Trial of Ibrutinib Plus Venetoclax Plus Obinutuzumab in Patients With CLL

NCT02758665 | Completed Phase 2

• 1 other identifier: CLL2-GIVe
• Study Type: interventional
• Target: 41
• Locations: 1 country
• Sites: 11

Brief Summary

A prospective, open-label, multicentre phase-II trial of ibrutinib plus venetoclax plus obinutuzumab in physically fit (CIRS ≤ 6 \& normal creatinine clearance) and unfit (CIRS \> 6 \& creatinine clearance ≥ 50 ml/min) patients with previously untreated chronic lymphocytic leukemia (CLL) with TP53 deletion (17p-) and/or mutation

Conditions

Leukemia, Lymphocytic, Chronic

Keywords

CLL; chronic lymphocytic leukemia; ibrutinib; venetoclax; obinutuzumab; TP53 Deletion

Outcome Measures

Primary Outcomes (1)

• Complete response (CR) rate

  at day 1 of cycle 15 (1 cycle = 28 days) after start of induction therapy

Secondary Outcomes (13)

• PD-free rate

  up to 336 days

• Overall Response rate

  up to 1176 days

• ORR

  at 1008 days (=end of maintenance treatment)

• MRD levels

  at the following days: 252, 336, 393, 381 as well as in bone marrow at day 393

• Progression-free survival (PFS)

  up to 1176 days

Study Arms (1)

Obinutuzumab, Ibrutinib, Venetoclax

EXPERIMENTAL

Obinutuzumab i.v.: Cycle 1 (3000 mg), Cycle 2-6 (1000 mg) Ibrutinib (tablet): Cycle 1-15 (420 mg daily) Venetoclax (tablet): Cycle 1 (last 7 days 20 mg daily), Cycle 2 (ramp up 50 mg to 400 mg) Cycle 3-12 (400 mg daily)

Drug: ibrutinib; Drug: obinutuzumab; Drug: venetoclax

Interventions

ibrutinib DRUG

Obinutuzumab, Ibrutinib, Venetoclax

obinutuzumab DRUG

Obinutuzumab, Ibrutinib, Venetoclax

venetoclax DRUG

Obinutuzumab, Ibrutinib, Venetoclax

Eligibility Criteria

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

You may qualify if:

• Have documented CLL according to iwCLL criteria, measurable disease (lymphocytosis \> 5x109 and/or palpable and measurable lymph nodes by physical exam and/or organomegaly assessed by physical exam)
• Subjects must have untreated CLL, i.e. no prior chemotherapy, antibody therapy or non-chemotherapeutic agent (BTK, PI3K, BCL2 inhibitor or similar). Local irradiation or short term (up to 1 month) corticosteroid treatment for autoimmune phenomena are allowed
• Subjects must have TP53 deletion (17p-) and/or mutation (in bone marrow or peripheral blood), with pre-existing local test results confirmed by central laboratory in Ulm
• CLL requiring treatment ("active disease") according to the iwCLL criteria
• ECOG ≤ 2
• Creatinine clearance ≥ 50 ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured after 24 h urine collection
• Adequate liver function as indicated by a total bilirubin ≤ 2 x, AST, and ALT ≤ 3 x the institutional ULN value, unless directly attributable to the patient's CLL or to Gilbert's Syndrome
• No cardiovascular disability of New York Heart Association (NYHA) Class \> 2. Class 2 is defined as comfortability at rest but moderate physical activity causes dyspnoea, angina pain or fatigue
• Adequate bone marrow function (unless directly attributable to CLL, BM examination required):
• ANC ≥ 1000/µl or
• ANC \< 1000/µl, if attributable to the underlying CLL (growth factor support may be administered after screening)
• Platelets \> 30.000/µl (unless directly attributable to the underlying CLL)
• Hemoglobin ≥ 8g/dl (unless directly attributable to the underlying CLL)
• Negative serological testing for hepatitis B (i.e. HBsAg negative and anti-HBc negative, patients positive for anti-HBc may be included if PCR for HBV DNA is negative) negative testing for hepatitis-C RNA and negative HIV test within 6 weeks prior to registration.
• \[Patients who are HBsAg negative/anti-HBc positive with undetectable serum HBV DNA should be monitored closely (every month) for HBV DNA by a real-time PCR quantification assay with a lower limit of detection of the order of 10 WHO IU/mL until at least 24 months after the last treatment cycle with obinutuzumab. If the HBV DNA assay becomes positive, patients should pre-emptively be treated with a nucleoside analogue (i.e. lamivudine) for at 24 months after the last cycle of therapy with obinutuzumab or be referred to a gastroenterologist for management.\]

You may not qualify if:

• Transformation of CLL (i.e. Richter's transformation, prolymphocyctic leukemia)
• One or more individual organ / system impairment score of 4 as assessed by the CIRS definition, excluding the Eyes, Ears, Nose, Throat and Larynx organ system
• Known central nervous system (CNS) involvement
• Patients with a history of PML
• Active malignancies other than CLL within the past 2 years prior to study entry, with the exception:
• Adequately treated in situ carcinoma of the cervix uteri
• Adequately treated basal cell carcinoma or localized squamous cell carcinoma of the skin
• Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent and in remission at time of screening
• Use of agents which would interfere with the study drug within 28 days prior to registration
• Uncontrolled infection requiring systemic treatment
• History of severe infusion-related reaction to humanized or murine monoclonal antibodies, and/ or known sensitivity or allergy to murine products or allergy to xanthin oxidase and rasburicase or glucose-6-phosphate dehydrogenase deficiency
• Requires treatment with the following drugs:
• Within 7 days prior to the first dose of study drug: No steroid therapy higher than 20 mg Prednisolone for anti-neoplastic intent; No CYP3A inhibitors (e.g. fluconazole, ketoconazole, clarithromycin, warfarin or phenprocoumon); No potent CYP3A inducers (e.g., rifampin, phenytoin or carbamazepine);
• Within 3 days prior to the first dose of study drug: Grapefruit or grapefruit products; Seville oranges (including marmalade); Star fruit.
• History of stroke or intracranial hemorrhage within 6 months prior to registration

Sponsors & Collaborators

• University of Ulm: lead
• German CLL Study Group: collaborator
• Roche Pharma AG: collaborator
• Janssen-Cilag Ltd.: collaborator
• AbbVie: collaborator

Study Sites (11)

Universitätsklinikum Köln

Cologne, 50937, Germany

Location

BAG Onkologische Gemeinschaftspraxis

Dresden, 01307, Germany

Location

Universitätsklinikum Essen

Essen, 45147, Germany

Location

Universitätsklinikum Freiburg

Freiburg im Breisgau, 79106, Germany

Location

Universitätsklinikum Heidelberg

Heidelberg, 69120, Germany

Location

Universitätsklinikum des Saarlandes

Homburg / Saar, 66421, Germany

Location

Universitätsklinikum Schleswig-Holstein

Kiel, 24105, Germany

Location

Universitätsmedizin der Johannes Gutenberg-Universität Mainz

Mainz, 55131, Germany

Location

Klinikum Schwabing

München, 80804, Germany

Location

Unimedizin Rostock

Rostock, 18057, Germany

Location

Universitätsklinikum Ulm

Ulm, 89081, Germany

Location

Related Publications (1)

• Langerbeins P, Giza A, Robrecht S, Cramer P, von Tresckow J, Al-Sawaf O, Fink AM, Furstenau M, Kutsch N, Simon F, Goede V, Hoechstetter M, Niemann CU, da Cunha-Bang C, Kater A, Dubois J, Gregor M, Staber PB, Tausch E, Schneider C, Stilgenbauer S, Eichhorst B, Fischer K, Hallek M. Reassessing the chronic lymphocytic leukemia International Prognostic Index in the era of targeted therapies. Blood. 2024 Jun 20;143(25):2588-2598. doi: 10.1182/blood.2023022564.

  PMID: 38620092 DERIVED

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

ibrutinib; obinutuzumab; venetoclax

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

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr. med.

Study Record Dates

• First Submitted: April 6, 2016
• First Posted: May 2, 2016
• Study Start: September 1, 2016
• Primary Completion: January 1, 2022
• Study Completion: March 1, 2022
• Last Updated: January 17, 2023

Record last verified: 2023-01

Data Sharing

• IPD Sharing: Will share

Locations

DE (11)