Ibrutinib + FCR for Chronic Lymphocytic Leukemia

(iFCR Trial)

Recruiting at 8 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Dana-Farber Cancer Institute

Must not be taking: Immunosuppressants, Live vaccines, Warfarin, others

Disqualifiers: Other malignancies, HIV, Hepatitis, 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: 6

Duration: 24 weeks

85 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does exclude those on certain immunosuppressants, warfarin, or strong CYP3A inhibitors or inducers. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

What data supports the effectiveness of the drug combination Ibrutinib + FCR for treating Chronic Lymphocytic Leukemia?

Research shows that combining ibrutinib with fludarabine, cyclophosphamide, and rituximab (FCR) can lead to durable responses in younger, fit patients with chronic lymphocytic leukemia. In a study, all patients treated with ibrutinib-FCR achieved complete responses, suggesting that ibrutinib may enhance the effectiveness of this combination without adding significant side effects. ^{1 2 3 4 5}

Is the combination of Ibrutinib with FCR safe for treating chronic lymphocytic leukemia?

The combination of Ibrutinib with chemoimmunotherapy (including FCR) has been studied for safety in patients with chronic lymphocytic leukemia. The studies show that Ibrutinib may enhance the effectiveness of treatment without adding extra harmful effects, and the safety profile is consistent with what is already known about these drugs. However, some serious side effects like infections and heart issues have been reported with Ibrutinib. ^{2 3 6 7 8}

What makes the drug combination of Ibrutinib + FCR unique for treating Chronic Lymphocytic Leukemia?

The combination of Ibrutinib with FCR (Fludarabine, Cyclophosphamide, and Rituximab) is unique because Ibrutinib, an oral drug that targets a specific protein involved in cancer cell growth, is added to the standard FCR regimen to potentially enhance its effectiveness without increasing toxicity. This approach aims to provide durable responses in patients, especially those who may not respond well to FCR alone. ^{1 2 3 5 9}

What is the purpose of this trial?

This research study is evaluating a new drug called ibrutinib in combination with the standard drugs fludarabine, cyclophosphamide, and rituximab (FCR) as a possible treatment for Chronic Lymphocytic Leukemia (CLL).

Research Team

Matthew S. Davids

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

Adults aged 18-65 with confirmed chronic lymphocytic leukemia or small lymphocytic lymphoma who need treatment based on specific criteria like worsening anemia, significant weight loss, fatigue, fevers without infection, and night sweats. They should not have had previous CLL therapy and must be able to perform daily activities (ECOG ≤1). Adequate blood counts and liver/renal function are required. Participants must use effective contraception.

Inclusion Criteria

I am too tired to work or do my usual activities.

My liver and kidney functions are within normal ranges.

Bilirubin ≤ 1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin)

Exclusion Criteria

I have not received any live vaccines in the last 4 weeks.

I am not on warfarin or vitamin K antagonists for blood thinning.

I am on preventive antibiotics with no active infection and my medication is not prohibited.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ibrutinib in combination with fludarabine, cyclophosphamide, and rituximab (FCR) for up to 6 cycles

24 weeks

6 cycles (28 days each)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including bone marrow biopsies and PET CT scans

2 months

Bone marrow biopsy and PET CT scan

Ibrutinib Maintenance

Participants continue with ibrutinib maintenance therapy to assess long-term response

24 months

Long-term Follow-up

Participants are monitored for progression-free survival and overall survival

63.24 months (median follow-up)

Treatment Details

Interventions

• Cyclophosphamide
• Fludarabine
• Ibrutinib
• Rituximab

Trial Overview The trial is testing a new drug combination for treating Chronic Lymphocytic Leukemia (CLL). It involves adding the drug Ibrutinib to the standard FCR regimen (Fludarabine, Cyclophosphamide, Rituximab) to see if it improves outcomes in younger patients who haven't been treated before.

Participant Groups

Group I: Ibrutinib Experimental Treatment 4 Interventions

- Ibrutinib- * Oral, daily during each cycle * fludarabine-administered at standard dosing for up to 6 cycles * cyclophosphamide-administered at standard dosing for up to 6 cycles * rituximab-administered at standard dosing for up to 6 cycles

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?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

Pharmacyclics LLC.

Industry Sponsor

Trials

114

Recruited

13,800+

Dr. Maky Zanganeh

Pharmacyclics LLC.

Chief Executive Officer

Degree from Louis Pasteur University in Strasbourg, France; MBA from Schiller International University in France

Dr. Ellie Im

Pharmacyclics LLC.

Chief Medical Officer

MD from an unspecified institution

The Leukemia and Lymphoma Society

Collaborator

Trials

87

Recruited

26,200+

Blood Cancer Research Partnership

Collaborator

Trials

5

Recruited

230+

Findings from Research

In a phase 1b study involving patients with relapsed/refractory chronic lymphocytic leukemia, the combination of ibrutinib with bendamustine and rituximab (BR) showed a high overall response rate of 93.3%, with significant improvements in complete responses over time.

The study demonstrated that ibrutinib can enhance the efficacy of chemoimmunotherapy without adding prolonged hematologic toxicity, suggesting a promising treatment strategy for patients with this type of leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia. Brown, JR., Barrientos, JC., Barr, PM., et al.[2021]

In the phase 3 HELIOS trial involving 578 patients with previously treated chronic lymphocytic leukemia (CLL), the combination of ibrutinib and bendamustine-rituximab (BR) significantly improved progression-free survival (PFS) compared to placebo+BR, with a median PFS not reached for ibrutinib+BR versus 14.3 months for placebo+BR.

The treatment with ibrutinib+BR also resulted in a higher rate of minimal residual disease (MRD)-negative responses (26.3% vs. 6.2% for placebo+BR), indicating a deeper response to therapy, while the safety profile remained consistent with earlier reports.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updated results from the phase 3 HELIOS study of ibrutinib, bendamustine, and rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma. Fraser, G., Cramer, P., Demirkan, F., et al.[2023]

In the HELIOS trial involving 578 subjects, the combination of bendamustine/rituximab and ibrutinib (BR-I) resulted in significantly higher systemic exposure to rituximab compared to bendamustine/rituximab with placebo (BR), particularly in the initial treatment cycles.

The study found no significant safety differences between the BR-I and BR groups, suggesting that the enhanced efficacy of BR-I may be achieved without compromising patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic Exposure of Rituximab Increased by Ibrutinib: Pharmacokinetic Results and Modeling Based on the HELIOS Trial. Lavezzi, SM., de Jong, J., Neyens, M., et al.[2021]

References

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

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

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

Long-term outcomes for ibrutinib-rituximab and chemoimmunotherapy in CLL: updated results of the E1912 trial. [2023]

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

The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia. [2021]

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

Updated results from the phase 3 HELIOS study of ibrutinib, bendamustine, and rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma. [2023]

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

Ibrutinib plus fludarabine, cyclophosphamide, and rituximab as initial treatment for younger patients with chronic lymphocytic leukaemia: a single-arm, multicentre, phase 2 trial. [2021]

6. France pubmed.ncbi.nlm.nih.gov

Ibrutinib (Imbruvica). Relapsed chronic lymphocytic leukaemia and mantle cell lymphoma: uncertain impact on survival. [2021]

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

Systemic Exposure of Rituximab Increased by Ibrutinib: Pharmacokinetic Results and Modeling Based on the HELIOS Trial. [2021]

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

Phase 3 SELENE study: ibrutinib plus BR/R-CHOP in previously treated patients with follicular or marginal zone lymphoma. [2023]

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

Chemoimmunotherapy with low-dose fludarabine and cyclophosphamide and high dose rituximab in previously untreated patients with chronic lymphocytic leukemia. [2015]