guidelines for radiosurgical treatment of multiple (≥5) brain metastases.

The data gained from this study could help define patient selection and treatment criteria for SRS of multiple brain metastases as a potential alternative to WBRT in a select group of patients. This will also be a first study of its kind to use online neurocognitive assessments for its primary endpoints to demonstrate feasibility and cost-effectiveness of such an approach in a multi-institutional setting.

Neurocognitive Outcomes In Patients Treated With Radiotherapy For Five Or More Brain Metastases

A Randomized Controlled Study Of Neurocognitive Outcomes In Patients With Five Or More Brain Metastases Treated With Radiosurgery Or Whole-Brain Radiotherapy

To determine what healthcare cost data can be collected in patients with metastatic disease within a context of a multi-institutional clinical trial.

All participants will be asked to complete:

1. Online brain function testing: Complete a short 20-minute online brain function (cognitive) assessment every 2 weeks (twice per month, at least 10-14 days apart).
2. Quality of Life Questionnaire: Complete a self-reported (if patient) and caregiver quality of life questionnaires every 10-12 weeks (2.5-3 months). These questionnaires take approximately 15-20 minutes to complete and can be done online or in clinic during follow-up visits.

* Neurocognitive function, 12-months post whole-brain radiation therapy (WBRT)/stereotactic radiosurgery (SRS)specifically the Gamma Knife (GK) system, treatment as measured by the online neurocognitive function (oNCF) composite z-score.
* Neurocognitive function at all time points as measured by the online neurocognitive function (oNCF) composite z-score.

• Quality of life (patient-reported measures) as measured by Beck Depression Inventory, Beck Anxiety Inventory, FACT-Br, FACT-Cog, Fatigue Severity Scale, EuroQol(EQ5D), EORTC-BN20, and QOL-30.

Quality of life as measured by caregiver assessments including Frontal Systems Behavior Scale, Neuropsychiatric Inventory, Functional Activities Questionnaire, and Everyday Cognition Questionnaire.

North American Gamma Knife Consortium

University of California, San Francisco

Skin and Connective Tissue Diseases

Breast Neoplasms

Breast Diseases

Skin Diseases

Antisickling Agents

All Drugs and Chemicals

Efaproxiral

75 mg/kg, administered over 30 minutes via a central venous access device (CVAD).

Administered 30 minutes prior to the start of whole brain radiation therapy (WBRT) on each WBRT treatment day for 10 days.

3.0 Gy per day for 10 days (30.0 Gy total) of WBRT.

Whole Brain Radiation Therapy (WBRT)

4 L/minute by nasal cannula.

Administered at least 35 minutes prior to WBRT, during WBRT and until 15 minutes after completion of WBRT on all WBRT treatment days.

Supplemental Oxygen

John Suh, MD

RSR13 (efaproxiral) is a radiation sensitizer that has shown positive results in a Phase 3, randomized clinical trial of patients with brain metastases. Of 111 eligible breast cancer patients with brain metastases in that trial, 59 patients who received RSR13 prior to radiation therapy had a median survival time that was twice as long as the 52 patients who did not receive RSR13 prior to radiation therapy.

RSR13 (efaproxiral) is an experimental drug that increases the amount of oxygen released from blood into the tissues. It is well known that certain types of cancer tumors, including those in brain metastases, lack oxygen. Lack of oxygen in a tumor can reduce the effect of radiation therapy (RT). RSR13 may increase the oxygen level in brain tumors so that radiation therapy works better.

This study will enroll up to 360 women with brain metastases from breast cancer, and will evaluate if whole brain radiation therapy given with RSR13 will have a better treatment effect than whole brain radiation therapy alone. RSR13 will be infused intravenously (IV) through a central catheter placed in a central vein. Women randomized (assigned) to receive RSR13, therefore, will need to have a central catheter placed for treatment unless one is already in place.

The screening process will include documentation of the cancer, which which will require a brain scan and may include a liver scan. Other screening measurements will include a Karnofsky Performance Status (KPS) assessment, measurement of the amount of oxygen in the blood, using a non-invasive device most often placed on the finger, lung function tests that will require blowing into a machine, and an electrocardiogram (ECG). About 2 teaspoons, or 10 mL, of blood will be taken for specific laboratory tests, and a pregnancy test will be done on the blood of women of childbearing potential.

All study patients will receive supplemental oxygen and whole brain radiation therapy (WBRT) (30 Gy, 3 Gy fractions) every weekday for 2 weeks. Half of the patients will be randomized (assigned) to receive RSR13 prior to WBRT, and will need to have a central catheter placed for treatment unless one is already in place. Patients who receive RSR13 will also need to continue to receive oxygen in the clinic until the amount of oxygen in their blood is near normal. This level has returned to near normal in most patients within 1 to 2 hours.

During treatment and follow-up visits, physical and neurological exam, KPS assessment, weight, height, and vital sign measurements, and about 2 teaspoons of blood may be required. Patients will need to return for follow-up visits 1 month after completion of treatment, 2 months later, and every 3 months thereafter until their doctor tells them otherwise.

Whole Brain Radiation Therapy With Oxygen, With or Without RSR13, in Women With Brain Metastases From Breast Cancer

A Phase 3 Randomized, Open-label Comparative Study of Standard Whole Brain Radiation Therapy With Supplemental Oxygen, With or Without Concurrent RSR13 (Efaproxiral), in Women With Brain Metastases From Breast Cancer

Spectrum Pharmaceuticals, Inc

Medical Monitor

Blood and Lymph Conditions

Immune System Diseases

Rare Diseases

Lymphoma

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphosarcoma

Primary Central Nervous System Lymphoma

Antineoplastic Agents

Micronutrients

Hematinics

Vitamins

Amino Acids

Pemetrexed

Zanubrutinib

Enzyme Inhibitors

Folic Acid

Vitamin B Complex

Folic Acid Antagonists

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Folinic Acid

Folate

Vitamin B9

Tyrosine

Participants will receive the induction therapy (oral zanubrutinib + IV pemetrexed) and be placed into one of the cohorts according to standard of care (SOC) treatment:

Cohort 1: Induction Therapy + Autologous Stem Cell Transplant (ASCT) After completion of the induction therapy, ASCT candidates will undergo transplant as per SOC. If the transplant is delayed and 8 induction cycles have been completed, oral zanubrutinib maintenance will proceed until transplant, but will not occur after transplant.

Cohort 2: Induction Therapy + Whole Brain Radiation Therapy (WBRT) After completion of the induction therapy, WBRT candidates will undergo WBRT as per SOC. Oral zanubrutinib maintenance will start 7-10 days after the completion of WBRT. 28-d maintenance cycles will continue until disease progression.

Cohort 3: Induction Therapy Alone After completion of the induction therapy, 28-day oral zanubrutinib maintenance cycles will begin and continue until disease progression

Participants will receive 900 mg/m\^2 via IV infusion over 10 minutes every 3 weeks x 4-8 induction cycles (21 days per cycle) as part of the induction therapy.

Participants will receive 320 mg PO daily or dose-adjusted when given concomitantly with CYP3A4 inhibitor on Days 3-19 of each induction cycle x 4-8 cycles (21 days per cycle) as part of the induction therapy.

For those on maintenance therapy, participants will receive 320 mg PO daily or dose-adjusted when given concomitantly with CYP3A4 inhibitor on Days 1-28 of each maintenance cycle (28 days per cycle) until the transplant (if applicable) or disease progression.

ASCT will occur in participants who are candidates for this procedure according to standard of care institutional protocols

Autologous Stem Cell Transplant (ASCT)

WBRT will occur in participants who are candidates for this procedure but not candidates for ASCT according to standard of care institutional protocols

Yuliya Linhares, M.D.

Allison Miller

This study is being conducted to evaluate the safety and efficacy of the combination of pemetrexed and zanubrutinib (called induction therapy) followed by zanubrutinib treatment alone (also called maintenance therapy) in people who have relapsed or refractory (RR) primary central nervous system lymphoma (PCNSL) or isolated central nervous system relapse of B cell lymphoma (SCNSL). Assessments include how well people respond to this treatment, whether their disease gets better or worse, and their survival. Safety of this treatment and its side effects also will be assessed.

Pemetrexed, when used by itself, is beneficial and is a standard of care therapy for RR PCNSL and can be used to treat SCNSL. Zanubrutinib is an oral drug that is approved by the Food and Drug Administration (FDA) as safe and effective to treat certain lymphoma types.

Zanubrutinib With Pemetrexed to Treat Relapsed/Refractory Primary and Secondary Central Nervous System (CNS) Lymphomas

Zanubrutinib With Pemetrexed for the Treatment of Relapsed/Refractory Primary and Secondary CNS Lymphomas: A Phase II Trial With a Safety Lead-In

Best ORR to induction therapy is defined as the best response between the start of induction therapy until the end of induction therapy based on the criteria set forth in "Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma" (2005).

Best ORR is defined as the best response between the transplant and end of study, WBRT and end of study, or start of maintenance therapy and end of study. Response is based on the criteria set forth in "Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma" (2005).

Rate of CR to induction therapy is defined as the number of participants out of the total who demonstrate CR between the start of induction therapy until the end of induction therapy based on the criteria set forth in "Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma" (2005).

Rate of CR to is defined as the number of participants out of the total who demonstrate CR between the transplant and end of study, WBRT and end of study, or start of maintenance therapy and end of study. Response is based on the criteria set forth in "Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma" (2005).

DOR is defined as the duration of time from when complete or partial response is first identified to the time when progression is identified. Response is based on the criteria set forth in "Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma" (2005).

DOCR is defined as the duration of time from when complete response is first identified to the time when partial response or progression is identified. Response is based on the criteria set forth in "Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma" (2005).

PFS is defined as time from start of induction therapy to the time when progression is identified or the participant expires, whichever comes first.

OS is defined as time from start of induction therapy to the time when a participant expires.

A DLT will be defined as the occurrence of any of the following adverse events at least possibly related to the study medication during the DLT review period. The DLT review period will be defined during the first three 21-day cycles of zanubrutinib-pemetrexed combination treatment. Adverse events unrelated to study drugs will not be considered DLTs.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Neurocognitive Outcomes In Patients Treated With Radiotherapy For Five Or More Brain Metastases	NCT01731704	Brain Metastase...	Stereotactic ra... Whole brain rad...	18 Years -	University of California, San Francisco
Neurocognitive Outcomes In Patients Treated With Radiotherapy For Five Or More Brain Metastases	NCT01731704	Brain Metastase...	Stereotactic ra... Whole brain rad...	18 Years -	University of California, San Francisco
Whole Brain Radiation Therapy With Oxygen, With or Without RSR13, in Women With Brain Metastases From Breast Cancer	NCT00083304	Breast Cancer Metastases	Efaproxiral Whole Brain Rad... Supplemental Ox...	18 Years -	Spectrum Pharmaceuticals, Inc
Whole Brain Radiation Therapy With Oxygen, With or Without RSR13, in Women With Brain Metastases From Breast Cancer	NCT00083304	Breast Cancer Metastases	Efaproxiral Whole Brain Rad... Supplemental Ox...	18 Years -	Spectrum Pharmaceuticals, Inc
Neurocognitive Outcomes In Patients Treated With Radiotherapy For Five Or More Brain Metastases	NCT01731704	Brain Metastase...	Stereotactic ra... Whole brain rad...	18 Years -	University of California, San Francisco
Whole Brain Radiation Therapy With Oxygen, With or Without RSR13, in Women With Brain Metastases From Breast Cancer	NCT00083304	Breast Cancer Metastases	Efaproxiral Whole Brain Rad... Supplemental Ox...	18 Years -	Spectrum Pharmaceuticals, Inc
Zanubrutinib With Pemetrexed to Treat Relapsed/Refractory Primary and Secondary Central Nervous System (CNS) Lymphomas	NCT05681195	Primary Central... Secondary Centr... Relapsed Cancer Refractory Canc...	Pemetrexed Zanubrutinib Autologous Stem... Whole Brain Rad...	18 Years -	Baptist Health South Florida
Zanubrutinib With Pemetrexed to Treat Relapsed/Refractory Primary and Secondary Central Nervous System (CNS) Lymphomas	NCT05681195	Primary Central... Secondary Centr... Relapsed Cancer Refractory Canc...	Pemetrexed Zanubrutinib Autologous Stem... Whole Brain Rad...	18 Years -	Baptist Health South Florida

Spots Global Cancer Trial Database for whole brain radiation therapy (wbrt)