Ublituximab in Combination With Ibrutinib Versus Ibrutinib Alone in Participants With Previously Treated High-Risk Chronic Lymphocytic Leukemia (CLL)

Study Overview
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Brief Summary
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This study evaluates the effect of the addition of ublituximab, a novel monoclonal antibody, to ibrutinib compared to ibrutinib alone on antitumor activity, as measured by the overall response rate (ORR = CR [complete response] + PR [partial response]) in previously treated Chronic Lymphocytic Leukemia (CLL) participants with high-risk cytogenetic features. Half of the participants will receive ublituximab in combination with ibrutinib, while the other half will receive ibrutinib alone.

Official Title
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A Phase 3, Randomized, Study to Assess the Efficacy and Safety of Ublituximab in Combination With Ibrutinib Compared to Ibrutinib Alone, in Patients With Previously Treated High-Risk Chronic Lymphocytic Leukemia (CLL)

Conditions
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Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Drug: Ublituximab
* Drug: Ibrutinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Previously treated Chronic Lymphocytic Leukemia (CLL) requiring treatment At least one high-risk cytogenetic feature defined by the presence of 17p deletion, 11q deletion and/or p53 mutation Eastern Cooperative Oncology Group (ECOG) score of 0 to 2 Exclusion Criteria: Any major surgery, chemotherapy or immunotherapy within the last 21 days Evidence of hepatitis B virus, hepatitis C virus or known human immunodeficiency virus (HIV) infection Autologous hematologic stem cell transplant within 3 months of study entry. Prior Allogeneic hematologic stem cell transplant is excluded Transformation of CLL to aggressive Non-Hodgkin's Lymphoma (NHL) (Richter's transformation) Previous therapy with ibrutinib, or any drug that specifically inhibits Bruton's tyrosine kinase (BTK)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ublituximab + Ibrutinib<br>Participants will receive ublituximab intravenous (IV) infusion, up to 150 milligrams (mg) once on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1 (Cycle duration=28 days) followed by 900 mg on Day 1 of Cycles 2 to 6 and 900 mg on Day 1 of every 3rd cycle thereafter for up to 62 months along with ibrutinib 420 mg capsules, orally, once daily (QD) in each 28-day cycle for up to 62 months. | Drug: Ublituximab<br>* Administered as an IV infusion<br>* Other names: TG-1101;Drug: Ibrutinib<br>* Administered orally<br>* Other names: IMBRUVICA;|
| Active Comparator: Ibrutinib<br>Participants will receive ibrutinib 420 mg capsules, orally, QD in each 28-day cycle up to 62 months. | Drug: Ibrutinib<br>* Administered orally<br>* Other names: IMBRUVICA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR: Percentage of participants with best overall response of partial response(PR) and complete response(CR). CR criteria: No evidence of new disease; Absolute lymphocyte count(ALC)<4x10^9/liter(L); Regression of all target nodal masses to ≤1.5 centimeters(cm) in longest diameter(LD); Normal spleen,liver size; Regression to normal of all nodal non-target disease and disappearance of all detectable; Non-nodal, non-target disease; Morphologically negative bone marrow; No lymphoid nodules; Absolute neutrophil count(ANC)>1.5x10^9/L,platelets≥100x10^9/L,hemoglobin (Hgb)≥110 gram per liter(g/L). PR criteria: No evidence of new disease; Response in 2 of following if abnormal at baseline: ALC<4x10^9/L or >=50% decrease from baseline in sum of products(SPD) of target nodal lesions; splenomegaly; hepatomegaly;>=50% decrease from baseline in CLL marrow infiltrate/B-lymphoid nodules; response in any 1:ANC>1.5x10^9/L,platelets>100x10^9/L,Hgb>110g/L or >=50% increase over baseline in any of these. | Up to 62 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response (CR) Rate | The CR rate was defined as the percentage of participants who achieved CR. CR criteria: No evidence of new disease; ALC <4 x 10^9/L; Regression of all target nodal masses to normal size ≤1.5 cm in the LD; Normal spleen and liver size; Regression to normal of all nodal non-target disease and disappearance of all detectable; Non-nodal, non-target disease; Morphologically negative bone marrow; No lymphoid nodules; ANC >1.5 x 10^9/L, platelets ≥100 x 10^9/L, Hgb ≥110 g/L. | Up to 62 months | 
| Minimum Residual Disease (MRD) Negativity Rate | MRD negativity rate was defined as the percentage of participants who were MRD negative post-baseline. If a participant was determined to be MRD negative by peripheral blood, a bone marrow aspirate was obtained to assess MRD in the bone marrow. | Up to 62 months | 
| Progression-Free Survival (PFS) | PFS was defined as the time from the date of randomization until the date of first documentation of definitive disease progression (PD) or date of death from any cause, whichever occurs first. PD requires at least one of the following: New nodes >1.5 cm in the LD and >1.0 in longest perpendicular diameter (LPD), new or recurrent hepatomegaly or splenomegaly, new or reappearance of an unequivocal extra-nodal lesion, ≥50% increase from the nadir in the sum of products of target lesions, ≥50% increase in the LD of an individual node or extra-nodal mass, splenic/hepatic enlargement of ≥50% from nadir, unequivocal increase in the size of non-target disease, transformation to a more aggressive histology, decrease in platelet count or Hgb, >50% decrease from the highest on-study platelet count, >20 g/L decrease from the highest on-study Hgb. | From the randomization until the first documentation of PD or death whichever occurs first or up to 62 months | 
| Duration of Response (DOR) | DOR:Interval from first documentation of CR/PR to first documentation of PD or death from any cause.CR:ALC<4x10^9/L;Regression to normal of target nodal masses,nodal non-target disease,and no detectable non-nodal,non-target disease;Normal spleen,liver size;Morphologically negative bone marrow,No lymphoid nodules;ANC>1.5x10^9/L,Platelets≥100x10^9/L,Hgb≥110 g/L.PR:Response in 2 or more:ALC<4x10^9/L,>=50% drop from baseline in ALC or SPD of target nodal lesions,Hepatosplenomegaly,>=50% decrease from baseline in CLL marrow infiltrate/B-lymphoid nodules;Response in 1 or more:ANC>1.5x10^9/L,Platelets>100x10^9/L,Hgb>110 g/L or >=50% increase over baseline in any.PD:Response in 1 or more:new nodes,Hepatosplenomegaly,unequivocal extra-nodal lesion;≥50% increase from nadir in SPD of target lesions or LD of node/extra-nodal mass or Splenic/Hepatic size,Unequivocal increase in non-target disease,More aggressive histology;Drop of >50% in platelets/>20g/L in Hgb from highest on-study count. | From the first dose of study drug until the first documentation of PD or death whichever occurs first or up to 62 months | 
| Time to Response (TTR) | TTR was defined as the interval from the randomization to the first documentation of CR or PR. CR criteria: No evidence of new disease; ALC <4 x 10^9/L; Regression of all target nodal masses to normal size ≤1.5 cm in the LD; Normal spleen and liver size; Regression to normal of all nodal non-target disease and disappearance of all detectable; Non-nodal, non-target disease; Morphologically negative bone marrow; No lymphoid nodules; ANC >1.5 x 10^9/L, platelets ≥100 x 10^9/L, Hgb ≥110 g/L. PR criteria: No evidence of new disease; Response in 2 of following when abnormal at baseline: ALC<4 x 10^9/L or >=50% decrease from baseline in SPD of target nodal lesions; splenomegaly; hepatomegaly; >=50% decrease from baseline in CLL marrow infiltrate/B-lymphoid nodules; and Response in 1 of the following: ANC>1.5 x 10^9/L, platelets>100 x 10^9/L, Hgb>110 g/L or >=50% increase over baseline in any of these. | From the randomization up to 62 months | 
| Percentage of Participants Experiencing at Least One Treatment-Emergent Adverse Event (TEAE) | An adverse event (AE) is any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporarily associated with the use of a medicinal product, whether or not considered related to the medicinal product. TEAE is any AE that occur after first dosing of study medication and through the end of the study or through 30 days after the last dose of study treatment, or is considered treatment-related regardless of the start date of the event, or is present before first dosing of study medication but worsens in intensity or the investigator subsequently considers treatment-related. | From the first dose up to 30 days after the last dose of study drug (up to 57.3 months) |