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)
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|ClinicalTrials.gov Identifier: NCT04692155|
Recruitment Status : Terminated (FDA hold)
First Posted : December 31, 2020
Last Update Posted : October 3, 2022
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|Condition or disease||Intervention/treatment||Phase|
|Mantle Cell Lymphoma||Drug: Ublituximab Drug: Umbralisib||Phase 1 Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||1 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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)|
|Actual Study Start Date :||August 31, 2021|
|Actual Primary Completion Date :||June 30, 2022|
|Actual Study Completion Date :||June 30, 2022|
Experimental: phase 1b and phase 2
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.
Ublituximab (900mg) will be administered as an intravenous infusion through a dedicated line.
Other Name: TG-1101
Umbralisib(800mg)will be administered orally once daily within 30 minutes of starting a meal.
Other Name: TGR-1202
- Rate of complete remission at the end of induction treatment [ Time Frame: Baseline through 2 years ]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)
- Progression free survival (PFS) [ Time Frame: Baseline through 3 years ]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
- Overall survival (OS) [ Time Frame: Baseline through 3 years ]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
- Rate of Overall Response Rate (Complete Response CR+ Partial Response PR) [ Time Frame: Baseline through 3 years ]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.
- Rate of disease control rate (CR+PR+SD) [ Time Frame: Baseline through 3 years ]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
- Rate of Minimal Residual Disease MRD negativity at the end of induction treatment [ Time Frame: Baseline through 2 years ]MRD status is a future exploratory endpoint for this trial. Peripheral blood samples are required at the end of induction treatment
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|Ages Eligible for Study:||18 Years and older (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
- 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
- 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.
- 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.
- 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)
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04692155
|United States, Alabama|
|University of Alabama at Birmingham|
|Birmingham, Alabama, United States, 35249|
|Principal Investigator:||Amitkumar Mehta||University of Alabama at Birmingham|
|Responsible Party:||Amitkumar Mehta, MD, Associate Professor, University of Alabama at Birmingham|
|Other Study ID Numbers:||
|First Posted:||December 31, 2020 Key Record Dates|
|Last Update Posted:||October 3, 2022|
|Last Verified:||September 2022|
|Studies a U.S. FDA-regulated Drug Product:||Yes|
|Studies a U.S. FDA-regulated Device Product:||No|
Neoplasms by Histologic Type
Immune System Diseases