Main info

Identificatie:

HOVON 172 MF

Sponsor:

HOVON

Working group party:

CML/MPN

Stadium:

2de lijn

Echelon:

Level A

Active sites:

0

(of 1)

6 sites are pending

Title:

Timeline

Details

Phase:

Prospective Phase I/II study

Monitoring Type:

HOVON Monitoring Visit

Objectives:

Phase 1b
Primary objectives:

• 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 confirm that the current dose can be used in the phase 2 part of this study

Phase 2
Primary objective:

• 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 (or CT scan/Echo) after 24 weeks (SVR35W24).

Secondary objectives:

• To evaluate the splenic response to tasquinimod by palpation after 12 weeks.
• To evaluate the splenic response to tasquinimod by palpation after 24 weeks.
• To evaluate the durability of splenic response defined as ≥50% spleen reduction from baseline assessed by palpation.
• To evaluate the splenic response defined as ≥35% spleen volume reduction from baseline (SVR35) (as determined by MRI (or CT scan/Echo)) after 12 weeks.
• To evaluate overall survival.
• To evaluate the safety and tolerability of tasquinimod in this population.
• 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.
• To evaluate changes in hematopoiesis and reduction of bone marrow fibrosis after 24 weeks.
• To evaluate effect of treatment on anemia and red blood cell transfusion support.
• To evaluate the effect of tasquinimod on the variant allele frequency (VAF) of the driver mutations (the Janus kinase 2 (JAK2), CaLR, or MPL mutations).

Eligibility

Inclusion Criteria:

In order to be eligible to participate in this study, a patient must meet all of the following criteria:

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. Refactory or intolerant to treatment with an approved JAK inhibitor or ineligible for JAK inhibitor treatment (appendix G).
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. Spleen ≥5 cm below costal margin as measured by palpation.
5. Age ≥18 years.
6. Peripheral blood blast count of <10%.
7. WHO/ECOG performance status of 0, 1, or 2.
8. Able to swallow and retain oral medication.
9. Willing and able to comply with scheduled visits, treatment plan and laboratory tests.
10. Negative pregnancy test at study entry for women of childbearing potential.
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 3 months after study treatment (see section 9.2.3).
12. Patient is capable of giving informed consent.
13. Written informed consent.

Exclusion Criteria:

A patient who meets any of the following criteria cannot be included in this study:

1. Patients eligible for hematopoietic stem cell transplantation (suitable candidate and a suitable donor is available).
2. Splenectomy.
3. Splenic irradiation within the last 6 months.
4. Prior allogeneic stem cell transplantation.
5. Following laboratory values within 14 days prior to registration:
1. Absolute Neutrophil Count (ANC) <0.5 x 109/L without G-CSF support
2. Platelet count <25 x 109/L without platelet transfusion
3. Serum creatinine >1.5 x Upper limit of normal (ULN) or GFR <30 ml/min
4. Serum amylase and lipase >1.5 x ULN
5. Alanine aminotransferase (ALT) ≥2.5 x ULN
6. 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
6. Known active (acute or chronic) Hepatitis A, B, or C; and Hepatitis B and C carriers, HIV.
7. Prior history of chronic liver disease (eg, chronic alcoholic liver disease, autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis, hemachromatosis).
8. 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.
9. 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).
10. 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).
11. 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.
12. 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.
13. 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; erythropoetin use within 28 days 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.
14. 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.
15. Any investigational treatment for MF within 2 weeks or 5 half-lives whichever is shorter.
16. History of severe hypersensitivity reaction to any component of tasquinimod.
17. 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.
18. Need for ongoing therapy with drug substances of narrow therapeutic range that are metabolized mainly by CYP3A4 as listed in appendix H.
19. Need for ongoing therapy with drug substances of narrow therapeutic range metabolized mainly by CYP1A2 as listed in appendix H.
20. Ongoing treatment with vitamin K antagonist, unless the INR is ≤ 3.0.
21. Prior treatment with tasquinimod.
22. Major surgery within 3 months.
23. Pregnant or breast feeding (lactating) women.
24. 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
25. Current participation (during interventional treatment) in another clinical trial. consent
26. Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

Registration Details

Participating Sites

= Active hospitals

= Inactive hospitals