Phase 2 Randomized Multicenter Trial of Vemurafenib and Rituximab Versus Cladribine in Treatment-Naïve Hairy Cell Leukemia Patients
- Trial ID
- 2024-520119-41-00
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this phase-2 randomized multicenter trial is to demonstrate that the experimental therapy combining **vemurafenib** and **rituximab** (VR) is no less effective and less toxic than the standard therapy of **cladribine** monotherapy (CDA) in previously untreated patients with a diagnosis of **hairy cell leukemia** (HCL). This is clinically relevant as it aims to provide a chemotherapy-free alternative that could potentially reduce treatment-related toxicities while maintaining efficacy.
Secondary objectives include:
- Time from starting treatment until resolution of cytopenias.
- Time from starting treatment until recovery of CD4+ T cells, CD8+ T cells, B cells, and NK cells to normal values.
- Proportion of patients in the control arm achieving complete remission (CR) with sequential rituximab among those not achieving CR after CDA monotherapy.
- Proportion of patients clearing measurable/minimal residual disease (MRD).
- Survival free from MRD, relapse, disease progression, subsequent anti-leukemic treatment, and death.
- Treatment-related toxicities and adverse events of any grade.
- Role of PET-CT in HCL staging and response to therapy.
- Quality of life assessments.
- Pharmaco-economic analysis of global treatment costs.
- Prospective evaluation of the efficacy and safety of any alternative treatment strategy in patients enrolled but not randomized due to concerns.
Participants
The clinical trial involves **previously untreated patients with a diagnosis of Hairy Cell Leukemia (HCL)**. The study population includes both male and female participants aged 18 years and older. Participants are required to have good renal and hepatic function, as well as an ECOG Performance Status of 0-2. The trial does not specify the total number of participants, as this information was not provided by the sponsor. The selection criteria emphasize the need for treatment, such as low neutrophil or hemoglobin levels, or symptomatic splenomegaly. Participants must not have any medical, psychological, or other conditions that could interfere with compliance or interpretation of the study results. Lifestyle considerations include the ability to swallow tablets and the use of highly effective contraception methods during and after treatment. The trial population was selected based on these criteria, ensuring that participants are suitable for the study's objectives.
Plans and Procedures
The clinical trial is designed as a **randomized**, **controlled**, and **double-blind** study to evaluate the efficacy and safety of a chemotherapy-free regimen in patients with previously untreated **hairy cell leukemia** (HCL). The trial aims to compare the experimental therapy, consisting of **vemurafenib** plus **rituximab**, against the standard therapy of **cladribine** monotherapy. The primary objective is to demonstrate that the experimental therapy is no less effective and less toxic than the standard treatment. The trial is expected to last until June 30, 2065, with recruitment having commenced on January 15, 2023.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a centrally reviewed diagnosis of HCL, adequate renal and hepatic function, and the absence of uncontrolled infections. Following randomization, participants will receive their assigned treatment and attend regular follow-up visits to monitor treatment response and safety. The primary efficacy endpoint is the rate of complete remission at approximately six months post-treatment initiation, while the primary safety endpoint is the incidence of drug-related toxicities of grade 3 or higher within the same timeframe.
The expected duration of participant involvement is contingent upon the treatment arm and individual response, with the maximum treatment period for cladribine being five days and for vemurafenib and rituximab up to 16 weeks. Conditions that may lead to early termination from the study include the development of severe adverse events, non-compliance with study procedures, or withdrawal of consent. The end-of-study visit will assess long-term outcomes such as survival free from minimal residual disease, relapse, and disease progression, as well as overall survival and quality of life.
Treatment
The clinical trial involves the administration of several treatments, including both experimental and standard therapies. **Cladribine**, marketed as LITAK 2 mg/ml solution for injection, is utilized as a standard therapy. It is a **solution for injection** administered via **subcutaneous injection**. The dosage is calculated at a maximum of 0.14 mg/kg per day, with a total treatment period not exceeding 5 days. This medication is chemically derived and is not formulated for pediatric use.
**Rituximab** is used in two formulations within the trial: MabThera 100 mg and MabThera 500 mg concentrates for solution for infusion. Both formulations are administered **intravenously**. The maximum daily dose for rituximab is 375 mg/m², with a treatment period extending up to 16 weeks. Rituximab is a protein-based therapeutic agent and is not intended for pediatric patients. The trial employs rituximab as part of the experimental therapy, in combination with vemurafenib, to evaluate its efficacy as a chemotherapy-free alternative in the treatment of **hairy cell leukemia**.
**Vemurafenib**, marketed as Zelboraf 240 mg film-coated tablets, is administered **orally**. The maximum daily dose is 1920 mg, with a total treatment period of up to 8 weeks. Vemurafenib is a chemically synthesized compound and is not designed for pediatric use. It is used in combination with rituximab in the experimental arm of the trial to assess its effectiveness and safety compared to the standard cladribine monotherapy.
Throughout the trial, participant compliance with the dosing schedules is monitored to ensure adherence to the treatment protocols. The trial aims to demonstrate that the combination of vemurafenib and rituximab is no less effective and less toxic than the standard cladribine therapy in the treatment of hairy cell leukemia.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the rate of complete remission (CR) at approximately 6 months after treatment initiation. This primary efficacy endpoint will be evaluated in randomized patients, with the adjudication of the primary endpoint being centrally performed by an external independent committee that is unaware of treatment assignments. The trial involves comparing the experimental therapy, a combination of **vemurafenib** and **rituximab** (VR), against the standard therapy, which is monotherapy with **cladribine** (CDA), in patients with front-line **hairy cell leukemia** (HCL).
Secondary efficacy endpoints include the time from starting treatment until the resolution of cytopenias, the proportion of patients clearing measurable/minimal residual disease (MRD) by PCR, flow cytometry, or immunohistochemistry in bone marrow and blood cell samples, and by PCR in plasma. Additional secondary endpoints involve survival metrics such as survival free from MRD, relapse, disease progression, subsequent anti-leukemic treatment, and death. The recovery time of CD4+ T cells, CD8+ T cells, B cells, and NK cells to normal values will also be measured. Furthermore, the role of PET-CT in HCL staging and response to therapy, quality of life through an ad hoc questionnaire, and a pharmaco-economic analysis of global treatment costs will be evaluated.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Previously untreated patients with centrally reviewed diagnosis of HCL
- Need of treatment, i.e. at least one of the following: neuthrophils <1x109 per liter, hemoglobin <10 g per deciliter, platelets <100x109 per liter, bulky/symptomatic splenomegaly, clinically relevant infiltration of other organs (e.g., lymphadenopathy), disease-related opportunistic infections or autoimmune disorders.
- ECOG Performance Status of 0-2.
- Male or female HCL patients > =18 years of age.
- Negative serum pregnancy test within 14 days prior to commencement of dosing in premenopausal women. Women of non-childbearing potential may be included if they are either surgically sterile or have been post-menopausal (i.e., with an intact uterus, but with no mestrual bleeding for >=1 year in the absence of hormonal contraception).
- Women of childbearing potential and men must use highly effective contraception methods during treatment, as well as for at least 6 months after treatment with cladribine or vemurafenib and at least 12 months after treatment with rituximab, including: intra-uterine devices or systems, hormonal implants or tube ligation for women; and vasectomy or condom for men. Oral contraceptives are not highly effective, also in light of potential drug-drug interaction. At the discretion of the investigator, acceptable methods of contraception may include total abstinence in cases where the lifestyle of the patient ensures compliance [Periodic abstinence (e.g. calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception]. Patients undergoing cladribine treatment should be counseled for fertilty preservation before cladribine treatment because of possible infertility due to cladribine therapy.
- No medical, psychological, familial, sociological or geographical condition which may hamper compliance with the study protocol and follow-up schedule, or interfere with the interpretation of study results or would anyway make the patient inappropriate for enrollment in this study.
- Signed informed consent (prior to performing any study-related procedures). After enrollment in the study, patients must also fulfill the following additional specific inclusion criteria for randomization to CDA+sR or VR:
- BRAF-V600E mutation centrally confirmed.
- No nausea, vomiting, malabsorption, external biliary shunt, significant bowel resection, or neurological disorder that would preclude adequate absorption. Patients must be able to swallow tablets.
- No (suspected or documented) active uncontrolled serious infection, as defined by the presence of: i) febrile neutropenia (a single temperature of >38.3°C or a sustained temperature of =38°C for >1 hour) in a neutropenic patient (<1000 neutrophils x 109/L without G-CSF support), which has not resolved within =7 days from its onset despite anti-microbial therapy; and/or ii) a radiologically or clinically documented focus of infection (e.g., abscess, pneumonia, cellulitis, etc.) that has not been resolved by medical or surgical therapy.
- Good renal function, as defined by creatinine clearance >50 ml/min.
- Good hepatic function, as defined by a Child-Pugh score =6 (online calculator available for example at https://www.mdcalc.com/calc/340/child-pugh-score-cirrhosismortality), noting that abnormalities of each component of this score (e.g., bilirubin or INR) must be attributed to hepatic insufficiency and not to other causes (e.g., Gilbert syndrome or treatment with anti-coagulant drugs, respectively; in this case the abnormality unrelated to hepatic impairment is given the lowest score).
- QTc interval < = 500 ms.
Exclusion Criteria
- 1.Concurrent administration of other any anti-cancer therapies. Prior splenectomy for diagnosis and/or therapy of HCL is not allowed.
- Pregnancy or lactation.
- Other active advanced cancer with projected life expectancy <1 year.
- Cytopenias do not represent exclusion criteria as they are caused by HCL.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Recruiting | 15 Jan 2023 | 120 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Zelboraf 240 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 1920 | 8 | PRD2154737 |
MabThera 100 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 375 | 16 | PRD2154041 |
MabThera 500 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 375 | 16 | PRD398759 |
LITAK 2 mg/ml solution for injection | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS INJECTION | 0.14 | 5 | PRD718230 |