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

NCT05036577 | Active Not Recruiting Phase 1 DMC

• 1 other identifier: KY2021-726
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

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.

Conditions

Primary Central Nervous System Lymphoma

Outcome Measures

Primary Outcomes (1)

• 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)

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

Secondary Outcomes (7)

• ORRi

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

• CRi

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

• TTR

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

• ORRm

  At the end of completion of 1 year of maintenance treatment

• CRm

  At the end of completion of 1 year of maintenance treatment

Other Outcomes (4)

• concentration of Orelabrutinib

  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)

• gene mutations and frequency

  At baseline

• cytokine in the CSF

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

Study Arms (1)

ORMD (Orelabrutinib, Rituximab, Methotrexate and Dexamethasone)

EXPERIMENTAL

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.

Drug: Orelabrutinib; Drug: Rituximab; Drug: Methotrexate (MTX); Drug: Dexamethasone

Interventions

Orelabrutinib DRUG

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).

ORMD (Orelabrutinib, Rituximab, Methotrexate and Dexamethasone)

Rituximab DRUG

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

ORMD (Orelabrutinib, Rituximab, Methotrexate and Dexamethasone)

Methotrexate (MTX) DRUG

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.

ORMD (Orelabrutinib, Rituximab, Methotrexate and Dexamethasone)

Dexamethasone DRUG

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

ORMD (Orelabrutinib, Rituximab, Methotrexate and Dexamethasone)

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Huashan Hospital: lead

Study Sites (1)

Department of Hematology, Huashan Hospital, Fudan University

Shanghai, Shanghai Municipality, 200040, China

Location

MeSH Terms

Interventions

orelabrutinib; Rituximab; Methotrexate; Dexamethasone

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Study Officials

• Tong Chen

  Huashan Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: August 27, 2021
• First Posted: September 5, 2021
• Study Start: October 10, 2021
• Primary Completion: December 31, 2023
• Study Completion: September 30, 2025
• Last Updated: October 18, 2024

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)