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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of drugs to evaluate their effectiveness in treating chronic lymphocytic leukemia (CLL), a type of blood cancer. The treatment includes ibrutinib, which blocks cancer cell growth; chemotherapy drugs like cyclophosphamide and fludarabine phosphate, which kill or inhibit cancer cells; and an immunotherapy drug called obinutuzumab, which enhances the immune system to fight cancer. The trial seeks participants with CLL who have not yet received treatment. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

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.

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

A previous study showed that ibrutinib was well-tolerated by patients with chronic lymphocytic leukemia (CLL), even those with higher-risk mutations. It has been used for over five years in more than 1,200 patients, with an average treatment duration of about four years. Common side effects include diarrhea, tiredness, and nausea, but these are usually not severe.

Research has shown that obinutuzumab can cause reactions during or soon after infusion and can lower white blood cell counts, increasing the risk of infections. The most common serious side effect is neutropenia, a low level of a type of white blood cell, occurring in about 50% of patients.

Cyclophosphamide is known to lower white blood cell counts, also raising the risk of infections. It is a commonly used chemotherapy drug, and its side effects are generally well-understood.

Fludarabine phosphate is another chemotherapy drug that can lower blood cell counts, leading to infections. Infections with unusual organisms have been reported in up to 67% of treated patients.

Overall, the safety profiles of these treatments are well-documented. While there are risks, these treatments have been widely used and are considered manageable with proper monitoring. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination therapy for Chronic Lymphocytic Leukemia (CLL) because it integrates multiple powerful agents—Cyclophosphamide, Fludarabine Phosphate, Ibrutinib, and Obinutuzumab—to tackle the disease from different angles. Unlike standard treatments which often rely on a single mechanism, this approach combines a chemotherapy backbone with targeted therapies like Ibrutinib, a Bruton's tyrosine kinase inhibitor, and Obinutuzumab, a monoclonal antibody. This combination aims to enhance the overall effectiveness by potentially reducing resistance and improving patient outcomes, offering new hope for those with CLL.

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

Research has shown that ibrutinib is highly effective in treating chronic lymphocytic leukemia (CLL). In one study, 96.8% of patients responded to ibrutinib, with 40.7% achieving complete remission, meaning their cancer was no longer detectable. Obinutuzumab has also proven successful, helping patients live longer without disease progression compared to other treatments. The combination of fludarabine and cyclophosphamide has benefited over 80% of CLL patients. This trial will evaluate the combination of these treatments, potentially offering a robust strategy against CLL by targeting cancer cells in different ways. ^{6 7 8 9 10}

Who Is on the Research Team?

Nitin Jain, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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 have a bleeding disorder like von Willebrand's disease or hemophilia.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

Citations

1.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/11230486/

Results of the fludarabine and cyclophosphamide ...

Results: Fludarabine and cyclophosphamide produced > or = 80% response rates in all patients not refractory to fludarabine at the start of therapy as well as a ...

2.

ashpublications.org

ashpublications.org/blood/article/112/4/975/25335/Long-term-results-of-the-fludarabine

Long-term results of the fludarabine, cyclophosphamide, and ...

The addition of rituximab to fludarabine and cyclophosphamide (FC) doubled the complete remission rate and remission duration of FC to 72% and ...

3.

pagepress.org

pagepress.org/journals/hmr/article/view/581/675

final results of Chronic Lymphocytic Leukemia 8 Study

7-8In order to validate this concept,Cyclophosphamide in chronic lymphocytic leukemia first line: final results of ChronicLymphocytic Leukemia 8 StudyM.

4.

annalsofoncology.org

annalsofoncology.org/article/S0923-7534(19)41246-5/fulltext

IX. Chronic lymphocytic leukemia for the clinician

FCR was more frequently associated with grade 3 and 4 neutropenia [136 (34%) of 404 compared with 83 (21%) of 396; P < 0.0001] and leukocytopenia [97 (24%) ...

5.

nature.com

nature.com/articles/s41408-022-00756-9

Chronic lymphocytic leukemia treatment algorithm 2022

In the most recent analysis with up to 74 months follow-up, the median PFS and OS were 44months and 68 months, respectively, with ibrutinib and ...

6.

accessdata.fda.gov

accessdata.fda.gov/drugsatfda_docs/label/2023/210852s000lbl.pdf

Cyclophosphamide Injection - accessdata.fda.gov

Data. Human Data. Malformations of the skeleton, palate, limbs and eyes as well as miscarriage have been reported after exposure to cyclophosphamide in the ...

7.

drugs.com

drugs.com/sfx/cyclophosphamide-side-effects.html

Cyclophosphamide Side Effects: Common, Severe, Long ...

Cyclophosphamide can temporarily lower the number of white blood cells in your blood, increasing the chance of getting an infection. It can also ...

8.

go.drugbank.com

go.drugbank.com/drugs/DB00531

Cyclophosphamide: Uses, Interactions, Mechanism of Action

Cyclophosphamide is a nitrogen mustard used to treat lymphomas, myelomas, leukemia, mycosis fungoides, neuroblastoma, ovarian adenocarcinoma, retinoblastoma ...

9.

pubchem.ncbi.nlm.nih.gov

pubchem.ncbi.nlm.nih.gov/compound/Cyclophosphamide

Cyclophosphamide | C7H15Cl2N2O2P | CID 2907 - PubChem

Cyclophosphamide (Hydrated) can cause cancer according to California Labor Code. It can cause developmental toxicity according to an independent committee ...

10.

accessdata.fda.gov

accessdata.fda.gov/drugsatfda_docs/label/2019/203856s003lbl.pdf

cyclophosphamide capsules - accessdata.fda.gov

Dosages should be adjusted based on evidence of antitumor activity, myelosuppression, or other severe adverse reactions [see WARNINGS and PRECAUTIONS. (5)].