Zanubrutinib, Obinutuzumab and Lenalidomide in Newly Diagnosed Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

NCT06547944 | Active Not Recruiting Phase 1 DMC

• 1 other identifier: IIT2023063
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

The ZGR regimen limited-course regimen was designed to combine three targeted agents, zanubrutinib, obinutuzumab (a third-generation CD20 monoclonal antibody), and lenalidomide, to deepen the depth of remission in patients with new-diagnosis CLL/SLL, with a view to achieving the goal of discontinuation of the drug and long-term remission after discontinuation of the drug, and prolonging the PFS, and at the same time, the regimen no longer includes cytotoxic chemotherapeutic agents, such as fludarabine and cyclophosphamide, which improves the CLL/ SLL patients' treatment tolerance, and can eliminate the treatment limitation for elderly or poorly tolerated CLL/SLL patients.

Conditions

Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma; Newly Diagnosed

Keywords

Zanubrutinib; Lenalidomide; Obinutuzumab; newly diagnosed CLL/SLL

Outcome Measures

Primary Outcomes (2)

• Maximum Tolerated Dose (MTD) of lenalidomide in combination regimens were determined in newly diagnosed CLL/SLL patients,

  From the date of first dose of study drugs until RP2D was determined(Approximately 4 months)]

• The incidence, nature and severity of adverse events (AE) were determined according to NCI-CTCAE v5.0 evaluation criteria

  From first dose to 30 days after the last dose of Zanubrutinib or lenalidomide or Obinutuzumab

Secondary Outcomes (4)

• overall response rate(ORR)

  From first dose to 30 days after the last dose of Zanubrutinib or lenalidomide or Obinutuzumab

• overall survival Overall survival(OS)

  Up to 5 years

• Progress-free survival(PFS)

  Up to 5 years

• Duration of tumor remission(DOR)

  Up to 5 years

Study Arms (1)

ZGR regimen

EXPERIMENTAL

Dose Escalation lenalidomide combined with Zanubrutinib and Obinutuzumab (Dose escalation will occur using a 3+3 design) Recommended phase II dose (RP2D) lenalidomide combined with Zanubrutinib and Obinutuzumab

Drug: Zanubrutinib; Drug: Lenalidomide; Drug: Obinutuzumab

Interventions

Zanubrutinib DRUG

160mg bid/d, from C1 to CR and MRD-negative or C24

ZGR regimen

Lenalidomide DRUG

From C3 dose escalation, all 3 dose groups climbed from 5 mg/d to 10 mg/d, 15 mg/d, and 20 mg/d respectively, Taking 21 days of medication and 7 days of rest, 1 cycle every 28 days to CR and MRD-negative or C24

ZGR regimen

Obinutuzumab DRUG

1000 mg C1, d1/d8/15; 1000 mg C2-6, d1

ZGR regimen

Eligibility Criteria

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

You may qualify if:

• ） Patients were not categorized by gender ，Age ≥18;
• ） Confirmed diagnosis of CLL or SLL;
• ）Patients must be untreated, or not undergoing standardized treatment for the first time, under the following conditions:
• a) Not treated with fludarabine-containing or bendamustine-containing or rituximab-containing regimens;
• b) Have not been treated with the application of chlorambucil, or have applied chlorambucil for less than 4 weeks (alone or in combination with adrenal glucocorticoids);
• (c) If the above treatment has been applied, it must be stopped for 2 weeks before enrollment in the group to start the treatment.
• ） Indications for treatment of CLL/SLL include, inter alia (at least one of the following conditions is met)
• Evidence of progressive bone marrow failure: as evidenced by progressive decrease in hemoglobin and/or platelets;
• Giant spleen (e.g., \>6 cm below the left costal margin) or symptomatic splenomegaly;
• Giant lymph node enlargement (e.g., longest diameter \>10 cm) or symptomatic lymph node enlargement;
• Progressive lymphocytosis, e.g., \>50% lymphocytosis within 2 months, or lymphocyte doubling time (LDT) \<6 months. When initial lymphocytes are \<30 x 10\^9/L, LDT alone cannot be used as a therapeutic indication;
• CLL/SLL resulting in symptomatic organ dysfunction (e.g., skin, kidney, lung, spine, etc.)
• Autoimmune hemolytic anemia (AIHA) and/or immune thrombocytopenia (ITP) that does not respond well to corticosteroids or other standard therapy;
• Presence of at least one of the following disease-related symptoms: i) weight loss ≥10% without apparent cause within the previous 6 months; ii) severe fatigue (e.g., ECOG physical status ≥2; inability to perform routine activities); iii) temperature \>38°C for ≥2 weeks without evidence of infection; iv) nocturnal night sweats for \>1 month without evidence of infection;
• ） ECOG≤2

You may not qualify if:

• Patients who met any of the following criteria were excluded from the study:
• (1) Malignancies other than CLL/SLL (including active CNS lymphoma) have been diagnosed or treated within the past year;
• (2) There has been clinical evidence of Richter transformation;
• (3) Non-lymphoma-related hepatic and renal impairment: alanine aminotransferase (ALT) \> 3 times the upper limit of normal, alanine transaminase (AST) \> 3 times the upper limit of normal, total bilirubin (TBIL) \> 2 times the upper limit of normal, and serum creatinine clearance \< 30 ml/min;
• (4) Other serious medical disorders that would interfere with the study (e.g., uncontrolled diabetes mellitus, gastric ulcers, grade 3 or 4 atrial fibrillation or persistent atrial fibrillation of any grade, other serious cardiorespiratory diseases, etc.). The judgmental decision is vested in the investigator;
• (5) Patient who had infected with Human Immunodeficiency Virus (HIV) or active Hepatitis B Virus (HBV) infection, or any uncontrolled active systemic infection requiring intravenous antibiotics;
• (6) Clinically manifested CNS dysfunction or invasion of the center;
• (7) Patients who have undergone a major surgical procedure (excluding lymph node biopsy) within the last 14 days or who require a major surgical procedure in anticipation of treatment;
• (8) Inability to swallow capsules or suffering from malabsorption syndromes, disorders significantly affecting gastrointestinal function, having undergone gastric or small bowel resection, symptomatic inflammatory bowel disease or ulcerative colitis, and partial or complete intestinal obstruction.
• (9) Requires treatment with potent cytochrome P450 (CYP) 3A inhibitors;
• (10) Pregnant or lactating women of childbearing age who are not using contraception;
• (11) Patients with clinically significant cardiovascular abnormalities (New York Heart Association (NYHA) classification: III/IV), myocardial infarction within 6 months prior to enrollment, malignant arrhythmias (including QTC ≥ 480 ms), poorly controlled blood pressure (systolic ≥ 150 mmHg, diastolic ≥ 100 mmHg) despite the use of antihypertensive medications, and uncontrolled angina;
• (12) Persistent uncontrolled bleeding;
• (13) History of life-threatening hemorrhage, especially from irreversible causes;
• (14) Need for high doses of several anticoagulants that cannot be briefly discontinued;

Sponsors & Collaborators

• Institute of Hematology & Blood Diseases Hospital, China: lead

Study Sites (1)

Institute of Hematology & Blood Diseases Hospital Chinese Academy of Medical Sciences & Peking Union Medical College

Tianjin, Tianjin Municipality, China

Location

Related Publications (5)

• Tam CS, Brown JR, Kahl BS, Ghia P, Giannopoulos K, Jurczak W, Simkovic M, Shadman M, Osterborg A, Laurenti L, Walker P, Opat S, Chan H, Ciepluch H, Greil R, Tani M, Trneny M, Brander DM, Flinn IW, Grosicki S, Verner E, Tedeschi A, Li J, Tian T, Zhou L, Marimpietri C, Paik JC, Cohen A, Huang J, Robak T, Hillmen P. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022 Aug;23(8):1031-1043. doi: 10.1016/S1470-2045(22)00293-5. Epub 2022 Jul 7.

  PMID: 35810754 BACKGROUND

• Ferrajoli A, Lee BN, Schlette EJ, O'Brien SM, Gao H, Wen S, Wierda WG, Estrov Z, Faderl S, Cohen EN, Li C, Reuben JM, Keating MJ. Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood. 2008 Jun 1;111(11):5291-7. doi: 10.1182/blood-2007-12-130120. Epub 2008 Mar 11.

  PMID: 18334676 BACKGROUND

• Badoux XC, Keating MJ, Wen S, Lee BN, Sivina M, Reuben J, Wierda WG, O'Brien SM, Faderl S, Kornblau SM, Burger JA, Ferrajoli A. Lenalidomide as initial therapy of elderly patients with chronic lymphocytic leukemia. Blood. 2011 Sep 29;118(13):3489-98. doi: 10.1182/blood-2011-03-339077. Epub 2011 Jul 1.

  PMID: 21725050 BACKGROUND

• Badoux XC, Keating MJ, Wen S, Wierda WG, O'Brien SM, Faderl S, Sargent R, Burger JA, Ferrajoli A. Phase II study of lenalidomide and rituximab as salvage therapy for patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2013 Feb 10;31(5):584-91. doi: 10.1200/JCO.2012.42.8623. Epub 2012 Dec 26.

  PMID: 23270003 BACKGROUND

• Ujjani C, Wang H, Skarbnik A, Trivedi N, Ramzi P, Khan N, Cheson BD. A phase 1 study of lenalidomide and ibrutinib in combination with rituximab in relapsed and refractory CLL. Blood Adv. 2018 Apr 10;2(7):762-768. doi: 10.1182/bloodadvances.2017015263.

  PMID: 29610115 BACKGROUND

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

zanubrutinib; Lenalidomide; obinutuzumab

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Piperidones; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 28, 2024
• First Posted: August 9, 2024
• Study Start: January 1, 2024
• Primary Completion: December 1, 2025
• Study Completion (Estimated): December 1, 2026
• Last Updated: August 9, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)