Pegylated Interferon Alpha-2b Versus Hydroxyurea in Polycythemia Vera

NCT ID: NCT01949805

Last Updated: 2016-11-28

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 257 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-09-30
• Study Completion Date: 2016-07-31

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).

Conditions

Polycythemia Vera

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Hydroxyurea

Hydroxyurea capsules (500 mg each). Daily intake of doses from 500 mg Q2D to 3000 mg QD

Group Type: ACTIVE_COMPARATOR

Hydroxyurea

Intervention Type: DRUG

Hydroyurea capsules taken daily po

Peg-P-IFN-alpha-2b (AOP2014)

Peg-P-IFN-alpha-2b at 50mcg to max 500 mcg, given every other week as one subcutanous injection

Group Type: EXPERIMENTAL

Peg-P-IFN-alpha-2b (AOP2014)

Intervention Type: DRUG

Pegylated interferon alpha 2b given Q2W as SC injection

Interventions

Peg-P-IFN-alpha-2b (AOP2014)

Pegylated interferon alpha 2b given Q2W as SC injection

Intervention Type: DRUG

Hydroxyurea

Hydroyurea capsules taken daily po

Intervention Type: DRUG

Other Intervention Names

AOP2014; P1101; HU; Hydroxycarbamide; brand name Litalir (or other)

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

PharmaEssentia (Co-Sponsor for USA)

UNKNOWN

Sponsor Role: collaborator

AOP Orphan Pharmaceuticals AG

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Heinz Gisslinger, MD

Role: PRINCIPAL_INVESTIGATOR

Medical University of Vienna

Locations

LKH Graz

Graz, , Austria

University Hospital Innsbruck

Innsbruck, , Austria

Elisabethinen Hospital Linz

Linz, , Austria

Salzburg Regional Hospital

Salzburg, , Austria

Hanusch Hospital

Vienna, , Austria

Medical University Vienna

Vienna, , Austria

Hospital Wels-Grieskirchen

Wels, , Austria

Centre du Cancer et D'hematologie

Brussels, , Belgium

UZA, Antwerp University Hospital

Edegem, , Belgium

UZ Leuven

Leuven, , Belgium

Haematolgy, University of Liège

Liège, , Belgium

University Multiprofile Hospital for Active Treatment "Sveti Georgi"

Plovdiv, , Bulgaria

Specialized Hospital for Active Treatment of Hematological Diseases

Sofia, , Bulgaria

Multiprofile Hospital for Active Treatment "Sveta Marina"

Varna, , Bulgaria

Multiprofile Hospital for Active Treatment - Hristo Botev, Vratsa, First Department of Internal Medicine

Vratsa, , Bulgaria

University Hospital Brno

Brno, , Czechia

University Hospital Hradec Kralove

Hradec Králové, , Czechia

Institute of Hematology and Blood Transfusion

Prague, , Czechia

University Hospital Kralovske Vinohrady

Prague, , Czechia

University Hospital Motol

Prague, , Czechia

Institute Paoli-Calmettes

Marseille, , France

Hospital Saint-Louis

Paris, , France

Clinical Research Center CIC

Poitiers, , France

Aachen University Hospital, Medical Clinic IV

Aachen, , Germany

University Hospital Bonn, Center for Internal Medicine, Medical Clinic and Outpatient Clinic III

Bonn, , Germany

University Hospital Carl Gustav Carus, Medical Clinic and Polyclinic I

Dresden, , Germany

St Istvan and St Laszlo Hospital of Budapest

Budapest, , Hungary

University of Debrecen

Debrecen, , Hungary

Bekes County Pandy Kalman Hospital, 1st Department of Medicine, Hematology

Gyula, , Hungary

Kaposi Mor County Teaching Hospital

Kaposvár, , Hungary

University of Szeged, Albert Szent-Gyorgyi Clinical Center, Koranyi fasor 6

Szeged, , Hungary

Careggi University Hospital

Florence, , Italy

Foundation IRCCS Policlinico San Matteo

Pavia, , Italy

Andrzej Mielecki Independent Public Clinical Hospital of Medical University of Silesia in Katowice

Katowice, , Poland

University Hospital in Cracow

Krakow, , Poland

Independent Public Teaching Hospital No.1 in Lublin

Lublin, , Poland

Fryderyk Chopin Provincial Specialized Hospital

Rzeszów, , Poland

Nicolaus Copernicus Municipal Specialist Hospital

Torun, , Poland

Institute of Hematology and Transfusion Medicine

Warsaw, , Poland

Emergency Clinical County Hospital Brasov

Brasov, , Romania

Bucharest University Emergency Hospital

Bucharest, , Romania

Coltea Clinical Hospital

Bucharest, , Romania

"Prof. Dr. Ion Chiricuta" Institute of Oncology

Cluj-Napoca, , Romania

Baranov Republican Hospital

Petrozavodsk, , Russia

First Pavlov State Medical University of St. Petersburg

Saint Petersburg, , Russia

Samara Kalinin Regional Clinical Hospital

Samara, , Russia

Komi Republican Oncology Center

Syktyvkar, , Russia

Tula Regional Clinical Hospital

Tula, , Russia

Yaroslavl Regional Clinical Hospital

Yaroslavl, , Russia

University Hospital with Outpatient Clinic F.D. Roosevelt

Banská Bystrica, , Slovakia

Saint Cyril and Metod University Hospital Bratislava

Bratislava, , Slovakia

Hospital Clinic i Provincial de Barcelona

Barcelona, , Spain

Hospital del Mar

Barcelona, , Spain

Cherkasy Regional Oncology Center, Regional Treatment and Diagnostics Hematology Center

Cherkasy, , Ukraine

Dnipropetrovsk City Multispecialty Clinical Hospital #4

Dnipropetrovsk, , Ukraine

National Research Center for Radiation Medicine, Institute of Clinical Radiology

Kiev, , Ukraine

Institute of Blood Pathology and Transfusion Medicine

Lviv, , Ukraine

O.F. Herbachevskyi Regional Clinical Hospital

Zhytomyr, , Ukraine

Countries

Austria; Belgium; Bulgaria; Czechia; France; Germany; Hungary; Italy; Poland; Romania; Russia; Slovakia; Spain; Ukraine

References

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.

Reference Type: DERIVED

PMID: 30287855 (View on PubMed)

Other Identifiers

2012-005259-18

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

PROUD-PV

Identifier Type: -

Identifier Source: org_study_id