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) (ULTRA-V)

Phase 2/3 Randomized Study to Assess the Efficacy and Safety of Ublituximab in Combination With Umbralisib and Venetoclax (U2-V) Compared to Ublituximab and Umbralisib (U2) in Subjects With Chronic Lymphocytic Leukemia (CLL)

ULTRA-V: Study to Assess the Efficacy and Safety of Ublituximab in Combination with Umbralisib and Venetoclax (U2-V) Compared to Ublituximab and Umbralisib (U2) in Subjects with Chronic Lymphocytic Leukemia (CLL)

Study Overview

• Status: Terminated
• Conditions: Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma
• Intervention / Treatment: Drug: Umbralisib; Drug: Ublituximab; Drug: Venetoclax

Detailed Description

This is an open-label, multicenter, Phase 2/3 study to evaluate the efficacy and safety of the combination of ublituximab + umbralisib + venetoclax (U2-V) compared to the combination of ublituximab + umbralisib (U2) in participants with either treatment naïve or previously treated CLL/ small lymphocytic lymphoma (SLL).

• Study Type: Interventional
• Enrollment (Actual): 277
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • TG Therapeutics Investigational Trial Site
    • Huntsville, Alabama, United States, 35805
      • TG Therapeutics Investigational Trial Site
  • Arizona
    • Tucson, Arizona, United States, 85711
      • TG Therapeutics Investigational Trial Site
  • California
    • Duarte, California, United States, 91010
      • TG Therapeutics Investigational Trial Site
    • La Jolla, California, United States, 92093
      • TG Therapeutics Investigational Trial Site
  • Colorado
    • Aurora, Colorado, United States, 80012
      • TG Therapeutics Investigational Trial Site
  • Connecticut
    • Stamford, Connecticut, United States, 06904
      • TG Therapeutics Investigational Trial Site
  • Florida
    • Boca Raton, Florida, United States, 33486
      • TG Therapeutics Investigational Trial Site
    • Fort Myers, Florida, United States, 33901
      • TG Therapeutics Investigational Trial Site
    • Jacksonville, Florida, United States, 32224
      • TG Therapeutics Investigational Trial Site
    • Saint Petersburg, Florida, United States, 33705
      • TG Therapeutics Investigational Trial Site
    • Tampa, Florida, United States, 33612
      • TG Therapeutics Investigational Trial Site
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • TG Therapeutics Investigational Trial Site
  • Illinois
    • Decatur, Illinois, United States, 62526
      • TG Therapeutics Investigational Trial Site
    • Niles, Illinois, United States, 60714
      • TG Therapeutics Investigational Trial Site
    • Peoria, Illinois, United States, 61615
      • TG Therapeutics Investigational Site
  • Indiana
    • Fort Wayne, Indiana, United States, 46804
      • TG Therapeutics Investigational Trial Site
    • Indianapolis, Indiana, United States, 46237
      • TG Therapeutics Investigational Trial Site
  • Iowa
    • Des Moines, Iowa, United States, 50309
      • TG Therapeutics Investigational Trial Site
  • Kansas
    • Westwood, Kansas, United States, 66210
      • TG Therapeutics Investigational Trial Site
  • Kentucky
    • Louisville, Kentucky, United States, 40207
      • TG Therapeutics Investigational Site
  • Maryland
    • Bethesda, Maryland, United States, 37210
      • TG Therapeutics Investigational Trial Site
    • Columbia, Maryland, United States, 21044
      • TG Therapeutics Investigational Trial Site
  • Michigan
    • Ann Arbor, Michigan, United States, 48197
      • TG Therapeutics Investigational Trial Site
    • Detroit, Michigan, United States, 48201
      • TG Therapeutics Investigational Trial Site
    • Detroit, Michigan, United States, 48202
      • TG Therapeutics Investigational Trial Site
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • TG Therapeutics Investigational Trial Site
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • TG Therapeutics Investigational Trial Site
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • TG Therapeutics Investigational Trial Site
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • TG Therapeutics Investigational Trial Site
    • Morristown, New Jersey, United States, 07960
      • TG Therapeutics Investigational Trial Site
  • New York
    • New York, New York, United States, 10065
      • TG Therapeutics Investigational Trial Site
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • TG Therapeutics Investigational Trial Site
  • Ohio
    • Columbus, Ohio, United States, 43210
      • TG Therapeutics Investigational Trial Site
  • Oregon
    • Eugene, Oregon, United States, 97401
      • TG Therapeutics Investigational Trial Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19106
      • TG Therapeutics Investigational Trial Site
  • South Carolina
    • Charleston, South Carolina, United States, 29414
      • TG Therapeutics Investigational Trial Site
    • Greenville, South Carolina, United States, 29616
      • TG Therapeutics Investigational Trial Site
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • TG Therapeutics Investigational Trial Site
    • Knoxville, Tennessee, United States, 37916
      • TG Therapeutics Investigational Trial Site
    • Nashville, Tennessee, United States, 37203
      • TG Therapeutics Investigational Trial Site
  • Texas
    • Austin, Texas, United States, 78705
      • TG Therapeutics Investigational Trial Site
    • San Antonio, Texas, United States, 78229
      • TG Therapeutics Investigational Trial Site
    • Tyler, Texas, United States, 75702
      • TG Therapeutics Investigational Trial Site
  • Utah
    • Ogden, Utah, United States, 84405
      • TG Therapeutics Investigational Trial Site
    • Salt Lake City, Utah, United States, 84106
      • TG Therapeutics Investigational Trial Site
  • Virginia
    • Blacksburg, Virginia, United States, 24060
      • TG Therapeutics Investigational Trial Site
    • Gainesville, Virginia, United States, 20155
      • TG Therapeutics Investigational Trial Site
  • Washington
    • Seattle, Washington, United States, 98104
      • TG Therapeutics Investigational Trial Site
    • Seattle, Washington, United States, 98108
      • TG Therapeutics Investigational Trial Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL) that warrants treatment
• Adequate organ system function as specified in the protocol
• Ability to follow protocol procedures.

Exclusion Criteria:

• Subjects receiving cancer therapy or any investigational drug within 21 days of Cycle 1, Day 1
• Prior exposure to any PI3K inhibitor or venetoclax
• Autologous hematologic stem cell transplant within 6 months of study entry. Prior allogeneic hematologic stem cell transplant is excluded
• Active Hepatitis B or Hepatitis C.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Umbralisib; inhibitor of phosphoinositide 3-kinase (PI3K) delta and casein kinase 1 epsilon (CK1e); Tablet form; Other Names: TGR-1202; UKONIQ; Drug: Ublituximab; recombinant chimeric anti-CD20 (cluster of differentiation 20) monoclonal antibody; administered as an IV infusion; Other Names: TG-1101; Drug: Venetoclax; B-cell lymphoma 2 (BCL-2) inhibitor; Tablet form; Other Names: Venclexta®
Experimental: 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).	Drug: Umbralisib; inhibitor of phosphoinositide 3-kinase (PI3K) delta and casein kinase 1 epsilon (CK1e); Tablet form; Other Names: TGR-1202; UKONIQ; Drug: Ublituximab; recombinant chimeric anti-CD20 (cluster of differentiation 20) monoclonal antibody; administered as an IV infusion; Other Names: TG-1101; Drug: Venetoclax; B-cell lymphoma 2 (BCL-2) inhibitor; Tablet form; Other Names: Venclexta®
Experimental: 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.	Drug: Umbralisib; inhibitor of phosphoinositide 3-kinase (PI3K) delta and casein kinase 1 epsilon (CK1e); Tablet form; Other Names: TGR-1202; UKONIQ; Drug: Ublituximab; recombinant chimeric anti-CD20 (cluster of differentiation 20) monoclonal antibody; administered as an IV infusion; Other Names: TG-1101

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 2: Complete Response (CR) Rate as Per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 Criteria	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).	Up to 43.2 months
Phase 2: Overall Response Rate (ORR) Per iwCLL 2018 Criteria	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.	Up to 43.2 months
Phase 3: Progression-Free Survival (PFS) Per iwCLL 2018 Criteria	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.	Up to 43.2 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Minimal Residual Disease (MRD) Negativity Rate	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.	Up to 43.2 months
Number of Participants Experiencing at Least One Treatment-Emergent Adverse Event (TEAE)	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.	Up to 43.2 months
Phase 2: Time to Response (TTR) Per iwCLL 2018 Criteria	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.	Up to 43.2 months
Phase 2: Duration of Response (DOR) Per iwCLL 2018 Criteria	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.	Up to 43.2 months
Phase 3: CR Rate as Assessed by an Independent Review Committee (IRC) Per iwCLL 2018 Criteria	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.	Up to 43.2 months
Phase 3: ORR as Assessed by IRC Per iwCLL 2018 Criteria	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.	Up to 43.2 months
Phase 3: Overall Survival (OS)	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.	Up to 43.2 months

Collaborators and Investigators

• Sponsor: TG Therapeutics, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): May 16, 2019
• Primary Completion (Actual): December 20, 2022
• Study Completion (Actual): December 20, 2022

Study Registration Dates

• First Submitted: January 9, 2019
• First Submitted That Met QC Criteria: January 9, 2019
• First Posted (Actual): January 11, 2019

Study Record Updates

• Last Update Posted (Actual): April 19, 2024
• Last Update Submitted That Met QC Criteria: April 10, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: CLL; SLL
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Hematologic Diseases; Leukemia, B-Cell; Chronic Disease; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Antineoplastic Agents; Venetoclax
• Other Study ID Numbers: U2-VEN-207

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Data for this study will be shared after the last patient visit has been completed.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No