Clinical Trial of Ublituximab and Umbralisib With CHOP (U2-CHOP) Followed by U2 Maintenance (U2-CHOP-U2) in Previously Untreated Mantle Cell Lymphoma (MCL) — CHOP U2  

Mantle Cell Lymphoma Clinical Trial

Official title: Phase Ib/II Trial of Ublituximab and Umbralisib With CHOP (U2-CHOP) Followed by U2 Maintenance (U2-CHOP-U2) in Previously Untreated Mantle Cell Lymphoma (MCL)

Status Terminated

Clinical Trial Summary

This is a single arm, multi-center, open label Phase Ib/II trial in adult patients with newly diagnosed Mantle Cell Lymphoma (MCL)(Stage II-IV). The Diagnosis of MCL (Stage II, III, IV) is supported by histology and over expression of cyclin D1 or by FISH (fluorescent in situ hybridization). In the proposed study, the primary endpoint is to estimate the biological response rate of the combination of Umbralisib at dose 800 mg with Ublituximab (900mg)-Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (CHOP), but a phase Ib portion with dose de-escalation at two does level (800 and 600 mg) will be built in to further confirm its safety and tolerability. Treatment will be administered on an outpatient basis in 3-week (21 day) cycles. Once Umbralisib dose is defined in phase Ib, the study will expand to phase II portion after SMC/DSMB (Safety monitoring committee/Data Safety Monitoring Committee) agreement.

Clinical Trial Description

Mantle cell lymphoma (MCL) is an aggressive and incurable hematologic malignancy with incidence of MCL increases with age (average age is 68 years) and is more common in males. Majority of the patients presents with advanced systemic and symptomatic disease requiring aggressive chemotherapy. Although some patients with MCL can have indolent course, majority of them pursue an aggressive course. Most patients with MCL presents with non-bulky lymphadenopathy and advanced stage with frequent extra-nodal involvement. In general, MCL carries an aggressive course with very poor outcome. MCL has wide spectrum of clinical presentation ranging from indolent disease to symptomatic aggressive disease. The initial treatment of MCL depends on many disease and patient related factors. Advanced, biologically aggressive ( by histology markers) disease in a young and fit patient needs aggressive/intense induction, Autologus stem cell transplant (ASCT) consolidation and maintenance treatment. While unfit patient usually is offered less intense treatment followed by maintenance treatment.

Investigational drugs ublituximab & umbralisib are highly active in various B cell lymphomas. Umbralisib is a highly-specific and orally available dual inhibitor of phosphoinositide-3-kinase (PI3K) delta (δ) and casein kinase 1 epsilon (CK1ε) with nanomolar inhibitory potency, and high selectivity over the alpha, beta, and gamma Class I isoforms of PI3K. The PI3Ks are a family of enzymes involved in various cellular functions, including cell proliferation and survival, cell differentiation, intracellular trafficking and immunity. The delta isoform of PI3K is highly expressed in cells of hematopoietic origin, and strongly upregulated, and often mutated in various hematologic malignancies.

Ublituximab is a novel third generation chimeric anti-CD20 monoclonal antibody bioengineered for potent activity, exhibiting a unique glycosylation profile with a low fucose content, designed to induce superior antibody-dependent cytotoxicity (ADCC). Ublituximab exhibits competitive complement-dependent cytotoxicity (CDC), on par with rituximab, and has also been demonstrated to induce programmed cell death (PCD) upon binding to the CD20 antigen on B-lymphocytes.

Pre-Clinical Development Of Ublituximab:

The antitumor effect of ublituximab was compared to that of rituximab with chemotherapy in follicular lymphoma (FL), and mantle cell lymphoma (MCL) xenograft murine models. Single agent ublituximab demonstrated dose-related anti-tumor activity with 100% tumor growth inhibition in the FL xenograft at a dose of 100mg/kg, and a superior tumor growth delay (21 days) compared to rituximab. Ublituximab also demonstrated superior anti-tumor activity compared to rituximab against MCL xenografts at all dose levels (Esteves IT, 2011).

Ublituximab in Combination with Umbralisib :

The combination of Ublituximab and Umbralisib is being evaluated in various clinical trials. The preliminary data suggests that the combination is safe and well tolerated. Results of a Phase I/Ib study of the combination of ublituximab + umbralisib (U2) in patients with relapsed or refractory Non-Hodgkin Lymphoma(NHL) and Chronic lymphocytic Leukemia(CLL) have been reported. Overall, results from this study suggest that the U2 regimen is well tolerated and active in patients with relapsed or refractory hematologic malignancies.

Rationale for this Study:

This is a Single arm, multi-center, open label Phase II trial with safety lead in Adult patients with newly diagnosed Mantle Cell Lymphoma (MCL)(Stage II-IV). MCL majority, is an aggressive and incurable lymphoma. As it is the lymphoma of elderly, aggressive treatment approaches like aggressive induction treatments and ASCT may be more risky in this population. Majority of these patients are treated with less intense approach like Rituximab-Bendamustine (BR), R-CHOP or VR-CAP. Nearly all the patients are treated with Rituximab maintenance after these induction approaches.

In this study, we will explore combination of novel CD20 monoclonal antibody (Ublituximab) with CHOP and a novel highly active PI3K inhibitor (Umbralisib) in ASCT ineligible untreated advanced MCL. Umbralisib is highly active in various B cell lymphomas. The combination of Ublituximab and Umbralisib is being evaluated in two signature clinical trials. The preliminary data suggests that the combination is safe and well tolerated. To improve upon the back bone of R-CHOP, we want to explore U2-CHOP (Ublituximab with Umbralixib)-CHOP followed by U2 maintenance in ASCT in eligible patients. Both the study agents (U2) are highly active in lymphomas. Study hypothesis is to improve rates of complete response at the end of induction treatment with this novel combination.

Study Objectives:

• To determine the safety of Umbralisib and Ublituximab in combination with CHOP chemotherapy for newly diagnosed MCL.

• To determine the efficacy of U2-CHOP in terms of Complete Response rates (CRR) in patients with untreated MCL after induction phase (6 cycles of U2-CHOP) by PET/CT response assessment criteria by Cheson 2014.

• To characterize the toxicity profile of U2-CHOP induction followed by U2 maintenance in newly diagnosed Mantle Cell Lymphoma (MCL) patients.

• To determine rates of Overall response rate, disease control rate

• Overall survival and progression free survival

• To explore minimal residual disease (MRD) negative rates at the end of induction treatment ;

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, Mantle-Cell
• Mantle Cell Lymphoma

• NCT number: NCT04692155
• Study type: Interventional
• Source: University of Alabama at Birmingham
• Status: Terminated
• Phase: Phase 1/Phase 2
• Start date: August 31, 2021
• Completion date: June 30, 2022