Triple Therapy for Chronic Lymphocytic Leukemia

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: OHSU Knight Cancer Institute

Must not be taking: Warfarin, PPIs, others

Disqualifiers: Other hematologic malignancy, HIV, 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: 3

Duration: 12 months

27 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of a combination of three drugs—tafasitamab, acalabrutinib, and obinutuzumab—to treat chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), both types of blood cancer. Acalabrutinib is a targeted therapy known as a Bruton's tyrosine kinase (BTK) inhibitor. The goal is to determine if these drugs can stop cancer cells from growing and spreading. Participants should have untreated CLL or SLL and experience symptoms like fatigue, night sweats, or weight loss. As a Phase 1 trial, the research focuses on understanding how the treatment works in people.

Will I have to stop taking my current medications?

The trial does not specify if you must stop all current medications, but certain medications like proton pump inhibitors and some blood thinners must be stopped before starting the trial. If you are on corticosteroids, you may need to taper off if the dose is above 20 mg daily.

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

Research has shown that acalabrutinib, a treatment for chronic lymphocytic leukemia (CLL), is generally well-tolerated. Common side effects include low red blood cell counts (anemia) and low white blood cell counts (neutropenia), occurring in many patients. Its heart-related safety surpasses that of some other CLL treatments.

For obinutuzumab, studies have found it can cause serious side effects, such as infections and allergic reactions. One study reported severe side effects like low white blood cell counts (neutropenia) and low platelet counts (thrombocytopenia) in about 80% of patients.

Tafasitamab has been linked to decreased bone marrow activity, leading to conditions like low white and red blood cell counts. However, adjusting the dosage often helps manage these effects.

Overall, while these treatments show promise, they come with potential risks that require careful monitoring. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for chronic lymphocytic leukemia (CLL), which often involve chemotherapy and targeted therapies, this triple therapy combines acalabrutinib, obinutuzumab, and tafasitamab, each with unique mechanisms of action. Acalabrutinib is a Bruton’s tyrosine kinase inhibitor that interrupts cancer cell survival pathways. Obinutuzumab is an anti-CD20 monoclonal antibody that enhances the immune system's ability to attack cancer cells. Tafasitamab is another monoclonal antibody that targets CD19 on B-cells, further boosting the immune response. Researchers are excited because this combination targets CLL cells from multiple angles, potentially leading to more effective and lasting results than current treatments.

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

Research shows that three treatments—acalabrutinib, obinutuzumab, and tafasitamab—are promising for chronic lymphocytic leukemia (CLL). Acalabrutinib, already approved for CLL, has proven effective for over six years. Combining acalabrutinib with obinutuzumab has achieved a 100% response rate in previously untreated patients, significantly reducing the disease in the bone marrow over 14 months. Tafasitamab, an immunotherapy, directly targets cancer cells. In this trial, participants will receive a combination of these three treatments, potentially destroying more cancer cells in people with CLL and offering new hope for those who have not yet received treatment. ^{1 6 7 8 9}

Who Is on the Research Team?

Stephen E. Spurgeon

Principal Investigator

OHSU Knight Cancer Institute

Are You a Good Fit for This Trial?

This trial is for adults with previously untreated chronic lymphocytic leukemia (CLL). Participants must not have had any prior CLL treatment, be able to swallow pills, and agree to use contraception. They should have a life expectancy over 12 months and meet specific health criteria like adequate organ function. Those with certain other cancers or severe medical conditions are excluded.

Inclusion Criteria

My bone marrow is failing or I have symptoms related to my disease.

Written informed consent from participant or legally authorized representative (LAR)

ANC > 1,000/uL

Exclusion Criteria

Known hypersensitivity to specified antibodies or medications

I am currently taking proton pump inhibitors.

I have or had another blood cancer diagnosis.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive obinutuzumab, tafasitamab, and acalabrutinib over 12 cycles of 28 days each

12 months

Multiple visits per cycle for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Acalabrutinib
• Obinutuzumab
• Tafasitamab

Trial Overview The trial tests the combination of tafasitamab, acalabrutinib, and obinutuzumab in treating CLL. These drugs include monoclonal antibodies that may stop cancer cells from growing and a kinase inhibitor that blocks abnormal proteins in B-cell cancers.

How Is the Trial Designed?

Group I: Treatment (tafasitamab, obinutuzumab, acalabrutinib) Experimental Treatment 9 Interventions

See Detailed DescriptionPatients receive obinutuzumab IV over a rate titrated up to 400 mg/hour on days 1, 2, 8, and 15 for cycle 1 then on day 1 for cycles 2-6 and tafasitamab IV over 1.5-2 hours on days 1, 4, 8, 15, and 22 for cycle 2, on days 1, 8, 15, and 22 for cycles 3-4, and on days 1 and 15 for cycles 5-7. Patients also receive acalabrutinib PO BID in each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and CT throughout the trial. Patients may undergo an ECHO at baseline as clinically indicated and may also undergo bone marrow biopsy and/or aspiration at baseline and/or follow-up.

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?

OHSU Knight Cancer Institute

Lead Sponsor

Trials

239

Recruited

2,089,000+

Oregon Health and Science University

Collaborator

Trials

1,024

Recruited

7,420,000+

Incyte Corporation

Industry Sponsor

Trials

408

Recruited

66,800+

Steven Stein

Incyte Corporation

Chief Medical Officer since 2015

MD from University of Witwatersrand

Hervé Hoppenot

Incyte Corporation

Chief Executive Officer since 2014

MBA from ESSEC Business School

Published Research Related to This Trial

Acalabrutinib, a selective BTK inhibitor, has shown improved progression-free survival in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) compared to standard treatments, indicating its efficacy as a treatment option.

The safety profile of acalabrutinib is favorable, with most side effects being mild (grade 1/2), such as headache and diarrhea, and a low rate of treatment discontinuation due to adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib: A Selective Bruton Tyrosine Kinase Inhibitor for the Treatment of B-Cell Malignancies. Abbas, HA., Wierda, WG.[2023]

In a murine model of chronic lymphocytic leukemia (CLL), the combination of the BTK inhibitor acalabrutinib and the PI3Kδ inhibitor ACP-319 significantly reduced tumor burden and extended survival by over 2 weeks compared to single-agent therapies.

The combination therapy was more effective in reducing tumor proliferation and key survival signaling pathways than either drug alone, suggesting a promising approach for improving treatment outcomes in CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined BTK and PI3Kδ Inhibition with Acalabrutinib and ACP-319 Improves Survival and Tumor Control in CLL Mouse Model. Niemann, CU., Mora-Jensen, HI., Dadashian, EL., et al.[2019]

Acalabrutinib, a selective Bruton tyrosine kinase inhibitor, showed improved safety outcomes compared to other targeted therapies for treatment-naïve chronic lymphocytic leukemia (CLL) patients, although it was associated with a higher risk of neutropenia and leukopenia in some cases.

The analysis indicated that acalabrutinib (with or without obinutuzumab) had similar efficacy in terms of progression-free survival compared to other treatments, suggesting it is a safe and effective option for CLL patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Matching-adjusted indirect comparisons of safety and efficacy of acalabrutinib versus other targeted therapies in patients with treatment-naïve chronic lymphocytic leukemia. Davids, MS., Telford, C., Abhyankar, S., et al.[2021]

Acalabrutinib, a selective Bruton's tyrosine kinase inhibitor, shows high response rates and durable remission in chronic lymphocytic leukemia (CLL) patients, although complete remissions are rare.

Combining acalabrutinib with venetoclax demonstrated optimal complementary effects in laboratory studies, suggesting a promising strategy for achieving deeper responses in CLL treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacodynamics and proteomic analysis of acalabrutinib therapy: similarity of on-target effects to ibrutinib and rationale for combination therapy. Patel, VK., Lamothe, B., Ayres, ML., et al.[2023]

In a phase III study involving 310 patients with relapsed/refractory chronic lymphocytic leukemia (CLL), acalabrutinib monotherapy significantly improved progression-free survival (PFS) compared to investigator's choice treatments, with a median PFS not reached for acalabrutinib versus 16.5 months for the comparator group.

Acalabrutinib demonstrated a favorable safety profile, with serious adverse events occurring in 29% of patients, compared to 56% for idelalisib plus rituximab and 26% for bendamustine plus rituximab, indicating it may be a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. Ghia, P., Pluta, A., Wach, M., et al.[2021]

Acalabrutinib has been approved in the EU for treating both treatment-naïve and relapsed/refractory chronic lymphocytic leukemia (CLL), showing significant improvements in progression-free survival compared to standard therapies in two phase III trials involving adult patients.

The safety profile of acalabrutinib is generally acceptable, with common side effects including headache, diarrhea, and infections, and the overall benefit-risk ratio is considered positive for its use in CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

EMA Review of Acalabrutinib for the Treatment of Adult Patients with Chronic Lymphocytic Leukemia. Delgado, J., Josephson, F., Camarero, J., 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]

Acalabrutinib, a selective BTK inhibitor, has been FDA approved for treating chronic lymphocytic leukemia (CLL) and shows improved efficacy and safety compared to standard treatments, including ibrutinib.

In multinational phase 1/2 and phase 3 studies, acalabrutinib demonstrated significant effectiveness in treatment-naïve and relapsed refractory CLL patients, with fewer treatment-limiting toxicities such as atrial fibrillation and bleeding.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib and Its Therapeutic Potential in the Treatment of Chronic Lymphocytic Leukemia: A Short Review on Emerging Data. Isaac, K., Mato, AR.[2020]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40736551/

Real-world efficacy and safety outcomes of acalabrutinib in ... Acalabrutinib is a second-generation BTK inhibitor approved for the treatment of chronic lymphocytic leukemia (CLL) after demonstrating efficacy ...

2. bloodcancerstoday.com bloodcancerstoday.com/post/data-update-verifies-superiority-of-acalabrutinib-in-patients-with-cll

Extended Follow-up Shows Sustained Benefits of ... Acalabrutinib with or without obinutuzumab had sustained safety and efficacy in patients with CLL in six years of follow-up.

3. iwcll2025.org iwcll2025.org/ajaxcalls/PosterInfo.asp?efp=UkpWR0RaQ0YyNDU0NA&PosterID=746331&rnd=0.1073753

A phase Ib study evaluating the safety and efficacy ... Acalabrutinib and obinutuzumab are commonly used for CLL treatment. Tafasitamab, an Fc-modified anti-CD19 immunotherapy approved in combination with

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8992498/

Promises and pitfalls of targeted agents in chronic lymphocytic ... Targeted agents have significantly improved outcomes for patients with chronic lymphocytic leukemia, particularly high-risk subgroups for whom ...

5. cllsociety.org cllsociety.org/2024/12/acalabrutinib-and-obinutuzumab-for-frontline-cll-treatment/

Acalabrutinib and Obinutuzumab for Frontline CLL Treatment Acalabrutinib plus obinutuzumab had a 100 percent response rate at 14 months and a deep reduction of disease in the bone marrow in treatment-naive CLL.

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2022/216387Orig2s000Correctedlbl.pdf

CALQUENCE® (acalabrutinib) tablets, for oral use In this pooled safety population, adverse reactions in ≥ 30% of 1029 patients were anemia, neutropenia, upper respiratory tract infection, ...

7. ashpublications.org ashpublications.org/bloodneoplasia/article/2/1/100064/534858/Real-world-safety-profile-of-therapy-with

Real-world safety profile of therapy with ibrutinib or ... The ELEVATE-RR trial compared treatment with ibrutinib vs acalabrutinib in previously treated CLL, showing similar progression-free survival with both agents.

8. clinicaltrials.gov clinicaltrials.gov/study/NCT04008706

NCT04008706 | Acalabrutinib Safety Study in Untreated ... To evaluate the safety and tolerability of acalabrutinib monotherapy in participants with treatment-naïve or relapsed/refractory chronic lymphocytic leukemia.

9. hematologyadvisor.com hematologyadvisor.com/news/chronic-leukemia-cll-safety-profile-acalabrutinib-superior-chemoimmunotherapy/

Safety Profile of Acalabrutinib Superior to ... The cardiovascular safety profile of acalabrutinib is superior to that of chemoimmunotherapy in treating patients with chronic lymphocytic leukemia (CLL).