Vemurafenib + Obinutuzumab for Hairy Cell Leukemia

Recruiting at 10 trial locations

Overseen By Jae Park, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Purine analogs, Rituximab

Disqualifiers: Liver disease, Uncontrolled infections, HIV, 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: 2

Duration: 16 weeks

30 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you are taking medications that could interact with vemurafenib or obinutuzumab, you may need to discuss this with the trial team.

What data supports the effectiveness of the drug Vemurafenib for treating Hairy Cell Leukemia?

Research shows that Vemurafenib, a BRAF inhibitor, is highly effective for patients with Hairy Cell Leukemia who have relapsed after other treatments, achieving almost a 100% response rate and complete remission rates of 35% to 42%. ^{1 2 3 4 5}

Is the combination of Vemurafenib and Obinutuzumab safe for humans?

Obinutuzumab, used in various treatments, has shown a generally manageable safety profile in humans, with common side effects including mild to moderate infusion-related reactions and neutropenia (low white blood cell count). Serious side effects can occur, but they are typically manageable with proper medical care. ^{6 7 8 9 10}

How is 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 with Vemurafenib, an oral BRAF inhibitor, and combines it with Obinutuzumab, a monoclonal antibody that enhances the immune system's ability to attack cancer cells. This dual approach may offer a novel treatment option for patients who have relapsed or are refractory to standard therapies. ^{1 5 11 12 13}

What is the purpose of this trial?

This is a multi-center, open label, single arm, phase II trial of the oral BRAF inhibitor, vemurafenib, plus obinutuzumab in patients with previously untreated HCL. A Simon mini-max two-stage design will be employed to assess the efficacy of the combination treatment of vemurafenib and obinutuzumab. In the first stage of the protocol, 9 patients will be treated. If fewer than 6 CRs are seen among the first 9 patients, the study will be closed for lack of efficacy. If at least 7 patients respond to the treatment, then an additional 19 patients will be accrued to the second stage, for a total of 28 patients. Eligible patients will receive vemurafenib at a dose of 960mg 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 at 1000mg per day on days 1, 8 and 15 during the cycle 2 and 1000mg per day every 4 weeks during the cycle 3 and 4 of treatment. After the completion of the treatment (i.e. after 4 cycles), a bone marrow aspirate and biopsy will be performed for assessment of response and evaluation of minimal residual disease (MRD). In case of certain defined toxicities, dose reductions of vemurafenib by 50% (480mg b.i.d.) or interruptions of up to 15 days are permitted. If additional dose reduction is required, vemurafenib may be reduced to 240mg oral b.i.d.

Research Team

Jae Park, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

Adults with previously untreated classical Hairy Cell Leukemia who meet specific blood count criteria and are in good physical condition. They must have normal organ function, agree to use contraception, and not be pregnant. Excluded are those with hepatitis B or C, HIV, other cancers needing treatment that could interact with the trial drugs, uncontrolled infections, or a history of liver disease.

Inclusion Criteria

My organs are functioning well according to recent tests.

Patients who meet the standard treatment initiation criteria, as defined by ANC </=1.0, Hgb </=10.0 or PLT </=100K

Total bilirubin </= 1.5 times the upper limit of normal (ULN)

Exclusion Criteria

I have been diagnosed with HIV or HTLV-1.

You have severe allergies to any of the study drugs.

Patients with uncorrectable electrolyte abnormalities with potassium (K) >ULN (upper limit of normal).

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive vemurafenib and obinutuzumab over 4 cycles of 4 weeks each

16 weeks

Cycle 2: 3 visits (in-person), Cycles 3-4: 1 visit per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including bone marrow aspirate and biopsy

4 weeks

Treatment Details

Interventions

• Obinutuzumab
• Vemurafenib

Trial Overview The trial is testing an oral drug called Vemurafenib combined with Obinutuzumab infusions against Hairy Cell Leukemia. Initially, 9 patients will receive this combination to see if it's effective; if successful, another 19 will join. The treatment spans over four cycles (16 weeks), followed by bone marrow tests for response evaluation.

Participant Groups

Group I: Untreated Hairy Cell Leukemia Experimental Treatment 2 Interventions

Participants with HCL with no prior treatment for the disease

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+

Dana-Farber Cancer Institute

Collaborator

Trials

1,128

Recruited

382,000+

Yale University

Collaborator

Trials

1,963

Recruited

3,046,000+

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]

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 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]

Moxetumomab pasudotox is an FDA-approved treatment for relapsed or refractory hairy cell leukemia, based on a pivotal phase III study demonstrating its efficacy in this rare cancer.

The treatment targets the CD22 protein on B-cells, and while it can lead to durable remission, practitioners should be aware of common adverse effects and management strategies as its use becomes more widespread.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Moxetumomab pasudotox: A first-in-class treatment for hairy cell leukemia. Fancher, KM., Lally-Montgomery, ZC.[2019]

Obinutuzumab, combined with bendamustine, significantly prolonged progression-free survival (PFS) in patients with indolent non-Hodgkin's lymphoma, particularly benefiting those with follicular lymphoma, as shown in the phase III GADOLIN study.

The treatment was generally well-tolerated, with mild to moderate infusion-related reactions being the most common side effects, while neutropenia was the most frequent severe adverse event, indicating a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obinutuzumab: A Review in Rituximab-Refractory or -Relapsed Follicular Lymphoma. Dhillon, S.[2018]

In a multinational phase III study, obinutuzumab combined with chlorambucil significantly improved progression-free survival and event-free survival in adults with previously untreated chronic lymphocytic leukaemia (CLL) compared to chlorambucil alone and rituximab plus chlorambucil.

Obinutuzumab plus chlorambucil had a manageable safety profile, with neutropenia and infusion-related reactions being the most common serious side effects, primarily occurring during the first infusion and generally manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obinutuzumab: a review of its use in patients with chronic lymphocytic leukaemia. Hoy, SM.[2018]

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 is an effective treatment for B-cell malignancies, specifically approved in the US for chronic lymphocytic leukaemia (CLL) in combination with chlorambucil, showcasing its efficacy in targeting cancer cells.

Utilizing GlycoMAb® technology, obinutuzumab enhances immune-mediated cell death through increased antibody-dependent cellular cytotoxicity, making it a promising option in ongoing phase III trials for various B-cell lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obinutuzumab: first global approval. Cameron, F., McCormack, PL.[2021]

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]

References

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

Phase 2 study of ibrutinib in classic and variant hairy cell leukemia. [2023]

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

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

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

Genomics of Hairy Cell Leukemia. [2018]

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

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

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

Moxetumomab pasudotox: A first-in-class treatment for hairy cell leukemia. [2019]

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

Obinutuzumab: A Review in Rituximab-Refractory or -Relapsed Follicular Lymphoma. [2018]

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

Obinutuzumab: a review of its use in patients with chronic lymphocytic leukaemia. [2018]

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

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

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

Obinutuzumab: first global approval. [2021]

10. 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]

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

Long-term outcomes in patients with relapsed or refractory hairy cell leukemia treated with vemurafenib monotherapy. [2023]

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

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

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

Vemurafenib plus Rituximab in Refractory or Relapsed Hairy-Cell Leukemia. [2021]