Neoplasms

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Rare Diseases

Lymphoma

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphosarcoma

Primary Central Nervous System Lymphoma

We will use DNA and RNA tumor samples. We will not use germline or blood DNA. These data will be combined with their magnetic resonance imaging (MRI) at different times: at diagnosis, at the end of treatment and at the progression of the disease.

Tumor samples and MRI

Khê HOANG-XUAN, MD, PhD

We plan to analyze 100 PCNSL homogenously treated with high-dose methotrexate based chemotherapy using NGS of PCNSL samples. We will perform DNA-seq and RNA-seq from tumor samples. This data will be combined with their magnetic resonance imaging (MRI) at different time points: at diagnosis, at the end of the treatment and at disease progression. Among the 100 PCNSL that will be included, 70 will be from a retrospective (training set) from patients included in the French National PCNSL dataset (LOC cohort) and 30 PCNSL from a prospective cohort from patients included in a phase III clinical trial (BLOCAGE, PHRC 2014). On the one hand, we will perform a radiomics analysis (quantitative imaging) using 3D tumor and edema segmentation. This analysis will help us to elucidate the potential correlation of MRI phenotypes and genotype (using high-throughput data). In addition, we will use the radiomics data combined with in vitro and in vivo data (using a mouse model of PCNSL) as well as immunohistochemistry data to obtain a multidimensional mathematical modeling of PCNSL clinical evolution that will allow us to better predict the clinical course of this rare subtype of brain tumor.

Primary central nervous system lymphomas (PCNSL) are extra-nodal, malignant non-Hodgkin lymphomas of diffuse large B-cell type confined to the CNS or eyes without evidence of systemic spread. PCNSL account for up to 1% of all lymphomas and 3% of primary brain tumors. Despite recent progress in PCNSL treatment, remissions are short lasting and the outcome remains poor with a minority of long-term survivors (20%). Moreover, treatments expose patients to a high risk of neurotoxicity. Even though PCNSL has been extensively studied, the pathogenic mechanisms underlying its remarkable tropism and its peculiar clinical behaviour are not well elucidated. Since 2010, the French National Institute of Cancer (INCa) has supported the creation of medical networks dedicated to rare cancers, including PCNSL (LOC network). LOC has developed a national clinical database of newly diagnosed PCNSL with a virtual tumor database to perform translational studies. Furthermore, LOC has launched several prospective trials including a phase III clinical trial (BLOCAGE - PHRC 2014) with an expected sample size of 300 patients to perform ancillary analysis. Modeling malignant extracerebral/systemic non-Hodgkin lymphoma therapy and outcome has been previously performed, however due to its peculiar anatomical and immunoprivileged microenvironment, and its specific therapeutic management, specific modeling of PCNSL is required. Interestingly, in glioblastoma, another primary brain tumor, a model prediction of expected tumor burden provided a personalized assessment of a therapy's effectiveness. Therefore, a comprehensive mechanistic view of mathematical modeling of PCNSL growth and treatment response could be used to better stratify PCNSL evolution and to predict the best treatment options. From a radiological point of view, PCNSL often display a characteristic presentation with periventricular contrast enhancing lesions. This is due to its hypercellularity, high nuclear/cytoplasmic ratio, disruption of the blood-brain barrier, and its predilection for the periventricular and superficial regions often in contact with ventricular or meningeal surface. Interestingly, some small studies suggest that the integration of radiological and high-throughput data would help to stratify the prognosis of PCNSL. In addition, MRI assesses therapeutic response but this evaluation lacks of sensitivity to detect non-enhancing lesions. Radiomics is a promising new paradigm for extending clinical imaging into the era of molecular and genomic imaging. Interesting results using MRI and molecular phenotypes have been obtained in different cancers and very recently in glioblastomas4. However, there is only some evidence suggesting that molecular phenotype of PCNSL could be related to some particular imaging morphophenotypes. Interestingly, our team has recently identified a potential molecular-radiological association between the presence of TERT promoter mutations and the localization of PCNSL within corpus callosum. Furthermore, using MRI data (macroscopic data) will be also used to explore predictors of MRI patterns in a multivariate framework, we will develop a linear modeling approach that measures the association of MRI patterns with a number of potential predictors, including expression levels on a gene-by-gene basis, driver mutations and clinical variables. Somatically acquired mutation and cytogenetic lesion will be encoded as being present/absent. We choose a linear model due to its interpretability and established statistical methods, enabling us to test which MRI morphological pattern are associated with deregulated transcripts in the presence of specific alterations after correcting for other confounding factors and other clinical variables and coexisting driver mutations. The total variance in the MRI data will be studied and dissected using data from selected driver genes, cytogenetic lesion and the most relevant principal components of MRI data will be analyzed in a Least Absolute Shrinkage and Selection Operator (LASSO) penalized model. The optimal model maximizes the explained variance R2.

We will evaluate prognosis accuracy of survival models using Harrel's C statistic, as implemented in Hmisc R package. This statistic measures the fraction of pairs of patients with concordant risk predictions, and outcome similarly to the area under the receiver operating characteristic curve. To reduce the bias of estimated risk, we will use a fivefold cross-validating scheme. In addition, we will also analyze survival impact of this multidimensional data using random forest as an alternative approach for predicting outcome and measuring variable importance. These are implemented in the randomForesetSRC R package. the preliminary results obtained on a sub sample of patient showed that the 100 patient cohort will be sufficient to build and assess the predictive values of the models we will study. Tools to integrate multiple sources data set described above for a small subset will be scaled up using all the variables available from the complete dataset: non negative matrix co-factorization and regularized generalized canonical correlation analysis.

Patient prognosis may tightly correlate with a characteristic morphological tumor phenotype on the histological level and with tumor shape, which itself may correlate with the gene expression pattern. For this reason, macro-level growth simulations with the above statistical model will be complemented by simulations with mechanistic models at the histological level, and at whole tumor level. The histological-level model will be calibrated with experiments using diffuse large B cell lymphoma (DLBCL) cell lines co-cultured with other microenvironment cells like glial cells, and with murine experiments. This model shall shed light on the mechanisms at cell level capable of explaining the observed cell proliferation and multicellular arrangement pattern.

Mathematic Modeling at Micro and Macroscopic Level of Primary Central Nervous System Lymphomas (PCNSL)

PCNSL characterization through the integration of radiomics, gene expression and genotyping features.

Mathematic modeling of morphological phenotypes and of prognosis and chemo-sensitivity or chemo-resistance of PCNSL using MRI and NGS data.

Analysis chemo-resistance pathways and development of new therapeutic targets in PCNSL using integrative data: mouse model of PNCSL, in vitro data and radiomics analysis.

Assistance Publique - Hôpitaux de Paris

Antineoplastic Agents

Antirheumatic Agents

Dermatologic Agents

Reproductive Control Agents

All Drugs and Chemicals

Methotrexate

Nivolumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

All patients will undergo cerebrospinal fluid (CSF) and blood collection as well as MRI imaging as standard of care prior to (- 21 days) first-line treatment initiation, during first-line therapy (before initiation of the 5th methotrexate dose (+/- 7 days)), at completion of first-line chemotherapy therapy (+/- 7 days) as well as 60, 180, and 360 days after enrollment into maintenance or observation (+/- 7 days). Those patients with persistent cfDNA in the CSF after completion of first-line chemotherapy and either complete or partial response on imaging will be enrolled into the nivolumab maintenance treatment arm. All other patients (no persistent cfDNA in the CSF and either complete or partial response on imaging) are followed with observation. Patients who do not respond to first-line therapy are not eligible for nivolumab maintenance and will no longer be followed in the biospecimen and clinical data collection cohort.

Nivolumab will be given every 4 weeks at 480mg flat dose intravenously for one year (total of 13 nivolumab doses).

Christian Grommes, MD

The purpose of this additional part of the study is to test whether the study drug, nivolumab, is a safe treatment that will prevent participants' primary central nervous system lymphoma (PCNSL) from growing again (recurrence). Participants will be people with PCNSL who continue to have cell free tumor DNA (cfDNA) in their CSF despite completion of their first treatment (first-line treatment).

The phase II nivolumab maintenance trial is an open-label trial for patients who have completed high-dose methotrexate-based first-line chemotherapy for primary central nervous system lymphoma (PCNSL) but have persistent cfDNA in their CSF after treatment despite imaging response.

Nivolumab Maintenance in Newly Diagnosed PCNSL With Persistent CSF Circulating Tumor DNA After Completion of First-Line Chemotherapy

Phase II Maintenance Trial of Nivolumab for Newly Diagnosed PCNSL Patients With Persistent Circulating Tumor DNA in the CSF After Completion of Methotrexate-Based First-Line Induction Chemotherapy

Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.

Frequencies of toxicities will be summarized based on the Common Toxicity Criteria (CTCAE) version 5.0. Adverse events.

Conversion rate is defined as the proportion of patients receiving maintenance nivolumab who have undetectable cfDNA at one-year from the start of nivolumab maintenance.

Bristol-Myers Squibb

Memorial Sloan Kettering Cancer Center

Symptoms and General Pathology

Heart and Blood Diseases

Leukemia

Leukemia, Lymphoid

Leukemia, Lymphocytic, Chronic, B-Cell

Lymphoma, Mantle-Cell

Lymphoma, Follicular

Lymphoma, B-Cell, Marginal Zone

Lymphoma, Large B-Cell, Diffuse

Lymphoma, B-Cell

Waldenstrom Macroglobulinemia

Lymphoma, Non-Hodgkin

Hematologic Diseases

Leukemia, B-Cell

Chronic Disease

Disease Attributes

Neoplasms, Plasma Cell

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hemorrhagic Disorders

Chronic Graft Versus Host Disease

Chronic Lymphocytic Leukemia

Mantle Cell Lymphoma

Follicular Lymphoma

B-cell Lymphoma

Marginal Zone Lymphoma

Diffuse Large B-Cell Lymphoma

Amino Acids

Antibodies

Antibodies, Monoclonal

Immunomodulating Agents

Immunoglobulins

Tyrosine Kinase Inhibitors

Tyrosine

Multiple dose levels of NX-5948 to be evaluated; determination of Maximum Tolerated Dose/Phase 1b recommended dose(s)

CLL or SLL with prior exposure to both a Bruton's tyrosine kinase inhibitor (BTKi) and BCL-2 inhibitor, unless previously deemed ineligible for those therapies. Patients enrolled in CLL/SLL arm will be randomized to one of two dose levels. This is the only randomization component in the trial.

MCL with prior exposure to a BTKi and an anti-CD20 monoclonal antibody (mAb)-based chemo-immunotherapy regimen

MZL (EMZL, MALT, NMZL, SMZL) with prior exposure to an anti-CD20 mAb-based chemo-immunotherapy regimen and an additional line of therapy

PCNSL patients who have progressed or had no response to at least 2 prior lines of therapy, or SCNSL patients meeting criteria for non-CLL/SLL arms above with secondary CNS involvement of lymphoma

WM with prior exposure to a BTKi and an additional line of therapy

DLBCL with prior exposure to an anthracycline (unless previously deemed ineligible to receive), an anti-CD20 mAb-based chemoimmunotherapy regimen, and an additional line of therapy

FL (grade 1-3a) with prior exposure to an anti-CD20 mAb-based chemoimmunotherapy regimen and an additional line of therapy

NX-5948

Patient Outreach

Ana Ayala

Paula O'Connor, MD

This is a first-in-human Phase 1a/1b multicenter, open-label study designed to evaluate the safety and anti-cancer activity of NX-5948 in patients with advanced B-cell malignancies.

Phase 1a is a dose escalation to evaluate the safety and tolerability of NX-5948 in adult patients with relapsed/refractory (R/R) B cell malignancies who have received at least 2 prior lines of therapy, or at least 1 prior line of therapy for Primary Central Nervous System Lymphoma (PCNSL), and for whom no other therapies are known to provide clinical benefit. Indications include: Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL), Diffuse Large B-cell Lymphoma (DLBCL), Mantle Cell Lymphoma (MCL), Waldenstrom Macroglobulinemia (WM), Marginal Zone Lymphoma (MZL), Follicular Lymphoma (FL), or Primary Central Nervous System Lymphoma (PCNSL).

Phase 1b will investigate the efficacy of NX-5948 at the dose(s) selected in Phase 1a in up to 7 expansion arms of patients with histologically confirmed R/R B-cell malignancy indications who have received the specified prior therapies based on indication:

* CLL or SLL (two dose levels will be investigated for CLL/SLL)
* MCL
* MZL
* WM
* DLBCL
* FL
* PCNSL/SCNSL

A Study of NX-5948 in Adults With Relapsed/Refractory B-cell Malignancies

A Phase 1, Dose Escalation, and Cohort Expansion Study Evaluating NX-5948, a Bruton's Tyrosine Kinase (BTK) Degrader, in Adults With Relapsed/Refractory B-cell Malignancies

Phase 1a/1b - Sampling following the first dose, pre- and post-dose at selected cycles and at the end of treatment

Phase 1a/1b - Sampling at screening, following the first dose, pre and post-dose at selected cycles and at the end of treatment

Nurix Therapeutics, Inc.

Nervous System Diseases

Substance Related Disorders

Neurotoxicity Syndromes

Syndrome

Poisoning

Chemically-Induced Disorders

Subjects with PCNSL who have survived disease-free for 2 years or more. Treatments will vary depending upon site of enrollment and will include chemotherapy, blood brain barrier disruption (BBBD) with chemotherapy, radiation, and stem cell transplantation.

Edward A Neuwelt, MD

This research is being done to investigate cognition in long term survivors of Primary Central Nervous System Lymphoma (PCNSL). Sometimes caregivers as well as patients who no longer have the disease report cognitive problems such as reduced memory or attentional dysfunction and decreased quality of life. Unfortunately, little is known about what may contribute to this cognitive dysfunction in part because PCNSL is a rare disease and sensitive tests have not often been used in the research studies. This project is being conducted to help understand what factors, such as radiation, may contribute to cognitive dysfunction and better define the relationship between brain structure and thinking in people who have had PCNSL.

This is an international, multi-center project that will enroll as many as 118 subjects of which approximately 35 will be enrolled at Oregon Health \& Science University (OHSU). Neuropsychological testing will consist of a battery of paper and pencil tests that examine abilities such as memory, motor skills, attention and speed of information processing. Questionnaires that assess quality of life will also be administered. These noninvasive tests are administered by a trained examiner or neuropsychologist and last about 30 minutes. Subjects will also undergo an MRI of the head which provides a picture of the brain's structure by placing an individual inside a powerful magnet. Statistical analyses will examine the relationship between the neuropsychological test scores and magnetic resonance (MR) images as well as examine the contribution of factors such as radiation, age, surgery, chemotherapy etc. to cognition.

Neurotoxicity in Primary Central Nervous System Lymphoma (PCNSL): An International Observational Study of Cognition in Long Term Survivors

Neurotoxicity in Primary Central Nervous System Lymphoma: An International, Collaborative, Observational Study of Cognition in Long-Term Survivors

National Institutes of Health (NIH)

National Institute of Neurological Disorders and Stroke (NINDS)

OHSU Knight Cancer Institute

Professor

Acalabrutinib

Rituximab

Durvalumab

Immunologic Factors

Protein Kinase Inhibitors

Enzyme Inhibitors

Dose level 1 Rituximab 375mg/m2 infusion once every 4 weeks for 8 cycles Acalabrutinib 100mg PO once every day Durvalumab 1500mg infusion once every 4 weeks Dose level 2 Rituximab 375mg/m2 infusion once every 4 weeks for 8 cycles Acalabrutinib 100mg PO twice every day Durvalumab 1500mg infusion once every 4 weeks

Dose level 1:Rituximab 375mg/m2 infusion once every 4 weeks for 8 cycles Acalabrutinib 100mg PO once every day Durvalumab 1500mg infusion once every 4 weeks Dose level 2:Rituximab 375mg/m2 infusion once every 4 weeks for 8 cycles Acalabrutinib 100mg PO twice every day Durvalumab 1500mg infusion once every 4 weeks Expansion:Determined by the result of the dose escalation phase

Shang-Ju Wu, M.D

Wei-Lan Yu, B.S

Shang-Ju Wu

Su-Peng Yeh, M.D

Kwang-Yu Chang, M.D

Ming Chung Wang, M.D

To evaluate the safety and tolerability and determine the recommended phase 2/phase 3 dose of RAD regimen in PCNSL

Target subject population Male and female patients with PCNSL who have failed to achieve a response or who have relapsed after prior therapy (R/R) or who are treatment naïve but are not candidates of standard high-dose methotrexate-based induction chemotherapy. Patients are not to have been previously treated with immune checkpoint inhibitors or Bruton tyrosine kinase (BTK) inhibitors; prior treatment with rituximab is allowed.

Duration of treatment Rituximab will be administered for up to 8 cycles or until intolerance or excessive toxicities relevant to the trial therapy, or withdrawal of consents; acalabrutinib and durvalumab will be continued until disease progression, intolerance, or excessive toxicities relevant to the trial therapy, or withdrawal of consents.

Investigational product, dosage, and mode of administration Dose level 1 Rituximab 375mg/m2 infusion once every 4 weeks for 8 cycles Acalabrutinib 100mg PO once every day Durvalumab 1500mg infusion once every 4 weeks Dose level 2 Rituximab 375mg/m2 infusion once every 4 weeks for 8 cycles Acalabrutinib 100mg PO twice every day Durvalumab 1500mg infusion once every 4 weeks Expansion Determined by the result of the dose escalation phase Statistical methods

This study will use the 3+3 design in the dose escalation phase. Analyses will be primarily descriptive in nature; no formal statistical hypothesis testing will be performed. The populations used for analysis will include the following:

Safety analysis set: patients who receive at least 1 dose of anyone of the study drugs will be used for safety analyses.

Dose level 1,Dose level 2,3+3 design in the dose escalation.

This study will use the 3+3 design in the dose escalation phase.

Rituximab, Acalabrutinib, and Durvalumab (RAD) in Primary CNS Lymphoma.

Phase Ib, Multi-center Study of Combining Rituximab, Acalabrutinib, and Durvalumab (RAD) in Primary Central Nervous System Lymphoma.

Dose-limiting toxicity (DLT) patients will be enrolled in cohort of 2 to receive escalating dose of acalabrutinib at two dose levels (level I 100mg PO once , level II 100mg PO twice every day) or more of defined events

Efficacy evaluation: objective tumor response according to International PCNSL Collaborative Group Guidelinefor Response Assessment

National Taiwan University Hospital

National Cheng-Kung University Hospital

China Medical University Hospital

Chang Gung Memorial Hospital

National Health Research Institutes, Taiwan

Lenalidomide

Pomalidomide

Multiple dose levels of NX-2127 to be evaluated; determination of MTD/Phase 1b recommended dose

CLL/SLL patients with no BTK C481 mutation whose disease has failed treatment with a BTK inhibitor

BTK C481 mutation-positive CLL/SLL patients whose disease has failed treatment with a BTK inhibitor

MCL patients whose disease has failed treatment with a BTK inhibitor and an anti-CD20 monoclonal antibody (mAb) based regimen

FL or MZL patients whose disease has failed treatment with an anti-CD20 mAb-based regimen; or PCNSL whose disease has failed at least 1 prior line of treatment

DLBCL patients whose disease has failed treatment with an anti-CD20 mAb-based regimen and either an anthracycline, an anti-CD19-based regimen, or another/palliative regimen; or WM patients whose disease has failed treatment with a BTK inhibitor

NX-2127

This is a first-in-human Phase 1a/1b multicenter, open-label oncology study designed to evaluate the safety and anti-cancer activity of NX-2127 in patients with advanced B-cell malignancies.

Phase 1a is a dose escalation to evaluate the safety and tolerability of NX-2127 in adult patients with relapsed/refractory (R/R) B-cell malignancies, who have required and received at least 2 prior systemic therapies (or at least 1 prior therapy for patients with WM or PCNSL) and for whom no other therapies are known to provide clinical benefit. Phase 1b will investigate the efficacy of NX-2127 at the dosage(s) selected in Phase 1a in up to 5 cohorts of patients with R/R B-cell malignancy indications who have received at least 2 prior systemic therapies (or at least 1 prior therapy for patients with WM or PCNSL):

* Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) with no BTK C481 mutation
* BTK C481 mutation-positive CLL/SLL
* Mantle Cell Lymphoma (MCL)
* Follicular lymphoma (FL) or Marginal Zone Lymphoma (MZL); or Primary Central Nervous System Lymphoma (PCNSL)
* Diffuse Large B-cell Lymphoma (DLBCL) or Waldenstrom Macroglobulinemia (WM)

A Study of NX-2127 in Adults With Relapsed/Refractory B-cell Malignancies

A Phase 1, Dose Escalation, Safety and Tolerability Study of NX-2127, a Bruton's Tyrosine Kinase (BTK) Degrader, in Adults With Relapsed/Refractory B-cell Malignancies

Phase 1a/1b - Sampling following the first dose, pre and post-dose at selected cycles, and at the end of treatment

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Mathematic Modeling at Micro and Macroscopic Level of Primary Central Nervous System Lymphomas (PCNSL)	NCT04253496	Primary Central...	Tumor samples a...	60 Years -	Assistance Publique - Hôpitaux de Paris
Nivolumab Maintenance in Newly Diagnosed PCNSL With Persistent CSF Circulating Tumor DNA After Completion of First-Line Chemotherapy	NCT04401774	Primary Central...	Nivolumab	18 Years -	Memorial Sloan Kettering Cancer Center
A Study of NX-5948 in Adults With Relapsed/Refractory B-cell Malignancies	NCT05131022	Chronic Lymphoc... Small Lymphocyt... Diffuse Large B... Follicular Lymp... Mantle Cell Lym... Marginal Zone L... Waldenstrom Mac... Primary Central...	NX-5948	18 Years -	Nurix Therapeutics, Inc.
Neurotoxicity in Primary Central Nervous System Lymphoma (PCNSL): An International Observational Study of Cognition in Long Term Survivors	NCT00710151	Primary Central...		18 Years - 75 Years	OHSU Knight Cancer Institute
Mathematic Modeling at Micro and Macroscopic Level of Primary Central Nervous System Lymphomas (PCNSL)	NCT04253496	Primary Central...	Tumor samples a...	60 Years -	Assistance Publique - Hôpitaux de Paris
Rituximab, Acalabrutinib, and Durvalumab (RAD) in Primary CNS Lymphoma.	NCT04688151	Primary Central...	Rituximab	20 Years -	National Health Research Institutes, Taiwan
A Study of NX-2127 in Adults With Relapsed/Refractory B-cell Malignancies	NCT04830137	Chronic Lymphoc... Small Lymphocyt... Waldenstrom Mac... Mantle Cell Lym... Marginal Zone L... Follicular Lymp... Diffuse Large B... Primary Central...	NX-2127	18 Years -	Nurix Therapeutics, Inc.

Spots Global Cancer Trial Database for primary central nervous system lymphoma (pcnsl)