Clinical trial NCT05036577: A Dose-escalating Pilot Study of Orelabrutinib for Newly-diagnosed PCNSL
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
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Primary Central Nervous System Lymphoma
Lead sponsor: Huashan Hospital
Sponsor class: OTHER
First posted: 2021-09-05
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: define the Maximum tolerated dose (MTD) contour of Orelabrutinib and MTX
timeFrame: From the start of the first dose of Orelabrutinib to the end of the first cycle of induction treatment (21 days/cycle)
Secondary outcomes:
measure: ORRi
timeFrame: At the end of cycle 6-8 (each cycle is 21 days)
measure: CRi
timeFrame: At the end of cycle 6-8 (each cycle is 21 days)
measure: TTR
timeFrame: At the end of cycle 6-8 (each cycle is 21 days)
measure: ORRm
timeFrame: At the end of completion of 1 year of maintenance treatment
measure: CRm
timeFrame: At the end of completion of 1 year of maintenance treatment
measure: Progression-free survival
timeFrame: Up to 2 years
measure: Overall survival
timeFrame: Up to 2 years
Other outcomes:
measure: concentration of Orelabrutinib
timeFrame: 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)
measure: gene mutations and frequency
timeFrame: At baseline
measure: cytokine in the CSF
timeFrame: At the baseline, day 1 at cycle 3, 5 (21 days/cycle), and every 3 months in the maintenance stage (up to 1 year))
measure: circulating tumor DNA (ctDNA) in the CSF
timeFrame: At the baseline, day 1 at cycle 3, 5 (21 days/cycle), and every 3 months in the maintenance stage (up to 1 year))
Locations:
city: Shanghai
country: China
facility: Department of Hematology, Huashan Hospital, Fudan University
state: Shanghai
Study officials:
affiliation: Huashan Hospital
name: Tong Chen
role: PRINCIPAL_INVESTIGATOR
References: