Pegylated Interferon Alpha-2b Versus Hydroxyurea in Polycythemia Vera

Polycythemia Vera Clinical Trial

— PROUD-PV  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01949805
• Other study ID #: PROUD-PV
• Secondary ID: 2012-005259-18
• Status: Completed
• Phase: Phase 3
• First received: September 6, 2013
• Last updated: November 24, 2016
• Start date: September 2013
• Est. completion date: July 2016

Study information

• Verified date: November 2016
• Source: AOP Orphan Pharmaceuticals AG
• Contact: n/a
• Is FDA regulated: No
• Health authority: Austria: Austrian Medicines and Medical Devices AgencyBulgaria: Ministry of HealthCzech Republic: State Institute for Drug ControlFrance: Agence Nationale de Sécurité du Médicament et des produits de santéGermany: Federal Institute for Drugs and Medical DevicesHungary: Ministry of Health, Social and Family AffairsItaly: Ministry of HealthPoland: Ministry of HealthRomania: National Agency for Medicines and Medical DevicesRussia: Ministry of Health of the Russian FederationSlovakia: State Institute for Drug ControlSpain: Ministry of HealthUkraine: Ministry of Health
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 257
• Est. completion date: July 2016
• Est. primary completion date: July 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Polycythemia
• Polycythemia Vera

Intervention

Drug:
• Peg-P-IFN-alpha-2b (AOP2014)
Pegylated interferon alpha 2b given Q2W as SC injection
• Hydroxyurea
Hydroyurea capsules taken daily po

Locations

Country	Name	City	State
Austria	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
Belgium	Centre du Cancer et D'hematologie	Brussels
Belgium	UZA, Antwerp University Hospital	Edegem
Belgium	UZ Leuven	Leuven
Belgium	Haematolgy, University of Liège	Liège
Bulgaria	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
Czech Republic	University Hospital Brno	Brno
Czech Republic	University Hospital Hradec Kralove	Hradec Kralove
Czech Republic	Institute of Hematology and Blood Transfusion	Prague
Czech Republic	University Hospital Kralovske Vinohrady	Prague
Czech Republic	University Hospital Motol	Prague
France	Institute Paoli-Calmettes	Marseilles
France	Hospital Saint-Louis	Paris
France	Clinical Research Center CIC	Poitiers
Germany	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
Hungary	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	Kaposvar
Hungary	University of Szeged, Albert Szent-Gyorgyi Clinical Center, Koranyi fasor 6	Szeged
Italy	Careggi University Hospital	Florence
Italy	Foundation IRCCS Policlinico San Matteo	Pavia
Poland	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	Rzeszow
Poland	Nicolaus Copernicus Municipal Specialist Hospital	Torun
Poland	Institute of Hematology and Transfusion Medicine	Warsaw
Romania	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
Russian Federation	Baranov Republican Hospital	Petrozavodsk
Russian Federation	Samara Kalinin Regional Clinical Hospital	Samara
Russian Federation	First Pavlov State Medical University of St. Petersburg	St. Petersburg
Russian Federation	Komi Republican Oncology Center	Syktyvkar
Russian Federation	Tula Regional Clinical Hospital	Tula
Russian Federation	Yaroslavl Regional Clinical Hospital	Yaroslavl
Slovakia	University Hospital with Outpatient Clinic F.D. Roosevelt	Banska Bystrica
Slovakia	Saint Cyril and Metod University Hospital Bratislava	Bratislava
Spain	Hospital Clinic i Provincial de Barcelona	Barcelona
Spain	Hospital del Mar	Barcelona
Ukraine	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

Sponsors (2)

Lead Sponsor	Collaborator
AOP Orphan Pharmaceuticals AG	PharmaEssentia (Co-Sponsor for USA)

Countries where clinical trial is conducted

Austria,  Belgium,  Bulgaria,  Czech Republic,  France,  Germany,  Hungary,  Italy,  Poland,  Romania,  Russian Federation,  Slovakia,  Spain,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Disease response rate	Disease response rate is defined as hematocrit <45% without phlebotomy (at least 3 months since last phlebotomy), platelets <400 G/L, leukocytes <10 G/L , and normal spleen size	Month 12	No
Secondary	Disease response		at month 3, 6 and 9	No
Secondary	JAK2 allelic burden changes		at month 6 and 12	No
Secondary	time to response	will be measured during the study period of 12 months	from inclusion until first response confirmation	No
Secondary	duration of response	from the first documented response on study	during the 12 months of study duration	No
Secondary	number of phlebotomies		from inclusion until month 12	No
Secondary	blood parameters	biweekly	from inclusion until month 12	No
Secondary	spleen size	both centrally (blinded assessment) and locally	at month 3, 6, 9 and 12	No
Secondary	disease related symptoms	biweekly	from inclusion until month 12	No
Secondary	adverse events	biweekly	from inclusion until month 12	Yes
Secondary	protocol-specific adverse events of special interest	biweekly	from inclusion until month 12	Yes