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Phase 2 Single Arm Study for Efficacy and Safety of Ropeginterferon alfa-2b for Japanese Polycythemia Vera (PV) Patients for Whom the Current Standard of Treatment is Difficult to Apply

Clinical study for investigating Ropeginterferon alfa-2b in Japanese Polycythemia Vera Patients

29

The ITT population and the safety population both comprised 29 patients. Patient characteristics were slightly more women (16/29 [55.2%]) than men (13/29 [44.8%]), and the median (range) age was 54.0 (26-72) years. All patients were Japanese, and all had an ECOG PS of 0. Approximately half had previously used HU (15/29 [51.7%]). Twenty-seven patients had a JAK2 V617F mutation (allele burden mean +- SD 72.2% +- 23.3%).

27 patients completed the study; one patient withdrew consent, and one discontinued due to a TEAE (silent thyroiditis that did not recover within 8 weeks). All 27 patients who completed the study subsequently transitioned into the extension study.

No new safety concerns were identified in Japanese patients when compared with previous studies of ropeginterferon alfa-2b in European populations; the most common treatment-related adverse events were alopecia (55.2%), fatigue (27.6%) and influenza-like illness (27.6%). Most treatment-related adverse events were mild or moderate, with none of grade >= 3.

CHRs to ropeginterferon alfa-2b treatment were observed in 1/29 (3.45%) patients at week 12, and increased over time. More than half of the patients (15/29 [51.7%]) had achieved a CHR at week 52. Eight of 29 (27.6%) patients achieved the primary endpoint (durable CHR without phlebotomy at weeks 36 and 52) during the study period.

Hematocrit, platelet count, and white blood cell count decreased over 52 weeks of treatment with ropeginterferon alfa-2b; mean (SD) changes from baseline at the end of treatment were - 5.5% (6.7%), - 493.6 x 10^9/ L (374.9), and - 11.7 x 10^9/L (8.4), respectively. The mean of all parameters improved to their target value (hematocrit less than 45%, platelets less than 400,000/microlitter and leukocytes less than 10,000/microlitter) ranges. The baseline JAK2 V617F allele burden decreased over 52 weeks of treatment, and the rate of molecular response to ropeginterferon alfa-2b increased over the 52-week treatment period . Twentyseven patients completed the study. Of the 27 patients, 26 patients had a JAK2 V617F mutation, and changes in the JAK2 V617F allele burden were analyzed for the 26 patients. The mean (SD) change in allele burden from baseline to end of treatment (n = 26) was - 19.2% (22.6%). The median (range) allele burden at week 52 (n = 26) was 52.5% (6.2%-92.0%)

This phase 2 study demonstrated ropeginterferon alfa-2b to be a safe and efficacious treatment option in Japanese patients with PV, regardless of patients' estimated risk of thrombosis.

April. 16, 2022

https://link.springer.com/article/10.1007/s12185-022-03341-9

No

PharmaEssentia Japan K.K.

Akasaka Center Bldg., 12F, 1-3-13 Moto-akasaka, Minato, Tokyo

hiroaki_kawase@pharmaessentia.com

PharmaEssentia Japan K.K.

Akasaka Center Bldg., 12F, 1-3-13 Moto-akasaka, Minato, Tokyo

+81-3-6910-5103

hiroaki_kawase@pharmaessentia.com

completed

Dec. 24, 2019

Interventional

Open, Single arm, multi-center trial

treatment purpose

2

1. Male or female patients more than or equal to 20 years old
2. Patients diagnosed with PV according to the WHO 2008 or WHO 2016 criteria
3. PV patients for whom the current standard of treatment is difficult to apply. (Patients with a documented history of refractory to HU are excluded.)
- Younger patients (long-term treatment is anticipated)
- Patients who are categorized as low risk, but cytoreduction is recommended due to disease-related signs and symptoms (headache, dizziness, pruritus, night sweats, fatigue, erythromelalgia, vision disorders, scintillating scotoma, early satiety, abdominal distension).
- Patients with HU intolerance
4. Total HU treatment duration shorter than 3 years (cumulatively) at screening
5. For cytoreduction naive patients only: PV in need of cytoreductive treatment, defined by fulfilling as one or more of the following criteria at baseline:
- at least one previous well documented major cardiovascular PV-related event in the medical history
- poor tolerance of phlebotomy (defined as a phlebotomy/ procedure-related adverse event causing significant adverse impact on the patient and limiting ability to apply phlebotomy with the intention to keep Hct less than45%)
- frequent need of phlebotomy (more than one phlebotomy within last month prior entering the study)
- platelet counts greater than 1,000,000/microliter (for two measurements within the month prior treatment start)
- leukocytosis (WBC greater than 10,000/microliter for two measurements within the month prior treatment start)
6. Adequate hepatic function defined as bilirubin less than or equal to 1.5 x upper limit normal (ULN), international normalized ratio (INR) less than or equal to 1.5 x ULN, albumin more than 3.5 g/dL, alanine aminotransferase (ALT) less than or equal to 2.0 x ULN, aspartate aminotransferase (AST) less than or equal to 2.0 x ULN at screening
7. Hemoglobin (HGB) more than or equal to 10 g/dL at screening
8. Neutrophil count more than or equal to 1,500/microliter at screening
9. Serum creatinine less than or equal to 1.5 x ULN at screening
10. Hospital Anxiety and Depression Scale (HADS) score 0-7 on both subscales (Patients with a borderline of HADS score [score 7 but less than10] or patients with necessity [expected benefits are higher than the risks] based on investigators' discretion are required to receive following assessment by psychiatric specialist to confirm the eligibility for IFN-alpha therapy).
11. Males and females of childbearing potential, as well as all women less than 2 years after the onset of menopause, must agree to use an acceptable form of birth control until 28 days following the last dose of the study drug
12. Written informed consent obtained from the patient or the patient's legal representative, and ability for the patient to comply with the requirements of the study

1. Patients with symptomatic splenomegaly
2. Previous use of IFN-alpha for any indication
3. Any contraindications or hypersensitivity to interferon-alfa
4. Co-morbidity with severe or serious conditions which may impact patient participation in the study in investigator's opinion
5. History of major organ transplantation
6. Pregnant or lactating females
7. Patients with any other medical conditions, which in the opinion of the Investigator would compromise the results of the study or may impair compliance with the requirements of the protocol
7-1. History or presence of thyroid dysfunction (clinical symptoms of hyper- or hypo-thyroidism) of the autoimmune origin, except late stages cases on the oral thyroid substitution therapy, where potential exacerbation under interferon therapy will not constitute any further harm to the patient
7-2.Documented autoimmune disease (e.g., hepatitis, idiopathic thrombocytopenic purpura [ITP], scleroderma, psoriasis, or any autoimmune arthritis)
7-3. Clinically relevant pulmonary infiltrates and pneumonitis at screening, patients with a history of interstitial pulmonary disease
7-4. Active infections with systemic manifestations (e.g., bacterial, fungal, hepatitis B [HBV], hepatitis C [HCV], or human immunodeficiency virus [HIV]) at screening)
7-5. Evidence of severe retinopathy (e.g., cytomegalovirus retinitis [CMV], macular degeneration) or clinically relevant ophthalmological disorder (due to diabetes mellitus or hypertension) based on the ophthalmological assessment by specialists.
7-6. Uncontrolled depression
7-7. Previous suicide attempts or at any risk of suicide at screening
8. Uncontrolled diabetes mellitus (HbA1c level of more than 7% at baseline)
9. History of any malignancy within for the past 5 years
10. History of alcohol or drug abuse within the last year
11. History or evidence of post polycythemia vera-myelofibrosis (PPV-MF), essential thrombocythemia, or any non-PV MPN
12. Presence of circulating blasts in the peripheral blood within the last 3 months
13. Use of any investigational drug(s), or investigational drug combinations less than 4 weeks prior to the first dose of study drug or not recovered from effects of prior administration of any investigational agent

Both

polycythemia vera (PV)

investigational material(s)
Generic name etc : Ropeginterferonum alfa-2b
INN of investigational material : ropeginterferonum alfa-2b
Therapeutic category code : 429 Other antitumor agents
Dosage and Administration for Investigational material : Ropeginterferon alfa-2b is administered subcutaneously every 2 weeks at the starting dose of 100 micrograms every two weeks (or 50 micrograms in patients under another cytoreductive therapy). The dose should be gradually increased by 50 micrograms every two weeks (in parallel, other cytoreductive therapy should be decreased gradually, as appropriate) until stabilization of the hematological parameters is achieved (hematocrit less than 45%, platelets less than 400,000/microlitter and leukocytes less than 10,000/microlitter). The maximum recommended single dose is 500 micrograms injected every two weeks. The dose will be maintained at the highest level which can be tolerated and delivers best possible disease response.

control material(s)
Generic name etc : -
INN of investigational material : -
Therapeutic category code : --- Other
Dosage and Administration for Investigational material : -

safety
efficacy
Proportion of subjects achieving durable phlebotomy-free complete hematological response (CHR) at Month 12.
The primary efficacy outcome measure is the proportion of subjects achieving durable phlebotomy-free complete hematologic response (CHR) at Month 12. Durable phlebotomy-free CHR is defined as any subject achieving phlebotomy-free CHR at Month 9 and maintaining the response up to Month 12. A responder in sense of a primary outcome measure is a subject who has met all the following criteria at the time points:
- Hematocrit less than 45% phlebotomy-free (absence of phlebotomy during the previous 3 months)
- Platelet count less than or equal to 400,000/microliter,
- WBC count less than or equal to 10,000/microliter

safety
efficacy
pharmacokinetics
- Changes in Hct, WBC, Plt count and spleen size from baseline- Time to requiring no phlebotomy
- Time required to first response
- Duration of response maintenance
- Proportion of subjects without thrombotic or hemorrhagic events
- Change of JAK2 V617F mutant allelic burden over time vs. baseline
- PK of P1101

Dec. 19, 2019