A Phase 2 Study of Acalabrutinib, Umbralisib, and Ublituximab (AU2) in Relapsed and Previously Untreated CLL Patients
Overview
- Phase
- Phase 2
- Intervention
- Acalabrutinib
- Conditions
- Chronic Lymphocytic Leukemia
- Sponsor
- Jennifer R. Brown, MD, PhD
- Enrollment
- 29
- Locations
- 1
- Primary Endpoint
- Complete Remission (CR) Rate After 24 Cycles
- Status
- Active, not recruiting
- Last Updated
- 2 months ago
Overview
Brief Summary
This study is testing the effectiveness of the study drug combination of acalabrutinib, umbralisib, and ublituximab in participants with Chronic Lymphocytic leukemia (CLL).
The names of the study drugs involved in this study are/is:
- Acalabrutinib (CALQUENCE®, ACP-196)
- Umbralisib (TGR-1202)
- Ublituximab (TG-1101)
Detailed Description
In this research study, Investigators are exploring the combination of acalabrutinib, umbralisib, and ublituximab and hoping to determine if the combination is effective at controlling cancer growth in participants with CLL. The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits. Participants will receive the study drugs for a maximum of 24 cycles (2 years) and will be followed for a maximum of 5 years after discontinuing the study drugs. The names of the study drugs involved in this study are/is: * Acalabrutinib (CALQUENCE®, ACP-196) * Umbralisib (TGR-1202) * Ublituximab (TG-1101) It is expected that about 60 people will take part in this research study. This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drugs to learn whether the drugs work in treating a specific disease. "Investigational" means that the drugs are being studied. * The U.S. Food and Drug Administration (FDA) has not approved umbralisib or ublituximab as a treatment for any disease. * The U.S. Food and Drug Administration (FDA) has approved acalabrutinib for CLL, but not in this combination. * Acalabrutinib is a type of drug called a kinase inhibitor. It blocks a type of protein called Bruton Tyrosine Kinase (BTK) that helps CLL cells live and grow. By blocking BTK, acalabrutinib may kill cancer cells or stop them from growing. * Umbralisib is an investigational drug which blocks a protein called PI3K. PI3K is a protein that helps CLL cells grow. * Ublituximab is a type of investigational drug called a monoclonal antibody. A monoclonal antibody is a type of protein made in the laboratory that can locate and bind to substances in the body, including tumor cells. By binding to the tumor cells, the antibody might prevent the tumor cell from growing and spreading. As of March 2023, TG therapeutics has decided to no longer provide umbralisib, ublituximab and funding for this study. Study participants still on treatment will still have access to acalabrutinib.
Investigators
Jennifer R. Brown, MD, PhD
Sponsor Investigator
Dana-Farber Cancer Institute
Eligibility Criteria
Inclusion Criteria
- •Confirmed diagnosis of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) per International Workshop on CLL (iwCLL) 2018 criteria.1
- •Participants must have an indication for treatment as defined by iwCLL 2018 criteria.1
- •Participants must have measurable disease, defined as lymphocytosis \> 5,000 / μL, or palpable or CT measurable lymphadenopathy ≥ 1.5 cm, or bone marrow involvement ≥ 30%.
- •For enrollment to Cohort 1: Participants must have relapsed or refractory disease as per iwCLL 2018 criteria,1 and must have received no more than 2 prior lines of anti-cancer therapy.
- •For enrollment to Cohort 2: Participants must have previously untreated disease (i.e.
- •must not have received any prior systemic therapy for CLL or SLL).
- •Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of umbralisib, acalabrutinib, and ublituximab in participants \< 18 years of age and CLL is extremely rare in this population, children are excluded from this study.
- •ECOG performance status ≤ 2 (Karnofsky ≥ 60%, see Appendix A).
- •Participants must have adequate organ and marrow function as defined below:
- •Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN) (unless due to hemolysis or Gilbert's disease, in which ≤ 3 × institutional ULN is acceptable)
Exclusion Criteria
- •Participants with progressive or refractory disease while receiving either a BTK inhibitor or PI3K inhibitor. Prior exposure to either a BTK inhibitor, PI3K inhibitor, or both is acceptable as long as the participant's disease did not progress during active therapy with the agent(s).
- •Participants who have undergone a major surgical procedure within 28 days of the first dose of study drug. If a participant had major surgery greater than 28 days prior to the first dose of study drug, they must have recovered adequately from any adverse event and/or complications from the intervention prior to the first dose (as judged by the treating investigator). For enrollment to Cohort 1: receipt of prior BTK inhibitor treatment within 7 days, or any other anti-cancer therapy (e.g. chemotherapy, immunotherapy, radiation, biologic therapy or any investigational agent) within 21 days of the first dose of study drug.
- •Participants who are receiving any other investigational agents.
- •History of prior allogeneic stem cell transplant.
- •History of autologous hematologic stem cell transplant within 6 months of the first dose of study drug.
- •Participants with known Richter's transformation, or histological transformation from CLL to large cell lymphoma.
- •Participants with known CNS involvement, because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Participants with no known history of CNS leukemia are not required to undergo CT scan or lumbar puncture (LP) for trial eligibility unless the participant is symptomatic as judged by the treating investigator.
- •Participants with uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP).
- •Participants with active clinically significant bleeding or history of bleeding diathesis (e.g. hemophilia or von Willebrand disease).
- •Participants requiring or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (other anticoagulants are permitted).
Arms & Interventions
Cohort 1-Relapsed Disease
Participants with relapsed disease * Treatment with Acalabrutinib \& Umbralisib beginning C1D1, * Ublituximab beginning C7D1 * Assessment of treatment response * Treatment continues for a maximum of 24 cycles. Participants followed post treatment for a maximum of 5 years
Intervention: Acalabrutinib
Cohort 1-Relapsed Disease
Participants with relapsed disease * Treatment with Acalabrutinib \& Umbralisib beginning C1D1, * Ublituximab beginning C7D1 * Assessment of treatment response * Treatment continues for a maximum of 24 cycles. Participants followed post treatment for a maximum of 5 years
Intervention: Umbralisib
Cohort 1-Relapsed Disease
Participants with relapsed disease * Treatment with Acalabrutinib \& Umbralisib beginning C1D1, * Ublituximab beginning C7D1 * Assessment of treatment response * Treatment continues for a maximum of 24 cycles. Participants followed post treatment for a maximum of 5 years
Intervention: Ublituximab
Cohort 2-Treatment Naive
Participants with previously untreated disease * Treatment with Acalabrutinib \& Umbralisib beginning C1D1, * Ublituximab beginning C7D1 * Assessment of treatment response * Treatment continues for a maximum of 24 cycles. Participants followed post treatment for a maximum of 5 years
Intervention: Acalabrutinib
Cohort 2-Treatment Naive
Participants with previously untreated disease * Treatment with Acalabrutinib \& Umbralisib beginning C1D1, * Ublituximab beginning C7D1 * Assessment of treatment response * Treatment continues for a maximum of 24 cycles. Participants followed post treatment for a maximum of 5 years
Intervention: Umbralisib
Cohort 2-Treatment Naive
Participants with previously untreated disease * Treatment with Acalabrutinib \& Umbralisib beginning C1D1, * Ublituximab beginning C7D1 * Assessment of treatment response * Treatment continues for a maximum of 24 cycles. Participants followed post treatment for a maximum of 5 years
Intervention: Ublituximab
Outcomes
Primary Outcomes
Complete Remission (CR) Rate After 24 Cycles
Time Frame: According to this endpoint is after 24 cycles. Overall median number of cycles is 24 with range 1-25.
The CR Rate is defined as the proportion of participants achieving complete remission (CR) based on 2018 IW-CLL criteria.
Secondary Outcomes
- Partial Remission (PR) Rate After 24 Cycles(According to this endpoint is after 24 cycles. Overall median number of cycles is 24 with range 1-25.)
- Median Progression-Free Survival (PFS)(Disease will be evaluated through imaging at cycle 1 day 1, 8, and 15, cycle 2-6 and cycle 8-25 day 1, and cycle 7 day 1, 2 and 8. Observation on treatment up to approximately 25 cycles. In long-term follow-up, survival follow-up up to 5 years.)