Ignite Creation Date:
2024-05-06 @ 3:36 PM
Last Modification Date:
2024-10-26 @ 1:53 PM
Study NCT ID:
NCT04692155
Status:
TERMINATED
Last Update Posted:
2023-09-28
First Post:
2020-12-28
Brief Title:
Clinical Trial of Ublituximab and Umbralisib With CHOP U2-CHOP Followed by U2 Maintenance U2-CHOP-U2 in Previously Untreated Mantle Cell Lymphoma MCL
Sponsor:
University of Alabama at Birmingham
Organization:
University of Alabama at Birmingham
Study Overview
Official Title:
Phase IbII 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
Status Verified Date:
2023-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
FDA hold
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
CHOP U2
Brief Summary:
This is a single arm multi-center open label Phase IbII trial in adult patients with newly diagnosed Mantle Cell Lymphoma MCLStage 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 SMCDSMB Safety monitoring committeeData Safety Monitoring Committee agreement
Detailed 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 aggressiveintense 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 100mgkg 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 IIb study of the combination of ublituximab umbralisib U2 in patients with relapsed or refractory Non-Hodgkin LymphomaNHL and Chronic lymphocytic LeukemiaCLL 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 MCLStage 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 PETCT 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
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 100mgkg 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 IIb study of the combination of ublituximab umbralisib U2 in patients with relapsed or refractory Non-Hodgkin LymphomaNHL and Chronic lymphocytic LeukemiaCLL 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 MCLStage 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 PETCT 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None