Trial Outcomes & Findings for Ublituximab in Combination With Ibrutinib Versus Ibrutinib Alone in Participants With Previously Treated High-Risk Chronic Lymphocytic Leukemia (CLL) (NCT NCT02301156)

Last Updated: 2022-05-20

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

126 participants

Primary outcome timeframe

Up to 62 months

Results posted on

2022-05-20

Participant Flow

A total of 126 participants were enrolled at investigative sites in Israel and the United States (US) from 27 January 2015 to 01 April 2020.

Participants with previously treated Chronic Lymphocytic Leukemia (CLL) who had at least one high-risk cytogenetic abnormality were enrolled and randomized in a 1:1 ratio to receive either ublituximab in combination with ibrutinib or ibrutinib alone.

Participant milestones

Participant milestones
Measure	Ublituximab + Ibrutinib Participants received 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 54.6 months along with ibrutinib 420 mg capsules, orally, once daily (QD) in each 28-day cycle for up to 51.6 months.	Ibrutinib Participants received ibrutinib 420 mg capsules, orally, QD in each 28-day cycle up to 56.3 months.
Overall Study STARTED	64	62
Overall Study Intent to Treat (ITT) Population	64	62
Overall Study Safety Population	59	58
Overall Study COMPLETED	11	10
Overall Study NOT COMPLETED	53	52

Reasons for withdrawal

Reasons for withdrawal
Measure	Ublituximab + Ibrutinib Participants received 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 54.6 months along with ibrutinib 420 mg capsules, orally, once daily (QD) in each 28-day cycle for up to 51.6 months.	Ibrutinib Participants received ibrutinib 420 mg capsules, orally, QD in each 28-day cycle up to 56.3 months.
Overall Study Adverse Event	13	14
Overall Study Death	1	5
Overall Study Investigator Decision (includes non-compliance with study drug, investigator determined suitability)	2	2
Overall Study Site Terminated by Sponsor at the End of Study	27	16
Overall Study Withdrawal of Consent by Subject	4	12
Overall Study Reason not Specified	6	3

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Ublituximab + Ibrutinib n=64 Participants Participants received ublituximab IV infusion, up to 150 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 54.6 months along with ibrutinib 420 mg capsules, orally, QD in each 28-day cycle for up to 51.6 months.	Ibrutinib n=62 Participants Participants received ibrutinib 420 mg capsules, orally, QD in each 28-day cycle up to 56.3 months.	Total n=126 Participants Total of all reporting groups
Age, Continuous	67.0 years n=5 Participants	67.2 years n=7 Participants	67.1 years n=5 Participants
Sex: Female, Male Female	20 Participants n=5 Participants	16 Participants n=7 Participants	36 Participants n=5 Participants
Sex: Female, Male Male	44 Participants n=5 Participants	46 Participants n=7 Participants	90 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	62 Participants n=5 Participants	59 Participants n=7 Participants	121 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	7 Participants n=5 Participants	6 Participants n=7 Participants	13 Participants n=5 Participants
Race (NIH/OMB) White	56 Participants n=5 Participants	55 Participants n=7 Participants	111 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Region of Enrollment Israel	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Region of Enrollment United States	63 Participants n=5 Participants	62 Participants n=7 Participants	125 Participants n=5 Participants

PRIMARY outcome

Timeframe: Up to 62 months

Population: ITT Population included all randomized participants.

Outcome measures

Outcome measures
Measure	Ublituximab + Ibrutinib n=64 Participants Participants received ublituximab IV infusion, up to 150 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 54.6 months along with ibrutinib 420 mg capsules, orally, QD in each 28-day cycle for up to 51.6 months.	Ibrutinib n=62 Participants Participants received ibrutinib 420 mg capsules, orally, QD in each 28-day cycle up to 56.3 months.
Overall Response Rate (ORR)	84.4 percentage of participants	69.4 percentage of participants

SECONDARY outcome

Timeframe: Up to 62 months

Population: ITT Population included all randomized participants.

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.

Outcome measures

Outcome measures
Measure	Ublituximab + Ibrutinib n=64 Participants Participants received ublituximab IV infusion, up to 150 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 54.6 months along with ibrutinib 420 mg capsules, orally, QD in each 28-day cycle for up to 51.6 months.	Ibrutinib n=62 Participants Participants received ibrutinib 420 mg capsules, orally, QD in each 28-day cycle up to 56.3 months.
Complete Response (CR) Rate	18.8 percentage of participants	4.8 percentage of participants

SECONDARY outcome

Timeframe: Up to 62 months

Population: ITT Population included all randomized participants.

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.

Outcome measures

Outcome measures
Measure	Ublituximab + Ibrutinib n=64 Participants Participants received ublituximab IV infusion, up to 150 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 54.6 months along with ibrutinib 420 mg capsules, orally, QD in each 28-day cycle for up to 51.6 months.	Ibrutinib n=62 Participants Participants received ibrutinib 420 mg capsules, orally, QD in each 28-day cycle up to 56.3 months.
Minimum Residual Disease (MRD) Negativity Rate	45.3 percentage of participants Interval 32.8 to 58.3	9.7 percentage of participants Interval 3.6 to 19.9

SECONDARY outcome

Timeframe: From the randomization until the first documentation of PD or death whichever occurs first or up to 62 months

Population: ITT Population included all randomized participants.

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.

Outcome measures

Outcome measures
Measure	Ublituximab + Ibrutinib n=64 Participants Participants received ublituximab IV infusion, up to 150 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 54.6 months along with ibrutinib 420 mg capsules, orally, QD in each 28-day cycle for up to 51.6 months.	Ibrutinib n=62 Participants Participants received ibrutinib 420 mg capsules, orally, QD in each 28-day cycle up to 56.3 months.
Progression-Free Survival (PFS)	NA months Median, upper and lower limit of 95% CI were not estimable due to low number of participants with event.	47.2 months Interval 18.9 to Upper limit of 95% CI was not estimable due to low number of participants with event.

SECONDARY outcome

Timeframe: From the first dose of study drug until the first documentation of PD or death whichever occurs first or up to 62 months

Population: Participants in the ITT Population (included all randomized participants) who achieved either CR or PR were analyzed.

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.

Outcome measures

Outcome measures
Measure	Ublituximab + Ibrutinib n=54 Participants Participants received ublituximab IV infusion, up to 150 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 54.6 months along with ibrutinib 420 mg capsules, orally, QD in each 28-day cycle for up to 51.6 months.	Ibrutinib n=43 Participants Participants received ibrutinib 420 mg capsules, orally, QD in each 28-day cycle up to 56.3 months.
Duration of Response (DOR)	NA months Median, upper and lower limit of 95% CI were not estimable due to low number of participants with event.	39.1 months Interval 16.7 to Upper limit of 95% CI was not estimable due to low number of participants with event.

SECONDARY outcome

Timeframe: From the randomization up to 62 months

Population: Participants in the ITT Population (included all randomized participants) who achieved either CR or PR were analyzed.

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.

Outcome measures

Outcome measures
Measure	Ublituximab + Ibrutinib n=54 Participants Participants received ublituximab IV infusion, up to 150 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 54.6 months along with ibrutinib 420 mg capsules, orally, QD in each 28-day cycle for up to 51.6 months.	Ibrutinib n=43 Participants Participants received ibrutinib 420 mg capsules, orally, QD in each 28-day cycle up to 56.3 months.
Time to Response (TTR)	2.0 months Interval 2.0 to 2.1	3.9 months Interval 2.2 to 8.3

SECONDARY outcome

Timeframe: From the first dose up to 30 days after the last dose of study drug (up to 57.3 months)

Population: Safety Population included all participants who received at least one dose of study medication (ublituximab + ibrutinib or ibrutinib alone).

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.

Outcome measures

Outcome measures
Measure	Ublituximab + Ibrutinib n=59 Participants Participants received ublituximab IV infusion, up to 150 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 54.6 months along with ibrutinib 420 mg capsules, orally, QD in each 28-day cycle for up to 51.6 months.	Ibrutinib n=58 Participants Participants received ibrutinib 420 mg capsules, orally, QD in each 28-day cycle up to 56.3 months.
Percentage of Participants Experiencing at Least One Treatment-Emergent Adverse Event (TEAE)	100 percentage of participants	100 percentage of participants

Adverse Events

Ublituximab + Ibrutinib

Serious events: 38 serious events

Other events: 59 other events

Deaths: 5 deaths

Ibrutinib

Serious events: 31 serious events

Other events: 57 other events

Deaths: 9 deaths

Serious adverse events

Other adverse events

Additional Information

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