Orelabrutinib in Combination With Thiotepa in Refractory and Relapsed Primary CNS Lymphoma

NCT05021770 | Unknown Phase 1

• 1 other identifier: OT
• Study Type: interventional
• Target: 29
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study was to investigate the maximum tolerated dose and efficacy of Orelabrutinib combined with Thiotepa in refractory and relapsed primary central nervous system lymphoma (PCNSL).

Conditions

Refractory and Relapsed Primary CNS Lymphoma; PCNSL; Non Hodgkin Lymphoma

Keywords

PCNSL

Outcome Measures

Primary Outcomes (2)

• Part 1 Dose Escalation：The maximum tolerated dose (MTD)

  To determine the maximum tolerated dose (MTD)

  Incidence of dose limiting toxicities (DLTs) up to 21 days

• Part 2 Dose Expansion：ORR (Investigator-Assessed)

  The overall response rate (ORR) including complete response (CR), unconfirmed complete (CRu) and partial response (PR) according to the 2005 Response Criteria of the International Primary CNS Lymphoma Collaborative Group (IPCG)

  Up to 2 years

Secondary Outcomes (12)

• Part 1 Dose Escalation：Objective response rate (ORR)

  Up to 2 years

• Part 1 Dose Escalation：Compelet response rate (CRR)

  Up to 2 years

• Part 1 Dose Escalation：Duration of overall response (DOR)

  Up to 2 years

• Part 1 Dose Escalation：Disease control rate (DCR)

  Up to 2 years

• Part 1 Dose Escalation：Progression-free survival (PFS)

  Up to 2 years

Other Outcomes (1)

• Describe the tumor mutation profile by NGS

  Up to 2 years

Study Arms (2)

Phase Ib

EXPERIMENTAL

Orelabrutinib dose escalation will occur using a standard 3+3 dose-escalation approach to determined the maximum tolerated dose(MTD) of orelabrutinib dose in combined with thiotepa, beginning at dose level I (150 mg daily) and potentially escalating to dose level 2 (200mg) with rules for escalation and de-escalation. If the dose-limiting toxicity is not found, the dose of 200mg will be used for phase II trial (RP2D). Orelabrutinib: 150mg or 200mg orally daily. Thiotepa: The dose of thiotepa is fixed as 30 mg/m2 intravenously every 3 weeks (maximum 6 cycle).

Drug: Orelabrutinib; Drug: Thiotepa

Phase II

EXPERIMENTAL

Participants will receive orelabrutinib and thiotepa at the pre-determined dosage level established in Phase 1b, until progression of the disease (PD), unacceptable toxicity, or patient/investigator discretion. The response will be evaluated every 2 cycles. Orelabrutinib: RP2D (150 mg or 200 mg qd) Thiotepa:Sintilimab: The dose of thiotepa is fixed as 30 mg/m2 intravenously every 3 weeks (maximum 6 cycle).

Drug: Orelabrutinib; Drug: Thiotepa

Interventions

Orelabrutinib DRUG

150mg or 200mg orally daily

Phase Ib

Thiotepa DRUG

30 mg/m2 intravenously every 3 weeks (maximum 6 cycle)

Phase II; Phase Ib

Eligibility Criteria

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

You may qualify if:

• Men and woman who aged 18 or older on the day of consenting to the study.
• Participants must be able to understand and willing to sign a written informed consent document.
• ECOG performance status of 0 to 2.
• Histologically documented primary central nervous system(CNS) lymphoma.
• Participants should have evidence of 1 measurable or evaluable enhancing disease on MRI, PET-CT or PET-MRI.
• Relapsed or refractory disease with at least 1 prior HD-MTX-based therapy.
• Life expectancy of \> 3 months (in the opinion of the investigator).
• Any non-hematologic toxicity associated with prior treatment should be stable and recovered to ≤ Grade 1 (according to NCI CTCAE V5.0，except for alopecia)
• Demonstrate adequate organ function as defined below: (all screening labs should be performed within 14 days of treatment initiation)
• Absolute neutrophil count (ANC) ≥ 1.0 x 10\^9/L, Platelets ≥ 75 x 10\^9/L，Hb ≥80 g/L;
• International normalized ratio (INR) and activated partial thromboplastin time (APTT) ≤1.5 times the upper limit of normal;
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times the upper limit of normal;
• Serum bilirubin ≤ 1.5 times the upper limit of normal;
• Creatinine clearance ≥ 60 mL/min calculated by the Cockcroft-Gault formula using actual body weight.
• Must be able to tolerate MRI/CT/PET-CT/PET-MRI scans and lumbar puncture.

You may not qualify if:

• The pathological diagnosis was T-cell lymphoma.
• Prior therapy with a checkpoint inhibitor or BTK inhibitor.
• Participation in another clinical study with an investigational product during the 12 weeks prior to the first day of study treatment.
• Participants requires more than 5 mg of dexamethasone daily or the equivalent for control of primary CNS symptoms lasting for more than 5 days within 14 days.
• Active bleeding within 4 weeks prior to first administration, or ongoing use of anticoagulant/antiplatelet agents, or tendency to bleeding (e.g., esophageal varices at risk for bleeding, locally active ulcerative lesions) or coagulation disorder as considered by the investigator.
• Has an uncontrolled or significant cardiovascular disease, including (but not limited to) :
• Any of the following conditions within 6 months prior to initial administration: congestive heart failure (NYHA class III or IV), myocardial infarction, unstable angina, or arrhythmia requiring treatment at the time of screening, left ventricular ejection fraction (LVEF) \<50%;
• Primary or secondary cardiomyopathy (e.g., dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmic right ventricular cardiomyopathy, restricted cardiomyopathy, undefined cardiomyopathy);
• Clinical history of prolonged QTc phase, grade II type II atrioventricular block or grade III atrioventricular block or QTc interval (F method) \& GT;470 msec (female) or \>;480msec (male).
• Hypertension, which is difficult to control, is not suitable for this study
• Uncontrolled infections or infections requiring intravenous antimicrobial treatment.
• Known active infection with hepatitis C virus (HCV)，hepatitis B virus (HBV) or syphilis as determined by serologic tests and/or PCR.
• History of or positive human immunodeficiency virus (HIV) screen result.
• Patient underwent major systemic surgery ≤ 6 weeks prior to starting the trial treatment or who has not recovered from the side effects of such surgery, or who plan to have surgery within 2 weeks of the first dose of the study drug.
• Previous organ transplantation or allogeneic stem cell transplantation.

Sponsors & Collaborators

• Huiqiang Huang: lead
• Guangdong 999 Brain Hospital: collaborator

Study Sites (1)

Department of Medical Oncology, Sun Yat-sen University Cancer Center

Guangzhou, Guangdong, 510060, China

Location

MeSH Terms

Conditions

Lymphoma, Non-Hodgkin

Interventions

orelabrutinib; Thiotepa

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Phosphoramides; Organophosphorus Compounds; Organic Chemicals; Triethylenephosphoramide; Aziridines; Azirines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Central Study Contacts

Huiqiang Huang, Professor

CONTACT

+86 020 87343350; huanghq@sysucc.org.cn

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: August 16, 2021
• First Posted: August 26, 2021
• Study Start: December 1, 2021
• Primary Completion: December 1, 2022
• Study Completion: June 1, 2024
• Last Updated: August 26, 2021

Record last verified: 2021-08

Locations

CN (1)