A Phase III multicenter study to evaluate the efficacy and safety of ropeginterferon alfa-2b in essential thrombocythaemia patients

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Aop Orphan Pharmaceuticals GmbH

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

4 Dec 2023 → ongoing

Decision date (initial)

2023-10-30

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

AOP Orphan Pharmaceuticals GmbH

External identifiers

EU CT number

2023-505160-12-00

WHO UTN

U1111-1291-9030

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Efficacy

To estimate the disease response rates as defined by ELN (European Leukemia Net) criteria of ropeginterferon alfa-2b in ET patients who are intolerant or refractory to or not eligible for other cytoreductive treatments.

Secondary objectives 3

1. To further assess efficacy of ropeginterferon alfa- 2b in terms of disease response, symptom improvement, vascular events, disease progression and quality of life.
2. To assess the efficacy of ropeginterferon alfa-2b in terms of disease modification defined by a sustained decline in mutant allele burden of either of the driver mutations CALR, MPL, or mutant JAK-2
3. To assess the safety and tolerability of ropeginterferon alfa-2b in the study population.

Conditions and MedDRA coding

Essential Thrombocythaemia

Study design 4 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. 1. Written informed consent obtained from the patient and ability for the patient to comply with the requirements of the study.
2. 2. Male or female patients ≥ 18 years old
3. 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 PB). Patients resistant/intolerant to HU must have documented resistance/intolerance as defined by modified ELN criteria, whereby at least one of the following criteria is met: a) Platelet count >600 x 10^9/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 b) Platelet count >400 x 10^9/L and WBC count <2.5 x 10^9/L at any dose and any duration of HU c) Platelet count >400 x 10^9/L and haemoglobin (Hb) <10 g/dL at any dose and any duration of HU d) 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: a) 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 b) 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. 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. 5. Interferon treatment-naïve
6. 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.Patients with a confirmed diagnosis of Gilbert's syndrome are eligible for inclusion in the study, even if their bilirubin levels exceed the limits as specified above. The diagnosis of Gilbert's syndrome and the corresponding bilirubin levels must be documented in the Medical History. Patients receiving anticoagulation therapy targeting an international normalised ratio (INR) exceeding 1.5 x ULN with otherwise adequate hepatic function are eligible. The anticoagulation therapy (including the corresponding INR levels) must be recorded under Prior and Concomitant Treatments and Medications.
7. 7. Hospital Anxiety and Depression Scale (HADS) score 0-7 on both subscales.
8. 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 16

1. 1. Any patient requiring a legally authorised representative
2. 11. End stage renal disease (GFR <15 mL/min)
3. 12. Symptomatic splenomegaly (per the investigator’s judgement)
4. 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: a) History of any malignancy within 5 years (except Stage 0 chronic lymphocytic leukaemia, basal cell, squamous cell, and superficial melanoma) b) Infections with systemic manifestations (e.g., bacterial, fungal, or human immunodeficiency virus [HIV], except hepatitis B [HBV] and/or hepatitis C [HCV], at screening) c) Evidence of severe retinopathy (e.g., cytomegalovirus retinitis, macular degeneration) or clinically relevant ophthalmological disorder (due to diabetes mellitus or hypertension) d) History of alcohol or drug abuse within the last year
5. 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
6. 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
7. 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.
8. 2. Any hypersensitivity to IFN-α or to any of the drug excipients
9. 3. Pre-existing thyroid disease, if not in remission or not controlled with conventional treatment
10. 4. Existence of, or history of severe psychiatric disorders, particularly severe depression, suicidal ideation or suicide attempt
11. 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
12. 7. History or presence of autoimmune disease (excluding well-controlled Hashimoto’s disease)
13. 8. Immunosuppressed transplant recipients
14. 9. Concomitant treatment with telbivudine
15. 10. Decompensated cirrhosis of the liver (Child-Pugh B or C)
16. 6. Patients with diabetes mellitus that cannot be effectively controlled by medicinal products

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Rate of disease response at month 12 according to modified ELN Criteria: 1. Durable (≥3 months) peripheral blood count remission (PLTs ≤400 x 10^9/L AND WBC <10 x 10^9/L), AND 2. Absence of haemorrhagic or thrombotic events and disease progression, AND 3. Absence or Non-progression in disease-related signs, AND 4. Durable (for at least 3 months) large symptoms improvement or maintenance of non-progression based on the MPN-SAF TSS

Secondary endpoints 13

1. Response at month 9, 18, 24, 30 and 36
2. Longitudinal changes in the ELN response rates over 12 months
3. Time to first response (as defined by ELN criteria)
4. Duration of first response (as defined by ELN criteria)
5. Duration of first durable response (as defined by ELN criteria)
6. Time to first peripheral blood count remission response
7. Duration of first durable peripheral blood count remission response
8. Occurrence of thromboembolic and bleeding events
9. Occurrence of disease progression
10. Symptomatic improvement assessed by EQ-5D-5L questionnaire
11. Symptomatic improvement assessed by the 10-item MPN-SAF TSS
12. Change in inflammation markers over time
13. Change in CALR, MPL, or JAK2 allelic burden over time

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Aop Orphan Pharmaceuticals GmbH

Sponsor organisation

Aop Orphan Pharmaceuticals GmbH

Address

Leopold-Ungar-Platz 2, Döbling Döbling

City

Vienna

Postcode

1190

Country

Austria

Scientific contact point

Organisation

Aop Orphan Pharmaceuticals GmbH

Contact name

Dr. Martin Unger

Public contact point

Organisation

Aop Orphan Pharmaceuticals GmbH

Contact name

Dr. Martin Unger

Third parties 7

Locations

10 EU/EEA countries · 29 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 109 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

15 submissions — initial application plus substantial / non-substantial modifications