Vemurafenib + Obinutuzumab vs Cladribine + Rituximab for Hairy Cell Leukemia

Recruiting at 9 trial locations

Overseen By Mark Geyer, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Purine analogs, Vemurafenib

Disqualifiers: Liver disease, HIV, Active infection, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 16 weeks

86 Participants Needed

Trial Summary

What is the purpose of this trial?

The researchers are doing this study to compare the safety of vemurafenib in combination with obinutuzumab to the standard of approach of cladribine in combination with rituximab. The researchers will look at which treatment causes fewer or milder side effects. Researchers think vemurafenib and obinutuzumab (non-chemotherapy drugs) may cause fewer side effects compared with the usual approach of chemotherapy drugs. They will also compare the two approaches to see which approach is more effective at eliminating cancer cells.

Do I have to stop taking my current medications for the trial?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.

What data supports the effectiveness of the drugs Vemurafenib, Obinutuzumab, Cladribine, and Rituximab for treating Hairy Cell Leukemia?

Research shows that Cladribine combined with Rituximab has a very high response rate of up to 99% in treating Hairy Cell Leukemia. Additionally, Vemurafenib, a BRAF inhibitor, has shown an almost 100% response rate in patients with multiple relapses, making these drugs effective options for this condition. ^{1 2 3 4 5}

Is the combination of Vemurafenib and Rituximab safe for treating Hairy Cell Leukemia?

Vemurafenib combined with Rituximab has been used in patients with relapsed Hairy Cell Leukemia, showing some positive outcomes, but there are risks such as infection and multi-organ failure, as seen in one patient who died during treatment. ^{1 2 3 6 7}

What makes the drug combination of Vemurafenib and Obinutuzumab unique for treating hairy cell leukemia?

The combination of Vemurafenib and Obinutuzumab is unique for treating hairy cell leukemia because it targets the BRAF V600E mutation, which is commonly found in this type of leukemia, offering a novel approach compared to traditional treatments like cladribine and rituximab that do not specifically target this mutation. ^{2 3 8 9 10}

Research Team

Jae Park, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

This trial is for individuals with Hairy Cell Leukemia. Participants should not have had previous treatments for this condition and must be suitable candidates for the drug interventions being tested.

Inclusion Criteria

Electrocardiogram (ECG) without evidence of clinically significant ventricular arrhythmias or ischemia as determined by the investigator and a rate-corrected QT interval (QTc, Bazett's formula) of < 480 msec

My cancer has the BRAF V600E mutation.

I am 18 years old or older.

Exclusion Criteria

I am infected with HIV or HTLV-1.

I cannot take medications by mouth due to a digestive condition.

Known hypersensitivity to any of the study drugs

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive vemurafenib orally twice daily continuously in cycles of 4 weeks for a total of 4 cycles. Obinutuzumab is administered concomitantly starting at cycle 2.

16 weeks

Multiple visits for drug administration

Treatment

Participants receive cladribine IV on days 1-5 concurrently with rituximab IV weekly for 8 times from day 1.

8 weeks

Weekly visits for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment, including incidences of ≥ grade 3 treatment-related toxicities.

6 months

Long-term follow-up

Participants are monitored for complete and partial response, including morphological absence of hairy cells and normalization of organomegaly and cytopenias.

2 years

Treatment Details

Interventions

• Cladribine
• Obinutuzumab
• Rituximab
• Vemurafenib

Trial Overview The study compares two treatment approaches: Vemurafenib with Obinutuzumab versus Cladribine with Rituximab. The goal is to determine which combination has fewer side effects and is more effective in eliminating cancer cells.

Participant Groups

Group I: Vemurafenib plus Obinutuzumab Experimental Treatment 2 Interventions

Patients assigned to the study arm will receive vemurafenib orally twice daily (b.i.d.) continuously in cycles of 4 weeks (28 days) for a total of 4 cycles. Obinutuzumab will be administered concomitantly with vemurafenib starting at cycle 2 of treatment in cycles of 4 weeks. Obinutuzumab infusions will be administered on days 1, 8 and 15 during the cycle 2 and every 4 weeks during the cycle 3 and 4 of treatment.

Group II: Standard treatment of Cladribine plus Rituximab Active Control 2 Interventions

Patients assigned to the SOC arm will receive cladribine IV on days 1-5 concurrently with rituximab IV per week for 8 times, i.e., weekly x8 from day 1.

Obinutuzumab is already approved in United States, European Union for the following indications:

Approved in United States as Gazyva for:

• Chronic Lymphocytic Leukemia (CLL)
• Follicular Lymphoma

Approved in European Union as Gazyva for:

• Chronic Lymphocytic Leukemia (CLL)
• Follicular Lymphoma

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Findings from Research

Hairy cell leukemia (HCL) is effectively treated with purine analogs, but about half of patients relapse and may become resistant to these treatments, necessitating alternative therapies.

Targeting the BRAF-V600E mutation with specific inhibitors like vemurafenib or dabrafenib offers a promising chemotherapy-free strategy, especially for patients at risk of severe infections or those with relapsed HCL, and can be combined with rituximab for enhanced efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

How I treat refractory/relapsed hairy cell leukemia with BRAF inhibitors. Falini, B., De Carolis, L., Tiacci, E.[2022]

In a study of 123 patients with hairy cell leukemia (HCL) diagnosed between 1996 and 2016, cladribine as a first-line treatment resulted in a high hematological complete response rate of 92%, demonstrating its efficacy in managing this rare cancer.

The median overall survival for HCL patients was over 15 years, with 5-year and 10-year survival rates of 84% and 70.5%, indicating a favorable long-term prognosis, especially compared to other treatments like IFN-α which had a higher relapse rate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A population-based study of hairy cell leukemia over a period of 20 years. Wiber, M., Maitre, E., Poncet, JM., et al.[2021]

A meta-analysis of 21 studies involving various treatments for hairy cell leukemia found that cladribine combined with rituximab and vemurafenib achieved a remarkable response rate of 99%.

Cladribine with rituximab was identified as the most effective therapy, especially for treatment-naïve patients and those in their first relapse, with a complete response rate of 97%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Response to the Therapy in Hairy Cell Leukemia: Systematic Review and Meta-Analysis. Andrasiak, I., Rybka, J., Wrobel, T.[2019]

The discovery of the BRAF-V600E mutation in nearly all patients with hairy cell leukemia (HCL) provides a genetic basis for the disease and allows for a genetics-based differential diagnosis, distinguishing HCL from similar B-cell neoplasms.

Treatment with the BRAF inhibitor vemurafenib has shown an almost 100% response rate in patients with relapsed HCL, achieving complete remission in 35% to 42% of cases, and importantly, this treatment does not cause myelotoxicity, making it a promising therapeutic option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genomics of Hairy Cell Leukemia. Tiacci, E., Pettirossi, V., Schiavoni, G., et al.[2018]

In a study of 54 patients with hairy cell leukemia (HCL) treated at a Brazilian reference center, the median age at diagnosis was 55 years, and most patients (68%) were treated with cladribine, showing a 10-year overall survival rate of 91.1%.

The study found that platelet count and B2M levels at diagnosis were significantly associated with achieving complete remission, and there was a notable incidence of second neoplasms, particularly skin cancers, highlighting the need for ongoing monitoring in HCL patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes and second neoplasms in hairy cell leukemia: A retrospective cohort. da Silva, WF., Neto, AC., da Rosa, LI., et al.[2020]

Vemurafenib, an oral BRAF inhibitor, demonstrated a high overall response rate of 96% in an Italian study and 100% in a U.S. study for patients with relapsed or refractory hairy-cell leukemia, with treatment durations averaging 16 to 18 weeks.

The treatment was generally safe, with most adverse events being mild (grade 1 or 2), although some patients developed secondary cutaneous tumors, indicating the need for monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting Mutant BRAF in Relapsed or Refractory Hairy-Cell Leukemia. Tiacci, E., Park, JH., De Carolis, L., et al.[2022]

In a case study of four relapsed hairy cell leukemia patients, treatment with vemurafenib combined with rituximab led to significant responses, including two patients achieving minimal residual disease negative complete responses after prior therapies failed.

The use of vemurafenib and rituximab improved outcomes for heavily pretreated patients, suggesting that these targeted therapies can enhance the prognosis for those with relapsed hairy cell leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vemurafenib and Rituximab in Patients with Hairy Cell Leukemia Previously Treated with Moxetumomab Pasudotox. Robak, T., Janus, A., Jamroziak, K., et al.[2021]

Combining cladribine with concurrent rituximab significantly improves the rates of minimal residual disease-free complete remission (MRD-free CR) in hairy cell leukemia patients, with 97% achieving MRD-free CR compared to only 24% with cladribine alone after 6 months.

Delayed rituximab treatment after cladribine resulted in lower rates and durability of MRD-free CR, highlighting the importance of timing in treatment for better long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized Phase II Study of First-Line Cladribine With Concurrent or Delayed Rituximab in Patients With Hairy Cell Leukemia. Chihara, D., Arons, E., Stetler-Stevenson, M., et al.[2021]

In a study of 221 patients with hairy cell leukemia treated with subcutaneous cladribine, the long-term outcomes were excellent, with most patients achieving long-lasting remissions and a median overall survival that was not reached.

Although 23.7% of patients required second-line treatment after a median of 5 years, the incidence of second primary malignancies was not higher than in the general population, indicating that subcutaneous cladribine is a safe and effective treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prospective long-term follow-up after first-line subcutaneous cladribine in hairy cell leukemia: a SAKK trial. Benz, R., Arn, K., Andres, M., et al.[2022]

Cladribine is the preferred treatment for hairy cell leukemia (HCL) due to its high complete response rate of about 95% when given as a single 7-day intravenous infusion, along with a favorable toxicity profile.

Approximately 40% of patients with HCL may relapse after initial treatment, but they can be effectively re-treated with purine nucleoside analogs or rituximab, which also shows a reasonable response rate in relapsed cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

My treatment approach to hairy cell leukemia. Naik, RR., Saven, A.[2021]

References

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

How I treat refractory/relapsed hairy cell leukemia with BRAF inhibitors. [2022]

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

A population-based study of hairy cell leukemia over a period of 20 years. [2021]

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

Response to the Therapy in Hairy Cell Leukemia: Systematic Review and Meta-Analysis. [2019]

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

Genomics of Hairy Cell Leukemia. [2018]

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

Outcomes and second neoplasms in hairy cell leukemia: A retrospective cohort. [2020]

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

Targeting Mutant BRAF in Relapsed or Refractory Hairy-Cell Leukemia. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Vemurafenib and Rituximab in Patients with Hairy Cell Leukemia Previously Treated with Moxetumomab Pasudotox. [2021]

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

Randomized Phase II Study of First-Line Cladribine With Concurrent or Delayed Rituximab in Patients With Hairy Cell Leukemia. [2021]

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

Prospective long-term follow-up after first-line subcutaneous cladribine in hairy cell leukemia: a SAKK trial. [2022]

10. England pubmed.ncbi.nlm.nih.gov

My treatment approach to hairy cell leukemia. [2021]