Neoplasms

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Rare Diseases

Lymphoma

Hodgkin Disease

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphosarcoma

Hodgkin Lymphoma

Primary Central Nervous System Lymphoma

Orelabrutinib dose escalation will occur using a standard 3+3 dose-escalation approach to determined the maximum tolerated dose(MTD) of orelabrutinib dose in combined regimen, beginning at dose level I (150 mg daily) and potentially escalating to dose level 2 (200mg) and dose level 3 (250mg) with rules for escalation and de-escalation. If the dose-limiting toxicity is not found, the dose of 250mg qd will be used for phase II trial.

Orelabrutinib: orally daily Sintilimab: The dose of sintilimab is fixed dose. 200 mg intravenously every 3 weeks (maximum 12 total dose)

Participants will receive orelabrutinib and sintilimab at the pre-determined dosage level established in Phase 1b, until progression of the disease (PD), unacceptable toxicity, or patient/investigator discretion. The response will be evaluated every 2 cycles.

Orelabrutinib: orally maximum tolerated dose from phase 1b daily (150 mg or 200 mg or 250mg) Sintilimab: The dose of sintilimab is fixed dose. 200 mg intravenously every 3 weeks

Orelabrutinib dose escalation will occur using a standard 3+3 dose-escalation approach to determined the maximum tolerated dose(MTD) of orelabrutinib dose in combined regimen, beginning at dose level I (150 mg daily) and potentially escalating to dose level 2 (200mg) and dose level 3 (250mg) with rules for escalation and de-escalation. If the DLT is not found, the dose of 250mg qd will be used for phase II trial.

Orelabrutinib

Orelabrutinib: orally maximum tolerated dose from phase 1b daily (150 mg or 200 mg or 250mg)

The dose of sintilimab is fixed dose. 200 mg intravenously every 3 weeks

Sintilimab

Wenbin Qian, Prof.

Xianggui Yuan, Dr.

Xianggui Yuan, MD, PhD

Wenbin Qian, MD, PhD

This phase Ib/II trial is evaluating the efficacy and side effect of orelabrutinib and sintilimab as possible treatments for relapsed or refractory central nervous system lymphoma.

Both orelabrutinib and sintilimab are promising classes of therapy for central nervous system lymphoma. Given the poor outcomes and limited options for relapsed or refractory central nervous system lymphoma. The investigators seek to evaluate the efficacy and toxicity of the combination of orelabrutinib with sintilimab in this patient population.

Phase 1b (maximum 12 total cycles) Orelabrutinib dose escalation will occur using a standard 3+3 dose-escalation approach to determined the maximum tolerated dose(MTD) of orelabrutinib dose in combined regimen, beginning at dose level I (150 mg daily) and potentially escalating to dose level 2 (200mg) and dose level 3 (250mg) with rules for escalation and de-escalation. If the dose-limiting toxicity is not found, the dose of 250mg qd will be used for phase II trial.

Orelabrutinib: orally daily Sintilimab: The dose of sintilimab is fixed dose. 200 mg intravenously every 3 weeks (maximum 12 total dose)

Phase 2 Participants will receive orelabrutinib and sintilimab at the pre-determined dosage level established in Phase 1b, until progression of the disease (PD), unacceptable toxicity, or patient/investigator discretion. The response will be evaluated every 2 cycles.

Orelabrutinib: orally maximum tolerated dose from phase 1b daily (150 mg or 200 mg or 250mg) Sintilimab: The dose of sintilimab is fixed dose. 200 mg intravenously every 3 weeks

Orelabrutinib and Sintilimab in Relapsed or Refractory Central Nervous System Lymphoma

A Phase Ib/II Study of Orelabrutinib and Sintilimab in Treating Patients With Relapsed or Refractory Central Nervous System Lymphoma

Types of ctDNA mutations and frequency are measured by next generation sequencing. The mean ctDNA concentration is the concentration of ctDNA expressed as mean tumor molecules /ml at specific time points.

The levels of cytokine will be analyzed by ELISA in all patients recruited. The cytokine profile includes IL-6, IL-10, TNF-α, IFN-γ, IL-2 and IL-4

The objective response rate (ORR) is defined as the proportion of patients with a best response of CR or PR

PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.

OS is defined as the duration of time from start of treatment to time of death.

The duration of overall response is measured from the time measurement

Sir Run Run Shaw Hospital

First Affiliated Hospital of Zhejiang University

Wenzhou Central Hospital

Second Affiliated Hospital of Wenzhou Medical University

Zhejiang Provincial Tongde Hospital

First People's Hospital of Hangzhou

Zhejiang Provincial People's Hospital

Jinhua Central Hospital

Jinhua People's Hospital

Yinzhou Hospital Affiliated to Medical School of Ningbo University

Huizhou Municipal Central Hospital

Second Affiliated Hospital, School of Medicine, Zhejiang University

Symptoms and General Pathology

Nervous System Diseases

Substance Related Disorders

Thrombocytopenia

Recurrence

Central Nervous System Neoplasms

Nervous System Neoplasms

Intraocular Lymphoma

Drug-Related Side Effects and Adverse Reactions

Blood Platelet Disorders

Hematologic Diseases

Cytopenia

Chemically-Induced Disorders

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Antirheumatic Agents

Etoposide

Antibodies

Cytarabine

Cyclophosphamide

Carboplatin

Rituximab

Lenograstim

Etoposide phosphate

Immunoglobulins

Sodium thiosulfate

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Antineoplastic Agents, Immunological

Enzyme Inhibitors

Antimetabolites

Antiviral Agents

Antidotes

Protective Agents

Antioxidants

Antitubercular Agents

Anti-Bacterial Agents

Chelating Agents

Total dose: 375mg/m2 infused IV; Every 4 weeks for up to one year.

Rituxan

Dose 330mg/m2 x 2 days infused IV; Every 4 weeks for up to 1 year

Dose 200mg/m2 x 2 days infused IV; Every 4 weeks for up to one year. Etoposide phosphate may be given instead.

Dose 200mg/m2 infused IV x 2 days; Every 4 weeks for up to one year. Etoposide may be given instead.

Dose: 200mg/m2 x 2 days infused IA with BBBD; Every 4 weeks for up to one year.

Dose: 4 hrs post carboplatin = 20gm/m2;

Dose: 8 hrs post carboplatin = 16gm/m2

Infused IV x 2 days

48 hours after chemotherapy, QD x 7-10 days until WBC greater than 5000. Neulasta (Pegfilgrastim) may be given instead.

Neupogen

Dose: 6mg, 24-72 hours after chemotherapy. Neupogen may be given instead.

Neulasta

Dose: 40mg on Day 14 following chemotherapy

Edward A. Neuwelt, MD

RATIONALE: Monoclonal antibodies, such as rituximab, can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. Drugs used in chemotherapy, such as carboplatin, cyclophosphamide, etoposide, etoposide phosphate, and cytarabine, use different ways to stop cancer cells from dividing so they stop growing or die. Osmotic blood-brain barrier disruption uses certain drugs to open the blood vessels around the brain and allow anticancer substances to be delivered directly to the brain tumor. Chemoprotective drugs such as sodium thiosulfate may protect normal cells from the side effects of carboplatin-based chemotherapy. Combining rituximab with chemotherapy given with osmotic blood-brain barrier disruption plus sodium thiosulfate may kill more cancer cells.

PURPOSE: Phase II trial to study the effectiveness of combining rituximab with combination chemotherapy given with osmotic blood-brain barrier disruption plus sodium thiosulfate in treating patients who have refractory or recurrent primary CNS lymphoma.

OBJECTIVES:

Primary

* Determine the efficacy of rituximab, carboplatin, cyclophosphamide, etoposide or etoposide phosphate and cytarabine administered in conjunction with osmotic blood-brain barrier disruption and high-dose sodium thiosulfate, in terms of complete response rate, in patients with refractory or recurrent primary CNS lymphoma.

Secondary

* Determine the overall survival and 2-year progression-free survival of patients treated with this regimen.
* Determine the quality of life and cognitive function of patients treated with this regimen.
* Determine the neurotoxicity of this regimen in these patients.
* Determine the percentage of patients with ototoxicity over time after treatment with this regimen.
* Determine the effect of delayed administration of sodium thiosulfate on granulocyte and erythrocyte counts in these patients.

OUTLINE: This is a multicenter study.

Patients receive rituximab IV on day 1. On days 2 and 3, patients receive carboplatin intra-arterially over 10 minutes, cyclophosphamide IV over 10 minutes, and etoposide or etoposide phosphate IV over 10 minutes in conjunction with blood-brain barrier disruption. Patients also receive high-dose sodium thiosulfate IV over 15 minutes administered 4 and 8 hours after carboplatin on days 2 and 3 and intraventricular or intrathecal cytarabine on day 14. Beginning 48 hours after the last dose of chemotherapy, patients receive filgrastim (G-CSF)\* subcutaneously (SC) daily for 7-10 days or until blood counts recover. Treatment repeats every 4 weeks for up to 12 courses.

NOTE: \* Alternatively, patients may receive a single dose of pegfilgrastim SC, administered 48 hours after the completion of chemotherapy

Patients with intraocular lymphoma also receive methotrexate intravitreally twice weekly until the vitreous is clear of cells by slit lamp exam; once weekly for 1 month; and then monthly for 1 year.

Quality of life is assessed at baseline, every 3 months during treatment, within 30 days of final treatment, then every 6 months for 1 year, and then annually thereafter.

Patients are followed monthly for 3 months, every 2 months for 8 months, every 3 months for 1 year, and then every 6 months thereafter.

PROJECTED ACCRUAL: A total of 11-25 patients will be accrued for this study within 7-10 years.

Treating Patients With Recurrent PCNSL With Carboplatin/BBBD and Adding Rituxan To The Treatment Regimen

A Phase II Trial Involving Patients With Recurrent PCNSL Treated With Carboplatin/BBBD, by Adding Rituxan (Rituximab), An Anti CD-20 Antibody, To The Treatment Regimen

Per RECIST criteria (v1.1) and assessed by magnetic resonance imaging (MRI): Complete response (CR), Disappearance of all target lesions.

Overall survival is measured from entry onto study until death from any cause or until death or progression of disease, respectively.

National Cancer Institute (NCI)

OHSU Knight Cancer Institute

Professor

Unanticipated Problems (UP) and Adverse Events (AE) were reported to IRB according to OHSU's (coordinating center) policies, procedures and guidelines posted on the OHSU IRB web site. NCI Common Toxicity Criteria used to assess AEs.

Rituximab: (i.v.) 375 mg/m\^2 given the evening before blood brain barrier disruption(BBBD) procedure day 1 Carboplatin: (i.a.) 200 mg/m\^2 /day x 2 days = 400 mg/m\^2

Rituximab and Carboplatin

Age, Categorical

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

Dr. Edward Neuwelt

Number of Participants With a Complete Response Rate to Chemotherapy Regimen Assessed by Radiographic Response at 2 Years.

Data not collected due to low accrual and early termination.

Number of Participants With Overall Survival Assessed by Clinical and Radiographic Response

Progression-free Survival Assessed by Clinical and Radiographic Response From First Day of Treatment Until Tumor Progression

Quality of Life Assessed by EORTC QOL Before Treatment and Then Every 3 Months

Ototoxicity Assessed by Audiology Hearing Test Done Monthly During Treatment

Effect of Sodium Thiosulfate (STS) on Granulocytes and Erythrocytes Assessed by Complete Blood Count Lab Values Done Weekly During Treatment

Overall Study

Neurotoxicity Syndromes

Syndrome

Poisoning

Dermatologic Agents

Reproductive Control Agents

Micronutrients

Hematinics

Vitamins

Methotrexate

Vincristine

Immunomodulating Agents

Procarbazine

Motexafin gadolinium

Folic Acid

Vitamin B Complex

Folic Acid Antagonists

Tubulin Modulators

Antimitotic Agents

Photosensitizing Agents

Folinic Acid

Folate

Vitamin B9

Infusion will be given at week 2, week 4, week 6 and week 8. Infusions can be administered at an initial rate of 100 mg/hr, and increased by 100 mg/hr increments at 30-minute intervals, to a maximum of 400 mg/hr as tolerated.

Administered by IV over 3 hours at a dose of 3 g/m2/day for 2 days given at week 17 and week 21.

Administered by IV at dose of 3.5 grams/m2 on day 1 of week 1, week 3, week 5, week 7 and week 9; if CSF was positive it will also be given intrathecally on day 8 of week 1, week 3, week 5, week 7 and week 9.

* Administered to the first five patients enrolled on trial, MGd will be given at 5 mg/kg q day x2 doses (completed on 2 consecutive days 1 to 2 weeks prior to day of cycle 1) to be followed by a non-infused MRI (without contrast) 1-5 hours after 2nd MGd dose (to evaluate for MGd tumor selective uptake).
* For induction chemotherapy, MGd 10 mg/kg will be given intravenously on day 8 of each cycle. MGd will be given immediately after Rituxan.
* During radiation therapy, MGd will be administered at 5 mg/kg 2-5 hours prior to WBRT, daily for the first 10 days (fractions) and then every other day of radiation thereafter.

Taken orally, 100 mg/m2 days 1-7 of the 1st, 3rd, and 5th cycles of induction therapy.

Procarbazine hydrochloride

Administered by IV at a dose of 1.4mg per meter squared on weeks 1, 3, 5, 7 and 9.

Vincristine sulfate

Radiation therapy

Andrew M. Evens, DO, MS

Jeffrey J. Raizer, MD

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Radiation therapy uses high-energy x-rays to kill cancer cells. Motexafin gadolinium may make cancer cells more sensitive to radiation therapy and combination chemotherapy. Giving motexafin gadolinium together with chemotherapy, rituximab, and radiation therapy may kill more cancer cells.

PURPOSE: This phase II trial is studying the side effects of giving motexafin gadolinium together with combination chemotherapy, rituximab, and whole-brain radiation therapy and to see how well it works in treating patients with newly diagnosed primary central nervous system lymphoma.

OBJECTIVES:

Primary

* Determine the safety and efficacy of motexafin gadolinium (MGd) combined with high-dose methotrexate-based chemotherapy and radiotherapy in patients with newly diagnosed primary CNS lymphoma.
* Determine the toxicity of MGd and rituximab combined with high-dose methotrexate, procarbazine hydrochloride, and vincristine (MPV) in these patients.
* Determine the toxicity of MGd in combination with whole-brain radiotherapy (WBRT) in these patients.
* Determine the tumor-selective uptake of MGd.

Secondary

* Determine the overall response rate (complete remission \[CR\] and partial remission \[PR\]) in patients treated with pre-radiotherapy and chemo-immunotherapy (R-MPV with MGd).
* Determine the complete response rate in patients treated with this regimen.
* Determine the overall response rate (CR and PR) in patients who complete all MGd combined with high-dose methotrexate-based chemotherapy and WBRT.
* Determine the event-free and overall survival at 1 year of patients treated with this regimen.
* Determine the progression-free survival at 1 year of patients treated with this regimen.
* Evaluate the neurotoxicity of R-MVP with MGd based on pre- and post-treatment neuropsychologic testing.

OUTLINE:

* Tumor-selective imaging: Patients receive motexafin gadolinium (MGd) IV on days 1-2 beginning 1-2 weeks prior to induction therapy. They then undergo an MRI of the brain.
* Induction therapy: Patients receive methotrexate IV over 2-3 hours and vincristine IV on day 1 and rituximab IV over 5 hours and MGd IV over 30-60 minutes on day 8. Patients also receive oral procarbazine hydrochloride on days 1-7 of courses 1, 3, and 5. Treatment repeats every 14 days for 5 courses in the absence of disease progression or unacceptable toxicity. Patients with partial response receive an additional 2 courses of induction therapy.
* Chemoradiotherapy: Beginning 4 weeks after completion of induction therapy, patients undergo reduced-dose whole-brain radiotherapy for 6 weeks. Patients also receive MGd IV over 30-60 minutes, beginning 2-5 hours prior to radiotherapy, for 10 days and then every other day during radiotherapy.
* Consolidation therapy: After completion of chemoradiotherapy, patients receive cytarabine IV over 3 hours on days 1-2. Treatment repeats every 30 days for 2 courses.

After completion of study therapy, patients are followed every 3 months for the first year, every 3-4 months for the second year, every 4-6 months until the fifth year, and then annually thereafter.

Pilot Study of MGd + High-dose MTX-Based Chemoimmunotherapy + RT for Newly Dx PCNSL

A Pilot Study Incorporating Motexafin Gadolinium (MGd) Into High-dose Methotrexate (MTX)-Based Chemo-immunotherapy and Radiation for Patients With Newly Diagnosed Primary CNS Lymphoma

To evaluate toxicity of motexafin gadolinium (MGd) and rituximab to high-dose methotrexate, procarbazine hydrochloride, and vincristine (MPV) chemotherapy at Day 1 (every 2 weeks), After 5th cycle, After 7th cycle, Pre Radiation Theray, Post Radiation Therapy, and Post ara-c.

To evaluate the toxicity of MGd added to whole-brain radiotherapy (WBRT).

To evaluate Tumor-selective uptake of MGd

MRI scan will be done with each neurologic evaluation. Neuropsychologic evaluation will be repeated approximately 6 months after the completion of therapy and at 6 months intervals thereafter for total of 2 years.

Repeat CSF or ocular exam will be done 3 months after completion of treatment in those patients who had evidence of CSF or ocular involvement at diagnosis. CSF will be sampled at each visit. Ocular exams will occur every 3 months for the 1st year then every 4-6 months. Further exams will only be done as needed to rule out recurrent lymphoma.

To assess progression-free survival rate.

MR perfusion and MR spectroscopy at baseline and serially when MRI imaging is done to assess response rates using these alternate forms of imaging.

Pharmacyclics LLC.

Northwestern University

Andrew M. Evens

Temozolomide

Topotecan

Topoisomerase I Inhibitors

Patient will take on days 1-5 of a 28-days schedule. Take Topotecan on days 2-6 of the 28 day schedule

Patient will take drug on day 1-5 of 28 day schedule

temozolomide

Patient will have IV on days 2-6 on a 28-day schedule

topotecan hydrochloride

Pamela Z. New, MD

RATIONALE: Drugs used in chemotherapy, such as temozolomide and topotecan, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells.

PURPOSE: This phase II trial is studying how well giving temozolomide together with topotecan works in treating patients with primary CNS lymphoma.

OBJECTIVES:

Primary

* Determine the complete radiologic response rate in patients with primary CNS lymphoma treated with salvage chemotherapy comprising temozolomide and topotecan.

Secondary

* Determine the median and failure-free survival of patients treated with this regimen.
* Determine the toxicity of this regimen in these patients.
* Determine the overall response rate in patients treated with this regimen.

OUTLINE: This is an open-label study.

Patients receive oral temozolomide once daily on days 1-5 and topotecan IV over 30 minutes once daily on days 2-6. Treatment repeats every 28 days for 6-8 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 3 months for 1 year, every 4 months for 1 year, and then every 6 months for 3 years.

PROJECTED ACCRUAL: A total of 6-25 patients will be accrued for this study.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Orelabrutinib and Sintilimab in Relapsed or Refractory Central Nervous System Lymphoma	NCT04961515	Primary Central...	Orelabrutinib Orelabrutinib Sintilimab	18 Years - 75 Years	Second Affiliated Hospital, School of Medicine, Zhejiang University
Treating Patients With Recurrent PCNSL With Carboplatin/BBBD and Adding Rituxan To The Treatment Regimen	NCT00074165	Brain and Centr... Drug/Agent Toxi... Lymphoma Thrombocytopeni...	Rituxan Cyclophosphamid... Etoposide Etoposide phosp... Carboplatin Sodium thiosulf... Neupogen Neulasta Cytarabine	18 Months - 75 Years	OHSU Knight Cancer Institute
Pilot Study of MGd + High-dose MTX-Based Chemoimmunotherapy + RT for Newly Dx PCNSL	NCT00734773	Brain and Centr... Lymphoma Neurotoxicity	Rituximab Cytarabine Methotrexate Motexafin gadol... Procarbazine hy... Vincristine sul... Radiation thera...	18 Years -	Northwestern University
Temozolomide and Topotecan in Treating Patients With Primary CNS Lymphoma	NCT00109798	Central Nervous... Lymphoma	temozolomide topotecan hydro...	18 Years - 75 Years	The Methodist Hospital Research Institute

Spots Global Cancer Trial Database for primary central nervous system hodgkin lymphoma