Mantle Cell LymphomaPhase 1/2CHOP U2NCT04692155
Clinical Trial of Ublituximab and Umbralisib With CHOP (U2-CHOP) Followed by U2 Maintenance (U2-CHOP-U2) in Previously Untreated Mantle Cell Lymphoma (MCL)
A Phase 1/2 study testing Ublituximab and Umbralisib in people with Mantle Cell Lymphoma, run by University of Alabama at Birmingham at 1 site in United States.
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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Mantle Cell Lymphoma
- What is being tested?
- Ublituximab and Umbralisib
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 1 participants
- Where
- 1 siteUnited States
- Study dates
- 31 Aug 2021to 30 Jun 2022
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Males or female patients >18 years of age
- Diagnosis of MCL (Ann Arbor Stage II, III, IV) as supported by histology and over expression of cyclin D1 (in association with CD20 and CD5) or evidence of t(11;14) by FISH (fluorescent in situ hybridization) with indication of initiation of therapy.
- At least one LN of >1.5 cm size as index/measurable site of disease
- No prior anti-cancer therapy for MCL
- Not eligible for bone marrow transplantation/ASCT (assessed by treating physician due to comorbidities) or not interested in bone marrow transplant/ASCT (clear documentation of patient's unwillingness to pursue transplant)
- Eastern cooperative Oncology Group (ECOG) performance status: 0,1 or 2
Show all 15Show fewer
- Absolute neutrophil count (ANC) >1500/microL (>1000 if bone marrow involvement with MCL) within 28 days prior to initiation of therapy. Growth factors are not permitted for the purpose of meeting eligibility criteria.
- Platelets >100000 cells/uL (>75000 cells/uL if bone marrow involvement with MCL) within 28 days prior to initiation of therapy. Growth factors are not permitted for the purpose of meeting eligibility criteria.
- Hemoglobin >9.0 gm/dL (>8.0 gm/dL if bone marrow involvement with MCL) within 28 days prior to initiation of therapy. Growth factors are not permitted for the purpose of meeting eligibility criteria.
- Alanine transaminase (ALT)/Aspartate Transaminase (AST) <2.5 X Upper limit of Normal (ULN) if no liver involvement or ≤ 5 x the ULN if known liver involvement within 28 days prior to initiation of therapy
- Total Bilirubin <1.5X ULN within 28 days prior to initiation of therapy (Except in Gilbert's disase <3XULN is allowed)
- Calculated Creatinine Clearance >35 mL/min by Cockcroft-Gault Equation
- Male patients must agree to use an acceptable method of contraception for the entire duration of study and for 4 months after the last dose of either study drug.
- All patients (or their legal representative) must have signed an informed consent indicating that they are willing to participate in the study and are willing to follow the procedure required by the study in accordance with federal, local and institutional guidelines.
- Female patients who are not of child-bearing potential, and female patients of child-bearing potential who have a negative serum pregnancy test within 3 days prior to initial trial treatment Female patients of child-bearing potential and all male partners must consent to use a medically acceptable method of contraception throughout the study period and for 4 months after the last dose of either study drug.
Who cannot join
- Any prior anti-neoplastic therapy for MCL
- CNS involvement by MCL
- Malignancy within the past 3 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, non-melanomatous skin cancer or localized thyroid cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less with stable prostate-specific antigen levels; or d) cancer considered cured by surgical resection/radiation or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder or benign tumors of the adrenal or pancreas.
- If patient has received prior anthracycline therapy, the cumulative anthracycline dose should be <150mg/m2 of doxorubicin equivalent
- H/O prior Allogeneic transplantation or autologous stem cell transplantation for any other reason.
- Use of immunosuppressive therapy (e.g. cyclosporine A, tacrolimus or high dose steroids). Patients receiving steroids must be at a dose of <10mg/day prednisone (or equivalent) within 7 days of the first day of the study treatment administration. Patients are allowed to use topical or inhaled corticosteroids.
Show all 29Show fewer
- Concurrent any systemic anticancer therapy for any other cancer (chemotherapy, radiation, surgery, immunotherapy, biologic therapy, hormonal therapy, investigational therapy or tumor embolization).
- Uncontrolled Diabetes Mellitus, Hyperglycemia (patients with endocrine consultation and proper plan with reasonable control of blood sugars are allowed)
- Any uncontrolled auto-immune condition like hepatitis, colitis, pneumonitis etc which in view of investigator is high risk to be treated on this combination
- History of stroke or intracranial hemorrhage within 6 months of the date of study treatment administration (unless complete and full recovery)
- Chronic or current active infections requiring intravenous antibiotics, antifungal or antiviral treatment or exposure to live vaccines within 30 days of study treatment.
- Known HIV infection or history of HIV.
- Evidence of Hepatitis B or Hepatitis C infection or risk of reactivation. HBV DNA or HCV RNA evidence of chronic active Hepatitis B (HBV, not including patients with prior hepatitis B vaccination; or positive serum Hepatitis B antibody) or chronic active Hepatitis C infection (HCV), active cytomegalovirus (CMV), or known history of HIV. If HBc antibody is positive, the subject must be evaluated for the presence of HBV DNA by PCR. If CMV IgG or IgM is reactive, the subject must be evaluated for the presence of CMV DNA by PCR. If HCV antibody is positive, the subject must be evaluated for the presence of HCV RNA by PCR. See Appendix: HEPATITIS B SEROLOGIC TEST RESULTS. Subjects with positive HBc antibody and negative HBV DNA by PCR are eligible. Subjects with positive HCV antibody and negative HCV RNA by PCR are eligible. Subjects who are CMV IgG or CMV IgM positive but who are CMV DNA negative by PCR are eligible.
- Known history of drug-induced liver injury, alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, ongoing extrahepatic obstruction caused by stones, cirrhosis of the liver
- Any severe and/or uncontrolled medical conditions or other conditions that could affect participation in the study such as:
- Symptomatic, or history of documented congestive heart failure (New York Heart Association functional classification II-IV)[see Appendix: NYHA Classifications]
- Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, CHF, or myocardial infarction within 6 months of enrollment.
- Concomitant use of medication known to cause QT prolongation or torsades de pointes should be used with caution and at investigator discretion.
- Poorly controlled or clinically significant atherosclerotic vascular disease including cerebrovascular accident (CVA), transient ischemic attack (TIA), angioplasty, cardiac or vascular stenting within 6 months of enrollment.
- Cardiac ejection fraction (EF) <45%.
- Current NY heart association Class II to IV congestive heart failure or uncontrolled arrhythmia
- Presence of an abnormal ECG that is clinically meaningful. Patients with QTc interval >450 for males and >470 milliseconds for females are excluded (corrected by Fridericia).
- Currently pregnant or breast feeding.
- Unable to swallow and retain oral medication, malabsorption syndrome, disease significantly affecting GI function, total resection of stomach or small bowel, ulcerative colitis, symptomatic IBD or complete or partial obstruction.
- Anaphylaxis, excluding infusion related reactions, to monoclonal antibody/Rituximab in past.
- Any condition that would, in investigator's judgment, interfere with full participation in the study, including administration of study medication/chemotherapy, attending study visits, pose a risk to the patient or interfere with interpretation of study data.
- Inability to comprehend or unwilling to sign the ICF.
- Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 21 days prior to registration
- Contraindication or intolerance to required supportive care medications (pegfilgrastim, acyclovir or bactrim/dapsone/pentamidine/atovaquone)
Trial locations and contacts
1 site in 1 country.
United States1 site
University of Alabama at Birmingham
Birmingham, Alabama, 35249
About this study
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)
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.
Read the 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 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
- Conditions
- Mantle Cell Lymphoma
- Being tested
- Ublituximab, Umbralisib
- Keywords
- Ublituximab, Umbralisib, TGR-1202, TG-1101
- Medical subject headings
- Lymphoma, Mantle-Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
UblituximabDrug
Also called TG-1101
Ublituximab (900mg) will be administered as an intravenous infusion through a dedicated line.
UmbralisibDrug
Also called TGR-1202
Umbralisib(800mg)will be administered orally once daily within 30 minutes of starting a meal.
| Study group | Role | What they receive |
|---|---|---|
| phase 1b and phase 2 | Experimental | for phase 1 B portion, Ublitixumab will be given IV at dosage 900mg from Cycle 1 Day1 till cycle 6. If investigator decides to continue the treatment as maintenance, Ublitixumab will be given IV every 8 weeks for 24 months Umbralisib (800mg) will be given orally once a day within 30 minutes of a meal from Cycle 1 Day1 till cycle 6.If investigator decides to continue the treatment as maintenance,• Umbralisib will be given at orally daily for 24 months.
Chemotherapy combination of CHOP-cyclophosphamide IV 750mg/m2 for Age <70 years, 500 mg/m2 for Age>70 years doxorubicin IV 50mg/m2for Age <70 years, 25 mg/m2 for Age>70 years , and vincristine IV 1mg/m2 (max 2mg)) are administered on Cycle 1 day 1 till Cycle 6. Prednisone 50-100mg will be given orally on days 1 through 5 of every cycle.
For Phase II portion- 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) agrees. Receives: Drug: Ublituximab; Drug: Umbralisib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Rate of Complete Remission at the End of Induction Treatment
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)-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. Rate of complete remission at the end of induction treatment (U2-CHOP X 6 cycles) per PET/CT assessment criteria for Lymphoma (Cheson et al, 2014).Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Measured: 10 months
Secondary outcomes (5)
Progression Free Survival (PFS)
To determine the efficacy of U2-CHOP in terms of PFS in patients with untreated MCL after induction phase (6 cycles of U2-CHOP) by PET/CT response assessment criteria by Cheson 2014
Measured: Baseline through 3 years
Overall Survival (OS)
To determine the efficacy of U2-CHOP in terms of OS in patients with untreated MCL after induction phase (6 cycles of U2-CHOP) by PET/CT response assessment criteria by Cheson 2014
Measured: Baseline through 3 years
Rate of Overall Response Rate (Complete Response CR+ Partial Response PR)
To determine the efficacy of U2-CHOP in terms of Overall Response rates (ORR) in patients with untreated MCL after induction phase (6 cycles of U2-CHOP) by PET/CT response assessment criteria by Cheson 2014.
Measured: Baseline through 3 years
Rate of Disease Control Rate (CR+PR+SD)
To determine the efficacy of U2-CHOP in terms of Rate of disease control rate in patients with untreated MCL after induction phase (6 cycles of U2-CHOP) by PET/CT response assessment criteria by Cheson 2014
Measured: Baseline through 3 years
Rate of Minimal Residual Disease MRD Negativity at the End of Induction Treatment
MRD status is a future exploratory endpoint for this trial. Peripheral blood samples are required at the end of induction treatment
Measured: Baseline through 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted31 Dec 2020
- Study start31 Aug 2021
- Primary completion30 Jun 2022
- Study completion30 Jun 2022
Why it stopped: FDA hold
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Mantle Cell LymphomaStudies of the same condition, open and under way.
- More trials run by University of Alabama at BirminghamThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 1 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Alabama at Birmingham
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Amitkumar Mehta, MD, University of Alabama at Birmingham
- Investigators
- Amitkumar Mehta, Principal investigator, University of Alabama at Birmingham
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04692155
- Sponsor's protocol ID
- IRB-300006404
- Acronym
- CHOP U2
- Status last verified
- Sep 2023
- First submitted
- 28 Dec 2020
- Last updated
- 28 Sep 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 28 Sep 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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)
- ClinicalTrials.gov ID
- NCT04692155
- Acronym / sponsor ID
- CHOP U2 / IRB-300006404
- Conditions
- Mantle Cell Lymphoma
- Keywords
- Ublituximab, Umbralisib, TGR-1202, TG-1101
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: FDA hold
- Enrolment
- 1 participants (actual)
- Lead sponsor
- University of Alabama at BirminghamUniversity, hospital or other
- Study start
- 31 Aug 2021 (actual)
- Primary completion
- 30 Jun 2022 (actual)
- Study completion
- 30 Jun 2022 (actual)
- First posted
- 31 Dec 2020 (actual)
- Results
- Posted 28 Sep 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 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
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| phase 1b and phase 2 | Experimental | Drug: Ublituximab, Drug: Umbralisibfor phase 1 B portion, Ublitixumab will be given IV at dosage 900mg from Cycle 1 Day1 till cycle 6. If investigator decides to continue the treatment as maintenance, Ublitixumab will be given IV every 8 weeks for 24 months Umbralisib (800mg) will be given orally once a day within 30 minutes of a meal from Cycle 1 Day1 till cycle 6.If investigator decides to continue the treatment as maintenance,• Umbralisib will be given at orally daily for 24 months. Chemotherapy combination of CHOP-cyclophosphamide IV 750mg/m2 for Age <70 years, 500 mg/m2 for Age>70 years doxorubicin IV 50mg/m2for Age <70 years, 25 mg/m2 for Age>70 years , and vincristine IV 1mg/m2 (max 2mg)) are administered on Cycle 1 day 1 till Cycle 6. Prednisone 50-100mg will be given orally on days 1 through 5 of every cycle. For Phase II portion- 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) agrees. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (15 listed)
- Males or female patients >18 years of age
- Diagnosis of MCL (Ann Arbor Stage II, III, IV) as supported by histology and over expression of cyclin D1 (in association with CD20 and CD5) or evidence of t(11;14) by FISH (fluorescent in situ hybridization) with indication of initiation of therapy.
- At least one LN of >1.5 cm size as index/measurable site of disease
- No prior anti-cancer therapy for MCL
- Not eligible for bone marrow transplantation/ASCT (assessed by treating physician due to comorbidities) or not interested in bone marrow transplant/ASCT (clear documentation of patient's unwillingness to pursue transplant)
Key exclusion criteria (29 listed)
- Any prior anti-neoplastic therapy for MCL
- CNS involvement by MCL
- Malignancy within the past 3 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, non-melanomatous skin cancer or localized thyroid cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less with stable prostate-specific antigen levels; or d) cancer considered cured by surgical resection/radiation or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder or benign tumors of the adrenal or pancreas.
- If patient has received prior anthracycline therapy, the cumulative anthracycline dose should be <150mg/m2 of doxorubicin equivalent
- H/O prior Allogeneic transplantation or autologous stem cell transplantation for any other reason.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| UblituximabAlso: TG-1101Ublituximab (900mg) will be administered as an intravenous infusion through a dedicated line. | Drug | phase 1b and phase 2 |
| UmbralisibAlso: TGR-1202Umbralisib(800mg)will be administered orally once daily within 30 minutes of starting a meal. | Drug | phase 1b and phase 2 |
Primary outcome
Rate of Complete Remission at the End of Induction Treatment
Time frame: 10 months
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)-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. Rate of complete remission at the end of induction treatment (U2-CHOP X 6 cycles) per PET/CT assessment criteria for Lymphoma (Cheson et al, 2014).Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
5 secondary outcomes
Progression Free Survival (PFS)
Time frame: Baseline through 3 years
Overall Survival (OS)
Time frame: Baseline through 3 years
Rate of Overall Response Rate (Complete Response CR+ Partial Response PR)
Time frame: Baseline through 3 years
Rate of Disease Control Rate (CR+PR+SD)
Time frame: Baseline through 3 years
Rate of Minimal Residual Disease MRD Negativity at the End of Induction Treatment
Time frame: Baseline through 2 years
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Sep 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Related trials for Mantle Cell Lymphoma
Not yet recruitingPhase 1
Testing the Addition of an Anti-Cancer Drug, Glofitamab, to the Usual Chemotherapy Treatment (Alternating R-CHOP/R-DHAP) for Previously Untreated Mantle Cell Lymphoma
Ann Arbor Stage II Mantle Cell Lymphoma, Ann Arbor Stage III Mantle Cell Lymphoma
RecruitingPhase 3
A Study to Evaluate Glofitamab as a Single Agent vs. Investigator's Choice in Participants With Relapsed/Refractory Mantle Cell Lymphoma
Lymphoma
RecruitingPhase 1
A Study of LY4152199 in Participants With Previously Treated B-cell Malignancies (BAF_FRontier-1 )
Lymphoma, Non-Hodgkin, B-cell Lymphoma
RecruitingPhase 2
Auto Stem Cell Transplant for Lymphoma Patients
Non-Hodgkin Lymphoma, Hodgkin Lymphoma
Active, not recruitingPhase 1
Study to Evaluate Adverse Events, Change in Disease Activity, and How Oral ABBV-101 Moves Through the Body in Adult Participants With B-Cell Malignancies
Hematologic Cancer
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Amitkumar Mehta principal investigator
University of Alabama at Birmingham
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Ublituximab and Umbralisib in people with Mantle Cell Lymphoma, run by University of Alabama at Birmingham at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 15 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 28 Sep 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 28 Sep 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Rate of Complete Remission at the End of Induction Treatment (time frame: 10 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Sep 2023.