Evaluation of Obinutuzumab, Vemurafenib, and Cobimetinib in Hairy Cell Leukemia Patients Refractory to Purine Analogues or Unfit for Chemotherapy
- Trial ID
- 2024-520121-36-00
- Protocol
- HCL-PG04
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to determine the depth of anti-leukemic activity of the study drugs **vemurafenib**, **cobimetinib**, and **obinutuzumab** in three distinct cohorts of eligible patients with **Hairy Cell Leukemia (HCL)** carrying the BRAF-V600E mutation. These patients will receive the study drugs in step-wise combinations across different phases and cohorts. This objective is clinically relevant as it aims to evaluate the potential of these drugs to effectively target and reduce leukemic cells in a specific patient population, potentially offering a new therapeutic approach for those who are refractory to or unfit for traditional chemotherapy.
Secondary objectives include:
- To assess the safety of the study drugs in each cohort, ensuring that the treatment is not only effective but also tolerable for patients.
- To determine the rapidity and duration of the anti-leukemic activity of the study drugs, providing insights into how quickly and for how long the drugs exert their effects.
- To evaluate the efficacy of further anti-leukemic treatments that patients might receive after those planned in the current study, which could inform future treatment strategies and improve patient outcomes.
Participants
The clinical trial involves participants diagnosed with **hairy cell leukemia** (HCL) who are 18 years of age or older. Both male and female subjects are included, and the study does not focus on a vulnerable population. The trial population was selected based on specific medical criteria, including the presence of the BRAF-V600E mutation and a clinical indication for treatment, such as low neutrophil or hemoglobin levels, or symptomatic splenomegaly. Participants must have completed any prior treatment at least 12 weeks before starting the study medication and must have recovered from any side effects of previous treatments. The study does not provide information on the total number of participants, as the sponsor has not disclosed this data. Lifestyle considerations such as diet or physical activity are not specified, but participants are required to use effective contraception during and after the trial if they are of childbearing potential. The selection criteria ensure that participants are medically fit for the study, with an ECOG performance status of 0-2, and without any psychological or geographical conditions that could affect compliance with the study protocol.
Plans and Procedures
The clinical trial is designed to evaluate the **anti-leukemic** activity of a combination of **vemurafenib**, **cobimetinib**, and **obinutuzumab** in patients with **hairy cell leukemia** (HCL) who have previously been treated with purine analogs or are unfit for chemotherapy. This is a Phase II, single-arm, non-randomized study. The trial will be conducted over an estimated duration from July 1, 2017, to August 31, 2046. The study involves three distinct cohorts of eligible HCL patients carrying the BRAF-V600E mutation, receiving the study drugs in step-wise combinations. The primary endpoint is to achieve a pre-determined rate of response, while secondary endpoints include the description of adverse events, time to response, and various survival metrics.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and previous treatment history. The inclusion criteria require patients to be 18 years or older, with a proven diagnosis of HCL and the presence of the BRAF-V600E mutation. Follow-up visits will be scheduled to monitor the response to treatment, assess adverse events, and ensure compliance with the study protocol. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted.
The expected length of participant involvement varies depending on the cohort and treatment response, with a maximum treatment period of 12 months for vemurafenib and cobimetinib, and 6 months for obinutuzumab. Conditions that may lead to early termination from the study include the occurrence of severe adverse events, withdrawal of consent, or non-compliance with the study protocol. Participants are required to use effective contraception during and after the study, and any psychological or geographical conditions that may hinder compliance should be addressed before trial entry.
Treatment
The clinical trial involves the administration of **Zelboraf** (vemurafenib) 240 mg film-coated tablets. Vemurafenib is a chemical compound administered orally. The maximum daily dose is 1920 mg, with a total maximum dose of 161280 mg over a treatment period of up to 12 months. The tablets are designed for oral consumption, and participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.
**Gazyvaro** (obinutuzumab) is provided as a 1,000 mg concentrate for solution for infusion. Obinutuzumab is a protein-based therapeutic administered intravenously. The maximum daily dose is 1000 mg, with a total maximum dose of 8000 mg over a treatment period of up to 6 months. Infusions are conducted under clinical supervision to monitor for any adverse reactions and to ensure proper administration.
**Cotellic** (cobimetinib) 20 mg film-coated tablets are also used in the trial. Cobimetinib is a chemical compound administered orally. The maximum daily dose is 60 mg, with a total maximum dose of 3780 mg over a treatment period of up to 12 months. As with Zelboraf, participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.
In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The trial focuses on the step-wise combination of the study drugs in patients with **hairy cell leukemia** carrying the BRAF-V600E mutation. The administration of these medications is carefully monitored to evaluate the depth of anti-leukemic activity in the specified patient cohorts.
Efficacy
Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is to achieve or surpass a pre-determined rate of response, which includes both complete and overall response rates, as per a per-protocol analysis. This trial is a phase-2, non-randomized study primarily designed to evaluate the anti-leukemic activity of the study drugs **vemurafenib**, **cobimetinib**, and **obinutuzumab** in patients with Hairy Cell Leukemia (HCL) carrying the BRAF-V600E mutation. The response rate will also be calculated according to the intention-to-treat analysis for informative purposes.
Secondary endpoints include the description of the type, incidence, grade, and relationship to the study drugs of adverse events occurring in each cohort. Additionally, the trial will separately describe in each cohort the time to response, relapse-free survival, treatment-free survival, progression-free survival, event-free survival, disease-specific survival, overall survival, and the specific type of, and response to, other anti-leukemic treatments. These parameters will be measured and analyzed to provide a comprehensive understanding of the efficacy and safety profile of the treatment regimen.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female HCL patients ≥ 18 years of age.
- Proven diagnosis of HCL according to the morphological and immunophenotypic criteria (co-expression of CD11c/CD25/CD103 and/or positivity for annexin-A1) of the World Health Organization (WHO-2008) classification of lymphoid neoplasms12, accompanied by the presence of the BRAF-V600E mutation as detected using a sensitive allele-specific polymerase chain reaction (AS-PCR) recently developed in our laboratory
- Patients with HCL must fall in one of the categories indicated in the “Overview” of study population.
- Any prior treatment (chemotherapy and/or immunotherapy) must have been completed at least 12 weeks prior to initiation of study medication, except if no response to this treatment is already manifestly evident earlier.
- ECOG performace status 0-2.
- Patients must have recovered from all side effects of their most recent treatment for HCL.
- 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 postmenopausal for ≥1 year.
- Fertile men and women must use an effective method of contraception during treatment and for at least 16 weeks (for men) and 12 months (for women) after completion of treatment as directed by their physician. Effective methods of contraception are defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly (for example implants, injectables, or intrauterine devices). Oral contraceptives are not reliable due to 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.
- Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before trial entry.
- Signed informed consent must be obtained prior to performing any study-related procedures.
- Clinical indication for treatment, i.e. the presence of one or more of the following: neutrophils <1.5x109 per liter, hemoglobin <11 g per deciliter, platelets <100x109 per liter, bulky and/or symptomatic splenomegaly, clinically relevant infiltration of other organs (e.g., lymphadenopathy), recurrent disease-related opportunistic infections.
Exclusion Criteria
- Concurrent administration of any anti-cancer therapies (e.g. chemotherapy, other targeted therapy, experimental drug, etc.) other than those administered in this study and concurrent treatment on another therapeutic clinical trial.
- Pregnant (negative serum pregnancy test is required in women of child-bearing potential) or lactating women.
- Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude adequate absorption. Patients must be able to swallow tablets.
- History of congenital long QT syndrome
- Corrected QT (QTc) interval ≥500 msec at baseline or uncorrectable electrolyte abnormalities.
- Active hepatitis infection.
- Uncontrolled medical illness.
- Other severe, acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, or which in the judgment of the investigator would make the patient inappropriate for entry into this study.
- Unwillingness to practice effective birth control.
- Inability to comply with other requirements of the protocol
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Not Recruiting | 01 Jul 2017 | 50 |
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 | 12 | PRD2154737 |
Gazyvaro 1,000 mg concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 1000 | 6 | PRD1753415 |
Cotellic 20 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 60 | 12 | PRD3439656 |