AOU SS Antonio e Biagio e Cesare Arrigo di Alessandria - Sindromi mieloprofliferative

MK3543-007

A Phase 3, Randomized, Double-blind, Active-Comparator-Controlled Clinical Study to Evaluate the Efficacy and Safety of Bomedemstat (MK-3543) versus Hydroxyurea in Cytoreductive Therapy Naïve Essential Thrombocythemia Participants

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Trattamento: Bomedemstat

Sindromi MIELOPROLIFERATIVE CRONICHE target: Essential Thrombocythemia

Principali Criteri Inclusione:

1. Based on the WHO diagnostic criteria for myeloproliferative neoplasms has a diagnosis of ET and an indication for cytoreductive therapy regardless of age or risk status. Indications for cytoreductive therapy include but are not limited to:

• High-risk patients (history of thrombosis at any age; or age >60 years with JAK2 V617F mutation),

• Acquired VWD and/or disease-related major bleeding,

• Splenomegaly (defined as a spleen volume greater than 450 mm3),

• Progressive thrombocytosis and/or leukocytosis,

• Disease-related symptoms (eg, pruritis, fatigue, night sweats), and

• Vasomotor/microvascular disturbances not responsive to ASA (eg, erythromelalgia, headaches/chest pain).

2. Has a bone marrow fibrosis score of Grade 0 or Grade 1, as per a modified version of the European Consensus Criteria for Grading Myelofibrosis (Appendix 10).

3. Has received no prior cytoreductive treatment for their ET.

4. Has a platelet count of >450 × 109/L (450k/μL) assessed up to 72 hours before first dose of study intervention.

5. Has an ANC ≥0.75 × 109/L assessed up to 72 hours before first dose of study intervention.

6. Has a life expectancy of >52 weeks in the opinion of the investigator.

13. Has an ECOG Performance Status of 0 to 2 assessed within 7 days before the start of study intervention

Principali Criteri Esclusione:

3. Evidence at the time of Screening of increased risk of bleeding, including any of the following:

- History of severe thrombocytopenia or platelet dysfunction unrelated to a myeloproliferative disorder or its treatment.

- Known hereditary bleeding disorder (eg, dysfibrinogenemia, factor IX deficiency, hemophilia, VWD, disseminated intravascular coagulation, fibrinogen deficiency, or other clotting factor deficiency).

- Active or chronic bleeding within 8 weeks before randomization.

- An autoimmune disorder causing bleeding.

4. History of a malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years

A Phase 3, Randomized, Open-label, Active-Comparator-Controlled Clinical Study to Evaluate the Safety and Efficacy of Bomedemstat (MK-3543/IMG-7289) versus Best Available Therapy (BAT) in Participants With Essential Thrombocythemia who have an Inadequate Response to or are Intolerant of Hydroxyurea.

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SCDU Ematologia, AOU SS Antonio e Biagio e Cesare Arrigo - Alessandria

Sindromi MIELOPROLIFERATIVE CRONICHE target: TROMBOCITEMIA ESSENZIALE

Studio di fase 3

Principali Criteri Inclusione:

1. Has a diagnosis of ET per WHO 2016 diagnostic criteria for myeloproliferative neoplasms (Appendix 9).

2. Has a bone marrow fibrosis score of Grade 0 or Grade 1, as per a modified version of the European Consensus Criteria for Grading Myelofibrosis (Appendix 11)

3. Has a history of inadequate response to or intolerance of hydroxyurea per at least 1 of the following criteria, based on modified ELN criteria for hydroxyurea resistance or intolerance [Barosi, G., et al 2007]

• Hydroxyurea Resistance (or Inadequate Response):

- Platelet count >600 × 109/L after 3 months of at least 2 g/day or MTD of hydroxyurea, or

- Platelet count >400 × 109/L and WBC <2.5 ×109/L at any dose and duration of hydroxyurea, or

- Platelet count >500 × 109/L and Hb <10 g/dL at any dose and duration of hydroxyurea, or

- Platelet count >450 × 109/L at any dose and duration of hydroxyurea if the above criteria are not met.

• Hydroxyurea Intolerance:

- ANC <1 × 109/L, or platelet count <150 × 109/L, or Hb <10 g/dL at the lowest dose of hydroxyurea to achieve a hematologic remission, defined as platelet count ≤400 × 109/L and WBC <10 × 109/L

- Unacceptable hydroxyurea-related non-hematologic toxicities (eg, pulmonary toxicities such as pneumonitis, fibrosis and allergic alveolitis; hepatotoxicity; hemolytic anemia; vasculitic toxicities; mucocutaneous manifestations; precancerous or cancerous skin lesions; gastrointestinal symptoms; or fever) at a dose of hydroxyurea needed to achieve CHR defined as:

◦ Toxicity that recurred after rechallenge with hydroxyurea

◦ Toxicity requiring permanent discontinuation of hydroxyurea

◦ Toxicity with intensity of Grade 4 (CTCAE v5.0) lasting >1 week

◦ Toxicity with intensity of Grade 3 (CTCAE v5.0) lasting >2 weeks

4. Has an inadequate or loss of response to their most recent prior ET therapy, requiring a change of cytoreductive therapy, as demonstrated by one of the following [National Comprehensive Cancer Network 2022]:

• Intolerance or inadequate response to hydroxyurea, formulations of interferon alfa, or anagrelide

• New thrombosis or disease-related major bleeding (eg, acquired Von Willebrand’s disorder)

• Progressive thrombocytosis (platelet count >600 × 109/L)

• Progressive leukocytosis (WBC >11 × 109/L)

• Uncontrolled disease-related symptoms (for study purposes this has been defined as a single symptom score of MFSAF v4.0 ≥4)

• Vasomotor/microvascular disturbances not responsive to aspirin (eg, headaches, chest pain or erythromelalgia)

5. Has a platelet count > 450 × 109/L (450k /μL) assessed up to 72 hours before first dose of study intervention

6. Has an ANC ≥0.75 × 109/L assessed up to 72 hours before first dose of study intervention

7. Has a life expectancy of >52 weeks

8. Participants may have received up to 3 prior lines of therapy including hydroxyurea.

15. Has an ECOG Performance Status of 0 to 1 assessed within 7 days before the start of study intervention.

Principali Criteri Esclusione:

3. Evidence at the time of Screening of increased risk of bleeding, including any of the following:

- History of severe thrombocytopenia or platelet dysfunction unrelated to a myeloproliferative disorder or its treatment.

- Known hereditary bleeding disorder (eg, dysfibrinogenemia, factor IX deficiency, hemophilia, VWD, disseminated intravascular coagulation, fibrinogen deficiency, or other clotting factor deficiency).

- Active or chronic bleeding within 8 weeks before randomization.

- An autoimmune disorder causing bleeding.

4. History of a malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years

A Randomized Open-Label, Phase 3 Study to Evaluate Imetelstat (GRN163L) Versus Best Available Therapy (BAT) in Patients with Intermediate-2 or High-risk Myelofibrosis (MF) Refractory to Janus Kinase (JAK)-Inhibitor

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SCDU Ematologia, AOU SS Antonio e Biagio e Cesare Arrigo - Alessandria

Sindromi MIELOPROLIFERATIVE CRONICHE target: MIELOFIBROSI

Studio di fase 3

Criteri di inclusione: diagnosi di mielofibrosi (primitiva o secondaria a TE/PV) con DIPSS intermedio-2 o alto, refrattarietà a JAK-inibitori, sintomatologia presente e splenomegalia

MK3543-017

A Multicenter, Open-Label, Extension Study Evaluating the Safety and Efficacy of Bomedemstat for the Treatment of Participants Enrolled in a Prior Bomedemstat Clinical Study

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Trattamento: Bomedemstat

Sindromi MIELOPROLIFERATIVE CRONICHE target: Essential Thrombocythemia – Myelofibrosis

Principali Criteri Inclusione:

1. Participant is from a bomedemstat study sponsored by Imago Biosciences, Inc. (a subsidiary of Merck & Co., Inc.) or MSD (feeder study) established by the Sponsor as MK-3543-017 ready.

2. Participants from the IMG-7289-202/MK-3543-005 study must have received at least 6 months of treatment with bomedemstat, must be safely tolerating bomedemstat, and must be receiving clinical benefit from its use in the estimation of the investigator.

3. ET and PV participants from established feeder studies other than IMG-7289-202/MK-3543-005 must have achieved confirmed hematologic remission, must be safely tolerating bomedemstat, and must be receiving clinical benefit from its use in the estimation of the investigator.

GRN163LMYF3001

Randomized Open-Label, Phase 3 Study to Evaluate Imetelstat (GRN163L) Versus Best Available Therapy (BAT) in Patients with Intermediate-2 or High-risk Myelofibrosis (MF) Refractory to Janus Kinase (JAK)-Inhibitor

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Trattamento: Imetelstat

Sindromi MIELOPROLIFERATIVE CRONICHE target:  Myelofibrosis

Principali Criteri Inclusione:

1. ≥18 years of age.

2. Diagnosis of PMF according to the revised WHO criteria or PET-MF or PPV-MF according to the IWG-MRT criteria confirmed by local pathology report. DIPSS intermediate-2 or high-risk MF.

4. Refractory to JAK-inhibitor treatment as defined in either inclusion 4.1 or 4.2:

4.1: Treatment with JAK-inhibitor for ≥ 6 months duration, including at least 2 months at an optimal dose as assessed by the investigator for that participant and ONE of the following:

a) no decrease in spleen volume (< 10% by MRI or CT) from the start of treatment with JAK-inhibitor.

b) no decrease in spleen size (< 30% by palpation or length by imaging) from start of treatment with JAK-inhibitor

c) no decrease in symptoms (< 20% by MFSAF or myeloproliferative neoplasm SAF) from start of treatment with JAK-inhibitor.

d) a score of at least 15 on TSS assessed using the MFSAF v4.0 (adapted as the MF Symptom Recall Form, Section 18.6) during screening. For patients on JAK-inhibitor at time of signing the informed consent form (ICF), this symptom assessment should be performed prior to tapering.

4.2: Treatment with JAK-inhibitor treatment for ≥ 3 months duration with maximal doses (e.g., 20-25 mg twice daily ruxolitinib) for that participant and no decrease in spleen volume/size or symptoms as defined in inclusion criterion 4.1 (a, b, or c).

5. Measurable splenomegaly demonstrated by a palpable spleen measuring ≥ 5 cm below the left costal margin or a spleen volume ≥ 450 cm3 by MRI or CT.

6. Active symptoms of MF on the MFSAF v4.0 (adapted as the MF Symptom Recall Form) demonstrated by a symptom score of at least 5 points (on a 0 to 10 scale) on at least 1 of the symptoms or a score of 3 or greater on at least 2 of the following symptoms: fatigue, night sweats, itchiness, abdominal discomfort, pain under ribs on left side, early satiety, and bone pain.

9. Eastern Cooperative Oncology Group Performance Status score of 0-2

Principali Criteri Esclusione:

1. Peripheral blood blast count of ≥ 10% or bone marrow blast count of ≥ 10%.

2. Known allergies, hypersensitivity, or intolerance to imetelstat or its excipients.

3. Prior treatment with imetelstat.

4. Any chemotherapy or MF directed therapy, including investigational drug regardless of class or mechanism of action, immunomodulatory or immunosuppressive therapy, corticosteroids > 30 mg/day prednisone or equivalent, and JAK-inhibitor treatment ≤ 14 days prior to randomization.

6. Diagnosis or treatment for malignancy other than MF except: • Malignancy treated with curative intent and with no known active disease present for ≥ 3 years before randomization.

• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.

• Adequately treated cervical carcinoma in situ without evidence of disease.

7. Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification.

ROPEG-PV

Observational study on the use of ropeginterferon alfa-2b in polycythemia vera

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Trattamento: ropeginterferon alfa-2b

Sindromi MIELOPROLIFERATIVE CRONICHE target: Polycythemia Vera

Criteri Inclusione:

1. Patients diagnosed with Polycythemia Vera by WHO 2016

2. Patient aged ≥ 18 years old

3. Patients in need of cytoreductive treatments with ropeginterferon alfa-2b in first or later lines according to the reimbursability criteria defined by the Italian National Health System

4. Patients who have signed the written informed consent for study participation.

IN ATTIVAZIONE

KRT-232-115

A Phase 3, Randomized, Double-blind, Add-on Study Evaluating the Safety and Efficacy of Navtemadlin Plus Ruxolitinib vs Placebo Plus Ruxolitinib in Patients with Myelofibrosis Who Have a Suboptimal Response to Ruxolitinib

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Trattamento: Navtemadlin, Ruxolitinib

Sindromi MIELOPROLIFERATIVE CRONICHE target: Myelofibrosis

Principali Criteri Inclusione:

Ruxolitinib Run-in Period

1. Adults ≥ 18 years of age able to provide informed consent.

2. Confirmed diagnosis of PMF, post-PV MF, or post-ET MF, as assessed by the treating physician according to the World Health Organization (WHO) criteria.

3. IPSS risk category of Intermediate-1, Intermediate-2, or High.

4. Spleen measuring ≥ 450 cm3 by MRI or CT scan (central review).

5. MF symptoms as defined by a baseline TSS of ≥ 10. Baseline TSS will be calculated as a 7-day average per MFSAF v4.0.

6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

7. Adequate hematological, hepatic, and renal organ function

Randomized Period

1. PMF, post-PV MF, or post-ET MF that is TP53WT as assessed by central testing.

2. Treatment with ruxolitinib monotherapy for ≥ 18 weeks but < 25 weeks and on a stable dose of ruxolitinib in the 8 consecutive weeks prior to study treatment.

3. Suboptimal response to standard of care ruxolitinib monotherapy, defined as SVR of > 0% but < 35% and TSS reduction of > 0% but < 50%, assessed from the start of the run-in period baseline to the end of the run-in period

Principali Criteri Esclusione:

Ruxolitinib Run-in Period

1.Participation in another interventional clinical trial within four weeks prior to the first dose of ruxolitinib monotherapy (participation in observational studies is permitted).

2. Prior therapy with any JAK inhibitor.

3. Prior therapy with BCL-XL, BET, MDM2, PI3K, PIM, or XPO1 inhibitors; prior p53-directed therapy. Subjects must have discontinued all drugs (including hydroxyurea) used to treat underlying MF ≥ 28 days prior to first dose of ruxolitinib monotherapy. Erythroid growth factors, danazol (or equivalent androgen), or prednisone (or equivalent corticosteroid) are permitted if the subject is on a stable dose for at least two months prior to starting ruxolitinib.

4. Prior splenectomy.

5. Splenic irradiation within three months prior to the first dose of ruxolitinib monotherapy.

6. Non-spleen-directed radiation therapy for MF or major surgery or planned major surgery within 28 days prior to the first dose of ruxolitinib monotherapy.

7. Prior allogeneic stem-cell transplantation or eligible for allogeneic stem cell transplantation. Subjects who are eligible for stem cell transplant but refuse transplant are not excluded.

8. Peripheral blood or bone marrow blast count ≥ 10% at any time within 28 days prior to the first dose of ruxolitinib monotherapy

Randomized Period

1. White blood cell count that meets both of the following criteria:

a. Increases by two-fold (ie, doubles) or more during therapy with ruxolitinib monotherapy (comparing baseline prior to the run-in period vs pre-randomization) and

b. Exceeds 50 × 109/L at pre-randomization.

2. Active treatment with BCL-XL, BET, MDM2, PI3K, PIM, or XPO1 inhibitors, or p53-directed therapy.

SLN124-004

Phase 1/2 study with an open-label dose escalation phase followed by a randomized, double-blind phase of SLN124 in patients with Polycythemia Vera

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Trattamento: SLN124

Sindromi MIELOPROLIFERATIVE CRONICHE target: Polycythemia Vera

Principali Criteri Inclusione:

1. Male and female patients aged 18 years or older.

2. A confirmed diagnosis of PV according to the revised 2016 WHO criteria

3. Prior to dosing, patients must have had ≥ 3 phlebotomies in the last 28 weeks, or 5 or more phlebotomies in the last 12 months, with documented raised Hct and/or documented presentation of symptoms of PV.

4. Records of phlebotomies and associated Hct performed for at least 28 weeks, or if available, for up to 12 months, prior to dosing, and any of the following associated data; soluble transferrin receptor 1 [sTfR1], ferritin or transferrin saturation [TSAT], if available.

5. Patients must have Hct < 43% prior to dosing. Hct test can be repeated during the screening period.

6. Patients who are not receiving cytoreductive therapy must have been discontinued from any prior cytoreductive therapy for at least 24 weeks before dosing and have recovered from any adverse events due to cytoreductive therapy.

7. Patients receiving cytoreductive therapy with hydroxyurea, interferon, busulfan or ruxolitinib must have received a stable dose of cytoreductive therapy for at least 12 weeks before dosing and with no planned change in cytoreductive dose

13. Patients must have had a dermatological examination within 6 months prior to screening or during screening.

14. Must have an Eastern Cooperative Oncology Group score of 0, 1, or 2.

Principali Criteri Esclusione:

3. Clinically significant thrombosis (e.g., deep vein thrombosis or splenic vein thrombosis) within 12 weeks of screening.

4. History of major bleeding events and/or a requirement for blood transfusion therapy owing to bleeding in the last 6 months prior to screening.

5. Meets the criteria for post-PV myelofibrosis as defined by the International Working Group-Myeloproliferative Neoplasms Research and Treatment