Study to Assess the Efficacy and Safety of Ublituximab and Umbralisib in Participants With Chronic Lymphocytic Leukemia (CLL) Currently Treated With Ibrutinib, Acalabrutinib or Venetoclax

Study Overview
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Brief Summary
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Phase 2, two cohort trial evaluating the addition of ublituximab and umbralisib on the rate of minimal residual disease (MRD) negativity in participants with Chronic Lymphocytic Leukemia (CLL), who are currently on treatment with ibrutinib, alacabrutinib or venetoclax.

Detailed Description
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This is a Phase 2 open label, two treatment cohort trial evaluating the addition of ublituximab and umbralisib on the rate of minimal residual disease (MRD) negativity in participants with CLL, who fail to achieve MRD negativity, after a minimum 6-month treatment with ibrutinib, alacabrutinib or venetoclax.

Official Title
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A Phase 2 Study to Assess the Efficacy and Safety of Ublituximab and Umbralisib in Subjects With Chronic Lymphocytic Leukemia (CLL) Currently Treated With Ibrutinib, Acalabrutinib or Venetoclax

Conditions
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Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Drug: Ublituximab
* Drug: Umbralisib
* Drug: Ibrutinib
* Drug: Venetoclax
* Drug: Acalabrutinib Oral Capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with Chronic Lymphocytic Leukemia (CLL) who have been on treatment for at least 6 months Minimal Residual Disease positive at screening Adequate organ system function as specified in the protocol Ability to follow protocol procedures. Exclusion Criteria: Participants receiving cancer therapy or any investigational drug within 21 days of Cycle 1, Day 1. Participants with a known histological transformation Active Hepatitis B or Hepatitis C.

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ublituximab + umbralisib + ibrutinib<br>Participants were administered with ublituximab, 900 milligrams (mg), intravenous (IV) infusion once every cycle through cycle 6, then every three cycles upto 24 cycles; umbralisib, 800 mg, oral tablet, daily through Cycles 1-24; ibrutinib oral tablet daily (1 Cycle = 28 days). | Drug: Ublituximab<br>* recombinant chimeric anti-CD20 monoclonal antibody administered as an IV infusion<br>* Other names: TG-1101;Drug: Umbralisib<br>* Phosphoinositide-3-kinase (PI3K) delta inhibitor Tablet form, to taken orally on a daily basis<br>* Other names: TGR-1202;Drug: Ibrutinib<br>* Bruton Tyrosine Kinase (BTK) inhibitor Tablet form, to taken orally on a daily basis<br>* Other names: Imbruvica;|
| Experimental: ublituximab + umbralisib + venetoclax<br>Participants were administered with ublituximab, 900 milligrams (mg), intravenous (IV) infusion once every cycle through cycle 6, then every three cycles upto 24 cycles; umbralisib, 800 mg, oral tablet, daily through Cycles 1-24; venetoclax oral tablet daily (1 Cycle = 28 days). | Drug: Ublituximab<br>* recombinant chimeric anti-CD20 monoclonal antibody administered as an IV infusion<br>* Other names: TG-1101;Drug: Umbralisib<br>* Phosphoinositide-3-kinase (PI3K) delta inhibitor Tablet form, to taken orally on a daily basis<br>* Other names: TGR-1202;Drug: Venetoclax<br>* BCL-2 inhibitor Tablet form, to be taken orally<br>* Other names: Venclexta;|
| Experimental: ublituximab + umbralisib + acalabrutinib<br>Participants were administered with ublituximab, 900 milligrams (mg), intravenous (IV) infusion once every cycle through cycle 6, then every three cycles upto 24 cycles; umbralisib, 800 mg, oral tablet, daily through Cycles 1-24; acalabrutinib oral capsule every 12 hours (1 Cycle = 28 days). | Drug: Ublituximab<br>* recombinant chimeric anti-CD20 monoclonal antibody administered as an IV infusion<br>* Other names: TG-1101;Drug: Umbralisib<br>* Phosphoinositide-3-kinase (PI3K) delta inhibitor Tablet form, to taken orally on a daily basis<br>* Other names: TGR-1202;Drug: Acalabrutinib Oral Capsule<br>* Kinase inhibitor, capsule form, to be taken orally<br>* Other names: Calquence;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Undetected Minimal Residual Disease (U-MRD) | U-MRD rate was defined as the proportion of participants who have undetectable MRD in the peripheral blood as confirmed by central lab. | Up to approximately 23 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR was defined as percent of participants who achieve complete response (CR) or partial response (PR). CR was defined as no evidence of new disease, regression of all target nodal masses to normal size < or = 1.5 cm in the longest diameter (LD) and an absolute lymphocyte count (ALC) in peripheral blood < 4*10^9/L. PR was defined as no evidence of new disease, a decrease in peripheral blood ALC by ≥50% from baseline or a decrease to <4 x 10^9/L or a decrease by ≥50% from the baseline in the sum of the products (SPD) of the target nodal lesions or a decrease by ≥50% from baseline in the CLL marrow infiltrate or in B lymphoid, no target, splenic, liver, or non-target disease with worsening that meets the criteria for definitive nodules, peripheral blood counts with ANC >1.5 x 10^9/L or platelet count ≥100 x 10^9/L or hemoglobin ≥110 g/L (11.0 g/dL) without red blood cell transfusions, all without need for exogenous growth factors. | Up to approximately 34 months | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) as Assessed by National Cancer Institute - Common Terminology Criteria for Adverse Events-Version (NCI-CTCAE-V5) | An adverse event (AE) is any untoward medical occurrence in a participant or 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. A TEAE is an AE that starts or worsens after receiving study drug. | Up to approximately 34 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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umbralisib, ublituximab, venetoclax, ibrutinib, CLL, acalabrutinib