Combination Therapy for Chronic Lymphocytic Leukemia

Overseen By Nitin Jain, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Warfarin, CYP3A inhibitors

Disqualifiers: Del(17p), Unmutated IGHV, Cardiovascular, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

81 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies how well ibrutinib, fludarabine phosphate, cyclophosphamide, and obinutuzumab work in treating patients with chronic lymphocytic leukemia. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fludarabine phosphate and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as obinutuzumab, may induce changes in the body's immune system and may interfere with the ability of tumor cells to grow and spread. Giving ibrutinib, fludarabine phosphate, cyclophosphamide, and obinutuzumab together may work better in treating chronic lymphocytic leukemia.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot use warfarin, other vitamin K antagonists, or strong CYP3A inhibitors while participating. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination therapy for chronic lymphocytic leukemia?

Research shows that the combination of drugs like ibrutinib and obinutuzumab is highly effective for treating chronic lymphocytic leukemia, with studies reporting a 100% overall response rate and significant remission in patients. Additionally, these drugs have shown impressive results in terms of tolerability and efficacy, suggesting they can change the treatment approach for this condition. ^{1 2 3 4 5}

Is the combination therapy for Chronic Lymphocytic Leukemia safe?

The combination therapy for Chronic Lymphocytic Leukemia, which includes drugs like obinutuzumab, ibrutinib, and fludarabine-cyclophosphamide, has been studied for safety. Obinutuzumab can cause infusion-related reactions, and serious side effects like neutropenia (low white blood cell count), thrombocytopenia (low platelet count), and infections were observed in some patients. Ibrutinib is generally well tolerated but may increase the risk of bleeding and heart rhythm issues. Overall, these treatments have manageable side effects, but serious adverse events can occur. ^{6 7 8 9 10}

How is the combination therapy for chronic lymphocytic leukemia unique?

This combination therapy is unique because it includes ibrutinib, a novel oral drug that blocks key pathways in cancer cells, and obinutuzumab, a newer antibody that targets cancer cells more effectively than older treatments, potentially leading to better outcomes. ^{3 4 6 10 11}

Research Team

Nitin Jain, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults with chronic lymphocytic leukemia who haven't had previous CLL treatments, have a certain type of gene mutation (mutated IGHV), and are in good physical condition (ECOG <=2). They must not be pregnant or breastfeeding, agree to use effective contraception, and cannot have other serious health issues like significant heart disease, uncontrolled infections, or bleeding disorders.

Inclusion Criteria

Patients or their legally authorized representative must provide written informed consent

Prothrombin time (PT)/international normalization ratio (INR) < 1.5 x ULN

Partial thromboplastin time (PTT) < 1.5 x ULN

Exclusion Criteria

I haven't had major treatments or experimental therapy for my condition in the last 3 to 6 weeks.

Concurrent use of investigational therapeutic agent

I need treatment with a strong medication that affects liver enzymes.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Patients receive obinutuzumab, fludarabine phosphate, cyclophosphamide, and ibrutinib over 3 cycles to achieve complete remission or CR with incomplete marrow recovery and bone marrow MRD negativity

12 weeks

Multiple visits for IV administration and monitoring

Maintenance

Patients receive maintenance therapy with obinutuzumab and ibrutinib based on disease status, with up to 12 cycles

Up to 48 weeks

Monthly visits for IV administration and monitoring

Follow-up

Participants are monitored for safety, progression-free survival, and overall survival

Up to 6 years

Treatment Details

Interventions

• Cyclophosphamide
• Fludarabine Phosphate
• Ibrutinib
• Obinutuzumab

Trial Overview The study tests a combination of the drug ibrutinib with chemotherapy drugs fludarabine phosphate and cyclophosphamide plus the monoclonal antibody obinutuzumab. The goal is to see if this mix can better stop cancer cells from growing compared to current treatments by using both targeted therapy and immune system activation.

Participant Groups

Group I: Treatment (iFCG) Experimental Treatment 4 Interventions

See Detailed Description.

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

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Findings from Research

Ibrutinib is a targeted therapy specifically designed for treating chronic lymphocytic leukemia (CLL), which is a type of cancer that affects the blood and bone marrow.

This novel treatment works by inhibiting Bruton's tyrosine kinase (BTK), a key enzyme that helps cancer cells survive and proliferate, leading to improved patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib (imbruvica): a novel targeted therapy for chronic lymphocytic leukemia. Parmar, S., Patel, K., Pinilla-Ibarz, J.[2021]

Chronic lymphocytic leukemia (CLL) treatment varies based on patient age and fitness, with younger patients typically receiving the FCR regimen and older, fit patients being treated with BR or bendamustine plus ofatumumab.

New oral medications like idelalisib and ibrutinib have shown impressive efficacy and tolerability in patients with high-risk genetic factors or relapsed CLL, indicating a shift in treatment strategies towards these novel agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Chronic lymphocytic leukemia: current standards and novel approaches]. Tausch, E., Stilgenbauer, S.[2018]

The combination therapy of obinutuzumab and ibrutinib, following a debulking phase with bendamustine, resulted in a 100% overall response rate in 61 patients with chronic lymphocytic leukemia (CLL), demonstrating its high efficacy.

The treatment was generally safe, with the most common severe side effects being neutropenia (14.8%) and thrombocytopenia (13.1%), and only one reported fatality, indicating a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CLL2-BIG: sequential treatment with bendamustine, ibrutinib and obinutuzumab (GA101) in chronic lymphocytic leukemia. von Tresckow, J., Cramer, P., Bahlo, J., et al.[2022]

Obinutuzumab combined with chlorambucil shows better treatment outcomes for patients with untreated chronic lymphocytic leukemia compared to rituximab plus chlorambucil, while maintaining a similar safety profile.

Infusion-related reactions (IRRs) are more common with obinutuzumab, particularly during the first infusion, but these reactions are generally manageable with proper monitoring and management strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Managing Infusion-Related Reactions for Patients With Chronic Lymphocytic Leukemia Receiving Obinutuzumab. Dawson, K., Moran, M., Guindon, K., et al.[2017]

In the phase III GALLIUM trial involving 1202 patients with previously untreated follicular lymphoma, obinutuzumab-based immunochemotherapy significantly improved progression-free survival (PFS) compared to rituximab-based therapy, with 7-year PFS rates of 63.4% versus 55.7%.

While both treatments had similar overall survival rates (88.5% for obinutuzumab vs. 87.2% for rituximab), serious adverse events were reported in about 49% of patients receiving obinutuzumab and 43% for rituximab, indicating comparable safety profiles without new safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obinutuzumab Versus Rituximab Immunochemotherapy in Previously Untreated iNHL: Final Results From the GALLIUM Study. Townsend, W., Hiddemann, W., Buske, C., et al.[2023]

Bruton's tyrosine kinase inhibitor (ibrutinib) and phosphatidylinositol 3-kinase inhibitor (idelalisib) are effective and well-tolerated treatment options for chronic lymphocytic leukemia, especially in older patients who may struggle with traditional chemotherapy side effects.

While these B cell receptor inhibitors are promising, they come with specific side effects: ibrutinib can increase the risk of bleeding and atrial fibrillation, while idelalisib may cause transaminitis, diarrhea, and pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

B cell receptor inhibition as a target for CLL therapy. Jeyakumar, D., O'Brien, S.[2021]

Obinutuzumab (Gazyva) is an effective treatment for chronic lymphocytic leukemia, targeting specific cancer cells to improve patient outcomes.

Ibrutinib (Imbruvica) is used for mantle-cell lymphoma and works by inhibiting a protein that helps cancer cells survive, while sofosbuvir (Sovaldi) effectively treats chronic hepatitis C by blocking the virus's ability to replicate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmaceutical approval update. Goldenberg, MM.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

CLL2-BXX Phase II trials: sequential, targeted treatment for eradication of minimal residual disease in chronic lymphocytic leukemia. [2018]

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

Ibrutinib (imbruvica): a novel targeted therapy for chronic lymphocytic leukemia. [2021]

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

Ibrutinib-Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia. [2023]

4. Germany pubmed.ncbi.nlm.nih.gov

[Chronic lymphocytic leukemia: current standards and novel approaches]. [2018]

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

CLL2-BIG: sequential treatment with bendamustine, ibrutinib and obinutuzumab (GA101) in chronic lymphocytic leukemia. [2022]

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

Managing Infusion-Related Reactions for Patients With Chronic Lymphocytic Leukemia Receiving Obinutuzumab. [2017]

7. Italy pubmed.ncbi.nlm.nih.gov

Safety of obinutuzumab alone or combined with chemotherapy for previously untreated or relapsed/refractory chronic lymphocytic leukemia in the phase IIIb GREEN study. [2019]

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

Obinutuzumab Versus Rituximab Immunochemotherapy in Previously Untreated iNHL: Final Results From the GALLIUM Study. [2023]

9. Netherlands pubmed.ncbi.nlm.nih.gov

B cell receptor inhibition as a target for CLL therapy. [2021]

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

Pharmaceutical approval update. [2021]

11. China pubmed.ncbi.nlm.nih.gov

[Efficacy of chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab for chronic lymphocytic leukemia]. [2015]