Trial Outcomes & Findings for Study to Assess the Efficacy and Safety of Ublituximab in Combination With Umbralisib and Venetoclax Compared to Ublituximab in Combination With Umbralisib in Subjects With CLL (ULTRA-V) (NCT NCT03801525)

Last Updated: 2024-04-19

Results Overview

CR rate=percent of participants who achieved CR or complete response with incomplete marrow recovery(CRi).CR=no evidence of new disease,absolute lymphocyte count(ALC) in peripheral blood\<4x10\^9 per liter(/L),regression of nodal masses to normal size \<1.5 centimeters(cm) in longest diameter(LD),normal spleen and liver size,no constitutional symptoms,cytological/pathological evaluation of bone marrow(BM) smear/biopsy must be at least normocellular for age without evidence for typical chronic lymphocytic leukemia(CLL)/small lymphocytic lymphoma(SLL) lymphocytes by morphological criteria,peripheral blood counts with absolute neutrophil count(ANC)≥1.5x10\^9/L or platelet≥100x10\^9/L or hemoglobin≥110 grams per liter(g/L) without red blood cell(RBC) transfusions,all without need for exogenous growth factors.CRi=all CR criteria but with persistent anemia,thrombocytopenia,or neutropenia or hypocellular BM that is related to prior/ongoing drug toxicity(and not to CLL/SLL).

Recruitment status

TERMINATED

Study phase

PHASE2/PHASE3

Target enrollment

277 participants

Primary outcome timeframe

Up to 43.2 months

Results posted on

2024-04-19

Participant Flow

A total of 277 participants were enrolled at investigative sites in the United States from 16 May 2019 to 20 December 2022.

Participant milestones

Participant milestones
Measure	Phase 2: Ublituximab + Umbralisib + Venetoclax (U2-V) Participants were administered ublituximab, 150 milligrams (mg), intravenous (IV) infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6; umbralisib, 800 mg, oral tablet, once daily (QD) through Cycles 1-24; venetoclax, oral tablet, QD, 20 mg on Days 1-7, 50 mg on Days 8-14, 100 mg on Days 15-21, 200 mg on Days 22-28 of Cycle 4, followed by 400 mg on Days 1-28 of Cycles 5-24. MRD positive participants were administered umbralisib, 800 mg, oral tablet, QD, on Days 1-28 from Cycle 25 onwards (1 Cycle = 28 days), until disease progression, unacceptable toxicity, or withdrawal from the study.	Phase 3: Ublituximab + Umbralisib + Venetoclax (U2-V) Participants were administered ublituximab, 150 mg, IV infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6, 9,12, and 15; umbralisib, 800 mg, oral tablet, QD through Cycles 1-15; venetoclax, oral tablet, QD, 20 mg on Days 1-7, 50 mg on Days 8-14, 100 mg on Days 15-21, 200 mg on Days 22-28 of Cycle 4, followed by 400 mg on Days 1-28 of Cycles 5-15 (1 Cycle = 28 days).	Phase 3: Ublituximab + Umbralisib (U2) Participants were administered ublituximab, 150 mg, IV infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6, then every three cycles along with umbralisib, 800 mg, oral tablet, QD (1 Cycle = 28 days) from Cycle 1 until disease progression, unacceptable toxicity, or withdrawal from the study.
Overall Study STARTED	165	56	56
Overall Study Intent-To-Treat (ITT) Population	149	56	56
Overall Study COMPLETED	11	0	0
Overall Study NOT COMPLETED	154	56	56

Reasons for withdrawal

Reasons for withdrawal
Measure	Phase 2: Ublituximab + Umbralisib + Venetoclax (U2-V) Participants were administered ublituximab, 150 milligrams (mg), intravenous (IV) infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6; umbralisib, 800 mg, oral tablet, once daily (QD) through Cycles 1-24; venetoclax, oral tablet, QD, 20 mg on Days 1-7, 50 mg on Days 8-14, 100 mg on Days 15-21, 200 mg on Days 22-28 of Cycle 4, followed by 400 mg on Days 1-28 of Cycles 5-24. MRD positive participants were administered umbralisib, 800 mg, oral tablet, QD, on Days 1-28 from Cycle 25 onwards (1 Cycle = 28 days), until disease progression, unacceptable toxicity, or withdrawal from the study.	Phase 3: Ublituximab + Umbralisib + Venetoclax (U2-V) Participants were administered ublituximab, 150 mg, IV infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6, 9,12, and 15; umbralisib, 800 mg, oral tablet, QD through Cycles 1-15; venetoclax, oral tablet, QD, 20 mg on Days 1-7, 50 mg on Days 8-14, 100 mg on Days 15-21, 200 mg on Days 22-28 of Cycle 4, followed by 400 mg on Days 1-28 of Cycles 5-15 (1 Cycle = 28 days).	Phase 3: Ublituximab + Umbralisib (U2) Participants were administered ublituximab, 150 mg, IV infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6, then every three cycles along with umbralisib, 800 mg, oral tablet, QD (1 Cycle = 28 days) from Cycle 1 until disease progression, unacceptable toxicity, or withdrawal from the study.
Overall Study Adverse Event	17	1	0
Overall Study Conditions Requiring Therapeutic Intervention Not Permitted by The Protocol	1	0	0
Overall Study Death	29	1	4
Overall Study Disease Progression	6	0	1
Overall Study Inability to Comply With Study Requirements	1	1	0
Overall Study Investigator Decision	18	1	0
Overall Study Minimal Residual Disease (MRD) Negativity and Tumor Response	14	0	0
Overall Study Sponsor Discontinuation of the Study	24	49	43
Overall Study Started Non-protocol Anti-cancer Therapy	2	1	3
Overall Study Withdrawal of Subject Consent	38	2	1
Overall Study Reason not Specified	4	0	4

Baseline Characteristics

Study to Assess the Efficacy and Safety of Ublituximab in Combination With Umbralisib and Venetoclax Compared to Ublituximab in Combination With Umbralisib in Subjects With CLL (ULTRA-V)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Phase 2: Ublituximab + Umbralisib + Venetoclax (U2-V) n=165 Participants Participants were administered ublituximab, 150 mg, IV infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6; umbralisib, 800 mg, oral tablet, QD through Cycles 1-24; venetoclax, oral tablet, QD, 20 mg on Days 1-7, 50 mg on Days 8-14, 100 mg on Days 15-21, 200 mg on Days 22-28 of Cycle 4, followed by 400 mg on Days 1-28 of Cycles 5-24. MRD positive participants were administered umbralisib, 800 mg, oral tablet, QD, on Days 1-28 from Cycle 25 onwards (1 Cycle = 28 days), until disease progression, unacceptable toxicity, or withdrawal from the study.	Phase 3: Ublituximab + Umbralisib + Venetoclax (U2-V) n=56 Participants Participants were administered ublituximab, 150 mg, IV infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6, 9,12, and 15; umbralisib, 800 mg, oral tablet, QD through Cycles 1-15; venetoclax, oral tablet, QD, 20 mg on Days 1-7, 50 mg on Days 8-14, 100 mg on Days 15-21, 200 mg on Days 22-28 of Cycle 4, followed by 400 mg on Days 1-28 of Cycles 5-15 (1 Cycle = 28 days).	Phase 3: Ublituximab + Umbralisib (U2) n=53 Participants Participants were administered ublituximab, 150 mg, IV infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6, then every three cycles along with umbralisib, 800 mg, oral tablet, QD (1 Cycle = 28 days) from Cycle 1 until disease progression, unacceptable toxicity, or withdrawal from the study.	Total n=274 Participants Total of all reporting groups
Age, Continuous	65.9 years n=99 Participants	65.5 years n=107 Participants	62.9 years n=206 Participants	65.3 years n=7 Participants
Sex: Female, Male Female	60 Participants n=99 Participants	22 Participants n=107 Participants	14 Participants n=206 Participants	96 Participants n=7 Participants
Sex: Female, Male Male	105 Participants n=99 Participants	34 Participants n=107 Participants	39 Participants n=206 Participants	178 Participants n=7 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	5 Participants n=99 Participants	2 Participants n=107 Participants	1 Participants n=206 Participants	8 Participants n=7 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	158 Participants n=99 Participants	53 Participants n=107 Participants	49 Participants n=206 Participants	260 Participants n=7 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	2 Participants n=99 Participants	1 Participants n=107 Participants	3 Participants n=206 Participants	6 Participants n=7 Participants
Race/Ethnicity, Customized Race · White/Caucasian	147 Participants n=99 Participants	51 Participants n=107 Participants	44 Participants n=206 Participants	242 Participants n=7 Participants
Race/Ethnicity, Customized Race · Black or African American	6 Participants n=99 Participants	2 Participants n=107 Participants	4 Participants n=206 Participants	12 Participants n=7 Participants
Race/Ethnicity, Customized Race · Asian	2 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants	2 Participants n=7 Participants
Race/Ethnicity, Customized Race · American Indian or Alaska Native	1 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants	1 Participants n=7 Participants
Race/Ethnicity, Customized Race · Hispanic	1 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants	1 Participants n=7 Participants
Race/Ethnicity, Customized Race · Unknown	8 Participants n=99 Participants	3 Participants n=107 Participants	5 Participants n=206 Participants	16 Participants n=7 Participants

PRIMARY outcome

Timeframe: Up to 43.2 months

Population: ITT population for Phase 2 consisted of all participants who received at least one dose of each study drug (ublituximab, umbralisib, and venetoclax). Percentages were rounded off to the nearest decimal point.

Outcome measures

Outcome measures
Measure	Phase 2: Ublituximab + Umbralisib + Venetoclax (U2-V) n=149 Participants Participants were administered ublituximab, 150 mg, IV infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6; umbralisib, 800 mg, oral tablet, QD through Cycles 1-24; venetoclax, oral tablet, QD, 20 mg on Days 1-7, 50 mg on Days 8-14, 100 mg on Days 15-21, 200 mg on Days 22-28 of Cycle 4, followed by 400 mg on Days 1-28 of Cycles 5-24. MRD positive participants were administered umbralisib, 800 mg, oral tablet, QD, on Days 1-28 from Cycle 25 onwards (1 Cycle = 28 days), until disease progression, unacceptable toxicity, or withdrawal from the study.	Phase 3: Ublituximab + Umbralisib (U2) Participants were administered ublituximab, 150 mg, IV infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6, then every three cycles along with umbralisib, 800 mg, oral tablet, QD (1 Cycle = 28 days) from Cycle 1 until disease progression, unacceptable toxicity, or withdrawal from the study.	Phase 3: Ublituximab + Umbralisib (U2) Participants were administered ublituximab, 150 mg, IV infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6, then every three cycles along with umbralisib, 800 mg, oral tablet, QD (1 Cycle = 28 days) from Cycle 1 until disease progression, unacceptable toxicity, or withdrawal from the study.
Phase 2: Complete Response (CR) Rate as Per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 Criteria	33.6 percentage of participants	—	—

PRIMARY outcome

Timeframe: Up to 43.2 months

ORR=percent of participants who achieve CR,CRi,partial response(PR) or PR with lymphocytosis(PR-L).CR=no evidence of new disease;ALC\<4x10\^9/L;regression of nodal masses to\<1.5cm LD;normal spleen,liver size;no constitutional symptoms;cytological/pathological evaluation of BM smear/biopsy must be at least normocellular for age;ANC≥1.5x10\^9/L,platelet≥100x10\^9/L,Hb≥110g/L.CRi=CR criteria but with persistent anemia,thrombocytopenia,or neutropenia/hypocellular BM related to prior/ongoing drug toxicity.PR=no evidence of new disease,meets≥2 criteria:≥50% decrease from baseline(BL) in ALC(or decrease to\<4x10\^9/L) or sum of products(SPD) of target nodal lesions or CLL/SLL marrow infiltrate/Blymphoid;no target,splenic,liver,or non-target disease with worsening that meets criteria for definitive progressive disease(PD);platelet\>100x10\^9/L or Hb≥110g/L or ≥50% increase from BL in each.PR-L=PR criteria but not had ≥50% decrease from BL in ALC/decrease to\<4x10\^9/L.

Outcome measures

Outcome measures
Measure	Phase 2: Ublituximab + Umbralisib + Venetoclax (U2-V) n=149 Participants Participants were administered ublituximab, 150 mg, IV infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6; umbralisib, 800 mg, oral tablet, QD through Cycles 1-24; venetoclax, oral tablet, QD, 20 mg on Days 1-7, 50 mg on Days 8-14, 100 mg on Days 15-21, 200 mg on Days 22-28 of Cycle 4, followed by 400 mg on Days 1-28 of Cycles 5-24. MRD positive participants were administered umbralisib, 800 mg, oral tablet, QD, on Days 1-28 from Cycle 25 onwards (1 Cycle = 28 days), until disease progression, unacceptable toxicity, or withdrawal from the study.	Phase 3: Ublituximab + Umbralisib (U2) Participants were administered ublituximab, 150 mg, IV infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6, then every three cycles along with umbralisib, 800 mg, oral tablet, QD (1 Cycle = 28 days) from Cycle 1 until disease progression, unacceptable toxicity, or withdrawal from the study.	Phase 3: Ublituximab + Umbralisib (U2) Participants were administered ublituximab, 150 mg, IV infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6, then every three cycles along with umbralisib, 800 mg, oral tablet, QD (1 Cycle = 28 days) from Cycle 1 until disease progression, unacceptable toxicity, or withdrawal from the study.
Phase 2: Overall Response Rate (ORR) Per iwCLL 2018 Criteria	93.3 percentage of participants	—	—

PRIMARY outcome

Timeframe: Up to 43.2 months

Population: ITT population for Phase 3 consisted of all participants who were randomized. Percentages were rounded off to the nearest decimal point.

PFS was assessed in participants treated with U2-V compared with U2. PFS was defined as the interval between randomization and the date of definitive PD (as confirmed by the IRC) or death due to any cause, whichever occurs first. Participants who had no event (progression or death) were censored at the day of their last adequate disease assessment. PD= appearance of new nodes \>1.5 cm in the LD, \>50% increase in greatest diameter, new or recurrent hepatomegaly or splenomegaly, new unequivocal extra-nodal lesion, new non-target disease, ≥50% increase from the nadir in the sum of products of diameters (SPD) 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	Phase 2: Ublituximab + Umbralisib + Venetoclax (U2-V) n=56 Participants Participants were administered ublituximab, 150 mg, IV infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6; umbralisib, 800 mg, oral tablet, QD through Cycles 1-24; venetoclax, oral tablet, QD, 20 mg on Days 1-7, 50 mg on Days 8-14, 100 mg on Days 15-21, 200 mg on Days 22-28 of Cycle 4, followed by 400 mg on Days 1-28 of Cycles 5-24. MRD positive participants were administered umbralisib, 800 mg, oral tablet, QD, on Days 1-28 from Cycle 25 onwards (1 Cycle = 28 days), until disease progression, unacceptable toxicity, or withdrawal from the study.	Phase 3: Ublituximab + Umbralisib (U2) n=56 Participants Participants were administered ublituximab, 150 mg, IV infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6, then every three cycles along with umbralisib, 800 mg, oral tablet, QD (1 Cycle = 28 days) from Cycle 1 until disease progression, unacceptable toxicity, or withdrawal from the study.	Phase 3: Ublituximab + Umbralisib (U2) Participants were administered ublituximab, 150 mg, IV infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6, then every three cycles along with umbralisib, 800 mg, oral tablet, QD (1 Cycle = 28 days) from Cycle 1 until disease progression, unacceptable toxicity, or withdrawal from the study.
Phase 3: Progression-Free Survival (PFS) Per iwCLL 2018 Criteria	NA months Interval 0.0 to 15.7 Median was not estimable due to low number of participants with events.	NA months Interval 0.0 to 13.1 Median was not estimable due to low number of participants with events.	—

SECONDARY outcome

Timeframe: Up to 43.2 months

Population: In Phase 2, ITT population consisted of all participants who received at least one dose of each study drug (ublituximab, umbralisib, and venetoclax); and in Phase 3, ITT population consisted of all participants who were randomized. Percentages were rounded off to the nearest decimal point.

The MRD negativity rate was defined as the percentage of participants who achieved MRD negative status post-baseline, defined as a quantitative detection of less than one CLL/SLL cell in 10000 leukocytes by flow cytometry (MRD level, 10\^-4) in blood or bone marrow (BM). 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. Participants who did not have an MRD assessment at any post-baseline visits were considered non-responders and were included in the denominator when calculating MRD negativity rate.

Outcome measures

Outcome measures
Measure	Phase 2: Ublituximab + Umbralisib + Venetoclax (U2-V) n=149 Participants Participants were administered ublituximab, 150 mg, IV infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6; umbralisib, 800 mg, oral tablet, QD through Cycles 1-24; venetoclax, oral tablet, QD, 20 mg on Days 1-7, 50 mg on Days 8-14, 100 mg on Days 15-21, 200 mg on Days 22-28 of Cycle 4, followed by 400 mg on Days 1-28 of Cycles 5-24. MRD positive participants were administered umbralisib, 800 mg, oral tablet, QD, on Days 1-28 from Cycle 25 onwards (1 Cycle = 28 days), until disease progression, unacceptable toxicity, or withdrawal from the study.	Phase 3: Ublituximab + Umbralisib (U2) n=56 Participants Participants were administered ublituximab, 150 mg, IV infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6, then every three cycles along with umbralisib, 800 mg, oral tablet, QD (1 Cycle = 28 days) from Cycle 1 until disease progression, unacceptable toxicity, or withdrawal from the study.	Phase 3: Ublituximab + Umbralisib (U2) n=56 Participants Participants were administered ublituximab, 150 mg, IV infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6, then every three cycles along with umbralisib, 800 mg, oral tablet, QD (1 Cycle = 28 days) from Cycle 1 until disease progression, unacceptable toxicity, or withdrawal from the study.
Minimal Residual Disease (MRD) Negativity Rate	94.0 percentage of participants Interval 88.8 to 97.2	50.0 percentage of participants Interval 36.3 to 63.7	19.6 percentage of participants Interval 10.2 to 32.4

SECONDARY outcome

Timeframe: Up to 43.2 months

Population: Safety population consisted of all participants who received at least one dose of any study drug (ublituximab, umbralisib, and venetoclax).

An adverse event (AE) is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product. An AE does not necessarily have to have a causal relationship with this treatment. An AE can therefore be 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	Phase 2: Ublituximab + Umbralisib + Venetoclax (U2-V) n=165 Participants Participants were administered ublituximab, 150 mg, IV infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6; umbralisib, 800 mg, oral tablet, QD through Cycles 1-24; venetoclax, oral tablet, QD, 20 mg on Days 1-7, 50 mg on Days 8-14, 100 mg on Days 15-21, 200 mg on Days 22-28 of Cycle 4, followed by 400 mg on Days 1-28 of Cycles 5-24. MRD positive participants were administered umbralisib, 800 mg, oral tablet, QD, on Days 1-28 from Cycle 25 onwards (1 Cycle = 28 days), until disease progression, unacceptable toxicity, or withdrawal from the study.	Phase 3: Ublituximab + Umbralisib (U2) n=56 Participants Participants were administered ublituximab, 150 mg, IV infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6, then every three cycles along with umbralisib, 800 mg, oral tablet, QD (1 Cycle = 28 days) from Cycle 1 until disease progression, unacceptable toxicity, or withdrawal from the study.	Phase 3: Ublituximab + Umbralisib (U2) n=53 Participants Participants were administered ublituximab, 150 mg, IV infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6, then every three cycles along with umbralisib, 800 mg, oral tablet, QD (1 Cycle = 28 days) from Cycle 1 until disease progression, unacceptable toxicity, or withdrawal from the study.
Number of Participants Experiencing at Least One Treatment-Emergent Adverse Event (TEAE)	165 Participants	56 Participants	51 Participants

SECONDARY outcome

Timeframe: Up to 43.2 months

Population: ITT population for Phase 2 consisted of all participants who received at least one dose of each study drug (ublituximab, umbralisib, and venetoclax). Only responders i.e., participants with ORR were assessed for this outcome measure.

TTR was defined as the interval from enrollment to first documentation of CR, CRi, PR, or PR-L. TTR was analyzed via Kaplan-Meier method. CR=no evidence of new disease; ALC\<4x10\^9/L; regression of nodal masses to \<1.5cm LD; normal spleen ,liver size; no constitutional symptoms; cytological/pathological evaluation of BM smear/biopsy must be at least normocellular for age; ANC≥1.5x10\^9/L, platelet≥100x10\^9/L, Hb≥110g/L. CRi=CR criteria but with persistent anemia, thrombocytopenia, or neutropenia/hypocellular BM related to prior/ongoing drug toxicity.PR=no evidence of new disease,meets≥2 criteria:≥50% decrease from BL in ALC (or decrease to\<4x10\^9/L) or SPD of target nodal lesions or CLL/SLL marrow infiltrate/B-lymphoid; no target, splenic, liver, or non-target disease with worsening that meets criteria for definitive PD; platelet\>100x10\^9/L or Hb≥110g/L or ≥50% increase from BL in each.PR-L=PR criteria but not had ≥50% decrease from BL in ALC/decrease to\<4x10\^9/L.

Outcome measures

Outcome measures
Measure	Phase 2: Ublituximab + Umbralisib + Venetoclax (U2-V) n=139 Participants Participants were administered ublituximab, 150 mg, IV infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6; umbralisib, 800 mg, oral tablet, QD through Cycles 1-24; venetoclax, oral tablet, QD, 20 mg on Days 1-7, 50 mg on Days 8-14, 100 mg on Days 15-21, 200 mg on Days 22-28 of Cycle 4, followed by 400 mg on Days 1-28 of Cycles 5-24. MRD positive participants were administered umbralisib, 800 mg, oral tablet, QD, on Days 1-28 from Cycle 25 onwards (1 Cycle = 28 days), until disease progression, unacceptable toxicity, or withdrawal from the study.	Phase 3: Ublituximab + Umbralisib (U2) Participants were administered ublituximab, 150 mg, IV infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6, then every three cycles along with umbralisib, 800 mg, oral tablet, QD (1 Cycle = 28 days) from Cycle 1 until disease progression, unacceptable toxicity, or withdrawal from the study.	Phase 3: Ublituximab + Umbralisib (U2) Participants were administered ublituximab, 150 mg, IV infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6, then every three cycles along with umbralisib, 800 mg, oral tablet, QD (1 Cycle = 28 days) from Cycle 1 until disease progression, unacceptable toxicity, or withdrawal from the study.
Phase 2: Time to Response (TTR) Per iwCLL 2018 Criteria	2.6 months Interval 2.3 to 18.5	—	—

SECONDARY outcome

Timeframe: Up to 43.2 months

DOR=interval from 1st documentation of CR,CRi,PR or PR-L to earlier of 1st documentation of definitive PD or death from any cause.CR=no evidence of new disease;ALC\<4x10\^9/L;regression of nodal masses to\<1.5cm LD;normal spleen,liver size;no constitutional symptoms;cytological/pathological evaluation of BM smear/biopsy must be at least normocellular for age;ANC≥1.5x10\^9/L,platelet≥100x10\^9/L,Hb≥110g/L.CRi=CR criteria but with persistent anemia,thrombocytopenia,neutropenia/hypocellular BM related to prior/ongoing drug toxicity.PR=no evidence of new disease,meets≥2 criteria:≥50% decrease from BL in ALC(or decrease to\<4x10\^9/L) or SPD of target nodal lesions or CLL/SLL marrow infiltrate/Blymphoid;no target,splenic,liver,or non-target disease with worsening that meets criteria for definitive PD;platelet\>100x10\^9/L or Hb≥110g/L or ≥50% increase from BL in each.PR-L=PR criteria;not≥50% decrease from BL in ALC/decrease to\<4x10\^9/L.PD=evidence of new disease per protocol-specififed criteria.

Outcome measures

Outcome measures
Measure	Phase 2: Ublituximab + Umbralisib + Venetoclax (U2-V) n=139 Participants Participants were administered ublituximab, 150 mg, IV infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6; umbralisib, 800 mg, oral tablet, QD through Cycles 1-24; venetoclax, oral tablet, QD, 20 mg on Days 1-7, 50 mg on Days 8-14, 100 mg on Days 15-21, 200 mg on Days 22-28 of Cycle 4, followed by 400 mg on Days 1-28 of Cycles 5-24. MRD positive participants were administered umbralisib, 800 mg, oral tablet, QD, on Days 1-28 from Cycle 25 onwards (1 Cycle = 28 days), until disease progression, unacceptable toxicity, or withdrawal from the study.	Phase 3: Ublituximab + Umbralisib (U2) Participants were administered ublituximab, 150 mg, IV infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6, then every three cycles along with umbralisib, 800 mg, oral tablet, QD (1 Cycle = 28 days) from Cycle 1 until disease progression, unacceptable toxicity, or withdrawal from the study.	Phase 3: Ublituximab + Umbralisib (U2) Participants were administered ublituximab, 150 mg, IV infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6, then every three cycles along with umbralisib, 800 mg, oral tablet, QD (1 Cycle = 28 days) from Cycle 1 until disease progression, unacceptable toxicity, or withdrawal from the study.
Phase 2: Duration of Response (DOR) Per iwCLL 2018 Criteria	21.1 months Interval 0.0 to 24.8	—	—

SECONDARY outcome

Timeframe: Up to 43.2 months

Population: ITT population for Phase 3 consisted of all participants who were randomized. Percentages were rounded off to the nearest decimal point.

CR rate=percent of participants who achieved CR or CRi. CR=no evidence of new disease; ALC\<4x10\^9/L; regression of nodal masses to \<1.5 cm LD; normal spleen, liver size; no constitutional symptoms; cytological/pathological evaluation of BM smear/biopsy must be at least normocellular for age; ANC ≥1.5x10\^9/L, platelet ≥100x10\^9/L, Hb ≥110g/L. CRi=CR criteria but with persistent anemia,thrombocytopenia,or neutropenia/hypocellular BM related to prior/ongoing drug toxicity. CR assessment was subject to independent confirmation by the IRC in participants enrolled to the Phase 3 stage of the study.

Outcome measures

Outcome measures
Measure	Phase 2: Ublituximab + Umbralisib + Venetoclax (U2-V) n=56 Participants Participants were administered ublituximab, 150 mg, IV infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6; umbralisib, 800 mg, oral tablet, QD through Cycles 1-24; venetoclax, oral tablet, QD, 20 mg on Days 1-7, 50 mg on Days 8-14, 100 mg on Days 15-21, 200 mg on Days 22-28 of Cycle 4, followed by 400 mg on Days 1-28 of Cycles 5-24. MRD positive participants were administered umbralisib, 800 mg, oral tablet, QD, on Days 1-28 from Cycle 25 onwards (1 Cycle = 28 days), until disease progression, unacceptable toxicity, or withdrawal from the study.	Phase 3: Ublituximab + Umbralisib (U2) n=56 Participants Participants were administered ublituximab, 150 mg, IV infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6, then every three cycles along with umbralisib, 800 mg, oral tablet, QD (1 Cycle = 28 days) from Cycle 1 until disease progression, unacceptable toxicity, or withdrawal from the study.	Phase 3: Ublituximab + Umbralisib (U2) Participants were administered ublituximab, 150 mg, IV infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6, then every three cycles along with umbralisib, 800 mg, oral tablet, QD (1 Cycle = 28 days) from Cycle 1 until disease progression, unacceptable toxicity, or withdrawal from the study.
Phase 3: CR Rate as Assessed by an Independent Review Committee (IRC) Per iwCLL 2018 Criteria	17.9 percentage of participants	8.9 percentage of participants	—

SECONDARY outcome

Timeframe: Up to 43.2 months

Population: ITT population for Phase 3 consisted of all participants who were randomized. Percentages were rounded off to the nearest decimal point.

ORR=percent of participants who achieve CR, CRi, PR or PR-L.CR=no evidence of new disease; ALC\<4x10\^9/L; regression of nodal masses to\<1.5cm LD; normal spleen and liver size; no constitutional symptoms; cytological/pathological evaluation of BM smear/biopsy must be at least normocellular for age; ANC≥1.5x10\^9/L, platelet≥100x10\^9/L, Hb≥110g/L. CRi=CR criteria but with persistent anemia, thrombocytopenia, or neutropenia/hypocellular BM related to prior/ongoing drug toxicity.PR=no evidence of new disease,meets≥2 criteria:≥50% decrease from baseline (BL) in ALC (or decrease to\<4x10\^9/L) or SPD of target nodal lesions or CLL/SLL marrow infiltrate/B-lymphoid; no target, splenic, liver, or non-target disease with worsening that meets criteria for definitive PD; platelet\>100x10\^9/L or Hb≥110g/L or ≥50% increase from BL in each.PR-L=PR criteria but not had ≥50% decrease from BL in ALC/decrease to\<4x10\^9/L.

Outcome measures

Outcome measures
Measure	Phase 2: Ublituximab + Umbralisib + Venetoclax (U2-V) n=56 Participants Participants were administered ublituximab, 150 mg, IV infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6; umbralisib, 800 mg, oral tablet, QD through Cycles 1-24; venetoclax, oral tablet, QD, 20 mg on Days 1-7, 50 mg on Days 8-14, 100 mg on Days 15-21, 200 mg on Days 22-28 of Cycle 4, followed by 400 mg on Days 1-28 of Cycles 5-24. MRD positive participants were administered umbralisib, 800 mg, oral tablet, QD, on Days 1-28 from Cycle 25 onwards (1 Cycle = 28 days), until disease progression, unacceptable toxicity, or withdrawal from the study.	Phase 3: Ublituximab + Umbralisib (U2) n=56 Participants Participants were administered ublituximab, 150 mg, IV infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6, then every three cycles along with umbralisib, 800 mg, oral tablet, QD (1 Cycle = 28 days) from Cycle 1 until disease progression, unacceptable toxicity, or withdrawal from the study.	Phase 3: Ublituximab + Umbralisib (U2) Participants were administered ublituximab, 150 mg, IV infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6, then every three cycles along with umbralisib, 800 mg, oral tablet, QD (1 Cycle = 28 days) from Cycle 1 until disease progression, unacceptable toxicity, or withdrawal from the study.
Phase 3: ORR as Assessed by IRC Per iwCLL 2018 Criteria	71.4 percentage of participants	62.5 percentage of participants	—

SECONDARY outcome

Timeframe: Up to 43.2 months

Population: ITT population for Phase 3 consisted of all participants who were randomized.

Overall Survival (OS) was defined as the interval from randomization to death from any cause. OS data was censored at the last documented date that the participant was confirmed alive for participants who withdrew consent or were lost to follow-up prior to the end of the study, and for participants whose vital status in the study could not be determined.

Outcome measures

Outcome measures
Measure	Phase 2: Ublituximab + Umbralisib + Venetoclax (U2-V) n=56 Participants Participants were administered ublituximab, 150 mg, IV infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6; umbralisib, 800 mg, oral tablet, QD through Cycles 1-24; venetoclax, oral tablet, QD, 20 mg on Days 1-7, 50 mg on Days 8-14, 100 mg on Days 15-21, 200 mg on Days 22-28 of Cycle 4, followed by 400 mg on Days 1-28 of Cycles 5-24. MRD positive participants were administered umbralisib, 800 mg, oral tablet, QD, on Days 1-28 from Cycle 25 onwards (1 Cycle = 28 days), until disease progression, unacceptable toxicity, or withdrawal from the study.	Phase 3: Ublituximab + Umbralisib (U2) n=56 Participants Participants were administered ublituximab, 150 mg, IV infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6, then every three cycles along with umbralisib, 800 mg, oral tablet, QD (1 Cycle = 28 days) from Cycle 1 until disease progression, unacceptable toxicity, or withdrawal from the study.	Phase 3: Ublituximab + Umbralisib (U2) Participants were administered ublituximab, 150 mg, IV infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6, then every three cycles along with umbralisib, 800 mg, oral tablet, QD (1 Cycle = 28 days) from Cycle 1 until disease progression, unacceptable toxicity, or withdrawal from the study.
Phase 3: Overall Survival (OS)	NA months Interval 0.5 to 16.6 Median was not estimable due to low number of participants with event.	NA months Interval 0.0 to 16.2 Median was not estimable due to low number of participants with event.	—

Adverse Events

Phase 2: Ublituximab + Umbralisib + Venetoclax (U2-V)

Serious events: 84 serious events

Other events: 165 other events

Deaths: 32 deaths

Phase 3: Ublituximab + Umbralisib + Venetoclax (U2-V)

Serious events: 12 serious events

Other events: 56 other events

Deaths: 1 deaths

Phase 3: Ublituximab + Umbralisib (U2)

Serious events: 16 serious events

Other events: 49 other events

Deaths: 5 deaths

Serious adverse events

Other adverse events

Additional Information

TG Therapeutics Clinical Support Team

TG Therapeutics

Phone: 1-877-575-8489

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place