A Prospective Clinical Study of BTK Inhibitor, PD-1 and Formustine in the First-line Treatment of Primary Central Nervous System Lymphoma

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ClinicalTrials.gov Identifier: NCT04831658

Recruitment Status : Recruiting

First Posted : April 5, 2021

Last Update Posted : November 15, 2021

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Sponsor:

Information provided by (Responsible Party):

Mingzhi Zhang, Zhengzhou University

Study Description

Brief Summary:

To observe the efficacy and safety of a new generation of BTK inhibitor Orelabrutinib combined with PD-1 and fotemustine in the treatment of patients with primary central nervous system lymphoma (PCNSL).

Condition or disease	Intervention/treatment	Phase
Primary Central Nervous System Lymphoma	Drug: the dose-escalation phase	Phase 2

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Detailed Description:

This study includes a dose escalation phase and an extended treatment phase . The dose-escalation phase： Primary study endpoint: Safety endpoint: including dose-limiting toxicity (DLT), adverse events, ECOG performance score, laboratory tests, vital signs, physical examination .

Secondary research endpoints: effectiveness endpoints: including complete response rate (CRR), objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).

The study adopts the "3+3" design, that is, 3-6 subjects in each group complete the administration, and the dose group determined as the maximum tolerated dose (MTD) is included in the group of 6 subjects, totaling 9-18 example. The dose planned to be explored is the daily oral dose of the BTK inhibitor abutinib, which is 100 mg, 150 mg and 200 mg, respectively. The doses of other drugs in the plan will not be escalated.

After the last subject in each dose group completes the 28-day restricted toxicity (DLT) assessment window after the administration, the investigator can start the entry into the next dose group after evaluating and agreeing to enter the next dose group based on clinical safety data.

When 1 case of DLT occurs among 3 subjects in a certain dose group, 3 subjects need to be added to the same dose group (6 subjects in this dose group complete the DLT assessment): If the additional 3 subjects are tested If there is no DLT, continue the dose escalation; if 1 of the 3 increased subjects has DLT, stop the dose escalation; if the increased 3 subjects have >1 of the subjects DLT, the dose escalation is stopped, and the dose needs to be lowered to continue to enroll 3 subjects for DLT evaluation. If DLT occurs in 2 of the 3 or 6 subjects in the dose group, then the previous low dose is defined as the maximum tolerated dose (MTD).

The extended treatment phase :

Primary study endpoints: objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) .

Secondary endpoints: time to disease progression (TTP), median survival (MST), adverse reactions (ADR), quality of life (QOL) .

The study adopts an open, one-arm, prospective clinical collaborative study . The initial treatment is BTK inhibitor (Obutinib), PD-1 monoclonal antibody combined with formustine ：Orelabrutinib continues to be taken orally until the tumor is relieved for 3 months; PD-1 monoclonal antibody is used by intravenous drip, 21 days as a treatment cycle, and a total of 1 year of observation; formustine is used by intravenous drip for 21 days It is a treatment cycle, a total of 6 cycles of observation; after 2 cycles, the efficacy is evaluated, and adverse reactions are recorded. At the same time, MTX 12mg+Ara-C 50mg+Dex 5mg was injected into the CSF cytology-positive sheath, and intrathecal injection once per treatment cycle, a total of 6 times.

Second stage treatment ：The efficacy was evaluated after 6 cycles of treatment in the initial stage. The CR patients continued to take orally abutinib (150mg, qd) for three months, and the PD-1 monoclonal antibody was used for maintenance treatment for up to 1 year; the PR patients received whole brain radiotherapy (WBRT), and at the same time Continue oral obritinib (150mg, qd) for three months and PD-1 monoclonal antibody maintenance treatment for up to one year; SD and PD patients choose methotrexate + pemetrexed combined chemotherapy for 4 cycles followed by whole brain radiotherapy (WBRT). WBRT: Regardless of age, supplementary WBRT 30-36Gy + partial reduction field irradiation up to 45Gy.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	40 participants
Allocation:	N/A
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Prospective Clinical Study of a New Generation of BTK Inhibitors Combined With PD-1 and Formustine in the First-line Treatment of Primary Central Nervous System Lymphoma
Actual Study Start Date :	March 29, 2021
Estimated Primary Completion Date :	September 15, 2023
Estimated Study Completion Date :	September 15, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Genetic and Rare Diseases Information Center resources: Lymphosarcoma Primary Central Nervous System Lymphoma

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Experimental: Orelabrutinib combined with PD-1 and fotemustine To observe the efficacy and safety of a new generation of BTK inhibitor abutinib combined with PD-1 and formustine in the treatment of newly-treated patients with primary central nervous system lymphoma (PCNSL)	Drug: the dose-escalation phase The study adopts the "3+3" design,The dose planned to be explored is the daily oral dose of the BTK inhibitor abutinib, which is 100 mg, 150 mg and 200 mg, respectively.Orelabrutinib continues to be taken orally until the tumor is relieved for 3 months; PD-1 monoclonal antibody is used by intravenous drip, 21 days as a treatment cycle, and a total of 1 year of observation; formustine is used by intravenous drip for 21 days It is a treatment cycle, a total of 6 cycles of observation; after 2 cycles, the efficacy is evaluated, and adverse reactions are recorded. At the same time, MTX 12mg+Ara-C 50mg+Dex 5mg was injected into the CSF cytology-positive sheath, and intrathecal injection once per treatment cycle, a total of 6 times. Other Name: The extended treatment phase

Arm

Intervention/treatment

Experimental: Orelabrutinib combined with PD-1 and fotemustine

To observe the efficacy and safety of a new generation of BTK inhibitor abutinib combined with PD-1 and formustine in the treatment of newly-treated patients with primary central nervous system lymphoma (PCNSL)

Drug: the dose-escalation phase

The study adopts the "3+3" design,The dose planned to be explored is the daily oral dose of the BTK inhibitor abutinib, which is 100 mg, 150 mg and 200 mg, respectively.Orelabrutinib continues to be taken orally until the tumor is relieved for 3 months; PD-1 monoclonal antibody is used by intravenous drip, 21 days as a treatment cycle, and a total of 1 year of observation; formustine is used by intravenous drip for 21 days It is a treatment cycle, a total of 6 cycles of observation; after 2 cycles, the efficacy is evaluated, and adverse reactions are recorded. At the same time, MTX 12mg+Ara-C 50mg+Dex 5mg was injected into the CSF cytology-positive sheath, and intrathecal injection once per treatment cycle, a total of 6 times.

Other Name: The extended treatment phase

Outcome Measures

Primary Outcome Measures :

DLT [ Time Frame: up to 24 months ]
Dose-limiting toxicity
AE [ Time Frame: up to 24 months ]
adverse events
ECOG performance score [ Time Frame: up to 24 months ]
ECOG performance score
laboratory tests [ Time Frame: up to 24 months ]
laboratory tests
vital signs [ Time Frame: up to 24 months ]
vital signs
physical examination [ Time Frame: up to 24 months ]
physical examination
ORR [ Time Frame: up to 24 months ]
Objective Responder Rate
DCR [ Time Frame: up to 24 months ]
Disease Control Rate
PFS [ Time Frame: up to 24 months ]
Progression Free Survival
OS [ Time Frame: up to 24 months ]
Overall Survival

Secondary Outcome Measures :

ORR [ Time Frame: up to 24 months ]
Objective Responder Rate
DCR [ Time Frame: up to 24 months ]
Disease Control Rate
PFS [ Time Frame: up to 24 months ]
Progression Free Survival
OS [ Time Frame: up to 24 months ]
Overall Survival
ADR [ Time Frame: up to 24 months ]
Adverse Reaction Rate
CRR [ Time Frame: up to 24 months ]
complete response rate
TTP [ Time Frame: up to 24 months ]
Time to disease progression
MST [ Time Frame: up to 24 months ]
median survival
ADR [ Time Frame: up to 24 months ]
adverse reactions
QOL [ Time Frame: up to 24 months ]
quality of life

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 69 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Age 18-69 years; KPS score ≥ 60 points or ECOG score ≤ 2 points; expected survival time of more than 3 months; PCNSL confirmed pathologically by tissue biopsy (limited to the brain, not accompanied by lymphoma in other parts of the body) , And histopathological type is diffuse large B-cell lymphoma; no chemotherapy contraindications (blood picture and physiological examination result time <7 days); at least one measurable lesion according to RECIST standards; no other serious diseases that conflict with this plan ; Follow-up is possible; other anti-tumor drugs are not used during this treatment period, and bisphosphonate anti-bone metastasis therapy and other symptomatic treatments can be applied; understand the situation of this study and sign the informed consent.

Exclusion Criteria:

Those who are currently receiving other chemical, radiotherapy and targeted therapies (received chemotherapy within 3 weeks, received radiotherapy within 2 weeks, or have not recovered from the acute toxicity of any previous treatment); pregnant or lactating women; yes Any uncontrollable medical disease (including active infection, uncontrolled diabetes, severe heart, liver, kidney dysfunction, and interstitial pneumonia, etc.); those who are contraindicated with chemotherapy such as cachexia; have had other malignant tumors in the past Those who have uncontrolled infections; those who have a history of uncontrollable mental illness; those who are considered unsuitable to participate in this trial by the investigator.

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04831658

Contacts

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Contact: Mingzhi zhang, Pro.Dr.	13838565629	Mingzhi_zhang@126.com

Locations

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China, Henan
Oncology Department of The First Affiliated Hospital of Zhengzhou University	Recruiting
Zhengzhou, Henan, China, 450052
Contact: Mingzhi Zhang, Doctor 13838565629 mingzhi_zhang@126.com

Sponsors and Collaborators

Mingzhi Zhang

Investigators

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Principal Investigator:	Mingzhi zhang	The First Affiliated Hospital of Zhengzhou University

More Information

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Responsible Party:	Mingzhi Zhang, the director of oncology department of the first affiliated hospital, Zhengzhou University
ClinicalTrials.gov Identifier:	NCT04831658
Other Study ID Numbers:	hnslblzlzx20210303
First Posted:	April 5, 2021 Key Record Dates
Last Update Posted:	November 15, 2021
Last Verified:	November 2021

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Studies a U.S. FDA-regulated Drug Product:	No
Studies a U.S. FDA-regulated Device Product:	No

Keywords provided by Mingzhi Zhang, Zhengzhou University:


BTK inhibitor PD-1 fotemustine CRR ORR DCR PFS OS ADR	Adverse events ECOG score laboratory examination vital signs physical examination Time to disease progression (TTP) median survival (MST) quality of life (QOL) adverse reactions (ADR)

Additional relevant MeSH terms:

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Lymphoma Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders	Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases

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