Phase 3 study to assess the efficacy and safety of Givinostat versus hydroxyurea in Polycythemia Vera patients

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Italfarmaco S.p.A.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

25 Apr 2024 → ongoing

Decision date (initial)

2024-04-08

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

ITALFARMACO S.p.A

External identifiers

EU CT number

2022-502276-23-00

ClinicalTrials.gov

NCT06093672

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy, Pharmacogenetic, Pharmacokinetic, Pharmacogenomic

The primary objective of the Core Treatment Phase is to demonstrate the superiority of givinostat vs HU on efficacy at Week 48. The primary objective of Extended Treatment Phase is to evaluate the long-term safety and tolerability of givinostat.

Secondary objectives 1

1. Safety, tolerability and efficacy parameters.

Conditions and MedDRA coding

JAK2V617F-positive high-risk Polycythemia Vera

Study design 2 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, Swedish Medical Products Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. To be eligible in the core treatment phase: 1. Patients must be able to provide informed consent and be willing to sign an ICF. 2. Patients must be 18 years of age or older. 3. Patients must have a diagnosis of PV confirmed according to the 2016 WHO criteria before randomization. 4. Patients must have JAK2V617F-positive disease. 5. Patients with PV must meet the definition for high risk of thrombosis within 3 years before screening (i.e., age > 60 years or prior thrombosis) 6. Patients must be in need of treatment at screening. 7. Patients must have normalized HCT (i.e., HCT < 45%) at randomization. 8. Patients must have an ECOG performance status ≤ 2 at screening.
2. 9. Patients must have a peripheral blood blast count of 0% at screening. 10. Female patients must be either postmenopausal, sterilized or, if of childbearing potential and sexually active, effectively practicing a highly effective method of contraception 11. Female patients of childbearing potential must agree to use highly effective contraception during the study and for at least 6 months after the last dose of study treatment if the patient received hydroxyurea. 12. Male patients must use condoms and ensure that they or their female partner(s) use a highly effective method of contraception as described above during the study and for at least 1 year after the last dose of study treatment if the patient received hydroxyurea 13. Male patients must be willing not to donate sperm during the study and for at least 1 year following the last study drug administration if the patient received hydroxyurea. 14. Patients must be willing and capable to comply with the requirements of the study. Please refer to Protocol, section 5.2 for detailed list of Inclusion criteria.
3. To be eligible in the extended treatment phase: 1. Patients must be able to provide informed consent and willing to sign an ICF.
4. 2. Patients must have completed the Week 48 visit of the DSC/08/2357/32 core treatment phase.
5. 3. Female patients must be either postmenopausal, sterilized or, if of childbearing potential and sexually active, effectively practicing a highly effective method of contraception.
6. 4. Female patients of childbearing potential must agree to continue to use highly effective contraception during the extended treatment phase.
7. 5. Male patients must continue to use condoms and ensure that they or their female partner(s) continue to use a highly effective method of contraception during the extended treatment phase.
8. 6. Male patients must be willing not to donate sperm during the extended treatment phase.
9. 7. Patients must be willing and capable to comply with the requirements of the study. Please refer to Protocol, section 5.2 for detailed list of Inclusion criteria

Exclusion criteria 11

1. 1. Patients pre-treated with HU with a documented history of resistance or intolerance to HU. 2. Patients with clinically significant bacterial, fungal, parasitic or viral infection that requires treatment 3. Patients with a positive test for hepatitis B virus surface antigen, hepatitis C virus antibodies (anti-HCV) or human immunodeficiency virus (HIV) antibodies at screening. 4. Patients diagnosed with primary immunodeficiency syndromes, e.g., X-linked agammaglobulinemia and common variable immune deficiency. 5. Patients with a QTcF value of > 450 msec for males and > 460 msec for females at the Screening visit (as the mean of 3 consecutive readings 5 minutes apart in the event a first ECG demonstrates a prolonged QTcF interval); congenital or acquired history of QTc prolongation or ventricular arrhythmias, at the Screening visit. 6. Patients with clinically significant cardiovascular disease, including uncontrolled hypertension, New York Heart Association Grade III or greater congestive heart failure, torsades de pointes (TdP) and hypokalemia at screening. 7. Patients with myocardial infarction, stroke or unstable angina within the 6 months prior to screening. 8. Splanchnic thrombosis and/or thrombosis of the cerebral venous sinuses and/or splenectomy in the medical history. 9. Patients with inadequate liver or renal function at screening.
2. 10. PLT count ≤ 150 × 109/L at screening (test may be repeated once). 11. ANC < 1.2 × 109/L at screening (test may be repeated once). 12. Uncontrolled hypertriglyceridemia at screening, i.e., triglycerides ˃ 1.5 × ULN (test may be repeated once). 13. Presence of other clinically significant disease that, in the Investigator’s opinion, could adversely affect the safety of the patient, making it unlikely that the course of treatment or FU is completed, or could impair the assessment of study results 14. History of major organ transplantation. 15. Patients with documented GI disease that may significantly alter the absorption of oral drugs. 16. Patients with an active malignancy over the 5 years prior to screening, except intraepithelial neoplasia, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, carcinoma in situ of the cervix or early-stage prostate cancer, treated and considered cured
3. 17. Previous treatment with a JAK2 or HDAC inhibitor or 32-phosphorus (radioactive isotope) therapy 18. Patients receiving treatment with interferon or pipobroman within the 5 weeks prior to screening 19. Patients receiving anagrelide within 7 days prior to screening. 20. Patients receiving busulfan or chlorambucil within 2 weeks prior to screening 21. Patients being treated concurrently with any investigational agent or prior participation in an interventional clinical trial within the 30 days prior to screening or within 5 half-lives of the investigational product, whichever is longer 22. Patients with known hypersensitivity to components of the study drugs 23. Pregnant or nursing (lactating) women Please refer to Protocol, section 5.3 for detailed list of exclusion criteria
4. Extended treatment phase: 1. Patients with known hypersensitivity to components of the study drug.
5. 2. Pregnant or nursing (lactating) women as assessed at Visit 15.
6. 3. Patients with a QTcF value at Week 48 of > 500 msec confirmed by central reading (for patients randomized to givinostat in the core treatment phase)
7. 4. PLT count ≤ 150 × 10^9/L at Week 48 (for patients randomized to HU in the core treatment phase).
8. 5. ANC < 1.2 × 10^9/L at Week 48 (for patients randomized to HU in the core treatment phase).
9. 6. Uncontrolled hypertriglyceridemia at Week 48, i.e., triglycerides ˃ 1.5 × ULN (for patients randomized to HU in the core treatment phase).
10. 7. Patients with a QTcF value at Week 48 of > 450 msec for males and > 460 msec for females confirmed by central reading; congenital or acquired history of QTc prolongation or ventricular arrhythmias, at Week 48.
11. 8. Being either resistant or intolerant to HU. Please refer to Protocol, section 5.3 for detailed list of exclusion criteria

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. Core treatment phase: Proportion of patients achieving a response at Week 48, with response assessment based on: • CHR defined as: HCT < 45% without phlebotomy in the previous 3 months, and WBC count ≤ 10 × 109/L, and PLT count ≤ 400 × 109/L and
2. • Normal spleen size as measured by imaging (i.e., MRI - recommended techique, or CT scan). Normal spleen size is defined as: a longitudinal diameter ≤ 12 cm for female and ≤ 13 cm for male, and
3. • From (Week 25 up to week 48), absence of: progressive disease (as defined in the revised ELN response criteria), major hemorrhagic events (as defined by the International Society on Thrombosis and Haemostasis) and major thrombotic events. Please refer to Protocol, section 3.1 for further details
4. Extended treatment phase: • Type, incidence and severity of TEAEs, including SAEs, TEAEs leading to discontinuation or deaths in eligible patients who continued in the extended treatment phase of the DSC/08/2357/32 study.

Secondary endpoints 7

1. Proportion of patients achieving a complete hematological response (CHR) at Week 48 based on: – HCT < 45% without phlebotomy in the previous 3 months, and – White blood cell (WBC) count ≤ 10 × 109/L, and – PLT count ≤ 400 × 109/L Please refer to Protocol, section 3.2 for further details
2. Time from randomization to the first observed CHR Please refer to Protocol, section 3.2 for further details
3. Proportion of patients with a normal spleen size at Week 48
4. Safety and tolerability. Please refer to Protocol, section 3.2 for further details
5. Long-term efficacy evaluated as: - Proportion of patients with a response at yearly assessment visits. - Duration of first CHR. Please refer to Protocol, section 3.2 for further details
6. Efficacy evaluated as: - time from randomization to first HCT response without phlebotomy in the previous 3 months; - time from randomization to first WBC response; - time from randomization to first PLT response up to week 48 and in patients with impairment for each parameter at baseline. Please refer to Protocol, section 3.2 for further details.
7. Changes from baseline in physical examination findings, Eastern Cooperative Oncology Group (ECOG) performance status and vital signs, electrocardiograms (ECGs) evaluations, serum chemistry, hematology, serology (if applicable) and urinalysis results. Please refer to Protocol, section 3.2 for further details

Investigational products

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

Test 3

Comparator 1

Auxiliary 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Italfarmaco S.p.A.

Sponsor organisation

Italfarmaco S.p.A.

Address

Via Dei Lavoratori 54

City

Cinisello Balsamo

Postcode

20092

Country

Italy

Scientific contact point

Organisation

Italfarmaco S.p.A.

Contact name

Mauricio Caserini

Public contact point

Organisation

Italfarmaco S.p.A.

Contact name

Paola Bettica

Third parties 10

Locations

11 EU/EEA countries · 54 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 162 files

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

Application history

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