Clinical trial NCT01949805: Pegylated Interferon Alpha-2b Versus Hydroxyurea in Polycythemia Vera
Official title: A Randomized, Open-label, Multicenter, Controlled, Parallel Arm, Phase III Study Assessing the Efficacy and Safety of AOP2014 vs. Hydroxyurea in Patients With Polycythemia Vera
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Polycythemia Vera
Lead sponsor: AOP Orphan Pharmaceuticals AG
Sponsor class: INDUSTRY
Collaborators: name: PharmaEssentia (Co-Sponsor for USA)
First posted: 2013-09-25
Enrollment: 257
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Phase III study to compare the efficacy and safety of the novel monopegylated interferon alpha 2b AOP2014 versus Hydroxyurea (the current licensed therapy for this disease). One year treatment of patients with polycythemia vera. Objective is to demonstrate non-inferiority of AOP2014 vs. HU in terms of disease response rate in both HU naïve and currently treated patients, diagnosed with Polycythemia Vera. Response is measured as normalisation of key lab parameters as well as normalized spleen size.

Detailed description: Hydroxyurea is an established first-line treatment option currently approved in several European countries for Polycythemia Vera (PV) patients requiring a cytoreductive therapy (Barbui et al, 2011). Clinical trials have shown that HU is an effective drug for preventing thrombosis in PV compared to phlebotomy (Michiels et al, 1999).

The main concern of a long term treatment with HU is its potential leukaemogenicity: based on the mechanism of action, HU can potentially accelerate the accumulation of mutations in DNA and increase the risk of leukaemic transformation (Dingli et Tefferi, 2006). However, there is currently no clear clinical data to confirm leukaemogenicity of HU in patients with PV (Tefferi, 2012).

Even though IFN-alpha has shown its activity in PV in the 1980s, it is still considered as an experimental treatment in Europe due to pending approval in this indication (Barbui et al, 2011). It induces major or complete molecular remissions in patients with PV accompanied by a reduction in the risk of thrombosis and bleeding - the major determinants of morbidity in this indication (Hasselbalch, 2011). However, only low doses are tolerated and significant adverse effects from long-term use may limit its usefulness.

Pegylated interferons are better tolerated and are the preferred options of treatment in PV patients (Kiladjian et al, 2008) despite the lack of evidences based on well-designed randomized controlled clinical studies.

AOP2014 is a next generation pegylated interferon (Peg-P-IFN-alpha-2b), with the addition of proline in the N-terminal end.

AOP2014 like all interferon suppresses the malignant clone causing PV and subsequently is expected to possibly defer the onset of or avoid long term sequelae of PV. In addition, a reduction in the frequency of phlebotomies should be achieved. The peg-P-IFN-alpha-2b might potentially have a positive impact on reducing the drop-out rate compared to conventional IFNs. It is expected that the reduced frequency of administration of AOP2014 will contribute to higher compliance rates.

The maximum tolerated dose as well as the safety, efficacy and pharmacokinetics of AOP2014 were assessed in a phase I/II study in patients with PV. After 24 evaluable patients had entered the Phase I dose finding part, the MTD was defined at the level of 540 µg administered every two weeks. Another 27 patients were recruited in order to further investigate the drug efficacy and safety in PV. Efficacy results of AOP2014 were promising. By visit 18, 53.0% of the patients had reached complete response (12 evaluable patients). Adverse events were manageable and rarely necessitated treatment discontinuation.

AOP2014 was shown to have a prolonged plasma half-life with a concomitant increase in AUC. This is expected to enhance the therapeutic window of peg-IFN-alpha-2b.

The safety profile of type I interferons alpha is believed to be well characterized after clinical experience for nearly 20 years. Since the dose is carefully titrated to the optimal effective dose no additional risks for the patients are expected. HU, the IMP-comparator in the study, is the standard reference treatment in PV.

This phase III study was designed to compare, for the first time, the efficacy and safety of HU with a pegylated prolin-interferon alpha-2b (AOP2014) in patients with PV. Two populations will be assessed: HU naïve patients and patients currently treated or pre-treated with HU for less than 3 years, not responding to HU treatment (according to criteria in this protocol).

Eligibility criteria: Inclusion Criteria:

1. 18 years or older
2. Diagnosis of Polycythemia Vera according to the WHO 2008 criteria (Barbui et al, 2011) with the mandatory presence of JAK2V617F mutation as the major disease criterion.
3. For previously cytoreduction untreated patients - documented need of cytoreductive treatment

   - leukocytosis (WBC\>10G/L for two measurements within one week)
4. For patients currently treated or pre-treated with HU, all of the following criteria:

   * being non responders (as defined by the response criteria for primary endpoint)
   * total HU treatment duration shorter than three years
   * no documented resistance or intolerance as defined by modified Barosi et al, 2009 criteria
5. Hospital Anxiety and Depression Scale (HADS) score 0-7 on both subscales
6. Patients 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 alpha
7. Signed written informed consent

Exclusion Criteria:

1. Any systematic cytoreduction for PV prior study entry with exception of HU for shorter than 3 years (see respective inclusion criterion)
2. Any contraindication to any of the IMPs (pegylated interferon or hydroxyurea) or their excipients
3. Any systemic exposure to a non-pegylated or pegylated interferon alpha
4. Documented autoimmune disease at screening or in the medical history
5. Clinically relevant pulmonary infiltrates, pneumonia, and pneumonitis at screening
6. Systemic infections, e.g. hepatitis B, hepatitis C, or HIV at screening
7. Known PV-related thromboembolic complications in the abdominal area (e.g. portal vein thrombosis, Budd-chiari syndrome) and/or splenectomy in the medical history
8. Any investigational drug less than 6 weeks prior to the first dose of study drug or not recovered from effects of prior administration of any investigational agent
9. History or presence of depression requiring treatment with antidepressant
10. HADS score equal to or above 11 on either or both of the subscales
11. Any risk of suicide at screening or previous suicide attempts
12. Any significant morbidity or abnormality which may interfere with the study participation
13. Pregnancy and breast-feeding females of reproductive potential and males not using effective means of contraception
14. History of active substance or alcohol abuse within the last year
15. Evidence of severe retinopathy (e.g. cytomegalovirus retinitis, macular degeneration) or clinically relevant ophthalmological disorder (due to diabetes mellitus or hypertension)
16. Thyroid dysfunction not adequately controlled
17. Patients tested positively with TgAb and / or TPOAb at screening
18. History of major organ transplantation
19. History of uncontrolled severe seizure disorder
20. Leukocytopenia at the time of screening
21. Thrombocytopenia at the time of screening
22. History of malignant disease, including solid tumours and hematological malignancies (except basal cell and squamous cell carcinomas of the skin and carcinoma in situ of the cervix that have been completely excised and are considered cured) within the last 3 years

Primary outcomes:
measure: Disease response rate
timeFrame: Month 12
Secondary outcomes:
measure: Disease response
timeFrame: at month 3, 6 and 9
measure: JAK2 allelic burden changes
timeFrame: at month 6 and 12
measure: time to response
timeFrame: from inclusion until first response confirmation
measure: duration of response
timeFrame: during the 12 months of study duration
measure: number of phlebotomies
timeFrame: from inclusion until month 12
measure: blood parameters
timeFrame: from inclusion until month 12
measure: spleen size
timeFrame: at month 3, 6, 9 and 12
measure: disease related symptoms
timeFrame: from inclusion until month 12
measure: adverse events
timeFrame: from inclusion until month 12
measure: protocol-specific adverse events of special interest
timeFrame: from inclusion until month 12
Other outcomes:
Locations:
city: Graz
country: Austria
facility: LKH Graz
city: Innsbruck
country: Austria
facility: University Hospital Innsbruck
city: Linz
country: Austria
facility: Elisabethinen Hospital Linz
city: Salzburg
country: Austria
facility: Salzburg Regional Hospital
city: Vienna
country: Austria
facility: Hanusch Hospital
city: Vienna
country: Austria
facility: Medical University Vienna
city: Wels
country: Austria
facility: Hospital Wels-Grieskirchen
city: Brussels
country: Belgium
facility: Centre du Cancer et D'hematologie
city: Edegem
country: Belgium
facility: UZA, Antwerp University Hospital
city: Leuven
country: Belgium
facility: UZ Leuven
city: Liège
country: Belgium
facility: Haematolgy, University of Liège
city: Plovdiv
country: Bulgaria
facility: University Multiprofile Hospital for Active Treatment "Sveti Georgi"
city: Sofia
country: Bulgaria
facility: Specialized Hospital for Active Treatment of Hematological Diseases
city: Varna
country: Bulgaria
facility: Multiprofile Hospital for Active Treatment "Sveta Marina"
city: Vratsa
country: Bulgaria
facility: Multiprofile Hospital for Active Treatment - Hristo Botev, Vratsa, First Department of Internal Medicine
city: Brno
country: Czech Republic
facility: University Hospital Brno
city: Hradec Kralove
country: Czech Republic
facility: University Hospital Hradec Kralove
city: Prague
country: Czech Republic
facility: Institute of Hematology and Blood Transfusion
city: Prague
country: Czech Republic
facility: University Hospital Kralovske Vinohrady
city: Prague
country: Czech Republic
facility: University Hospital Motol
city: Marseilles
country: France
facility: Institute Paoli-Calmettes
city: Paris
country: France
facility: Hospital Saint-Louis
city: Poitiers
country: France
facility: Clinical Research Center CIC
city: Aachen
country: Germany
facility: Aachen University Hospital, Medical Clinic IV
city: Bonn
country: Germany
facility: University Hospital Bonn, Center for Internal Medicine, Medical Clinic and Outpatient Clinic III
city: Dresden
country: Germany
facility: University Hospital Carl Gustav Carus, Medical Clinic and Polyclinic I
city: Budapest
country: Hungary
facility: St Istvan and St Laszlo Hospital of Budapest
city: Debrecen
country: Hungary
facility: University of Debrecen
city: Gyula
country: Hungary
facility: Bekes County Pandy Kalman Hospital, 1st Department of Medicine, Hematology
city: Kaposvar
country: Hungary
facility: Kaposi Mor County Teaching Hospital
city: Szeged
country: Hungary
facility: University of Szeged, Albert Szent-Gyorgyi Clinical Center, Koranyi fasor 6
city: Florence
country: Italy
facility: Careggi University Hospital
city: Pavia
country: Italy
facility: Foundation IRCCS Policlinico San Matteo
city: Katowice
country: Poland
facility: Andrzej Mielecki Independent Public Clinical Hospital of Medical University of Silesia in Katowice
city: Krakow
country: Poland
facility: University Hospital in Cracow
city: Lublin
country: Poland
facility: Independent Public Teaching Hospital No.1 in Lublin
city: Rzeszow
country: Poland
facility: Fryderyk Chopin Provincial Specialized Hospital
city: Torun
country: Poland
facility: Nicolaus Copernicus Municipal Specialist Hospital
city: Warsaw
country: Poland
facility: Institute of Hematology and Transfusion Medicine
city: Brasov
country: Romania
facility: Emergency Clinical County Hospital Brasov
city: Bucharest
country: Romania
facility: Bucharest University Emergency Hospital
city: Bucharest
country: Romania
facility: Coltea Clinical Hospital
city: Cluj-Napoca
country: Romania
facility: "Prof. Dr. Ion Chiricuta" Institute of Oncology
city: Petrozavodsk
country: Russian Federation
facility: Baranov Republican Hospital
city: Samara
country: Russian Federation
facility: Samara Kalinin Regional Clinical Hospital
city: St. Petersburg
country: Russian Federation
facility: First Pavlov State Medical University of St. Petersburg
city: Syktyvkar
country: Russian Federation
facility: Komi Republican Oncology Center
city: Tula
country: Russian Federation
facility: Tula Regional Clinical Hospital
city: Yaroslavl
country: Russian Federation
facility: Yaroslavl Regional Clinical Hospital
city: Banska Bystrica
country: Slovakia
facility: University Hospital with Outpatient Clinic F.D. Roosevelt
city: Bratislava
country: Slovakia
facility: Saint Cyril and Metod University Hospital Bratislava
city: Barcelona
country: Spain
facility: Hospital Clinic i Provincial de Barcelona
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Cherkasy
country: Ukraine
facility: Cherkasy Regional Oncology Center, Regional Treatment and Diagnostics Hematology Center
city: Dnipropetrovsk
country: Ukraine
facility: Dnipropetrovsk City Multispecialty Clinical Hospital #4
city: Kiev
country: Ukraine
facility: National Research Center for Radiation Medicine, Institute of Clinical Radiology
city: Lviv
country: Ukraine
facility: Institute of Blood Pathology and Transfusion Medicine
city: Zhytomyr
country: Ukraine
facility: O.F. Herbachevskyi Regional Clinical Hospital
Study officials:
affiliation: Medical University of Vienna
name: Heinz Gisslinger, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Verger E, Soret-Dulphy J, Maslah N, Roy L, Rey J, Ghrieb Z, Kralovics R, Gisslinger H, Grohmann-Izay B, Klade C, Chomienne C, Giraudier S, Cassinat B, Kiladjian JJ. Ropeginterferon alpha-2b targets JAK2V617F-positive polycythemia vera cells in vitro and in vivo. Blood Cancer J. 2018 Oct 4;8(10):94. doi: 10.1038/s41408-018-0133-0.