Roginolisib + Venetoclax + Rituximab for Chronic Lymphocytic Leukemia

Overseen By Megan Forsyth

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Jennifer R. Brown, MD, PhD

Must not be taking: CYP3A inducers

Disqualifiers: Autoimmune disease, Richter's transformation, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 5

64 Participants Needed

Trial Summary

What is the purpose of this trial?

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)

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot participate if you are taking strong or moderate CYP3A inducers, and you may need to adjust the dose of venetoclax if you are on moderate CYP3A inhibitors. It's important to discuss your current medications with the study team to ensure there are no interactions.

What data supports the effectiveness of the drug combination Roginolisib, Venetoclax, and Rituximab for treating chronic lymphocytic leukemia?

Research shows that the combination of Venetoclax and Rituximab is effective for treating chronic lymphocytic leukemia, providing longer progression-free survival and durable responses compared to other treatments. Venetoclax alone or with Rituximab has shown high response rates and is well-tolerated, making it a promising option for patients with relapsed or refractory chronic lymphocytic leukemia. ^{1 2 3 4 5}

What makes the drug combination of Roginolisib, Venetoclax, and Rituximab unique for treating chronic lymphocytic leukemia?

This drug combination is unique because it includes Roginolisib, which is not commonly used in standard treatments for chronic lymphocytic leukemia. Venetoclax and Rituximab are known to work well together, with Venetoclax targeting BCL-2 proteins to help kill cancer cells and Rituximab enhancing this effect by targeting CD20 proteins on the surface of cancer cells, potentially offering a new synergistic approach. ^{1 2 3 5 6}

Research Team

Jennifer R Brown, MD, PhD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

This trial is for people with Chronic Lymphocytic Leukemia (CLL) that has come back or hasn't responded to treatment. Participants should have had at least one prior therapy and be suitable for treatment with Venetoclax and Rituximab.

Inclusion Criteria

My brain condition is stable and not causing symptoms.

I have had at least two treatments for CLL, one with a BTK inhibitor.

Willingness to use adequate contraception prior to study entry and for the duration of study participation

Exclusion Criteria

I cannot swallow pills due to a condition in my upper GI tract.

I am not on high doses of steroids or immunosuppressants.

My CLL has transformed into a more aggressive form of lymphoma.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Phase 1b Treatment

Participants receive Venetoclax, Roginolisib, and Rituximab to establish a Recommended Phase 2 Dose (RP2D)

13 cycles (approximately 12 months)

Baseline visit, imaging, bone marrow biopsy, CT scan every 2 cycles

Phase 2 Treatment

Participants are randomized to receive either Venetoclax + Roginolisib + Rituximab or Venetoclax + Rituximab

13 cycles (approximately 12 months)

Baseline visit, imaging, bone marrow biopsy, CT scan every 2 cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Follow-up visits

Treatment Details

Interventions

• Rituximab
• Roginolisib
• Venetoclax

Trial Overview The study tests a combination of three drugs: Roginolisib, an experimental PI3Kδ inhibitor; Venetoclax, which targets B-cell lymphoma 2 proteins; and Rituximab, an antibody. It aims to evaluate the safety and cancer-fighting effects of this mix in CLL patients.

Participant Groups

Group I: Phase 2 Arm A: Venetoclax + Roginolisib + Rituximab Experimental Treatment 3 Interventions

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

Group II: Phase 1b Arm B: Venetoclax + Roginolisib + Rituximab Dose Level 1 Experimental Treatment 3 Interventions

* 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

Group III: Phase 1b Arm A: Venetoclax + Roginolisib + Rituximab Dose Level -1 Experimental Treatment 3 Interventions

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

Group IV: Phase 2 Arm B: Venetoclax + Rituximab Active Control 2 Interventions

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

Rituximab is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Rituxan for:

• Non-Hodgkin's lymphoma
• Chronic lymphocytic leukemia
• Rheumatoid arthritis
• Granulomatosis with polyangiitis
• Microscopic polyangiitis

Approved in European Union as MabThera for:

• Non-Hodgkin's lymphoma
• Chronic lymphocytic leukemia
• Rheumatoid arthritis
• Granulomatosis with polyangiitis
• Microscopic polyangiitis

Approved in Canada as Rituxan for:

• Non-Hodgkin's lymphoma
• Chronic lymphocytic leukemia
• Rheumatoid arthritis
• Granulomatosis with polyangiitis
• Microscopic polyangiitis

Who Is Running the Clinical Trial?

Jennifer R. Brown, MD, PhD

Lead Sponsor

Trials

3

Recruited

140+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Findings from Research

Venetoclax is an effective oral treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), showing durable responses and a manageable safety profile in clinical trials, including patients with poor prognostic factors.

In combination with rituximab, venetoclax significantly improved progression-free survival and achieved undetectable minimal residual disease compared to bendamustine plus rituximab, with benefits lasting for at least 36 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Relapsed/Refractory Chronic Lymphocytic Leukemia. Scott, LJ.[2020]

The combination of venetoclax with rituximab showed remarkable efficacy and a manageable safety profile in treating chronic lymphocytic leukemia (CLL), both in relapsed/refractory cases and as a first-line therapy for high-risk patients.

Similarly, the combination of ibrutinib with venetoclax also demonstrated striking efficacy, suggesting that these combinations could become new standard treatment options for CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic lymphocytic leukemia at ASH 2017. Wanner, D., Steurer, M.[2020]

In a study of 323 patients with relapsed or refractory chronic lymphocytic leukemia (CLL), a daily dose of 400 mg of venetoclax resulted in a median progression-free survival (PFS) of 1.8 years.

The addition of 6 cycles of rituximab to venetoclax treatment significantly increased the median PFS to 3.9 years, demonstrating a synergistic effect that enhances treatment efficacy beyond increasing the venetoclax dose alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relationship between venetoclax exposure, rituximab coadministration, and progression-free survival in patients with relapsed or refractory chronic lymphocytic leukemia: demonstration of synergy. Freise, KJ., Jones, AK., Menon, RM., et al.[2018]

Venetoclax is a highly effective treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), achieving response rates of about 80% in clinical trials involving 240 patients from 2011 to 2016.

While venetoclax has an acceptable safety profile, common side effects include neutropenia and diarrhea, and there is a risk of tumor lysis syndrome (TLS), which can be managed through careful dose ramp-up and patient education, leading to no reported TLS events in ongoing trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . Brumbaugh Paradis, H., Alter, D., Llerandi, D.[2018]

In a study involving 10 patients with relapsed/refractory chronic lymphocytic leukemia (CLL), the addition of rituximab to venetoclax therapy resulted in a 50% response rate, with three patients achieving complete responses and two achieving partial responses.

The combination treatment was well tolerated, suggesting that adding rituximab after progression on venetoclax may provide a beneficial option for some patients with R/R CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addition of rituximab in relapsed/refractory chronic lymphocytic leukemia after progression on venetoclax monotherapy. Handunnetti, S., Anderson, MA., Roberts, AW., et al.[2022]

Venetoclax has been confirmed as an effective and well-tolerated treatment for patients with relapsed/refractory chronic lymphocytic leukemia (CLL) in Italy, particularly in those with high-risk disease characteristics, based on three real-world studies.

Combining venetoclax with rituximab resulted in more complete responses in patients, although those with higher disease burden or who progressed while on prior Bruton's tyrosine kinase inhibitors had poorer outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world evidence on venetoclax in chronic lymphocytic leukemia: The Italian experience. Laurenti, L., Scarfò, L., Frustaci, AM., et al.[2023]

References

1. France pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Relapsed/Refractory Chronic Lymphocytic Leukemia. [2020]

2. Austria pubmed.ncbi.nlm.nih.gov

Chronic lymphocytic leukemia at ASH 2017. [2020]

3. England pubmed.ncbi.nlm.nih.gov

Relationship between venetoclax exposure, rituximab coadministration, and progression-free survival in patients with relapsed or refractory chronic lymphocytic leukemia: demonstration of synergy. [2018]

4. United States pubmed.ncbi.nlm.nih.gov

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . [2018]

5. United States pubmed.ncbi.nlm.nih.gov

Addition of rituximab in relapsed/refractory chronic lymphocytic leukemia after progression on venetoclax monotherapy. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Real-world evidence on venetoclax in chronic lymphocytic leukemia: The Italian experience. [2023]