Vemurafenib + Obinutuzumab vs Cladribine + Rituximab for Hairy Cell Leukemia
Recruiting in Palo Alto (17 mi)
+9 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Memorial Sloan Kettering Cancer Center
Must not be taking: Purine analogs, Vemurafenib
Disqualifiers: Liver disease, HIV, Active infection, others
No Placebo Group
Prior Safety Data
Breakthrough Therapy
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.12345
Is the combination of Vemurafenib and Rituximab safe for treating Hairy Cell Leukemia?
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.238910
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.
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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
See 10 more
Trial 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 (Nucleoside Analog)
- Obinutuzumab (Monoclonal Antibodies)
- Rituximab (Monoclonal Antibodies)
- Vemurafenib (Kinase Inhibitor)
Trial OverviewThe 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
2Treatment groups
Experimental Treatment
Active Control
Group I: Vemurafenib plus ObinutuzumabExperimental Treatment2 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 RituximabActive Control2 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Memorial Sloan Kettering Monmouth (Limited Protocol Activities)Middletown, NJ
Memorial Sloan Kettering Bergen (Limited Protocol Activities)Montvale, NJ
Memorial Sloan Kettering Cancer Commack - Suffolk (Limited Protocol Activities)Commack, NY
Memorial Sloan Kettering Nassau (Limited Protocol Activities)Uniondale, NY
More Trial Locations
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Who Is Running the Clinical Trial?
Memorial Sloan Kettering Cancer CenterLead Sponsor
Genentech, Inc.Industry Sponsor
References
How I treat refractory/relapsed hairy cell leukemia with BRAF inhibitors. [2022]Hairy cell leukemia (HCL) responds very well to frontline chemotherapy with purine analogs (cladribine and pentostatine). However, approximately half of patients experience 1 or more relapses, which become progressively resistant to these myelotoxic and immunosuppressive agents. At progression, standard therapeutic options include a second course of purine analogs alone or in combination with rituximab and, upon second relapse, therapy with the anti-CD22 immunotoxin moxetumomab pasudotox. Furthermore, blockade of the mutant BRAF-V600E kinase (the pathogenetic hallmark of HCL) through orally available specific inhibitors (vemurafenib or dabrafenib) effaces the peculiar morphologic, phenotypic, and molecular identity of this disease and its typical antiapoptotic behavior and is emerging as an attractive chemotherapy-free strategy in various clinical scenarios. These include patients with, or at risk of, severe infections and, in a highly effective combination with rituximab, patients with relapsed or refractory HCL. Other treatments explored in clinical trials are BTK inhibition with ibrutinib and co-inhibition of BRAF (through dabrafenib or vemurafenib) and its downstream target MEK (through trametinib or cobimetinib). Here, we focus on our experience with BRAF inhibitors in clinical trials and as off-label use in routine practice by presenting 3 challenging clinical cases to illustrate their management in the context of all available treatment options.
A population-based study of hairy cell leukemia over a period of 20 years. [2021]There are limited population-based studies of hairy cell leukemia (HCL), a rare chronic lymphoproliferative disorder of B-cells. We conducted a population-based study that included all patients diagnosed with HCL between 1996 and 2016 in Western Normandy. Recorded data focused on medical history, clinical presentation, biological results, treatment modalities in the first line and in relapsed/refractory patients and the occurrence of secondary malignancies. One hundred and twenty-three HCL patients were registered in the database. HCL represented 0.7% of all malignant hematological disorders and 3.0% of all leukemia. The overall age-standardized incidence ratio (SIR) was 0.39/100,000 inhabitants in men and 0.09/100,000 in women, and it remained stable over the 20-year period analyzed. One hundred and seven patients (88%) received first-line treatment, 33 patients (27%) received at least 2 lines of treatment and 14 patients (11%) received more than 2 lines. Cladribine used as first-line treatment induced a high hematological complete response (HCR) rate of 92%. The median overall survival (OS) was over 15 years, with 5-year and 10-year survival rates of 84% and 70.5%. No significant differences in OS were observed between men and women, between the calendar periods studied or between patients who received a single line treatment with IFN-α or PNA. The risk of relapse was higher with IFN-α treatment, requiring subsequent treatments in that patients. The time to next treatment (TTN) tends to be longer for PNAs compared to IFN-α even if difference is not significant. Secondary cancers were observed in 9/123 patients (7.3%) with solid tumors in 8 patients and hematological malignancy in one patient. Our data confirm in real life that single courses of cladribine administered to patients with HCL induce high response rates, the majority of which are HCR. Relapses seem less frequent than with IFN-α and the administration schedule is less restrictive for the patients. The emergence of chemo-immunotherapy and the development of effective new drugs such as recombinant immunotoxins and BRAF targeting will offer new possibilities in the management of HCL patients.
Response to the Therapy in Hairy Cell Leukemia: Systematic Review and Meta-Analysis. [2019]Hairy cell leukemia is an uncommon chronic B-cell lymphoproliferative disorder. Various treatment options are available. The objective of the study was to evaluate through meta-analysis the pooled proportions of patients responding to each therapeutic agent. We conducted a systematic review and meta-analysis to estimate the pooled response rate to modern hairy cell leukemia therapies. Articles published between January 1992 and August 2017 were identified by searching PubMed, Web of Science, and the Cochrane Library. Weighted meta-analysis of proportion using a random-effects model was performed for each treatment option. Of 3287 articles viewed, 20 articles describing 21 studies were included in the meta-analysis. The pooled random effect of the response rate was up to 99% in both cladribine with rituximab at 0.99 (95% confidence interval [CI], 0.98-1.0) and vemurafenib treatment at 0.99 (95% CI, 0.95-1.0). The pooled random effect of the complete response rate was up to 97% (0.97; 95% CI, 0.88-1.0) in cladribine followed by rituximab. The most effective therapy in patients treatment naïve and in first relapse was cladribine with rituximab maintenance.
Genomics of Hairy Cell Leukemia. [2018]Hairy cell leukemia (HCL) is a chronic mature B-cell neoplasm with unique clinicopathologic features and an initial exquisite sensitivity to chemotherapy with purine analogs; however, the disease relapses, often repeatedly. The enigmatic pathogenesis of HCL was recently clarified by the discovery of its underlying genetic cause, the BRAF-V600E kinase-activating mutation, which is somatically and clonally present in almost all patients through the entire disease spectrum and clinical course. By aberrantly activating the RAF-MEK-ERK signaling pathway, BRAF-V600E shapes key biologic features of HCL, including its specific expression signature, hairy morphology, and antiapoptotic behavior. Accompanying mutations of the KLF2 transcription factor or the CDKN1B/p27 cell cycle inhibitor are recurrent in 16% of patients with HCL and likely cooperate with BRAF-V600E in HCL pathogenesis. Conversely, BRAF-V600E is absent in other B-cell neoplasms, including mimickers of HCL that require different treatments (eg, HCL-variant and splenic marginal zone lymphoma). Thus, testing for BRAF-V600E allows for a genetics-based differential diagnosis between HCL and HCL-like tumors, even noninvasively in routine blood samples. BRAF-V600E also represents a new therapeutic target. Patients' leukemic cells exposed ex vivo to BRAF inhibitors are spoiled of their HCL identity and then undergo apoptosis. In clinical trials of patients with HCL who have experienced multiple relapses after purine analogs or who are refractory to purine analogs, a short course of the oral BRAF inhibitor vemurafenib produced an almost 100% response rate, including complete remission rates of 35% to 42%, without myelotoxicity. To further improve on these results, it will be important to clarify the mechanisms of incomplete leukemic cell eradication by vemurafenib and to explore chemotherapy-free combinations of a BRAF inhibitor with other targeted agents (eg, a MEK inhibitor and/or an anti-CD20 monoclonal antibody).
Outcomes and second neoplasms in hairy cell leukemia: A retrospective cohort. [2020]Hairy cell leukemia (HCL) is a rare chronic B-cell lymphoproliferative disease which is treated on the basis of small studies, making the literature still scarce of reports, especially of those conducted in Latin America. Here we intend to describe clinical characteristics, rates of response, survival and second neoplasms in HCL patients treated in a reference center in Brazil. All patients diagnosed with HCL between July/1987 and Jun/2018 were included in this analysis. Fifty-four patients were included in this analysis. Median age at diagnosis was 55 years (range, 26-88), with 37% being above 60 years-old. Most patients were treated with cladribine in our cohort (n = 36; 68%), administered through intravenous continuous infusion. Remaining patients were firstly managed with splenectomy (n = 7; 13%), IFN (n = 6; 11%) and rituximab (n = 2; 4%). In a univariate analysis, platelet count and B2M level at diagnosis were statistically associated with CR achievement (p = 0.004 and p = 0.024, respectively). A median follow-up time of 9 years was calculated. Estimated 10-year overall survival was 91.1% (95% confidence interval, 77-97). In this cohort, 10 patients had any second neoplasm, diagnosed before or after HCL. Regarding the sites of cancer, 69% were of skin - 8/16 carcinoma-type and 3/16 melanoma-type. Our response and survival data are similar to those reported by literature, which reaffirms the role of purine analogs in current HCL management. With a very long follow-up we also have observed a high incidence of second neoplasm.
Targeting Mutant BRAF in Relapsed or Refractory Hairy-Cell Leukemia. [2022]BRAF V600E is the genetic lesion underlying hairy-cell leukemia. We assessed the safety and activity of the oral BRAF inhibitor vemurafenib in patients with hairy-cell leukemia that had relapsed after treatment with a purine analogue or who had disease that was refractory to purine analogues.
Vemurafenib and Rituximab in Patients with Hairy Cell Leukemia Previously Treated with Moxetumomab Pasudotox. [2021]The purine nucleoside analogues cladribine and pentostatin are highly-active first-line therapeutic treatments for hairy cell leukemia (HCL), resulting in complete response rates of 80% to 90%. However, HCL patients continue to relapse, and sooner or later, most require subsequent lines of treatment. This report presents the cases of four relapsed patients with classic HCL who were treated with vemurafenib (mostly at the low dose of 240 mg twice daily for 16 weeks) combined with rituximab after the failure of several lines of therapy including cladribine with or without rituximab and moxetumomab pasudotox. Two patients achieved minimal residual disease negative complete response after combined treatment with vemurafenib and rituximab, with a hematologic response ongoing after 38 months from the end of treatment in one patient and a relapse of cytopenias occurring after 13 months in the other patient. A third patient normalized her blood counts and this hematologic response, which was not evaluated in the bone marrow at the end of treatment, was lost after 18 months. The last patient died due to infection and multi-organ failure, too early to verify response to vemurafenib. Two patients who had relapsed after vemurafenib and rituximab derived meaningful clinical benefit from retreatment with the same agents, but eventually relapsed again and started indefinite therapy with dabrafenib and trametinib leading to normalization of the blood counts (despite heavy bone marrow infiltration in the only patient so far evaluable in that regard). The outcomes of these cases indicate that novel targeted agents and, in particular, vemurafenib, combined with rituximab, improve the prognosis of HCL patients, even those heavily pretreated with PNAs and moxetumomab pasudotox.
Randomized Phase II Study of First-Line Cladribine With Concurrent or Delayed Rituximab in Patients With Hairy Cell Leukemia. [2021]Single-agent purine analog, usually cladribine, has been the standard first-line therapy of hairy cell leukemia (HCL) for 30 years. High complete remission (CR) rates often include minimal residual disease (MRD), leading to relapse and repeated treatments. Rituximab can clear MRD, but long-term results are unknown and optimal timing of rituximab undefined.
Prospective long-term follow-up after first-line subcutaneous cladribine in hairy cell leukemia: a SAKK trial. [2022]Hairy cell leukemia (HCL) remains an incurable disease. However, first-line treatment with either intravenous or subcutaneous cladribine generally leads to long-lasting remissions. Although there are excellent long-term data for intravenous application, similar data regarding subcutaneous administration are lacking. We therefore analyzed the long-term outcome of 3 prospective multicenter clinical trials on subcutaneous cladribine performed by the Swiss Group for Clinical Cancer Research (SAKK), which recruited 221 patients with classical HCL between 1993 and 2005. Median overall survival from start of treatment was not reached. Pretreatment anemia, higher Eastern Cooperative Oncology Group score, and higher age were associated with poorer overall survival in multivariable analysis, whereas early progression at 24 and 36 months had no significant impact on overall survival. Second-line treatment was necessary in 53 (23.7%) patients after a median of 5 (range, 0.2-20.4) years, and first retreatment was mainly monotherapy with cladribine (66%) or rituximab (15.1%) or a combination of these drugs (15.1%). A total of 44 (19.9%) patients developed second primary malignancies with a median time to occurrence of 5.7 (range, 0.01-17.5) years. Second primary malignancies were the main cause for death (14; 27.5%). Compared with a matched normal Swiss population, the incidence of second primary malignancies was not increased. However, survival of patients with HCL was slightly inferior by comparison (P = .036). In conclusion, the outcome of HCL patients treated with subcutaneous cladribine is excellent, and in most patients, 1 cycle of subcutaneous cladribine is sufficient for long-term disease control.
My treatment approach to hairy cell leukemia. [2021]Hairy cell leukemia (HCL) is a rare chronic lymphoproliferative disorder characterized by circulating B cells with cytoplasmic projections, pancytopenia, splenomegaly, and a typical flow cytometry pattern. Recently, the BRAF V600E mutation was uniformly identified in one HCL series, which may provide insights into the pathogenic mechanisms. The disease course is usually indolent but inexorably progressive. Patients require treatment when they have significant cytopenia or occasionally recurrent infections from immunocompromise. In the mid-1980s, interferon replaced splenectomy as the initial treatment. A few years later, 2 purine nucleoside analogs, cladribine and pentostatin, showed promising activity in HCL. Complete response rates approached 95% with cladribine given as a single 7-day intravenous infusion. Newer methods of cladribine administration and modified dosing schedules have since been studied. Pentostatin response rates are comparable. We generally prefer cladribine because of its ease of administration, single infusion schema, and favorable toxicity profile. Since the introduction of these drugs, which have never been randomly compared, long-term follow-up studies have confirmed impressive and durable response durations. However, roughly 40% of patients with HCL eventually relapse. In this setting, patients can be re-treated with purine analogs. Rituximab also has a reasonable response rate in relapsed HCL; it can be given as a single agent sequentially after purine nucleosides or concurrently. Immunotoxins have robust responses but remain in development. Targeting the BRAF pathway will be an exciting future area of research. Many patients have minimal residual disease after initial treatment, but the clinical significance of this remains unknown.