The Ruxo-BEAT Trial in Patients With High-risk Polycythemia Vera or High-risk Essential Thrombocythemia
Sleutelwoorden
Abstract
Omschrijving
Polycythemia vera (PV) and essential thrombocythemia (ET) are classical Philadelphia-negative myeloproliferative neoplasms (MPN) that are characterized by an excess of cells in the peripheral blood, clonal bone marrow hyperplasia, and extramedullary hematopoiesis. The symptoms of these patients may range from asymptomatic disease to symptomatic disease that may significantly affect their activities of daily living, such as severe generalized pruritus, night sweats and fevers, erythromelalgia, bone and muscle pain, weight loss, and fatigue. Moreover, the patients may develop thromboembolic and hemorrhagic complications, transition to myelofibrosis (MF), and transformation to acute leukemia. In principle, the only potentially curative therapy for MPNs is allogenic stem cell transplantation (allo-SCT). However, due to significant transplant-associated morbidity and mortality, this therapeutic option is only applied in exceptional cases of ET or PV. The majority of patients do not qualify for allo-SCT since the risks of this treatment clearly outweigh the potential benefits. Moreover, even with a non-transplantation approach, patients with ET and PV have a life expectancy comparable to or close to healthy age-matched control persons. For patients with standard risk PV, phlebotomy and acetylsalicylic acid are standard of care (target hematocrit below 45 %), while patients with standard risk ET should receive either no specific treatment or acetylsalicylic acid (provided that no microvascular symptoms or secondary acquired von Willebrand syndrome are present).
However, in patients who are at high risk to develop thromboembolic or hemorrhagic complications (high-risk patients), cytoreductive treatment is generally indicated to prevent these potentially life-threatening complications. In PV and ET, high risk patients are characterized by advanced age (> 60 years) and / or a history of thromboembolic or hemorrhagic events {1,2,3}. In ET, a platelet count > 1500 x 109/l is associated with an increased risk of bleeding, and thus should result in a platelet lowering treatment {2}. In PV, in addition to the risk-score based therapy, cytoreduction is also required in patients with progressive or marked myeloproliferation (leukocytosis, thrombocytosis, symptomatic splenomegaly, increase of frequency of phlebotomy requirement), or devastating constitutional symptoms {1,2,4}. In Germany, best available therapy (BAT) includes approved drugs such as hydroxyurea (HU; approved for both PV and ET) and anagrelide (approved for second-line treatment of ET) and non-approved options such as alpha-interferon, pipobroman, busulfan (in elderly patients), and radioactive phosphorus (32P). In rare cases, patients may also benefit from splenic irradiation or splenectomy.
Ruxolitinib is a JAK1/2-specific tyrosine kinase inhibitor (TKI) which has been approved for the treatment of symptomatic myelofibrosis. The compound was shown to be superior to hydroxyurea in reducing splenomegaly and constitutional symptoms. Ruxolitinib is currently studied in phase 2 and phase 3 clinical trials for HU-resistant or HU-intolerant PV and ET. The aim of the present study is to assess the feasibility, efficacy, and safety of ruxolitinib treatment vs. BAT in patients with high-risk PV or -ET.
Datums
| Laatst geverifieerd: | 06/30/2020 |
| Eerste ingediend: | 09/30/2015 |
| Geschatte inschrijving ingediend: | 10/13/2015 |
| Eerst geplaatst: | 10/15/2015 |
| Laatste update ingediend: | 07/14/2020 |
| Laatste update geplaatst: | 07/15/2020 |
| Werkelijke startdatum van het onderzoek: | 09/30/2015 |
| Geschatte primaire voltooiingsdatum: | 11/30/2022 |
| Geschatte voltooiingsdatum van het onderzoek: | 11/30/2027 |
Conditie of ziekte
Interventie / behandeling
Drug: Ruxolitinib
Drug: Best available therapy (BAT)
Fase
Armgroepen
| Arm | Interventie / behandeling |
|---|---|
| Experimental: Ruxolitinib Ruxolitinib will be administered orally at a dose of 10 mg twice daily (both PV and ET) for two consecutive years. | Drug: Ruxolitinib Ruxolitinib is a JAK1/2-specific tyrosine kinase inhibitor (TKI) which has been approved for the treatment of symptomatic myelofibrosis. The compound was shown to be superior to hydroxyurea in reducing splenomegaly and constitutional symptoms. |
| Active Comparator: Best available therapy (BAT) BAT may include all currently used treatment options. BAT is at the choice of the investigator (monotherapy with i.e. hydroxyurea, anagrelide, interferon, busulfan, immunomodulators etc). BAT will be administrated for two consecutive years. | Drug: Best available therapy (BAT) BAT is at the choice of the investigator (monotherapy with i.e. hydroxyurea, anagrelide, interferon, busulfan, immunomodulators etc). |
Geschiktheidscriteria
| Leeftijden die in aanmerking komen voor studie | 18 Years Naar 18 Years |
| Geslachten die in aanmerking komen voor studie | All |
| Accepteert gezonde vrijwilligers | Ja |
| Criteria | Inclusion Criteria: 1. written informed consent and willing to comply with treatment and to follow up assessments and procedures 2. >18 years old 3. Patient´s ECOG performance status: 0-2 4. Patient must fulfill WHO 2008 diagnostic criteria for either PV or ET. PV- and ET-patients have to be classified as high risk according to defined criteria. 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: - 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 - 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: - Age > 60 years - Platelet count> 1500 x 10^9/L - Previous thrombosis or thromboembolism - Previous severe hemorrhage related to ET. 5. Patients must fulfill the following criteria regarding prior therapy: PV patients: Never treated with cytoreductive drugs except short- term therapy (up to 6 weeks maximum) with ONE of the following drugs: hydroxyurea, anagrelide, or interferon (phlebotomy and/or aspirin are allowed) ET patients: Naïve and pretreated patients may be entered in this trial 7. adequate liver function, AST, and ALT ≤ 2 the institutional ULN value, unless directly attributable to the patient's MPN 8. creatinine clearance >40ml/min calculated according to the modified formula of Cockcroft and Gault, eGFR, or directly measured after 24h-urine collection 9. ability to swallow and retain oral medication Exclusion Criteria: 1. criteria for post PV-MF or post ET-MF are met 2. previous ruxolitinib treatment 3. history of anaphylaxis following exposure to the BAT drug of choice 4. inadequate bone marrow reserve as demonstrated by ANC ≤ 1 x 10^9/l OR platelet count <50 x 10^9/l 5. known hepatitis B or C or HIV infection 6. other severe, concurrent diseases, including tuberculosis, serious cardiac functional dysfunction (class III or IV), uncontrolled diabetes, uncontrolled hypertension, severe pulmonary disease, or major organ malfunction 7. history of active substance or alcohol abuse within the last year 8. Female patients who are pregnant or nursing 9. participation in another interventional trial and/or used investigational agents or concurrent anticancer treatment for concomitant disease within the last 4 weeks of registration 10. Any circumstances at the time the study entry that would preclude completion of the study or the required follow-up prohibits inclusion into this study 11. 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 12. active bacterial, viral, or fungal infection 13. medical condition requiring prolonged use of oral corticosteroids with a dose of more than 20 mg per day (> 1 month) 14. severe cerebral dysfunction and/or legal incapacity 15. history of active splanchnic vein thrombosis within the last 3 months (includes Budd-Chiari, portal vein, splenic and mesenteric thrombosis) 16. thyroid dysfunction which is not adequately controlled 17. 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) 18. patients who are taking any of the following prohibited medication: clarithromycin, telithromycin, troleandomycin, ritonavir, indinavir, saquinavir, nelfinavir, amprenavir, lopinavir -itraconazole, ketoconazole, voriconazole, fluconazole 19. Patients who suffer from galactose intolerance, lack of lactose or a glucose-galactose-malabsortion |
Resultaat
Primaire uitkomstmaten
1. The rate of complete clinicohematologic response rate (CHR) as defined by Barosi et al Blood 2009 [at month 6]
Secundaire uitkomstmaten
1. Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [at month 6 and 12]
2. The complete response rate (CR) at month 6 as defined by Barosi et al Blood 2013 (revised ELN response criteria) [month 6]
3. The rate of complete responses (CHR) at month 12 as defined by Barosi et al Blood 2009 [month 12]
4. The efficacy as assessed by the absence of phlebotomy (Hct <45%) [through study completion, an average of 2 years]
5. The efficacy as assessed by the reduction in spleen size (palpable spleen that is reduced by > 50% from baseline measured by palpation and ultrasound) OR platelet count < 600 x 10^9/l (ET) [through study completion, an average of 2 years]
6. Proportion of subjects achieving both durable absence of phlebotomy eligibility AND durable spleen volume reduction measured by palpation and ultrasound (PV) OR durable platelet count <600 x 10^9/l (ET) (durable defined as >3 months) {Barosi et al 2013) [through study completion, an average of 2 years]
7. The rate of overall clinicohematologic remissions (CR + PR) according to both guidelines (Barosi et al 2009 and 2013) [through study completion, an average of 2 years]
