HOVON 172 MF: Study on tasquinimod treatment in patients with myelofibrosis

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04], Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

12 Feb 2025 → ongoing

Decision date (initial)

2024-10-23

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Oncode · Active Biotech

External identifiers

EU CT number

2024-511565-11-00

ClinicalTrials.gov

NCT06605586

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

Phase 1b:
- To assess the feasibility and safety of once daily dose of tasquinimod in subjects who are JAK inhibitor refractory or intolerant and with a current diagnosis of primary myelofibrosis (PMF), postpolycythemia vera myelofibrosis (post-PV MF), or post-essential thrombocythemia myelofibrosis (post-ET MF)
- To determine the dose limiting toxicity (DLT) of tasquinimod and recommended phase 2 dose level (RP2D) for the phase 2 part of this study

Phase 2:
- To evaluate the efficacy of once daily dose of tasquinimod in subjects who are JAK inhibitor refractory or intolerant and with a current diagnosis of primary myelofibrosis (PMF), postpolycythemia vera myelofibrosis (post-PV MF), or post-essential thrombocythemia myelofibrosis (post-ET MF) based on the reduction of spleen volume (SVR≥ 35%) measured by MRI after 32 weeks (SVR35W32).

Secondary objectives 10

1. To evaluate the splenic response to tasquinimod by palpation after 12 weeks on the RP2D
2. To evaluate the splenic response to tasquinimod by palpation after 24 weeks on the RP2D
3. To evaluate the durability of splenic response defined as ≥50% spleen reduction from baseline assessed by palpation
4. To evaluate the splenic response defined as ≥35% spleen volume reduction from baseline (SVR35) (as determined by MRI) after 12 weeks on the RP2D
5. To evaluate overall survival
6. To evaluate the safety and tolerability of tasquinimod in this population
7. To evaluate the effect of tasquinimod on Myelofibrosis (MF) associated symptoms as measured by the modified Myeloproliferative Neoplasm (MPN) Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) questionnaire
8. To evaluate changes in hematopoiesis and reduction of bone marrow fibrosis after 32 weeks
9. To evaluate effect of treatment on anemia and red blood cell transfusion support
10. To evaluate the effect of tasquinimod on the variant allele frequency (VAF) of the driver mutations (the Janus kinase 2 (JAK2), CaLR and MPL mutations)

Conditions and MedDRA coding

Myelofibrosis

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. 1 Diagnosis of PMF or Post-PV MF or Post-ET MF based on a bone marrow (BM) biopsy not older than 6 months, according to the 2016 World Health Organization (appendix A)
2. 2 Refactory or intolerant to treatment with an approved JAK inhibitor or ineligible for JAK inhibitor treatment (appendix G)
3. 3 MF classified as Intermediate-1 with disease-related symptoms (e.g. symptomatic splenomegaly), Intermediate-2 or high-risk by Dynamic International Prognostic Scoring System Plus (Passamonti et al., Blood 2010) (Appendix C)
4. 4 Spleen ≥5 cm below costal margin as measured by palpation
5. 5 Age ≥18 years
6. 6 Peripheral blood blast count of <10%
7. 7 WHO/ECOG performance status of 0,1, or 2
8. 8 Able to swallow and retain oral medication
9. 9 Willing and able to comply with scheduled visits, treatment plan and laboratory tests
10. 10 Negative pregnancy test at study entry for women of childbearing potential
11. 11 Women of child-bearing potential and sexually active males must be willing and able to use highly effective methods of contraception, during treatment, and for 4 months and 6 months respectively, after study treatment (see section 9.2.3)
12. 12 Patient is capable of giving informed consent
13. 13 Written informed consent

Exclusion criteria 27

1. 1 Patients eligible for hematopoietic stem cell transplantation (suitable candidate and a suitable donor is available)
2. 11 Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of tasquinimod (e.g., ulcerative diseases, pancreatitis uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection)
3. 12 Evidence of severe or currently uncontrolled cardiovascular condition (e.g. cardiac amyloidosis, pulmonary embolism, angina, hypertension, peripheral vascular disease, congestive heart failure class III or IV of the NYHA classification (appendix F), cardiac arrhythmia, acute coronary syndrome, myocardial infarction, cerebrovascular accident, major hemorrhage, intracranial hemorrhage, transient ischemic attack, or limb claudication) within 6 months prior to registration
4. 13 Patients with clinically significant bacterial, fungal, parasitic or viral infection which require therapy. Patients with acute bacterial infections requiring antibiotic use should delay screening/ enrollment until the course of antibiotic therapy has been completed
5. 14 Any chemotherapy, immunomodulatory drug therapy (eg, thalidomide, interferon-alpha), anagrelide, immunosuppressive therapy, corticosteroids >10 mg/day prednisone or equivalent, or growth factor treatment (eg, erythropoietin), or hormones (eg, androgens, danazol) within 2 weeks prior to initiation of tasquinimod. The only chemotherapy allowed will be hydroxyurea which has to be stopped within 1 day prior to initiation of tasquinimod
6. 15 Treatment with fedratinib within 7 days, or momelotinib within 2 days prior to initiation of tasquinimod. For ruxolitinib no wash-out period is required before start of tasquinimod
7. 16 Any investigational treatment for MF within 2 weeks or 5 half-lives whichever is shorter
8. 17 History of severe hypersensitivity reaction to any component of tasquinimod
9. 18 Systemic treatment within 14 days prior to the initiation of tasquinimod with any of the moderate or strong inhibitor, or moderate or strong inducer of cytochrome P-3A4 (CYP3A4) listed in appendix H
10. 19 Need for ongoing therapy with drug substances of narrow therapeutic range that are metabolized mainly by CYP3A4 as listed in appendix H
11. 20 Need for ongoing therapy with drug substances of narrow therapeutic range metabolized mainly by CYP1A2 as listed in appendix H
12. 2 Splenectomy
13. 21 Ongoing treatment with vitamin K antagonist, unless the INR is ≤ 3.0
14. 22 Prior treatment with tasquinimod
15. 23 Major surgery within 3 months
16. 24 Pregnant or breast feeding (lactating) women
17. 25 Any other condition that would, in the Investigator’s judgment, contraindicate subject’s participation in the clinical study due to safety concerns or compliance with clinical study procedures e.g. any uncontrolled disease such as pulmonary disease, infection or seizure disorder; intestinal obstruction, inability to swallow medication, any altered mental status or psychiatric condition that would interfere with the understanding of the informed consent
18. 26 Current participation (during interventional treatment) in another clinical trial
19. 27 Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule
20. 3 Splenic irradiation within the last 6 months
21. 4 Prior allogeneic stem cell transplantation
22. 5 Following laboratory values within 14 days prior to registration: - Absolute Neutrophil Count (ANC) <0.5 x 109/L without G-CSF support - Platelet count <25 x 109/L without platelet transfusion - Serum creatinine >1.5 x Upper limit of normal (ULN) or GFR <30 ml/min - Serum amylase and lipase >1.5 x ULN - Alanine aminotransferase (ALT) ≥2.5 x ULN - Total bilirubin >1.5 times the upper limit of the normal range (ULN), unless elevated bilirubin is due to unconjugated hyperbilirubinemia from Gilbert’s syndrome or related to MF
23. 6 Known active (acute or chronic) Hepatitis A, B, or C; and Hepatitis B and C carriers, HIV
24. 7 Prior history of chronic liver disease (eg, chronic alcoholic liver disease, autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis, hemachromatosis)
25. 9 Patients with any other prior malignancies are not eligible, except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which subject has been disease-free for at least 5 years
26. 10 Failure to have fully recovered (i.e. to CTCAE Grade 1 or previous baseline) from clinically significant adverse effects of prior chemotherapy (examples of adverse effects that are not clinically significant include alopecia and lymphopenia)
27. 8 Previous history of pancreatitis or risk factors for pancreatitis (eg, non-alcoholic fatty liver disease (NAFLD), history of alcohol abuse, hypertriglyceridaemia).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Phase 1b: Dose limiting toxicity (DLT), as defined in section 7.1 and recommended phase 2 dose level (RP2D), as defined in section 7.2
2. Phase 2: Proportion of participants with at least 35% reduction in spleen volume from baseline at Week 32 (SVR35W32) as measured by magnetic resonance imaging (MRI), per International Working Group (IWG) criteria, based on MRI review

Secondary endpoints 9

1. Proportion of participants with at least 50% reduction in palpable splenomegaly from baseline per IWG criteria
2. Proportion of patients with at least 35% reduction in spleen volume from baseline (SVR35) as measured by MRI, per IWG criteria, based on MRI review
3. Overall survival, as defined from date of registration until date of death from any cause. Participants still alive at the date last contact, will be censored
4. Safety, as assessed by clinical, laboratory, and vital sign events; graded by the NCI CTCAE v5
5. Proportion of participants with at least 50% reduction in total symptom score (TSS) after 32 weeks from baseline as measured by MPN-SAF TSS
6. Reduction in grade of bone marrow fibrosis from baseline as measured by the European consensus grading system
7. Anemia response per IWG criteria
8. Red blood cell (RBC) transfusion (number of packed cells) during tasquinimod treatment
9. The effect of tasquinimod on the allelic burden of the driver mutations

Investigational products

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

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

Sponsor organisation

Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

Address

Dr. Molewaterplein 40

City

Rotterdam

Postcode

3015 GD

Country

Netherlands

Scientific contact point

Organisation

Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

Contact name

Dr. P.A.W. te Boekhorst

Public contact point

Organisation

Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

Contact name

HOVON

Third parties 4

Locations

2 EU/EEA countries · 6 investigational sites

By country

Investigational sites

Country notifications

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

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 1 · Art. 38 CTR

Results and documents

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

Documents 11 files

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

Application history

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