Orelabrutinib and Sintilimab in Relapsed or Refractory Central Nervous System Lymphoma

A Phase Ib/II Study of Orelabrutinib and Sintilimab in Treating Patients With Relapsed or Refractory Central Nervous System Lymphoma

This phase Ib/II trial is evaluating the efficacy and side effect of orelabrutinib and sintilimab as possible treatments for relapsed or refractory central nervous system lymphoma.

Study Overview

• Status: Recruiting
• Conditions: Primary Central Nervous System Hodgkin Lymphoma
• Intervention / Treatment: Drug: Orelabrutinib; Drug: Orelabrutinib; Drug: Sintilimab

Detailed Description

Both orelabrutinib and sintilimab are promising classes of therapy for central nervous system lymphoma. Given the poor outcomes and limited options for relapsed or refractory central nervous system lymphoma. The investigators seek to evaluate the efficacy and toxicity of the combination of orelabrutinib with sintilimab in this patient population.

Phase 1b (maximum 12 total cycles) 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 regimen, beginning at dose level I (150 mg daily) and potentially escalating to dose level 2 (200mg) and dose level 3 (250mg) with rules for escalation and de-escalation. If the dose-limiting toxicity is not found, the dose of 250mg qd will be used for phase II trial.

Orelabrutinib: orally daily Sintilimab: The dose of sintilimab is fixed dose. 200 mg intravenously every 3 weeks (maximum 12 total dose)

Phase 2 Participants will receive orelabrutinib and sintilimab 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: orally maximum tolerated dose from phase 1b daily (150 mg or 200 mg or 250mg) Sintilimab: The dose of sintilimab is fixed dose. 200 mg intravenously every 3 weeks

• Study Type: Interventional
• Enrollment (Anticipated): 48
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Xianggui Yuan, Dr.; Phone Number: +8613989883884; Email: yuanxg@zju.edu.cn

Study Locations

• China
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310009
      • Recruiting
      • 2nd Affiliated Hospital, School of Medicine, Zhejiang University
      • Contact: Xianggui Yuan, MD, PhD; Phone Number: +8613989883884; Email: yuanxg@zju.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Histologically documented primary central nervous system(CNS) lymphoma or secondary diffuse large B-cell lymphoma (DLBCL) isolated to CNS.
2. Relapsed or refractory disease with at least 1 prior methotrexate-based therapy
3. Participant must be able to understand and willing to sign a written informed consent document.
4. Participant must have signed and dated written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal subject care.
5. Participant must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, and other requirements of the study.
6. Participant must be at least 18 years old on day of signing informed consent.
7. PCNSL subjects should have evidence of measurable or evaluable enhancing disease on MRI
8. Able to submit at least 10 but up to 20 unstained formalin-fixed, paraffin-embedded (FFPE) slides from the initial or most recent tissue diagnosis for correlative studies. Histologically confirmed tissue will be required from the time of relapse or at the time of initial surgery. If tissue is unavailable and/or diagnosis was made from cerebrospinal fluid or vitreal biopsy, approval from the overall principal investigator is needed.
9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 3.
10. Life expectancy of >3 months (in the opinion of the investigator)
11. Toxicities due to prior therapy must be stable and recovered to ≤ Grade 1
12. Must be able to tolerate lumbar puncture and MRI/CT.

13. Demonstrate adequate organ function as defined below, all screening labs should be performed within 14 days of treatment initiation.

    1. Absolute neutrophil count (ANC) ≥ 1.0 x 109/L
    2. Platelets ≥ 75 x 10^9/L and no platelet transfusion within the past 7 days prior to initiation of protocol treatment
    3. Prothrombin time (PT), partial thromboplastin time (PTT), and international normalized ratio (INR) < 2 times the upper limit of normal
    4. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times the upper limit of normal
    5. Serum bilirubin ≤ 1.5 times the upper limit of normal
    6. Creatinine clearance > 30 mL/min calculated by the Cockcroft-Gault formula using actual body weight
14. Women of child-bearing potential, must agree to use a highly effective method of contraception consistently and correctly as described below during study treatment and for 120 days after study discontinuation.
15. Male participants must agree to use at least one of the following methods of contraception starting with the first dose of study therapy through 120 days after the last dose of therapy:
16. Ability to swallow oral medications.

Exclusion Criteria:

1. CNSL with systematic disease.
2. The pathological diagnosis was T-cell lymphoma.
3. Prior chemotherapy within 4 weeks or prior targeted small molecule therapy within 2 weeks , prior antibody-drug-conjugates within 10weeks, autologous stem cell transplant within 6 months, prior to the first day of study treatment, prior to the first day of study treatment.
4. Prior allogenic stem cell transplant.
5. Participation in another clinical study with an investigational product during the 4 weeks prior to the first day of study treatment.
6. External beam radiation therapy to the CNS within 14 days of the first day of study treatment.
7. Patient requires more than 8 mg of dexamethasone daily or the equivalent for control of CNS symptoms at the time of initiation of study therapy. Patients must taper off high dose corticosteroids for the control of CNS symptoms within 14 days after starting on study therapy.
8. History of intracranial hemorrhage or clinically significant stroke within 6 months prior to first day of study treatment
9. History of significant gastrointestinal disease that would limit absorption of oral medications.
10. Active concurrent malignancy requiring active therapy.
11. Prior therapy with a checkpoint inhibitor or BTK inhibitor.
12. Warfarin or any other Coumadin-derivative anticoagulant or vitamin K antagonists. Patients must be off warfarin-derivative anticoagulants for at least seven days prior to starting the study drug. Use of low molecular weight heparin and novel oral anticoagulants (eg. rivaroxaban, apixaban) is permitted if required.
13. Concurrent use of a moderate or strong inhibitor or inducer of the P450 isoenzyme CYP3A. Participants must be off P450/CYP3A inhibitors and inducers prior to starting the study drug.
14. Receipt of live attenuated vaccine within 30 days prior to the first day of study treatment. Note: Patients, if enrolled, should not receive live vaccine while receiving IP and up to 30 days after the last day of study treatment.
15. Suspicion of or confirmed progressive multifocal leukoencephalopathy

16. Active autoimmune disease (including autoimmune hemolytic anemia and immune thrombocytopenia purpura) requiring systemic treatment within the past two years (i.e. with the use of disease modifying agents, corticosteroids, or immunosuppressive drugs). The following are exceptions to this criterion:

    1. Patients with vitiligo or alopecia
    2. Patients with hypothyroidism (e.g., due to Hashimoto syndrome) stable on hormone replacement
    3. Any chronic skin condition that does not require systemic therapy
    4. Patients without active disease in the last 5 years may be included but only after consultation with the study physician
    5. Patients with celiac disease controlled by diet alone
    6. Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroids replacement therapy for adrenal or pituitary insufficiency, etc.)
17. Significant medical diseases or conditions, as assessed by the investigator, that would substantially increase the risk to benefit ratio of participating in the study. This includes, but is not limited to, acute myocardial infarction in the past 6 months, unstable angina, uncontrolled diabetes mellitus, significant active infections, severely immunocompromised state, and congestive heart failure, New York Heart Association Class III-IV.
18. Known bleeding diathesis (e.g. von Willebrand's disease), hemophilia, or active bleeding.
19. Known Human immunodeficiency virus (HIV) infection.
20. Known active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) as determined by serologic tests and/or PCR.
21. History of invasive fungal infection, including invasive aspergillosis, or known active tuberculosis.
22. Major surgery ≤ 6 weeks prior to starting the trial treatment (or has not recovered from the side effects of such surgery) or plans to have surgery within 2 weeks of the first dose of the study drug.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SEQUENTIAL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Phase Ib; 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 regimen, beginning at dose level I (150 mg daily) and potentially escalating to dose level 2 (200mg) and dose level 3 (250mg) with rules for escalation and de-escalation. If the dose-limiting toxicity is not found, the dose of 250mg qd will be used for phase II trial. Orelabrutinib: orally daily Sintilimab: The dose of sintilimab is fixed dose. 200 mg intravenously every 3 weeks (maximum 12 total dose)	Drug: Orelabrutinib; 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 regimen, beginning at dose level I (150 mg daily) and potentially escalating to dose level 2 (200mg) and dose level 3 (250mg) with rules for escalation and de-escalation. If the DLT is not found, the dose of 250mg qd will be used for phase II trial.; Drug: Orelabrutinib; Orelabrutinib: orally maximum tolerated dose from phase 1b daily (150 mg or 200 mg or 250mg); Drug: Sintilimab; The dose of sintilimab is fixed dose. 200 mg intravenously every 3 weeks
EXPERIMENTAL: Phase II; Participants will receive orelabrutinib and sintilimab 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: orally maximum tolerated dose from phase 1b daily (150 mg or 200 mg or 250mg) Sintilimab: The dose of sintilimab is fixed dose. 200 mg intravenously every 3 weeks	Drug: Orelabrutinib; 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 regimen, beginning at dose level I (150 mg daily) and potentially escalating to dose level 2 (200mg) and dose level 3 (250mg) with rules for escalation and de-escalation. If the DLT is not found, the dose of 250mg qd will be used for phase II trial.; Drug: Orelabrutinib; Orelabrutinib: orally maximum tolerated dose from phase 1b daily (150 mg or 200 mg or 250mg); Drug: Sintilimab; The dose of sintilimab is fixed dose. 200 mg intravenously every 3 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safe and tolerable dose of regimen for phase Ib study		Completion of first 12 cycles of treatment within phase I portion of study (estimated to be 10 months)
Objective response rate (ORR) for Phase II study	The objective response rate (ORR) is defined as the proportion of patients with a best response of CR or PR	2years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS)	PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.	2 years
Overall survival (OS)	OS is defined as the duration of time from start of treatment to time of death.	2 years
Duration of response	The duration of overall response is measured from the time measurement	2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
ctDNA mutation and mean ctDNA concentration in serum and cerebrospinal fluid	Types of ctDNA mutations and frequency are measured by next generation sequencing. The mean ctDNA concentration is the concentration of ctDNA expressed as mean tumor molecules /ml at specific time points.	Baseline, every two months for up to three years after treatment
The levels of cytokine concentration in serum and cerebrospinal fluid	The levels of cytokine will be analyzed by ELISA in all patients recruited. The cytokine profile includes IL-6, IL-10, TNF-α, IFN-γ, IL-2 and IL-4	Baseline, every two months for up to three years after treatment

Collaborators and Investigators

• Sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University
• Collaborators: First People's Hospital of Hangzhou; First Affiliated Hospital of Zhejiang University; Jinhua People's Hospital; Second Affiliated Hospital of Wenzhou Medical University; Sir Run Run Shaw Hospital; Zhejiang Provincial People's Hospital; Wenzhou Central Hospital; Jinhua Central Hospital; Huizhou Municipal Central Hospital; Zhejiang Provincial Tongde Hospital; Yinzhou Hospital Affiliated to Medical School of Ningbo University

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 1, 2021
• Primary Completion (ANTICIPATED): December 31, 2024
• Study Completion (ANTICIPATED): December 31, 2026

Study Registration Dates

• First Submitted: June 15, 2021
• First Submitted That Met QC Criteria: July 13, 2021
• First Posted (ACTUAL): July 14, 2021

Study Record Updates

• Last Update Posted (ACTUAL): November 8, 2022
• Last Update Submitted That Met QC Criteria: November 6, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma
• Other Study ID Numbers: I2021001524

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No