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

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

Disease background, therapy background and aim

Mantle cell lymphoma (MCL) is a distinct subtype of B-cell lymphoma. It represents \~5% of all lymphomas and typically is present in advanced stages, a median age of 60-65 years and a dismal prognosis with a median survival of \~3 years. Currently, it remains incurable, as the patients will relapse after first line treatment and require subsequent therapy. The disease-free survival is progressively shorter with each subsequent relapse.

Currently, there is no standard therapy for relapsed MCL patients. MCL is predominantly a disease of the elderly who are not suitable for aggressive chemotherapy. Allogeneic transplants are preferred in young and fit patients, whereas (preferably single agent) chemotherapy is used to treat older patients, but usually with short duration of responses. Recently, the therapeutic armamentarium has been expanded with the availability of novel agents targeting crucial and deregulated pathways in MCL. These include the Bruton's Kinase (BTK) inhibitor ibrutinib with excellent single agent activities. New therapeutic options in the targeted patient population are clearly needed to prolong remissions especially for elderly patients where aggressive chemotherapy and allogeneic transplants are no suitable treatment options. Recently, a synergistic increase in the proteasomal inhibition of ibrutinib in both bortezomib-sensitive and refractory MCL cells was shown.

This trial is targeting patients with diagnosis of refractory or relapsed MCL disease after pretreatment with ≤2 lines of non-bortezomib-containing chemotherapy. The proposed treatment of ibrutinib in combination with bortezomib might lead to an improvement of the therapy in the targeted relapsed/refractory patient population. Given the absence of a dose-limiting toxicity also when applied long-term, ibrutinib is well suited in this patient population as a maintenance therapy. Therefore, the combination treatment of the trial is followed by a maintenance therapy part for patients that had no disease progression. New treatment options should control the disease as best and long as possible.

Treatment

Treatment consists of 6 cycles of 21 days each of ibrutinib in combination with bortezomib, followed by a maintenance therapy with ibrutinib monotherapy. In the maintenance therapy courses repeat every 28-days in the absence of disease progression or unacceptable toxicity.

Objectives Phase I The primary object of the trial is to establish the recommended phase II dose (RP2D) of ibrutinib in combination with bortezomib in patients with relapsed or refractory MCL.

The secondary objectives are

* to determine the safety and tolerability of ibrutinib in combination with bortezomib and
* to assess the preliminary antitumor activity of ibrutinib in combination with bortezomib Phase II The main object of the trial is to define the efficacy of the combination treatment of ibrutinib with bortezomib in patients with relapsed or refractory MCL.

The secondary objectives are

* to determine the safety and tolerability of the RP2D and
* to assess the efficacy of ibrutinib in combination with bortezomib in patients with relapsed MCL followed by an ibrutinib maintenance therapy.

Eligibility Criteria:
Inclusion Criteria:

* 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.

Exclusion Criteria:

* 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
* Exclusion of the following prior treatments prior to trial registration

  * 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
* Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion,

  * could impair the ability of the patient to participate in the trial
  * could compromise the patient's safety,
  * could interfere with the absorption or metabolism of ibrutinib capsules, or
  * could put the trial outcomes at undue risk
  * could prevent compliance with trial treatment.
* Psychiatric disorder precluding understanding of trial information, giving informed consent, or interfering with compliance for oral drug intake.
* Known hypersensitivity to trial drug(s) or hypersensitivity to any other component of the trial drugs.
* Any concomitant drugs contraindicated for use with the trial drugs according to the approved product information.
* Any psychological, familial, sociological or geographical condition potentially hampering compliance with the trial protocol and follow-up.