Clinical trial NCT06514807: A Study to Evaluate the Efficacy and Safety of Ropeginterferon Alfa-2b in Essential Thrombocythaemia Patients
Official title: A Phase III, Single Arm, Multicentre Study to Evaluate the Efficacy and Safety of Ropeginterferon Alfa-2b in Essential Thrombocythaemia Patients Who Are Intolerant or Refractory to or Not Eligible for Other Cytoreductive Treatments
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Essential Thrombocythaemia
Keywords: Ropeginterferon alfa-2b
essential thrombocythaemia
intolerant to cytoreductive treatment
refractory to cytoreductive treatment
not eligible for other cytoreductive treatments
JAK2
CALR
MPL mutation status
BESREMi
Thrombocythaemia
Lead sponsor: AOP Orphan Pharmaceuticals AG
Sponsor class: INDUSTRY
First posted: 2024-07-23
Enrollment: 117
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Open-label, single-arm, multicentre, descriptive study of ropeginterferon alfa-2b in essential thrombocythaemia patients
Primary purpose: TREATMENT

Brief summary: The primary objective of this study is to assess the efficacy of ropeginterferon alfa-2b in patients with ET who need cytoreductive treatment but are intolerant or refractory to, and/or ineligible for cytoreductive treatments approved and available for the treatment of ET (i.e., HU, ANA, BUS, and PB, when they are available and approved for ET treatment).

Ropeginterferon alfa-2b is currently the only interferon authorised as a cytoreductive treatment of a myeloproliferative neoplasm (MPN), and the long-term treatment data from its comprehensive clinical development program show its efficacy in the induction of haematologic remission, resolution of disease-associated symptoms, disease-modifying effect, as well as its favourable safety profile (Gisslinger et al., 2020; Kiladjian et al. 2022).

Available clinical data and experience show that ropeginterferon alfa-2b normalises various haematological parameters, including platelets. In addition, suppression of the malignant clone causing ET may be achieved, at least after long-term treatment, which is expected to possibly defer the onset of, or avoid long-term sequelae of ET.


Eligibility criteria: Inclusion Criteria:

1. Written informed consent obtained from the patient and ability for the patient to comply with the requirements of the study.
2. Male or female patients ≥ 18 years old
3. Patients diagnosed with ET according to the World Health Organization (WHO) 2016 criteria (with a bone marrow biopsy test result not more than 5 years old) who need cytoreductive treatment but are intolerant or refractory to, and/or ineligible for all cytoreductive treatments approved for the treatment of ET (i.e., HU, ANA, BUS, and PB1).

   Patients resistant/intolerant to HU must have documented resistance/intolerance as defined by modified ELN criteria (Barosi, et al. 2007), whereby at least one of the following criteria is met:
   1. Platelet count \>600 x 109/L at ≥2 g/day (or ≥2.5 g/day if patient body weight \>80 kg) or maximally tolerated dose if \<2 g/day or at maximum dose per local practice after at least 3 months of HU
   2. Platelet count \>400 x 109/L and WBC count \<2.5 x 109/L at any dose and any duration of HU
   3. Platelet count \>400 x 109/L and haemoglobin (Hb) \<10 g/dL at any dose and any duration of HU
   4. Presence of HU-related toxicities at any dose and any duration of therapy (e.g., leg ulcers, mucocutaneous manifestations, pneumonitis, or HU-related fever)

   Patients resistant/intolerant to ANA, BUS, or PB must meet at least one of the following criteria:
   1. Patient designated as non-responder according to the primary efficacy endpoint of this protocol (modified ELN criteria) after at least 3 months of treatment with the recommended dosing defined in SmPC or local practice
   2. Presence of treatment-related toxicities at any dose and any duration of therapy Patients ineligible for HU: with contraindication as defined by locally available HU SmPC or designated as such by investigator due to benefit-risk concerns (e.g., patients with toxic ranges of myelosuppression, teratogenic/leukaemogenic/carcinogenic concerns, male patients of reproductive, age not willing or unable to use an effective method of contraception). Patients ineligible for ANA: with contraindication as defined by locally available ANA SmPC or designated as such by investigator due to benefit-risk concerns (e.g., cardiovascular risk factors, including heart failure, QT prolongation, the risk for progression to myelofibrosis). Patient ineligible for BUS and PB (in countries where BUS or PB is available and approved for treatment of ET): with contraindication as defined by locally available BUS/PB SmPC or designated as such by investigator due to benefit-risk concerns (e.g., teratogenic/leukaemogenic/carcinogenic concerns, male patients of reproductive age not willing or unable to use an effective method of contraception).
4. If a patient received prior cytoreductive treatment for ET, the washout period between the last dose of treatment and the first dose of the study drug must be at least 14 days, or longer. (If the washout period not completed at time of first patients screening, washout may be done after obtaining ICF during the 28-day screening phase).
5. Interferon treatment-naïve
6. Adequate hepatic function defined as bilirubin ≤1.5 x upper limit normal (ULN), international normalised ratio ≤1.5 x ULN, albumin \>3.5 g/dL, alanine aminotransferase ≤2.0 x ULN, aspartate aminotransferase ≤2.0 x ULN at screening.
7. Hospital Anxiety and Depression Scale (HADS) score 0-7 on both subscales.
8. Patient with HADS score of 8-10 inclusive on either, or both, of the subscales may be eligible following psychiatric assessment that excludes clinical significance of the observed symptoms in the context of potential treatment with an interferon alfa.

Exclusion Criteria:

1. Any patient requiring a legally authorised representative
2. Any hypersensitivity to IFN-α or to any of the drug excipients
3. Pre-existing thyroid disease, if not in remission or not controlled with conventional treatment
4. Existence of, or history of severe psychiatric disorders, particularly severe depression, suicidal ideation or suicide attempt
5. Severe cardiovascular disease (i.e., uncontrolled hypertension, congestive heart failure (≥ NYHA class 2), serious cardiac arrhythmia, significant coronary artery stenosis, unstable angina) or recent stroke or myocardial infarction or pulmonary hypertension
6. Patients with diabetes mellitus that cannot be effectively controlled by medicinal products
7. History or presence of autoimmune disease (excluding well-controlled Hashimoto's disease)
8. Immunosuppressed transplant recipients
9. Concomitant treatment with telbivudine
10. Decompensated cirrhosis of the liver (Child-Pugh B or C)
11. End stage renal disease (GFR \<15 mL/min)
12. Symptomatic splenomegaly (per the investigator's judgement)
13. Patients with any other significant medical conditions that, in the opinion of the Investigator, would compromise the results of the study or may impair compliance with the requirements of the protocol, including but not limited to:

    1. History of any malignancy within 5 years (except Stage 0 chronic lymphocytic leukaemia, basal cell, squamous cell, and superficial melanoma)
    2. Infections with systemic manifestations (e.g., bacterial, fungal, or human immunodeficiency virus \[HIV\], except hepatitis B \[HBV\] and/or hepatitis C \[HCV\], at screening)
    3. Evidence of severe retinopathy (e.g., cytomegalovirus retinitis, macular degeneration) or clinically relevant ophthalmological disorder (due to diabetes mellitus or hypertension)
    4. History of alcohol or drug abuse within the last year
14. Use of any investigational drug \<4 weeks prior to the first dose of study drug, or ongoing effects/symptoms due to prior administration of any investigational agent
15. HADS score of 11 or higher on either, or both, of the subscales, and /or development or worsening of the clinically significant depression or suicidal thoughts
16. Pregnant patients or breastfeeding patients or females of childbearing potential not willing to comply with contraceptive requirements as described in Section 16.1.4

Primary outcomes:
measure: Durable (for at least 3 months) peripheral blood count remission
timeFrame: At month 12
measure: Absence of haemorrhagic or thrombotic events and absence of disease progression*
timeFrame: At month 12
measure: Absence or Non-progression* in disease-related signs
timeFrame: At month 12
measure: Durable (for at least 3 months) large symptoms improvement or maintenance of non-progression based on the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS)#
timeFrame: At month 12
Secondary outcomes:
measure: Response at month 9, 18, 24, 30 and 36
timeFrame: Month 9, 18, 24, 30 and 36
measure: Longitudinal changes in the ELN response rates over 12 months
timeFrame: up to 36 months
measure: Time to first response (as defined by ELN criteria)
timeFrame: up to 36 months
measure: Duration of first response (as defined by ELN criteria)
timeFrame: up to 36 months
measure: Duration of first durable response (as defined by ELN criteria)
timeFrame: up to 36 months
measure: Time to first peripheral blood count remission response
timeFrame: up to 36 months
measure: Duration of first durable peripheral blood count remission response
timeFrame: up to 36 months
measure: Occurrence of thromboembolic and bleeding events response
timeFrame: up to 36 months
measure: Occurrence of disease progression response
timeFrame: up to 36 months
measure: Symptomatic improvement assessed by EQ-5D-5L questionnaire response
timeFrame: up to 36 months
measure: Symptomatic improvement assessed by the 10-item MPN-SAF TSS
timeFrame: up to 36 months
measure: Change in inflammation markers over time
timeFrame: up to 36 months
measure: Change in CALR, MPL, or JAK2 allelic burden over time
timeFrame: up to 36 months
Other outcomes:
measure: Safety endpoints
timeFrame: up to 36 months
Locations:
city: Graz
country: Austria
facility: University Hospital Graz, Department of Internal Medicine, Clinical Department of Hematology
state: Styria
city: Innsbruck
country: Austria
facility: Medical University Innsbruck, Department of Internal Medicine V (Hematology and Oncology)
state: Tyrol
city: Linz
country: Austria
facility: Ordensklinikum Linz GmbH Elisabethinen Hospital, Department of Internal Medicine I - Hemato-Oncology
state: Upper Austria
city: Vienna
country: Austria
facility: Medical University Vienna, Department of Internal Medicine I, Clinical Department of Hematology and Hemostaseology
city: Brno
country: Czechia
facility: University Hospital Brno, Clinic of Internal Medicine - Hematology and Oncology
city: Prague
country: Czechia
facility: University Hospital Kralovske Vinohrady, Clinic of Internal Hematology
city: Paris
country: France
facility: Saint-Louis Hospital, Department of Adult Hematology
city: Pessac
country: France
facility: Bordeaux University Hospital, Haut-Leveque Hospital
city: Poitiers
country: France
facility: Centre Hospitalier Universitaire De Poitiers
city: Aachen
country: Germany
facility: University Hospital Aachen, Clinic of Oncology, Hematology and Stem Cell Transplantation (Medical Clinic IV)
city: Halle
country: Germany
facility: University Hospital Halle (Saale), Department of Internal Medicine IV - Hematology and Oncology
city: Hannover
country: Germany
facility: Hannover Medical School, Clinic for haematology, haemostaseology, oncology and stem cell transplantation
city: Mannheim
country: Germany
facility: University Hospital Mannheim, Medical Clinic III, Hematology and Internistic Oncology
city: Minden
country: Germany
facility: Johannes Wesling Hospital Minden, Department of Oncology and Hematology
city: Ulm
country: Germany
facility: University Hospital Ulm, Center for Internal Medicine, Clinic of Internal Medicine III, Department of Hematology, Oncology, Rheumatology, Infectious Diseases
city: Athens
country: Greece
facility: General Hospital of Athens Alexandra, Therapeutic Clinic, Department of Therapeutics
city: Athens
country: Greece
facility: University General Hospital "Attikon"
city: Budapest
country: Hungary
facility: Semmelweis University, Department of Internal Medicine and Haematology, Division of Hematology
city: Debrecen
country: Hungary
facility: University of Debrecen Clinical Center, Clinic of Internal Medicine, Department of Hematology
city: Bologna
country: Italy
facility: Polyclinic S. Orsola-Malpighi
city: Florence
country: Italy
facility: Careggi University Hospital, Department of Hematology
city: Rome
country: Italy
facility: Umberto I Polyclinic of Rome
city: Rome
country: Italy
facility: University Polyclinic Foundation "Agostino Gemelli" - IRCCS, Service of Hematology
city: Turin
country: Italy
facility: University Hospital City of Health and Science of Turin - Hospital Molinette, Complex Structure of Hematology - U
city: Gdansk
country: Poland
facility: University Teaching Centre, Hematology and Transplantology Clinic
city: Katowice
country: Poland
facility: Pratia Oncology Katowice
city: Kraków
country: Poland
facility: Independent Public Healthcare Facility University Hospital in Krakow, Teaching Unit of the Hematology Department
city: Łódź
country: Poland
facility: Nicolaus Copernicus Provincial Multispecialty Oncology and Traumatology Center in Lodz, Department of Hematooncology with Subdivision of Daytime Chemotherapy
city: Brasov
country: Romania
facility: Onco Card Srl
city: Cluj-Napoca
country: Romania
facility: "Prof. Dr. Ion Chiricuta" Institute of Oncology, Hematology Department
city: Crisan
country: Romania
facility: Fundeni Clinical Institute, Center for Hematology and Bone Marrow Transplantation
city: Iasi
country: Romania
facility: Iasi Regional Institute of Oncology, Department of Hematology
city: Badalona
country: Spain
facility: University Hospital Germans Trias i Pujol
city: Barcelona
country: Spain
facility: Hospital Clinic of Barcelona, Department of Hematology
city: Madrid
country: Spain
facility: University Hospital Ramon y Cajal, Hematology Service
city: Murcia
country: Spain
facility: Morales Meseguer University General Hospital
Study officials:
References: