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A Dose-escalating Pilot Study of Orelabrutinib for Newly-diagnosed PCNSL (ORMD2021)

Primary Purpose

Primary Central Nervous System Lymphoma

Status

Recruiting

Phase

Phase 1

Locations

China

Study Type

Interventional

Intervention

Orelabrutinib

Rituximab

Methotrexate (MTX)

Dexamethasone

About this trial

This is an interventional treatment trial for Primary Central Nervous System Lymphoma

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

anti-neoplasm systemic treatement naive primary central nervous system lymphoma
Pathological type is diffuse large B cell lymphoma
Enough residual sample of tumor after pathological diagnosis
ECOG =<3
Life expectancy >3 months
Adequate organ function and adequate bone marrow reserve
Must be able to tolerate lumbar puncture and/or have Omaya tube
Participant or his/her legal agent must be willing to sign a written informed consent document.

Exclusion Criteria:

Lymphoma invading outside CNS
Lymphoma only existed in vitreo-retina
Severe or uncontrolled cardiovascular disease
Active hemorrhage within 2 months prior screening
Cerebral ischemic stroke or bleeding within 6 months prior screening
Organ transplantation or allogeneic hematopoietic stem cell transplantation history
Other surgery history within 6 weeks prior screening
Anti-tumor herbal medicine treatment within 4 weeks prior screening
Activated or uncontrolled hepatitis virus B infection (HBsAg positive with/or HBc Ab positive and HBV-DNA titration positive), hepatitis virus C antibody positive, HIV positive.
Uncontrolled active systemic fungal, bacterial, virus or other microbe infection, or intravenous injection of antibiotics needed
Accepted live vaccine or immunization within 4 weeks prior eligibility
Continuously taking drugs with medium / strong inhibition or induction of cytochrome P450 CYP3A is needed
Allergy to orelabrutinib or the subsidiary (or supplementary) material (Hydroxypropyl methylcellulose acetate succinate, mannitol, cross-linked sodium carboxymethylcellulose, hydroxypropyl cellulose, silica and magnesium stearate)
Obvious gastro-bowel disease which may influence the intaking, transportation or absorption of the drug, or total gastrectomy
Past or present pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonia, or drug-related pneumonia, with severe impairment of pulmonary function
Chronic liver damage, severe fatty liver or alcoholic liver disease
Intention to undergo autologous stem cell transplantation
Pregnant or breeding women, or women of childbearing age who are unwilling to take contraceptive measures during the whole study period and within 180 days after the last administration of the study drug; non surgically sterilized men who are unwilling to take contraceptive measures during the whole study period and within 180 days of the last administration of the study drug.
Potentially life-threatening situation, or severe organ dysfunction, or situations the researchers believe not suitable for the trial
Any mental or cognitive impairment which may limit the understanding and implementation of informed consent or the compliance with the study.
previously exposed with WBRT

Sites / Locations

Department of Hematology, Huashan Hospital, Fudan UniversityRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

ORMD (Orelabrutinib, Rituximab, Methotrexate and Dexamethasone)

Arm Description

Patients were treated for 6-8 cycles of induction therapy with 21 days per cycle, receiving rituximab (375mg/m2 on day 1), dexamethasone (10-15mg on d1-d4), MTX (d2, 3.5g/m2 or 5g/m2), and orelabrutinib (once daily, after MTX clearance, 150mg/d, or 200mg/d), followed by orelabrutinib maintenance up to one year among CR/CRu patients or until disease progression, intolerable toxicity, death, informed consent withdrawal or lost of follow up (whichever occurs first). The primary objective was to determine the maximum tolerated dose (MTD) of the combination of orelabrutinib and MTX with R and D and investigate the safety and tolerability of this regimen using Bayesian Optimal Interval (BOIN) waterfall design to determine rule of dose escalation and movement among dose combination matrix to identify MTD contour.

Outcomes

Primary Outcome Measures

define the Maximum tolerated dose (MTD) contour of Orelabrutinib and MTX

A BOIN waterfall design will be employed. Two dose levels of Orelabrutinib (dose level 1: 150 mg/d, dose level 2: 200 mg/d) and two dose levels of MTX (dose level 1: 3.5g/m2, dose level 2: 5g/m2) will be investigated, generating 4 dose combination. DLT was defined by the occurrence of severe toxicities during the first cycle: any grade 4 hematologic toxicity, grade 3 febrile neutropenia and grade 3 thrombocytopenia with hemorrhage, or any grade 3 non-hematologic toxicity that failed to respond to supportive therapy and possibly related to orelabrutinib and/or MTX (assessed according to NCI CTCAE V5.0)

Secondary Outcome Measures

ORRi

ORRi is defined as the proportion of patients with a best response of CR, CRu or PR during induction therapy

CRi

CRi is defined as the proportion of patients with a best response of CR or CRu during induction treatment

TTR

Time to response during induction therapy

ORRm

ORRm is defined as the proportion of patients with a best response of CR, CRu or PR during maintenance therapy

CRm

CRm is defined as the proportion of patients with a best response of CR or CRu during maintenance therapy

Progression-free survival

Progression-free survival is calculated from the date of start of therapy until the date of first documented progress or death due to any cause.

Overall survival

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

Full Information

NCT ID

NCT05036577

First Posted

August 27, 2021

Last Updated

July 26, 2022

Sponsor

Huashan Hospital

1. Study Identification

Unique Protocol Identification Number

NCT05036577

Brief Title

A Dose-escalating Pilot Study of Orelabrutinib for Newly-diagnosed PCNSL

Acronym

ORMD2021

Official Title

A Dose-escalating Pilot Study of Orelabrutinib in Combination With Rituximab, Methotrexate and Dexamethasone for Newly-diagnosed Primary Central Nervous System Lymphoma

Study Type

Interventional

2. Study Status

Record Verification Date

July 2022

Overall Recruitment Status

Recruiting

Study Start Date

October 10, 2021 (Actual)

Primary Completion Date

December 31, 2022 (Anticipated)

Study Completion Date

September 30, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Huashan Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

This is a single arm, single center, open label pilot study of Orelabrutinib combined with Rituximab, high-dose (HD) Methotrexate and Dexamethasone in newly-diagnosed primary central nervous system lymphpoma (PCNSL). The purpose is to evaluate the safety and to find the optimal dose of Orelabrutinib and Methotrexate in this combination treatment for newly-diagnosed PCNSL patients.

Detailed Description

The eligible patients will be treated with Orelabrutinib combined with Rituximab, high-dose Methotrexate and Dexamethasone during induction treatment (6-8 cycles; 21 days/cycle): Rituximab 375 mg/m2, intravenous infusion, d1; HD-MTX 3.5 g/m2 intravenous infusion (3h), d2; Dexamethasone 10-15 mg, iv, d1-4. Orelabrutinib will be given 72h after MTX infusion or until MTX clearance. The study will investigate optimal dose combination of Orelabrutinib and MTX implementing BOIN waterfall design. The starting dose of Orelabrutinib is 150 mg/d and the dose will be escalated to 200 mg/d, throughout the whole cycle. Meanwhile, the starting dose of MTX is 3g/m2 and will be escalated to 5g/m2, throughout induction phase. Dose escalation and movement in dose matrix will be determined by BOIN algorithm. For CR/CRu patients after completion of induction treatment, daily Orelabrutinib will be administered as maintenance treatment for up to 1 year or until disease progression, intolerable toxicity, death, informed consent withdrawal or lost of follow up (whichever occurs first). Patients will be evaluated every 2 cycles during induction therapy and every 12 weeks during maintenance therapy.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Primary Central Nervous System Lymphoma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

15 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

ORMD (Orelabrutinib, Rituximab, Methotrexate and Dexamethasone)

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Orelabrutinib

Intervention Description

Orelabrutinib will be given as 150 mg/d or 200 mg/d orally 72h after MTX infusion or MTX clearance, every 21 days for 6-8 cycles during combination induction treatment. Daily Orelabrutinb with dose in last cycle of induction will be administered as maintenance treatment for up to 1 year or until disease progression, intolerable toxicity, death, informed consent withdrawal or lost of follow up (whichever occurs first).

Intervention Type

Drug

Intervention Name(s)

Rituximab

Intervention Description

Rituximab 375 mg/m2 intravenous infusion d1, every 21 days for 6-8 cycles during combination induction treatment.

Intervention Type

Drug

Intervention Name(s)

Methotrexate (MTX)

Intervention Description

high-dose Methotrexate 3.5 g/m2 or 5g/m2 intravenous infusion (3h) d2, every 21 days for 6-8 cycels during combination induction treatment.

Intervention Type

Drug

Intervention Name(s)

Dexamethasone

Intervention Description

Dexamethasone 10-15 mg, iv, d1-4, every 21 days for 6-8 cycles during combination induction treatment.

Primary Outcome Measure Information:

Title

define the Maximum tolerated dose (MTD) contour of Orelabrutinib and MTX

Description

Time Frame

From the start of the first dose of Orelabrutinib to the end of the first cycle of induction treatment (21 days/cycle)

Secondary Outcome Measure Information:

Title

ORRi

Description

ORRi is defined as the proportion of patients with a best response of CR, CRu or PR during induction therapy

Time Frame

At the end of cycle 6-8 (each cycle is 21 days)

Title

CRi

Description

CRi is defined as the proportion of patients with a best response of CR or CRu during induction treatment

Time Frame

At the end of cycle 6-8 (each cycle is 21 days)

Title

TTR

Description

Time to response during induction therapy

Time Frame

At the end of cycle 6-8 (each cycle is 21 days)

Title

ORRm

Description

ORRm is defined as the proportion of patients with a best response of CR, CRu or PR during maintenance therapy

Time Frame

At the end of completion of 1 year of maintenance treatment

Title

CRm

Description

CRm is defined as the proportion of patients with a best response of CR or CRu during maintenance therapy

Time Frame

At the end of completion of 1 year of maintenance treatment

Title

Progression-free survival

Description

Progression-free survival is calculated from the date of start of therapy until the date of first documented progress or death due to any cause.

Time Frame

Up to 2 years

Title

Overall survival

Description

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

Time Frame

Up to 2 years

Other Pre-specified Outcome Measures:

Title

concentration of Orelabrutinib

Description

To detect the blood and CSF concentration of Orelabrutinib

Time Frame

The blood and CSF concentration of Orelabrutinib will be evaluated 1.5-2 hours after Orelabrutinib administration before first day of cycle 3.(each cycle is 21 days)

Title

gene mutations and frequency

Description

The types of gene mutations and frequency of tumor are measured by whole exon sequencing.

Time Frame

At baseline

Title

cytokine in the CSF

Description

The levels of cytokine will be analyzed by flow cytometry.

Time Frame

At the baseline, day 1 at cycle 3, 5 (21 days/cycle), and every 3 months in the maintenance stage (up to 1 year))

Title

circulating tumor DNA (ctDNA) in the CSF

Description

The levels of ctDNA will be analyzed by next-generation sequencing.

Time Frame

At the baseline, day 1 at cycle 3, 5 (21 days/cycle), and every 3 months in the maintenance stage (up to 1 year))

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: anti-neoplasm systemic treatement naive primary central nervous system lymphoma Pathological type is diffuse large B cell lymphoma Enough residual sample of tumor after pathological diagnosis ECOG =<3 Life expectancy >3 months Adequate organ function and adequate bone marrow reserve Must be able to tolerate lumbar puncture and/or have Omaya tube Participant or his/her legal agent must be willing to sign a written informed consent document. Exclusion Criteria: Lymphoma invading outside CNS Lymphoma only existed in vitreo-retina Severe or uncontrolled cardiovascular disease Active hemorrhage within 2 months prior screening Cerebral ischemic stroke or bleeding within 6 months prior screening Organ transplantation or allogeneic hematopoietic stem cell transplantation history Other surgery history within 6 weeks prior screening Anti-tumor herbal medicine treatment within 4 weeks prior screening Activated or uncontrolled hepatitis virus B infection (HBsAg positive with/or HBc Ab positive and HBV-DNA titration positive), hepatitis virus C antibody positive, HIV positive. Uncontrolled active systemic fungal, bacterial, virus or other microbe infection, or intravenous injection of antibiotics needed Accepted live vaccine or immunization within 4 weeks prior eligibility Continuously taking drugs with medium / strong inhibition or induction of cytochrome P450 CYP3A is needed Allergy to orelabrutinib or the subsidiary (or supplementary) material (Hydroxypropyl methylcellulose acetate succinate, mannitol, cross-linked sodium carboxymethylcellulose, hydroxypropyl cellulose, silica and magnesium stearate) Obvious gastro-bowel disease which may influence the intaking, transportation or absorption of the drug, or total gastrectomy Past or present pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonia, or drug-related pneumonia, with severe impairment of pulmonary function Chronic liver damage, severe fatty liver or alcoholic liver disease Intention to undergo autologous stem cell transplantation Pregnant or breeding women, or women of childbearing age who are unwilling to take contraceptive measures during the whole study period and within 180 days after the last administration of the study drug; non surgically sterilized men who are unwilling to take contraceptive measures during the whole study period and within 180 days of the last administration of the study drug. Potentially life-threatening situation, or severe organ dysfunction, or situations the researchers believe not suitable for the trial Any mental or cognitive impairment which may limit the understanding and implementation of informed consent or the compliance with the study. previously exposed with WBRT

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Tong Chen

Phone

+862152887102

chentong@fudan.edu.cn

First Name & Middle Initial & Last Name or Official Title & Degree

Yan Yuan

Phone

+862152888283

yuanyan@fudan.edu.cn

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Tong Chen

Organizational Affiliation

Huashan Hospital

Official's Role

Principal Investigator

Facility Information:

Facility Name

Department of Hematology, Huashan Hospital, Fudan University

City

Shanghai

State/Province

Shanghai

ZIP/Postal Code

200040

Country

China

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Tong Chen

Phone

+862152887102

chentong@fudan.edu.cn

First Name & Middle Initial & Last Name & Degree

Yan Yuan

Phone

+862152888283

yuanyan@fudan.edu.cn

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

A Dose-escalating Pilot Study of Orelabrutinib for Newly-diagnosed PCNSL

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