Combination of Ibrutinib and Bortezomib Followed by Ibrutinib Maintenance to Treat Patients With Relapsed and Refractory Mantle Cell Lymphoma; a Multicenter Phase I/II Trial.
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
• 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
‣ Ibrutinib: 3 month after the last dose of trial drug for males and 1 month for females.
⁃ Bortezomib: during trial treatment (for males and females): no restrictions of birth control after last dose of trial drug. Donation of sperm: 6 month after the last dose of trial drug.
• Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin \[β-hCG\]) or urine pregnancy test at baseline. Women who are pregnant or breastfeeding are ineligible for this trial.