Evaluation of Ruxolitinib Versus Best Available Therapy in High-Risk Polycythemia Vera and Essential Thrombocythemia Patients

Trial ID: 2024-515619-23-00
Protocol: 12-181
Sponsor: Universitaetsklinikum Aachen AöR

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Diseases & Conditions

Polycythaemia vera Essential thrombocythaemia

Objectives

The primary objective of the Ruxo-BEAT trial is to evaluate the **feasibility**, safety, and efficacy of administering **ruxolitinib** compared to the best available therapy in patients diagnosed with high-risk **polycythemia vera** or high-risk **essential thrombocythemia**. This assessment is clinically significant as it aims to determine the potential benefits and risks associated with ruxolitinib, a JAK1 and JAK2 inhibitor, in managing these high-risk hematological conditions. The trial seeks to provide insights into optimizing treatment strategies for these patients, potentially improving clinical outcomes and quality of life.

Participants

The clinical trial involves participants diagnosed with **essential thrombocythemia** or **polycythemia vera**, specifically those classified as high-risk according to established criteria. The study population includes both male and female subjects aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, indicating they are ambulatory and capable of self-care. Participants must have adequate liver and renal function, as well as the ability to swallow and retain oral medication. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Selection criteria emphasize the inclusion of individuals who have not been extensively treated with cytoreductive drugs, except for specific exceptions, and who meet the World Health Organization's 2008 diagnostic criteria for the conditions under study. Lifestyle factors such as diet and physical activity are not specified as part of the selection process.

Plans and Procedures

The clinical trial is designed to evaluate the **feasibility**, safety, and efficacy of **ruxolitinib** compared to the best available therapy in patients with high-risk **polycythemia vera** or high-risk **essential thrombocythemia**. This is a randomized, double-blind, controlled trial, categorized as a Phase 4 study. The trial is expected to run from November 2, 2015, to December 31, 2027, with a maximum treatment period of 145 days for each participant. Participants will be randomly assigned to receive either ruxolitinib or the best available therapy, with the primary endpoint being the rate of complete clinicohematologic responses at month 6.

The study involves several key visits, starting with an inclusion (screening) visit where eligibility criteria are assessed. Participants must provide written informed consent and meet specific inclusion criteria, such as being 18 years or older, having an ECOG performance status of 0-2, and fulfilling the WHO 2008 diagnostic criteria for either polycythemia vera or essential thrombocythemia. Follow-up visits will occur at regular intervals to monitor safety and efficacy, with assessments including clinicohematologic responses and spleen size reduction. The end-of-study visit will conclude the participant's involvement, summarizing the overall outcomes and any adverse events experienced.

Participant involvement is expected to last up to 145 days, with conditions for early termination including non-compliance with study procedures, withdrawal of consent, or adverse events that compromise safety. Secondary endpoints include safety assessments, the rate of complete clinicohematologic responses at months 12 and 24, and the efficacy of treatment as measured by the absence of phlebotomy and reduction in spleen size. The trial aims to provide comprehensive data on the comparative effectiveness of ruxolitinib in managing high-risk polycythemia vera and essential thrombocythemia.

Treatment

The clinical trial involves the administration of **ruxolitinib**, marketed under the name Jakavi, in two different dosages: 20 mg and 5 mg tablets. The pharmaceutical form of both medications is a tablet, and they are intended for **oral use**. The active substance, ruxolitinib, is a **JAK1 and JAK2 inhibitor** of chemical origin. The 20 mg tablets have a maximum daily dose of 40 mg, while the 5 mg tablets have a maximum daily dose of 50 mg. The maximum total dose for both formulations is 50 mg. The treatment period for both dosages is up to 145 days. The medication is manufactured by Novartis Europharm Limited and is authorized for use in the European Union.

In addition to the experimental treatment with ruxolitinib, the study includes a comparator treatment referred to as "best available therapy" for patients with high-risk polycythemia vera or high-risk essential thrombocythemia. This comparator treatment serves as the standard-of-care therapy against which the efficacy and safety of ruxolitinib are assessed. The trial aims to evaluate the feasibility, safety, and efficacy of ruxolitinib compared to this standard treatment. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the prescribed regimen.

Efficacy

The efficacy of the Ruxo-BEAT trial will be assessed through several primary and secondary endpoints. The primary endpoint is the rate of complete clinicohematologic responses (CHR) at month 6, compared to baseline, as defined by Barosi et al., 2009. Secondary endpoints include the safety of both regimens, the rate of CHR at month 12 and month 24, and the complete response (CR) rate at month 6 as defined by Barosi et al., 2013. Additionally, efficacy will be evaluated by the absence of phlebotomy (hematocrit <45%) and reduction in spleen size (palpable spleen reduced by >50% from baseline) or platelet count <600 x 10^9/l (for essential thrombocythemia) at month 6 and month 24. The proportion of subjects achieving both durable absence of phlebotomy eligibility and durable spleen size reduction or durable platelet count <600 x 10^9/l will also be measured at month 6, month 12, and month 24. The rate of overall clinicohematologic responses (CR + PR) according to both guidelines (Barosi et al. 2009 and 2013) will be assessed at month 6 and month 24.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Subjects must provide written informed consent prior to study-specific procedures or assessments which are not routinely performed for diagnosis or monitoring of PV or ET, and the subjects must be willing to comply with treatment and to follow up assessments and procedures
Patient must be 18 years of age or older
Patient´s ECOG performance status must be 0-2
Patient must fulfill WHO 2008 diagnostic criteria for either polycythemia vera (PV) or essential thrombocythemia (ET). Moreover, PV- and ET-patients have to be classified as high risk according to defined criteria as outlined below. - For patients with high risk PV OR PV with indication for cytoreductive therapy due to progressive myeloproliferation, AT LEAST ONE of the following must be fulfilled (according to DGHO onkopedia) (Barbui, et al., 2011), (Passamonti, 2009): Age > 60 years; Previous documented thrombosis or thromboembolism; Platelet count > 1500 x 10^9/l; Poor tolerance of phlebotomy or frequent phlebotomy requirement; Symptomatic or progressive splenomegaly; Severe disease-related symptoms (according to the investigators definition); Progressive leukocytosis with leukocyte count > 20 x 10^9/l. - For patients with high risk ET, AT LEAST ONE of the following must be fulfilled (according to DGHO guidelines): Age > 60 years; Platelet count > 1500 x 10^9/l; Previous thrombosis or thromboembolism; Previous severe hemorrhage related to ET (defined as decrease of Hgb of at least 2 g/dl)
Patients must fulfill the following criteria regarding prior therapy: PV patients: Never treated with cytoreductive drugs except hydroxyurea, anagrelide, or interferon for up to 6 weeks maximum (phlebotomy and/or aspirin are allowed). ET patients: Naïve and pretreated patients may be entered in this trial.
Patient must have adequate liver function as indicated by a total bilirubin, AST, and ALT ≤ 2 of the institutional upper limit of normal (ULN) value, unless directly attributable to the patient’s MPN.
Patient must have a creatinine clearance >40ml/min calculated according to the modified formula of Cockcroft and Gault, eGFR, or directly measured after 24h-urine collection.
Patient must be able to swallow and retain oral medication

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Exclusion Criteria

Patients who meet criteria for post PV-MF or post ET-MF (IWG-MRT).
Patients who have received previous ruxolitinib treatment
Patients who have a history of anaphylaxis following exposure to the BAT drug of choice.
Patients who have an inadequate bone marrow reserve as demonstrated by ANC ≤ 1 x 10^9/l OR platelet count <50 x 10^9/l.
Patients who have known hepatitis B or C or HIV infection.
Patients who suffer from other severe, concurrent diseases, including tuberculosis, serious cardiac functional dysfunction (class III or IV as defined by the New York Heart Association Classification), uncontrolled diabetes, uncontrolled hypertension, severe pulmonary disease (i.e. COPD with hypoxemia), or major organ malfunction that could interfere with the patient’s ability to participate in the study.
Patients who have history of active substance or alcohol abuse within the last year.
Female patients who are pregnant or nursing.
Patients who have participated in another interventional trial and/or used investigational agents or concurrent anticancer treatment for concomitant disease within the last 4 weeks of registration.
Any circumstance at the time of study entry that would preclude completion of the study or the required follow-up prohibits inclusion into this study.
Subjects who have had an active malignancy during the previous 3 years except for treated cervical intraepithelial neoplasia, basal cell carcinoma of the skin, or squamous cell carcinoma of the skin, each with no evidence for recurrence in the past 3 years.
Patients who have uncontrolled bacterial, viral, or fungal infection.
Patients who have any medical condition requiring prolonged use of oral corticosteroids with a dose of more than 20 mg per day (> 1 month).
Patients who have severe cerebral dysfunction and/or legal incapacity.
Patients who have had active splanchnic vein thrombosis within the last 3 months (includes Budd-Chiari, portal vein, splenic and mesenteric thrombosis).
Patients who have thyroid dysfunction which is not adequately controlled.
Fertile men or women of childbearing potential cannot be included unless they are: -surgically sterile or > 2 years after the onset of menopause and/or -willing to use a highly effective contraceptive method (Pearl Index <1) such as oral contraceptives, intrauterine device, sexual abstinence, or barrier method of contraception (i.e. condoms) in conjunction with spermicidal jelly during study treatment.
Patients who are taking any of the following prohibited medication: -clarithromycin, telithromycin, troleandomycin (antibiotics) -ritonavir, indinavir, saquinavir, nelfinavir, amprenavir, lopinavir (HIV protease inhibitors) -itraconazole, ketoconazole, voriconazole, fluconazole (antifungals).
Patients with a diagnosis of galactose or lactose intolerance or a glucosegalactose- malabsorption.