Description:
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.
Title
- 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)
- 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)
Clinical Trial IDs
- ORG STUDY ID:
IRB-300006404
- NCT ID:
NCT04692155
Conditions
Interventions
Drug | Synonyms | Arms |
---|
Ublituximab | TG-1101 | phase 1b and phase 2 |
Umbralisib | TGR-1202 | phase 1b and phase 2 |
Purpose
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
Trial Arms
Name | Type | Description | Interventions |
---|
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. | |
Eligibility Criteria
Inclusion Criteria:
- 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.
Exclusion Criteria:
- 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)
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Rate of complete remission at the end of induction treatment |
Time Frame: | Baseline through 2 years |
Safety Issue: | |
Description: | 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) |
Secondary Outcome Measures
Measure: | Progression free survival (PFS) |
Time Frame: | Baseline through 3 years |
Safety Issue: | |
Description: | 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 |
Measure: | Overall survival (OS) |
Time Frame: | Baseline through 3 years |
Safety Issue: | |
Description: | 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 |
Measure: | Rate of Overall Response Rate (Complete Response CR+ Partial Response PR) |
Time Frame: | Baseline through 3 years |
Safety Issue: | |
Description: | 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. |
Measure: | Rate of disease control rate (CR+PR+SD) |
Time Frame: | Baseline through 3 years |
Safety Issue: | |
Description: | 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 |
Measure: | Rate of Minimal Residual Disease MRD negativity at the end of induction treatment |
Time Frame: | Baseline through 2 years |
Safety Issue: | |
Description: | MRD status is a future exploratory endpoint for this trial. Peripheral blood samples are required at the end of induction treatment |
Details
Phase: | Phase 1/Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Not yet recruiting |
Lead Sponsor: | University of Alabama at Birmingham |
Trial Keywords
- Ublituximab
- Umbralisib
- TGR-1202
- TG-1101
Last Updated
January 6, 2021