Acalabrutinib + Anti-CD20 + Venetoclax for Chronic Lymphocytic Leukemia

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Acerta Pharma BV

Must not be taking: Anticoagulants, Proton-pump inhibitors

Disqualifiers: Active cardiovascular disease, GI disorders, Infections, 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: 28

Duration: Approximately 6 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and early effectiveness of combining three drugs—acalabrutinib (a targeted therapy), obinutuzumab, and venetoclax—to treat chronic lymphocytic leukemia (CLL) and related conditions. The trial includes four groups, each receiving a unique combination of these medications. It seeks participants who have either never been treated for CLL or have had at least one prior treatment. Ideal candidates may experience symptoms like extreme tiredness or significant weight loss due to CLL. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop taking your current medications. However, you must have completed all CLL therapies at least 4 weeks before starting the study, and certain medications like proton-pump inhibitors and anticoagulants like warfarin are not allowed.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of acalabrutinib and obinutuzumab is generally safe for patients with chronic lymphocytic leukemia (CLL). In a study involving 511 patients, the treatment was well-tolerated, and the safety results aligned with previous studies. Common side effects included headache and diarrhea, which were usually mild and manageable.

The combination of acalabrutinib, rituximab, and venetoclax has also been studied. Venetoclax, already approved by the FDA for use with rituximab in similar conditions, has demonstrated promising safety results. Side effects were noted, but they were consistent with expectations for these medications.

For the trio of acalabrutinib, obinutuzumab, and venetoclax, research indicates it was well-tolerated in previously untreated patients. This combination effectively reduced symptoms such as swollen lymph nodes and an enlarged spleen or liver.

Overall, these treatments appear safe, with side effects that are generally mild and expected for these drugs. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the treatments in this trial for chronic lymphocytic leukemia (CLL) because they combine targeted therapies with different mechanisms to potentially enhance effectiveness. Acalabrutinib, a key player in each treatment group, specifically inhibits the BTK protein, which is crucial for cancer cell survival. This precision targeting is different from standard chemotherapy, which can affect healthy cells too. Additionally, combining acalabrutinib with anti-CD20 antibodies like obinutuzumab or rituximab, and adding venetoclax in some groups, offers a multifaceted attack on cancer cells. Venetoclax works by promoting cancer cell death through a unique BCL-2 inhibition mechanism, offering an exciting alternative to current treatments. These combinations aim to improve outcomes by using a strategic approach that targets cancer cells more specifically and effectively.

What evidence suggests that this trial's treatments could be effective for chronic lymphocytic leukemia?

This trial will evaluate different treatment combinations for chronic lymphocytic leukemia (CLL). Research has shown that combining acalabrutinib and obinutuzumab, which participants in Cohorts 1 and 2 may receive, can extend the lives of people with CLL. One study found that this combination allowed patients to live longer without disease progression compared to acalabrutinib alone. Another study showed that this treatment reduced cancer cells to very low levels. Participants in Cohort 4 will receive acalabrutinib, obinutuzumab, and venetoclax, a combination that lowered the risk of disease progression or death by 58% compared to standard treatments. Additionally, participants in Cohort 3 will receive acalabrutinib with venetoclax and rituximab, which has achieved high success rates in treating CLL. These findings suggest that these treatment combinations are promising options for managing CLL. ^{4 6 7 8 9}

Who Is on the Research Team?

AstraZeneca Study Information Center

Principal Investigator

1-877-240-9479; [e-mail]

Are You a Good Fit for This Trial?

This trial is for adults with certain types of leukemia and lymphoma, including CLL/SLL/PLL. Participants can be treatment-experienced or untreated, depending on the cohort they qualify for. They must have adequate organ function, not be pregnant or breastfeeding, agree to contraception if applicable, and cannot have secondary cancers affecting life expectancy or confounding factors.

Inclusion Criteria

Participant must provide written informed consent

My organs work well, I don't have another cancer, and my doctor thinks I'll live more than 2 years.

I can go to the clinic for my treatment and follow-up visits.

Exclusion Criteria

I have received treatment for CLL before.

I have heart disease or a long QT interval.

I do not have HIV, hepatitis B or C, or any uncontrolled infections.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive acalabrutinib in combination with obinutuzumab, rituximab, and/or venetoclax depending on cohort assignment. Treatment includes dose-escalation and dose-expansion phases.

Approximately 6 months

Multiple visits per cycle (28-day cycles)

Maintenance

Participants continue to receive acalabrutinib until disease progression, unacceptable toxicity, or other criteria are met.

Until disease progression or unacceptable toxicity

Follow-up

Participants are monitored for safety and effectiveness after treatment

Approximately 6 years 8 months

What Are the Treatments Tested in This Trial?

Interventions

• Acalabrutinib
• Obinutuzumab
• Rituximab
• Venetoclax

Trial Overview The safety and efficacy of acalabrutinib combined with obinutuzumab are being tested in four cohorts of participants with different disease statuses (treated/untreated). The study will assess how well this combination works for those who meet specific health criteria.

How Is the Trial Designed?

Group I: Cohort 4: Acalabrutinib+Obinutuzumab+Venetoclax (Treatment-naive) Experimental Treatment 3 Interventions

The treatment-naïve participants with CLL will receive oral acalabrutinib, IV infusion of obinutuzumab, and oral venetoclax. Participants will receive acalabrutinib Dose 2 BID in 28-day continuous cycles until disease progression, an unacceptable drug-related toxicity, or per the investigator the study treatment is intolerable or no longer in participant's best interest, whichever occurs first. Participants will receive obinutuzumab for total 6 cycles (from Cycles 2 to 7) as Dose 1 on Cycle 2 Day 1, Dose 2 on Cycle 2 Day 2, Dose 3 on Cycle 2 Days 8 and 15, and Dose 3 on Day 1 of Cycles 3 to 7. Participants will receive venetoclax weekly ramp-up schedule over 5 weeks from Cycles 3 to 15 as Dose 1 QD for 1 week on Cycle 3 Day 1, Dose 2 QD for 1 week on Cycle 3 Day 8, Dose 3 QD for 1 week on Cycle 3 Day 15, Dose 4 QD for 1 week on Cycle 3 Day 22, and from Cycle 4 Day 1 participants will receive Dose 5 QD until completion of Cycle 15.

Group II: Cohort 3: Acalabrutinib+Rituximab+Venetoclax (R/R) Experimental Treatment 3 Interventions

The R/R participants with CLL will receive oral acalabrutinib, IV infusion of rituximab, and oral venetoclax. Participants will receive acalabrutinib Dose 2 BID in 28-day continuous cycles until disease progression, an unacceptable drug-related toxicity, or per the investigator the study treatment is intolerable or no longer in participant's best interest, whichever occurs first. Participants will receive rituximab for total 6 cycles (from Cycles 2 to 7) as Dose 1 on Cycle 2 Day 1, followed by Dose 1 every 3 weeks (Q3W) for 3 doses, then every 4 weeks (Q4W) for 5 doses (total 9 infusions through the end of Cycle 7). Participants will receive venetoclax weekly ramp-up schedule over 5 weeks from Cycles 3 to 15, Dose 1 QD for 1 week on Cycle 3 Day 1, Dose 2 QD for 1 week on Cycle 3 Day 8, Dose 3 QD for 1 week on Cycle 3 Day 15, Dose 4 QD for 1 week on Cycle 3 Day 22, and Dose 5 QD from Cycle 4 Day 1 until completion of Cycle 15.

Group III: Cohort 2: Acalabrutinib+Obinutuzumab (Treatment-naive) Experimental Treatment 2 Interventions

Dose-escalation and dose-expansion phases will be conducted for treatment-naïve participants with CLL/ small lymphocytic lymphoma (SLL). In dose-escalation phase, participants will receive oral acalabrutinib Dose 2 BID in first cycle (28-day cycle). In dose- expansion phase, participants will receive oral acalabrutinib Dose 2 BID in 28-day continuous cycles; and will receive IV infusion of obinutuzumab for total 6 cycles (from Cycles 2 to 7) as on Cycle 2 Day 1 participants will receive Dose 1, on Cycle 2 Day 2 participants will receive Dose 2, on Cycle 2 Days 8 and 15 participants will receive Dose 3, and on Day 1 of Cycles 3 to 7 participants will receive Dose 3. Participants will continue to receive acalabrutinib Dose 2 BID until disease progression, an unacceptable drug-related toxicity, or per the investigator the study treatment is intolerable or no longer in participant's best interest, whichever occurs first.

Group IV: Cohort 1: Acalabrutinib+Obinutuzumab (R/R) Experimental Treatment 2 Interventions

Dose-escalation and dose-expansion phases will be conducted for relapsed/refractory (R/R) participants with CLL. In dose-escalation phase, participants will receive oral acalabrutinib Dose 1 once daily (QD), later the dose was switched to Dose 2 twice daily (BID) per Amendment 02. In dose- expansion phase, participants will receive oral acalabrutinib Dose 2 BID in 28-day continuous cycles; and will receive intravenous (IV) infusion of obinutuzumab for total 6 cycles (from Cycles 2 to 7) as on Cycle 2 Day 1 participants will receive Dose 1, on Cycle 2 Day 2 participants will receive Dose 2, on Cycle 2 Days 8 and 15 participants will receive Dose 3, and on Day 1 of Cycles 3 to 7 participants will receive Dose 3. Participants will continue to receive acalabrutinib Dose 2 BID until disease progression, an unacceptable drug-related toxicity, or per the investigator the study treatment is intolerable or no longer in participant's best interest, whichever occurs first.

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

Approved in United States as Calquence for:

• Mantle cell lymphoma
• Chronic lymphocytic leukemia
• Small lymphocytic lymphoma

Approved in European Union as Calquence for:

• Chronic lymphocytic leukemia
• Small lymphocytic lymphoma
• Mantle cell lymphoma

Who Is Running the Clinical Trial?

Acerta Pharma BV

Lead Sponsor

Trials

46

Recruited

5,900+

Published Research Related to This Trial

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 phase 3 trial involving 432 patients with untreated chronic lymphocytic leukaemia, the combination of venetoclax plus obinutuzumab resulted in significantly longer progression-free survival compared to chlorambucil plus obinutuzumab, with a hazard ratio of 0.31, indicating a strong treatment advantage.

After a median follow-up of 39.6 months post-treatment, patients receiving venetoclax plus obinutuzumab had not yet reached median progression-free survival, while those on chlorambucil plus obinutuzumab had a median of 35.6 months, highlighting the long-term efficacy of the venetoclax regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Al-Sawaf, O., Zhang, C., Tandon, M., et al.[2020]

The combination of venetoclax with bendamustine-rituximab (BR) was found to be safe and tolerable in a study of 60 patients with relapsed/refractory non-Hodgkin's lymphoma, with the recommended phase II dose established at 800 mg daily.

The overall response rate to the treatment was 65%, with a median duration of response of 38.3 months, indicating preliminary efficacy for this combination therapy in managing B-cell NHL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax, bendamustine, and rituximab in patients with relapsed or refractory NHL: a phase Ib dose-finding study. de Vos, S., Swinnen, LJ., Wang, D., et al.[2021]

In a phase 2 study involving 37 patients with chronic lymphocytic leukaemia, the combination therapy of acalabrutinib, venetoclax, and obinutuzumab achieved a complete remission with undetectable minimal residual disease (MRD) in 38% of participants by cycle 16, indicating promising efficacy.

The treatment was generally well tolerated, with the most common serious adverse event being neutropenia, affecting 43% of patients, and no deaths reported during the study, suggesting a favorable safety profile for this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib, venetoclax, and obinutuzumab as frontline treatment for chronic lymphocytic leukaemia: a single-arm, open-label, phase 2 study. Davids, MS., Lampson, BL., Tyekucheva, S., et al.[2021]

In the phase III CLL14 trial, a 12-month treatment with venetoclax combined with obinutuzumab significantly improved progression-free survival and rates of undetectable minimal residual disease compared to traditional chemoimmunotherapy with chlorambucil and obinutuzumab in patients with untreated chronic lymphocytic leukaemia.

Venetoclax + obinutuzumab is a well-tolerated, chemotherapy-free treatment option for CLL, with manageable side effects like neutropenia, making it suitable for patients who cannot undergo intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Previously Untreated Chronic Lymphocytic Leukaemia. Blair, HA.[2021]

Venetoclax, an oral BCL-2 inhibitor, combined with obinutuzumab, has demonstrated superior efficacy compared to traditional chemoimmunotherapy in both treatment-naive and relapsed/refractory chronic lymphocytic leukemia (CLL) patients.

Obinutuzumab, a novel anti-CD20 monoclonal antibody, has been safely used with other targeted therapies like venetoclax, showing better outcomes than the older drug rituximab when paired with chlorambucil.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An update of venetoclax and obinutuzumab in chronic lymphocytic leukemia. Salvaris, R., Opat, S.[2021]

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