Combination of Ibrutinib and Bortezomib to Treat Patients With Mantle Cell Lymphoma

NCT02356458 | Terminated Phase 1

• 3 other identifiers: SAKK 36/132014-003893-17SNCTP000001235
• Study Type: interventional
• Target: 58
• Locations: 3 countries
• Sites: 19

Brief Summary

Mantle cell lymphoma (MCL) remains an incurable disease with frequent relapses and no standard therapeutic options in case of relapse. Prolongation of remissions or induction of longer remissions is therefore crucial. Recently, a synergistic increase in the proteasomal inhibition of ibrutinib in both bortezomib-sensitive and refractory MCL cells was shown. These findings, along with the reported single agent activities of both drugs and the non-overlapping toxicities, are the rationale to combine ibrutinib and bortezomib in MCL in this trial

Conditions

Mantle Cell Lymphoma

Keywords

Mantle cell lymphoma; Relapsed; Refractory; Cancer; Lymphoma; Ibrutinib Imbruvica; Bortezomib Velcade

Outcome Measures

Primary Outcomes (2)

• Phase I: Dose limiting toxicity (DLT) observed during the first cycle of trial treatment

  DLTs are defined based on adverse events observed in cycle 1 that are possibly, probably or definitively related to ibrutinib and/or bortezomib.

  At day 8, 14, 21 during cycle 1 (1 cycle = 21 days)

• Phase II: Overall response (OR) (combination therapy)

  OR is defined as the proportion of patients whose best overall response, is either complete response (CR), complete response unconfirmed (CRu) or partial response (PR) according to the International Working group criteria for NHL. The primary endpoint of phase II is OR observed during the combination therapy.

  4 1/2 months after registration.

Other Outcomes (7)

• Phase I and II: Adverse events (AE) until 30 days after end of trial therapy

  Until 30 days after up to 2 years of trial therapy

• Phase I: OR (combination therapy)

  4 1/2 months after inclusion of each patient

• Phase I: OR based on best response observed during treatment (combination and maintenance therapy)

  Estimated at 1 1/2 years after patient registration.

Study Arms (1)

Ibrutinib & Bortezomib

EXPERIMENTAL

Combination therapy (trial treatment of ibrutinib in combination with bortezomib) followed by ibrutinib maintenance therapy

Drug: Ibrutinib; Drug: bortezomib

Interventions

Ibrutinib DRUG

Combination therapy: Trial treatment of ibrutinib in combination with bortezomib Cycles 1-6 (1 cycle = 21 days) Ibrutinib: p.o daily; Phase I: according to DL; Phase II: RP2D established in phase I Maintenance therapy: p.o daily: 560 mg

Also known as: Imbruvica

Ibrutinib & Bortezomib

bortezomib DRUG

Combination therapy: Trial treatment of ibrutinib in combination with bortezomib Cycles 1-6 (1 cycle = 21 days) Injection of Bortezomib (s.c.), dose of 1.3 mg/m2 on day 1, 4, 8, 11

Also known as: Velcade®

Ibrutinib & Bortezomib

Eligibility Criteria

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

You may qualify if:

• Patient must give written informed consent before registration indicating that the patient understands the purpose of the procedures required for the trial and is willing to participate in the trial.
• Histologically confirmed mantle cell lymphoma with either overexpression of cyclin D1 protein or evidence of t(11;14)(q13;q32) assessed by cytogenetics, by fluorescence, in situ hybridization (FISH) or by polymerase chain reaction (PCR).
• Refractory or relapsed disease in need of systemic therapy after pretreatment with non-bortezomib-containing chemotherapy (including high-dose therapy)
• At least one measurable lesion ≥11 mm in its greatest transverse diameter measured with CT scan (contrast enhanced) or MRI (in case of the disease cannot be adequately imaged using CT and if contrast is not appropriate for patients according to the treating physician)
• WHO performance status 0-2
• Age ≥ 18 years
• Adequate hematological values:
• Absolute neutrophil count (ANC) \> 1.0 x 109/L independent of growth factor support
• Platelets ≥ 100 x 109/L or ≥ 50 x 109/L if bone marrow involvement independent of transfusion support in either situation,
• Hb ≥ 80 g/L
• Adequate hepatic function:
• Total bilirubin ≤1.5xupper limit of normal (ULN) unless bilirubin is due to Gilbert's syndrome ≤ 5.0 x ULN
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3xULN
• Adequate renal function: Body surface area (BSA) corrected creatinine clearance \>40mL/min/1.73m2 (calculated according to the formula of Cockcroft-Gault)
• Women of childbearing potential and men who are sexually active must be practicing a highly effective method of birth control during and after the trial (see below) consistent with local regulations regarding the use of birth control methods for patients participating in clinical trials (see section 9.12). Men must agree to not donate sperm during and after the trial. These restrictions apply for

You may not qualify if:

• Prior therapy with ibrutinib or bortezomib
• Adverse event neuropathy of prior therapy grade ≥2 (according to CTCAE criteria) at registration
• Previous malignancy within 5 years with the exception of adequately treated in situ cervical cancer or localized non-melanoma skin cancer.
• Presence or history of CNS disease (either CNS lymphoma or lymphomatous meningeosis)
• Evidence of ongoing systemic infections of all kind
• major surgery within 4 weeks
• concurrent treatment with other experimental drugs or treatment in a clinical trial within 30 days.
• treatment with chemotherapy and radiotherapy within ≥ 3 weeks
• vaccinated with live, attenuated vaccines within 4 weeks
• History of stroke or intracranial hemorrhage within 6 months prior to trial registration.
• Requires anticoagulation with warfarin or equivalent vitamin K antagonists (e.g. phenprocoumon)
• Requires treatment with strong or moderate CYP3A inhibitors (see http://medicine.iupui.edu/)
• Clinically significant cardiovascular disease such as congestive heart failure NYHA III or IV (as defined by the New York Heart Association Functional Classification), uncontrolled or symptomatic arrhythmias, significant QT-prolongation, unstable angina pectoris myocardial infarction within 6 months of prior to registration,
• Known history of human immunodeficiency virus (HIV) or active Hepatitis C virus or active Hepatitis B virus infection or any uncontrolled active systemic infection requiring treatment.
• Prior allogeneic bone marrow or solid organ transplantation

Sponsors & Collaborators

• Swiss Cancer Institute: lead
• European Mantle Cell Lymphoma Network: collaborator

Study Sites (19)

Universitätsmedizin Mainz

Mainz, 55131, Germany

Location

Klinikum der Universität München

München, 81377, Germany

Location

Universitätsmedizin Rostock

Rostock, 18057, Germany

Location

Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo

Alessandria, 15100, Italy

Location

European Institute of Oncology

Milan, 20141, Italy

Location

Università di Torino

Torino, 10126, Italy

Location

Kantonsspital Aarau

Aarau, CH-5001, Switzerland

Location

Kantonsspital Baden

Baden, 5404, Switzerland

Location

Inselspital, Bern

Bern, CH-3010, Switzerland

Location

Kantonsspital Graubünden

Chur, 7000, Switzerland

Location

Hopitaux Universitaires de Geneve

Geneva, 1211, Switzerland

Location

Centre Pluridisciplinaire d'Oncologie CHUV

Lausanne, 1011, Switzerland

Location

Kantonsspital Baselland

Liestal, 4410, Switzerland

Location

Istituto Oncologico della Svizzera Italiana

Lugano, CH-6900, Switzerland

Location

Kantonsspital Luzern

Luzerne, CH-6000, Switzerland

Location

Kantonsspital - St. Gallen

Sankt Gallen, CH-9007, Switzerland

Location

Onkozentrum - Klinik Im Park

Zurich, 8038, Switzerland

Location

UniversitätsSpital Zürich

Zurich, 8091, Switzerland

Location

Klinik Hirslanden

Zurich, CH-8032, Switzerland

Location

Related Publications (1)

• Novak U, Fehr M, Schar S, Dreyling M, Schmidt C, Derenzini E, Zander T, Hess G, Mey U, Ferrero S, Mach N, Boccomini C, Bottcher S, Voegeli M, Cairoli A, Ivanova VS, Menter T, Dirnhofer S, Scheibe B, Gadient S, Eckhardt K, Zucca E, Driessen C, Renner C. Combined therapy with ibrutinib and bortezomib followed by ibrutinib maintenance in relapsed or refractory mantle cell lymphoma and high-risk features: a phase 1/2 trial of the European MCL network (SAKK 36/13). EClinicalMedicine. 2023 Sep 22;64:102221. doi: 10.1016/j.eclinm.2023.102221. eCollection 2023 Oct.

  PMID: 37781158 DERIVED

MeSH Terms

Conditions

Lymphoma, Mantle-Cell; Recurrence; Neoplasms; Lymphoma

Interventions

ibrutinib; Bortezomib

Condition Hierarchy (Ancestors)

Lymphoma, Non-Hodgkin; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Organic Chemicals; Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Urban Novak, PD Dr. med.

  University Hospital Bern - Inselspital

  STUDY CHAIR

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: February 2, 2015
• First Posted: February 5, 2015
• Study Start: August 31, 2015
• Primary Completion: March 30, 2021
• Study Completion: March 30, 2021
• Last Updated: March 11, 2022

Record last verified: 2022-02

Data Sharing

• IPD Sharing: Will not share

Locations

IT (3); DE (3); CH (13)