Roginolisib (IOA-244) With Venetoclax and Rituximab for Refractory/Relapsed Chronic Lymphocytic Leukemia (CLL)

NCT06644183 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: 24-449
• Study Type: interventional
• Target: 64
• Locations: 1 country
• Sites: 1

Brief Summary

This research study will test the safety and anticancer activity of the combination of three drugs (Roginolisib, Venetoclax, and Rituximab) for participants with relapsed or refractory Chronic Lymphocytic Leukemia (CLL). The names of the study drugs involved in this study are:

• Roginolisib (a novel type of PI3-kinase delta inhibitor)
• Venetoclax (a type of B-cell lymphoma 2 inhibitor)
• Rituximab (a type of monoclonal antibody)

Conditions

Leukemia; Relapsed Leukemia; Chronic Lymphocytic Leukemia; Relapsed Cancer; Refractory Leukemia

Keywords

Leukemia; Relapsed Leukemia; Chronic Lymphocytic Leukemia; Relapsed Cancer; Refractory Leukemia; CLL; Relapsed Chronic Lymphocytic Leukemia; Refractory Chronic Lymphocytic Leukemia

Outcome Measures

Primary Outcomes (1)

• Undetectable Minimal Residual Disease(uMRD) rate by ClonoSEQ assay

  uMRD rate is defined as the proportion of participants with uMRD after treatment with either roginolisib plus venetoclax + rituximab, or venetoclax+ rituximab, as measured in bone marrow at a level of 10-4 by the clonoSEQ assay.

  1 year

Secondary Outcomes (7)

• Adverse Event of Interest Rate

  1 year

• Undetectable Minimal Residual Disease(uMRD) rate by flow cytometry

  5 years

• Median Progression Free Survival(PFS)

  5 years

• Median Overall Survival (OS)

  5 years

• Overall Response Rate (ORR)

  1 year

Study Arms (4)

Phase 1b Arm A: Venetoclax + Roginolisib + Rituximab Dose Level -1

EXPERIMENTAL

3+3 design to establish a Recommended Phase 2 Dose (RP2D) for Roginolisib, starting at Dose Level -1. * Baseline visit, imaging, bone marrow biopsy * CT scan every 2 cycles * Cycle 1 (5 weeks): Predetermined dose of Venetoclax 1x daily * Cycle 2: Days 1 through 28 of 28 day cycle: Predetermined dose of Venetoclax 1x daily and predetermined dose of Roginolisib 1 x daily --If 0 of 3 participants do not experience a dose-limiting toxicity (DLT), the study will proceed. If 1 of 3 participants experience a DLT, 3 more participants will be enrolled, and if 1 of those 6 participants experience a DLT, this is the RP2D for phase 2. If a DLT is observed in 2 of 3 or 2 of 6, the study will be stopped. * Cycles 3 through Cycle 8: Day 1 of 28 day cycle: Predetermined dose of Rituximab once * Cycles 3 through 13: Days 1 through 28 of 28 day cycle: Predetermined dose of Venetoclax 1x daily and predetermined dose of Roginolisib 1 x daily * End of treatment visit * Follow up visits for up to 5 years

Drug: Roginolisib; Drug: Venetoclax; Drug: Rituximab

Phase 1b Arm B: Venetoclax + Roginolisib + Rituximab Dose Level 1

EXPERIMENTAL

* Baseline visit, imaging, bone marrow biopsy * CT scan every 2 cycles * Cycle 1 (5 weeks): Predetermined dose of Venetoclax 1x daily * Cycle 2: Days 1 through 28 of 28 day cycle: Predetermined dose of Venetoclax 1x daily and predetermined dose of Roginolisib 1 x daily --If 0 of 3 participants do not experience a DLT, Phase 2 will start at this dose level. If 1 of 3 participants experience a DLT, 3 more participants will be enrolled, and if 1 of those 6 participants experience a DLT, this dose level will be used for Phase 2. If a DLT is observed in 2 of those 6, de-escalate to Dose Level -1. * Cycles 3 through Cycle 8: Day 1 of 28 day cycle: Predetermined dose of Rituximab once * Cycles 3 through 13: Days 1 through 28 of 28 day cycle: Predetermined dose of Venetoclax 1x daily and predetermined dose of Roginolisib 1 x daily * End of treatment visit * Follow up visits for up to 5 years

Drug: Roginolisib; Drug: Venetoclax; Drug: Rituximab

Phase 2 Arm A: Venetoclax + Roginolisib + Rituximab

EXPERIMENTAL

Participants will be randomized 1:1 and stratified by TP53 aberrant disease and by the number of prior therapies. * Baseline visit, imaging, bone marrow biopsy. * CT scan every 2 cycles. * Cycle 1 (5 weeks): Predetermined dose of Venetoclax 1x daily * Cycles 2 through 13: * Days 1 through 28 of 28 day cycle: Predetermined dose of Venetoclax 1x daily. * Days 1 through 28 of 28 day cycle: Predetermined dose of Roginolisib 1 x daily. * Cycles 3 through Cycle 8: --Day 1 of 28 day cycle: Predetermined dose of Rituximab once. * End of treatment visit * Follow up visits for up to 5 years

Drug: Roginolisib; Drug: Venetoclax; Drug: Rituximab

Phase 2 Arm B: Venetoclax + Rituximab

ACTIVE COMPARATOR

Participants will be randomized 1:1 and stratified by TP53 aberrant disease and by the number of prior therapies. * Baseline visit, imaging, bone marrow biopsy. * CT scan every 2 cycles. * Cycle 1 (5 weeks): Predetermined dose of Venetoclax 1x daily * Cycles 2 through 13: --Days 1 through 28 of 28 day cycle: Predetermined dose of Venetoclax 1x daily. * Cycle 3 through 8: --Day 1 of 28 day cycle: Predetermined dose of Rituximab once. * End of treatment visit * Follow up visits for up to 5 years

Drug: Venetoclax; Drug: Rituximab

Interventions

Roginolisib DRUG

Phosphoinositide 3-kinase delta inhibitor, 40 mg capsule, taken orally per protocol.

Also known as: MSC2360844A, [6-fluoro-1-(4-morpholin-4-ylmethyl-phenyl)-5,5-dioxo-4,5-dihydro-1H-5λ6-thiochro-meno[4,3-c]pyrazol-3-yl]-morpholin-4-yl-methanone hemi-fumarate, C26 H27 F N4 O5 S. 0.5 C4H4O4

Phase 1b Arm A: Venetoclax + Roginolisib + Rituximab Dose Level -1; Phase 1b Arm B: Venetoclax + Roginolisib + Rituximab Dose Level 1; Phase 2 Arm A: Venetoclax + Roginolisib + Rituximab

Venetoclax DRUG

B-cell lymphoma 2 inhibitor, 10, 50, and 100mg tablets, taken orally per standard of care.

Also known as: ABT-199, GDC-0199

Phase 1b Arm A: Venetoclax + Roginolisib + Rituximab Dose Level -1; Phase 1b Arm B: Venetoclax + Roginolisib + Rituximab Dose Level 1; Phase 2 Arm A: Venetoclax + Roginolisib + Rituximab; Phase 2 Arm B: Venetoclax + Rituximab

Rituximab DRUG

Chimeric anti-CD 20 monoclonal antibody, single-use 10 and 50mL vials, via intravenous (into the vein) infusion per standard of care.

Also known as: Riabni, Ruxience, Truxima, Rituxan, ABP 798, IDEC-C2B8, PF-05280586, MabThera

Phase 1b Arm A: Venetoclax + Roginolisib + Rituximab Dose Level -1; Phase 1b Arm B: Venetoclax + Roginolisib + Rituximab Dose Level 1; Phase 2 Arm A: Venetoclax + Roginolisib + Rituximab; Phase 2 Arm B: Venetoclax + Rituximab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with relapsed/refractory CLL who meet iwCLL criteria for requiring treatment.
• Patients with measurable disease as defined by at least one of: circulating lymphocytosis \> 5000 B cells/microliter, bone marrow involvement \> 30%, palpable splenomegaly or lymph nodes \> 1.5 cm. Computer tomography (CT) at screening must be performed and followed every 2 cycles (1 cycle = 28 days).
• Patients must have received at least two prior therapies for CLL including systemic therapy containing a covalent BTK inhibitor.
• Patients willing to undergo a pre-treatment and on treatment bone marrow biopsy.
• Age ≥18 years, at the time of signing the IRB approved informed consent. Because no dosing or adverse event data are currently available on the use of venetoclax in combination with roginolisib in participants \<18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
• Participants must meet the following organ and marrow function as defined below:
• Platelet count ≥50 x 109/L\^\^\^
• Total bilirubin ≤ 1.5 ×institutional upper limit of normal (ULN)\*
• AST(SGOT)/ALT(SGPT) ≤3.0 × institutional ULN
• Creatinine clearance ≥ 60 mL/min\*\*
• \^\^\^Thrombocytopenia due to marrow involvement of CLL: \> 30 x 109/L for the safety run-in, and 20 x 109/L for the randomized portion of the study
• \*unless increase attributed to leukemic organ involvement, hemolysis or Gilbert's syndrome. Patients who are \< 75 years may have bilirubin of ≤ 3.0 × ULN
• \*\* calculated by the Cockcroft Gault formula or measured by 24 hours urine collection
• Patients with clinically inactive CNS disease or treated CNS disease that is no longer symptomatic, or who need corticosteroids or anticonvulsants may be enrolled in the study. For patients who have symptoms present, imaging and lumbar puncture must be performed to exclude a CNS condition that may impact the study conduct.

You may not qualify if:

• Patients who have received prior treatment with venetoclax or PI3K inhibitors in the last 6 months. Patients must not have had any CLL-directed anticancer therapy within 5 half- lives of the therapy prior to Cycle 1 Day 1.
• Patients who have received a live vaccine within 30 days of planned start of study therapy. With regards to other type of vaccines, including SARS-Co2 vaccines, these are allowed.
• Patients requiring ongoing treatment with chronic high dose immunosuppressants (e.g., cyclosporine) or systemic steroids \> 20 mg prednisone (or equivalent) QD. For example, patients with uncontrolled autoimmune haemolytic anaemia (AIHA) or idiopathic thrombocytopenia purpura (ITP), which requires \> 20 mg once daily (QD) of prednisone (or equivalent) to maintain haemoglobin levels of \>8.0 g/dL or platelets \> 10,000 mL without transfusion support.
• History of transformation of CLL to aggressive non-Hodgkin lymphoma (Richter´s transformation or pro-lymphocytic leukaemia) which may otherwise interfere with the interpretation of the outcome of the study (including biomarker evaluation).
• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities \> Grade 1) with the exception of alopecia or fatigue. Any irAEs from prior immunotherapy must have complete resolution and must have resolved at least 2 weeks before Cycle1 Day1.
• Participants who are receiving any other investigational agents for this condition.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to roginolisib or venetoclax or their formulation components or prior anti- CD20 targeting agents more than 6 months before initiating study treatments.
• Patients with a history of systemic autoimmune disease.
• Participants receiving any medications or substances that are strong inhibitors or inducers of CYP3A are ineligible. Moderate CYP3A inhibitors and P-gp inhibitors can be administered when venetoclax dose is reduced to 50%. Otherwise, venetoclax is contraindicated in patients requiring strong or moderate CYP3A inducers.
• Because of ongoing research, regularly consulting medical reference databases is recommended. One such reference is the Website of the US-FDA: (Drug Interactions \| Relevant Regulatory Guidance and Policy Documents \| FDA)
• As part of the enrollment/informed consent procedures, the participant will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the participant is considering a new over-the-counter medicine or herbal product.
• Pregnant women are excluded from this study because venetoclax has the potential to cause embryo-fetal harm, and the potential for teratogenic or abortifacient effects with roginolisib is currently unknown. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with roginolisib or venetoclax breastfeeding should be discontinued if the mother is treated with these agents.
• Patients with a history of other primary malignancy are excluded when they require therapy that will interfere with the investigational treatments. Exceptions are if the natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen. For example:
• Malignancies surgically treated with curative intent and with no known active disease present for ≥2 years before the first dose of study treatment.
• Adequately treated nonmelanoma skin cancer or lentigo maligna without evidence of disease.

Sponsors & Collaborators

• Jennifer R. Brown, MD, PhD: lead
• United States Department of Defense: collaborator

Study Sites (1)

Dana-Farber Cancer Institute

Boston, Massachusetts, 02115, United States

RECRUITING

MeSH Terms

Conditions

Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Recurrence

Interventions

venetoclax; Rituximab

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, B-Cell; Leukemia, Lymphoid; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Jennifer Brown, MD, PhD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Hang Phan, BS

CONTACT

857-215-1258; hang_phan@dfci.harvard.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Sponsor Investigator

Model Details: Phase 1: single arm, Phase 2: two arm, randomized trial

Study Record Dates

• First Submitted: October 14, 2024
• First Posted: October 16, 2024
• Study Start: March 19, 2025
• Primary Completion (Estimated): October 1, 2028
• Study Completion (Estimated): October 1, 2032
• Last Updated: February 11, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu

Locations

US (1)