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

25 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase Ib trial tests the safety and effectiveness of tafasitamab, acalabrutinib, and obinutuzumab in treating patients with previously untreated chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). CLL and SLL are types of cancer that develops from a specific white blood cell called B cells or B lymphocytes. Tafasitamab and obinutuzumab are monoclonal antibodies that may interfere with the ability of cancer cells to grow and spread. Acalabrutinib is in a class of medications called kinase inhibitors. It blocks a protein called BTK, which is present on B-cell cancers such as CLL at abnormal levels. This may help keep cancer cells from growing and spreading. Giving tafasitamab, acalabrutinib, and obinutuzumab may kill more cancer cells in patients with previously untreated CLL and SLL.

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.

What data supports the effectiveness of the drug combination Acalabrutinib, Obinutuzumab, and Tafasitamab for treating chronic lymphocytic leukemia?

Research shows that Acalabrutinib, when used with Obinutuzumab, has a favorable safety profile and can effectively delay disease progression in chronic lymphocytic leukemia. Acalabrutinib has been shown to significantly extend the time before the disease worsens compared to standard treatments, and combining it with other drugs like Venetoclax has shown promising results in achieving deeper remissions. ^{1 2 3 4 5}

Is the triple therapy for chronic lymphocytic leukemia safe for humans?

Acalabrutinib, a key component of the triple therapy, has been shown to have a generally favorable safety profile in clinical trials for chronic lymphocytic leukemia, with common side effects including headache, diarrhea, and infections. It is considered to have an acceptable safety profile compared to other treatments, although it may increase the risk of certain blood-related side effects like neutropenia (low white blood cell count). ^{1 2 3 6 7}

What makes the triple drug therapy of Acalabrutinib, Obinutuzumab, and Tafasitamab unique for treating chronic lymphocytic leukemia?

This triple drug therapy is unique because it combines Acalabrutinib, a highly selective Bruton tyrosine kinase inhibitor, with Obinutuzumab and Tafasitamab, which are antibodies targeting specific proteins on cancer cells. This combination aims to enhance the effectiveness of treatment by attacking the cancer cells through different mechanisms, potentially improving outcomes compared to using these drugs individually. ^{1 2 3 7 8}

Research Team

Stephen E. Spurgeon

Principal Investigator

OHSU Knight Cancer Institute

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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 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 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]

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 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]

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]

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]

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]

References

1. United States 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. [2021]

2. England pubmed.ncbi.nlm.nih.gov

EMA Review of Acalabrutinib for the Treatment of Adult Patients with Chronic Lymphocytic Leukemia. [2021]

3. United States 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. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Acalabrutinib, venetoclax, and obinutuzumab as frontline treatment for chronic lymphocytic leukaemia: a single-arm, open-label, phase 2 study. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Pharmacodynamics and proteomic analysis of acalabrutinib therapy: similarity of on-target effects to ibrutinib and rationale for combination therapy. [2023]

6. Switzerland pubmed.ncbi.nlm.nih.gov

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

7. New Zealand pubmed.ncbi.nlm.nih.gov

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

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

Combined BTK and PI3Kδ Inhibition with Acalabrutinib and ACP-319 Improves Survival and Tumor Control in CLL Mouse Model. [2019]