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

Primary Central Nervous System Lymphoma Clinical Trial

— 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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05036577
• Other study ID #: KY2021-726
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: October 10, 2021
• Est. completion date: September 30, 2024

Study information

• Verified date: October 2023
• Source: Huashan Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 15
• Est. completion date: September 30, 2024
• Est. primary completion date: December 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Lymphoma
• Primary Central Nervous System Lymphoma

Intervention

Drug:
• Orelabrutinib
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).
• Rituximab
Rituximab 375 mg/m2 intravenous infusion d1, every 21 days for 6-8 cycles during combination induction treatment.
• Methotrexate (MTX)
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.
• Dexamethasone
Dexamethasone 10-15 mg, iv, d1-4, every 21 days for 6-8 cycles during combination induction treatment.

Locations

Country	Name	City	State
China	Department of Hematology, Huashan Hospital, Fudan University	Shanghai	Shanghai

Sponsors (1)

Lead Sponsor	Collaborator
Huashan Hospital

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	concentration of Orelabrutinib	To detect the blood and CSF 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)
Other	gene mutations and frequency	The types of gene mutations and frequency of tumor are measured by whole exon sequencing.	At baseline
Other	cytokine in the CSF	The levels of cytokine will be analyzed by flow cytometry.	At the baseline, day 1 at cycle 3, 5 (21 days/cycle), and every 3 months in the maintenance stage (up to 1 year))
Other	circulating tumor DNA (ctDNA) in the CSF	The levels of ctDNA will be analyzed by next-generation sequencing.	At the baseline, day 1 at cycle 3, 5 (21 days/cycle), and every 3 months in the maintenance stage (up to 1 year))
Primary	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	ORRi	ORRi is defined as the proportion of patients with a best response of CR, CRu or PR during induction therapy	At the end of cycle 6-8 (each cycle is 21 days)
Secondary	CRi	CRi is defined as the proportion of patients with a best response of CR or CRu during induction treatment	At the end of cycle 6-8 (each cycle is 21 days)
Secondary	TTR	Time to response during induction therapy	At the end of cycle 6-8 (each cycle is 21 days)
Secondary	ORRm	ORRm is defined as the proportion of patients with a best response of CR, CRu or PR during maintenance therapy	At the end of completion of 1 year of maintenance treatment
Secondary	CRm	CRm is defined as the proportion of patients with a best response of CR or CRu during maintenance therapy	At the end of completion of 1 year of maintenance treatment
Secondary	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.	Up to 2 years
Secondary	Overall survival	Overall survival is defined as the duration from start of treatment to time of death.	Up to 2 years