AOU Città della Salute e della Scienza di Torino - Sindromi mieloprofliferative

CAMN107AIT15 -DANTE: A phase II, single-arm, multicenter study of full treatment-free remission in patient with chronic myeloid leukemia in chronic phase treated with nilotinib in first-line therapy who have archived a sustained deep molecular response for at leats 1 year

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Sindromi MIELOPROLIFERATIVE CRONICHE target: LEUCEMIA MIELOIDE CRONICA

Inclusion Criteria

1) Diagnosis of CP-CML according to the WHO and no previous history of progression to AP/BP CML.
2) First-line treatment with nilotinib for at least 3 calendar years, followed by first TFR attempt.
3) Failed first TFR attempt followed by at least 1 year of nilotinib retreatment before enrollment in TFR2 stage.
3) MR4 or better (BCR-ABL ≤ 0.01% IS) assessed at screening.
4) Patient must meet the following laboratory
a. Absolute neutrophil count ≥1.0 x 109/L
b. Platelets ≥75 x 109/L
c. Hemoglobin (Hgb) ≥ 9 g/dL
d. Serum creatinine < 1.5 mg/dL
e. Total bilirubin ≤ 2 x ULN except for patients with Gilbert’s syndrome who may only be included if total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN
f. AST and ALT ≤ 3.0 x ULN
g. ALP ≤ 2.5 x ULN
h. Serum lipase ≤ 1.5 x ULN.
j. Serum levels of potassium, magnesium, total calcium within the normal limits. Correction of electrolytes levels with supplements to fulfil enrolment criteria is allowed.

Exclusion criteria

1) Patients with known atypical transcript.
2) CML treatment resistant mutation(s) (T315I, E255K/V, Y253H, F359C/V) detected if testing was done in the past (there is no requirement to perform mutation testing at study entry if it was not done in the past).
3) Dose reductions/interruptions due to neutropenia or thrombocytopenia in the past 6 months
4) History of acute pancreatitis within 1 year prior to study entry or past medical history of chronic pancreatitis
5) Patients actively receiving therapy with strong CYP3A4 inhibitors and/or inducers, and the treatment cannot be either discontinued or switched to a different medication prior to study entry.

Randomized, open-label, multicenter phase 3 study to assess the efficacy and safety of GIVinostat versus hydroxyurea IN JAK2V617F-positive high-risk Polycythemia Vera patients: the GIV-IN PV TRIAL (DSC/08/2357/32)

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AOU Città della Salute e della Scienza di Torino, SC Ematologia Universitaria - P.O. Molinette

Sindromi MIELOPROLIFERATIVE CRONICHE target: POLICITEMIA VERA

Inclusion Criteria
To be eligible for inclusion in this study, patients must meet all the following inclusion criteria:

• Patients (or their legally authorized representative) must be able to provide informed consent and willing to sign an ICF.
• Patients must be 18 years of age or older.
• Patients must have been diagnosed with PV according to the 2016 WHO criteria within 3 years before randomization.
• Patients must have JAK2V617F-positive disease.
• Patients with PV must meet the definition of HR for thrombosis (i.e., HR) at screening as follows:
  – Age > 60 years, and/or
  – Prior thrombosis.
• Patients must be in need of treatment at screening, defined by the presence of at least one of the following:
  – HCT ≥ 45% or HCT < 45% with at least 1 phlebotomy performed in the 3 months before screening, or
  – WBC count > 10 × 109/L, or
  – PLT count > 400 × 109/L.
  In addition, patients pre-treated with HU must not have a documented history of resistance or intolerance to HU (see exclusion criterion 1).
• Patients must have normalized HCT (i.e., HCT < 45%) at randomization
• Patients must have an ECOG performance status ≤ 2 at screening.
• Patients must have a peripheral blood blast count of 0% at screening.
• Female patients must be either postmenopausal, sterilized or, if of childbearing potential and sexually active, effectively practicing a highly effective method of contraception (either oral, parenteral, intravaginal, transdermal, injectable or implantable hormonal contraceptives; intrauterine device; intrauterine hormone-releasing system, bilateral tubal occlusion; vasectomized/sterilized partner; or sexual abstinence).
• 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.
• Male patients must use condoms and ensure that they or their female partner(s) use a highly effective method of contraception as described in inclusion criterion 10 during the study and for at least 1 year after the last dose of study treatment if the patient received hydroxyurea.
• Male patients must not donate sperm during the study and for at least 1 year following the last study drug administration if the patient received hydroxyurea.
• Patients must be willing and capable to comply with the requirements of the study.

Exclusion criteria

To be eligible for this study, patients must not meet any of the following criteria:

• Patients pre-treated with HU with a documented history of resistance or intolerance to HU defined by the original ELN criteria as:
  - Need for phlebotomy to keep HCT < 45% after 3 months of at least 2 g/day of HU OR
  – Uncontrolled myeloproliferation, defined as PLT count > 400 × 109/L and WBC count > 10 × 109/L after 3 months of at least 2 g/day of HU OR
  – Failure to reduce massive splenomegaly (defined as organ extending by ˃10 cm from the costal margin) by more than 50% as measured by palpation after 3 months of at least 2 g/day of HU OR
  – ANC < 1 × 109/L or Hb level < 100 g/L or PLT count < 100 × 109/L at the lowest dose of HU required to achieve a CR or PR, as assessed by ELN response criteria
  OR
  – Presence of leg ulcers or other unacceptable HU-related non-hematologic toxicities e.g., muco-cutaneous manifestations, GI symptoms, pneumonitis or fever at any HU dose.
• Patients with clinically significant bacterial, fungal, parasitic or viral infection that requires treatment.
• 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.
• Patients diagnosed with primary immunodeficiency syndromes, e.g., X-linked agammaglobulinemia and common variable immune deficiency.

• 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.

• 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.

• Patients with myocardial infarction, stroke or unstable angina within the 6 months prior to screening.

• Splanchnic thrombosis and/or thrombosis of the cerebral venous sinuses and/or splenectomy in the medical history.

• Patients with inadequate liver or renal function at screening, as demonstrated by any of the following:

  – Encephalopathy grade 2 or higher as per the Child-Pugh System
  – Known hepatocellular disease, including active hepatitis B virus or HCV infection,cirrhosis or other hepatocellular disease
  – Total serum bilirubin > 1.5 × ULN, except in case of documented Gilbert’s disease
  or pattern consistent with Gilbert’s disease (test may be repeated once)
  – Serum aspartate aminotransferase/alanine aminotransferase (AST/ALT) levels> 3 × ULN (test may be repeated once)
  – Serum creatinine levels > 2 × ULN (test may be repeated once)
  – Serum cystatin C levels > 2 × ULN for 2 subsequent evaluations (i.e., if the value of serum cystatin C is > 2 × ULN, the test will be repeated once, and if the value is again > 2 × ULN, this becomes an exclusion criterion).
  1PLT count ≤ 150 × 109/L at screening (test may be repeated once).

• ANC < 1.2 × 109/L at screening (test may be repeated once).

• Uncontrolled hypertriglyceridemia at screening, i.e., triglycerides ˃ 1.5 × ULN (test may be repeated once).

• 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.

• History of major organ transplantation.

• Patients with documented GI disease that may significantly alter the absorption of oral drugs.

• 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.

• Previous treatment with a JAK2 or HDAC inhibitor or 32-phosphorus (radioactive isotope) therapy.

• Patients receiving treatment with interferon or pipobroman within the 5 weeks prior to screening.

• Patients receiving anagrelide within the 7 days prior to screening.

• Patients receiving busulfan or chlorambucil within the 2 weeks prior to screening.

• Patients being treated concurrently with any investigational agent or prior participation in an interventional clinical study within the 30 days prior to screening or within 5 half-lives of the investigational product, whichever is longer.

• Patients with known hypersensitivity to the components of the study drugs.

• Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception, confirmed by a positive serum human chorionic gonadotropin (hCG) laboratory test (i.e., > 5 mIU/mL) and until the termination of gestation.

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) Relapsed / Refractory (R/R) to Janus Kinase (JAK) Inhibitor.

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AOU Città della Salute e della Scienza di Torino, SC Ematologia Universitaria - P.O. Molinette

Sindromi MIELOPROLIFERATIVE CRONICHE target: MIELOFIBROSI

Inclusion Criteria

Each potential participant must satisfy all of the following criteria to be enrolled in the study:

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.
3. Dynamic International Prognostic Scoring System intermediate-2 or high-risk MF.
4. Relapsed / refractory to JAK inhibitor treatment as defined in either inclusion 4.1, 4.2 or 4.3 and not eligible for ASCT at screening:
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 at least 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 during screening.
4.2: Treatment with JAK inhibitor for ≥ 3 months duration with maximal doses for that participant (e.g., 20-25 mg twice daily ruxolitinib) without a spleen or symptom response as defined in inclusion criterion 4.1 (a, b, or c) and would not benefit from remaining on treatment for 6 months.
4.3: Following maximum tolerated doses of JAK inhibitor therapy for ≥3 months duration, having documented relapsed disease defined as either:
• Increase in spleen volume from time of best response by 25% measured by MRI or CT, or
• Increase in spleen size by palpation, CT, or ultrasound o For splenomegaly of 5-10 cm at the start of JAK inhibitor treatment, at least 100% increase in palpable spleen size from time of best response; o For splenomegaly of > 10 cm at the start of JAK inhibitor treatment, at least 50% increase in palpable spleen size from time of best response;
AND not a candidate for further JAK inhibitor at screening per investigator.
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.
7. Hematology laboratory test values within the following limits: • absolute neutrophil count (ANC) ≥ 1.5 x 109 /L independent of growth factor support, AND • platelets ≥ 75 x 109 /L independent of platelet transfusion support.
8. Biochemical laboratory test values must be within the following limits:
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN);
• Alkaline phosphatase (ALP) ≤ 5 x ULN;
• Serum creatinine ≤ 2 x ULN;
• Total bilirubin ≤ 3 x ULN; and direct bilirubin ≤ 2 x ULN (unless due to Gilbert’s syndrome or underlying MF).
9. Eastern Cooperative Oncology Group Performance Status score of 0, 1, or 2.
10. Women of childbearing potential and men who are sexually active must use a highly effective method of birth control during and after the study consistent with local regulations regarding the use of birth control methods for participants participating in clinical trials. Men must use a highly effective method of birth control and agree not to father a child or donate sperm during and after the study. For females, these restrictions apply for 1 month after the last dose of study drug. For males, these restrictions apply for 3 months after the last dose of study drug.
11. A woman of childbearing potential must have a negative serum (-human chorionic gonadotropin) or urine pregnancy test at screening.
12. Each participant (or their legally acceptable representative) must sign an informed consent form (ICF) indicating the participant understands the purpose of and procedures required for the study and are willing to participate in the study.

Exclusion Criteria

Any potential participant who meets any of the following criteria will be excluded from participating in the study:

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 (refer to the current IB).
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.
5. Persistent unresolved toxicity from prior treatment, i.e., has not returned to Grade ≤ 1 or pre-treatment baseline.
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.
8. Known history of human immunodeficiency virus or any uncontrolled active systemic infection requiring IV antibiotics.
9. Active systemic hepatitis infection requiring treatment (carriers of hepatitis virus are permitted to enter the study), or any known acute or chronic liver disease requiring treatment unless related to underlying hepatosplenomegaly due to MF.
10. Major surgery within 28 days prior to randomization.
11. Female participants who are pregnant or are currently breastfeeding or planning to become pregnant while enrolled in this study or within 30 days after the end of dosing.
12. Male participants who plan to father a child while enrolled in this study or within 90 days after the end of dosing.
13. Any life-threatening illness (e.g., COVID-19), medical condition, or organ system dysfunction which, in the investigator’s opinion, could compromise the participant’s safety, interfere with the imetelstat metabolism, or put the study outcomes at undue risk; if participant has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (e.g., compromise the well- being) or that could prevent, limit, or confound the protocol-specified assessments.

A Phase 1/2, Open-label, Dose-escalation, Safety, Pharmacokinetic, and Pharmacodynamic Study of Oral TP-3654 in Patients with Intermediate or High-risk Primary or Secondary Myelofibrosis (BBI-TP-3654-102).

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AOU Città della Salute e della Scienza di Torino, SC Ematologia Universitaria - P.O. Molinette

Sindromi MIELOPROLIFERATIVE CRONICHE target: MIELOFIBROSI

Inclusion Criteria

Patients must meet all of the following inclusion criteria to be eligible:

1. Adult (age defined by local/country law or regulation)
2. Confirmed pathological diagnosis of primary myelofibrosis (PMF) or post-PV- MF/post-ET- MF as per WHO diagnostic criteria (Section 10.2.4), and intermediate or high-risk primary or secondary MF based on the Dynamic International Prognostic Scoring System (DIPSS)65; (Section 10.2.2)
3. Previously treated with a JAK inhibitor and are intolerant, resistant, refractory or lost response to the JAK inhibitor, or are ineligible to be treated with ruxolitinib or fedratinib as determined by the Investigator in accordance with the local product labels
4. Grade ≥ 2 bone marrow fibrosis, as confirmed by bone marrow biopsy within 12 weeks prior to Screening; (Section 10.2.3)
5. Fulfill the following clinical laboratory parameters:
a. Platelet count ≥ 25 × 109/L (without the assistance of growth factors or platelet transfusions)
b. Absolute Neutrophil Count (ANC) ≥ 1 × 109/L without the assistance of granulocyte growth factors
6. Peripheral blood blast count < 10%
7. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (see Section 10.11)
8. Life expectancy ≥ 3 months
9. Adequate renal function, as determined by clinical laboratory tests (serum creatinine ≤ 1.5 x upper limit of normal (ULN), and calculated creatinine clearance ≥ 30 mL/min) (using Cockcroft-Gault formula)
10. Adequate hepatic function (ALT/AST ≤ 3 × ULN, total bilirubin ≤ 1.5 × ULN; or ALT/AST ≤ 5 × ULN, direct bilirubin ≤ 2 × ULN if due to myelofibrosis); and coagulation ([PT and PTT] ≤ 1.5 × ULN)
11. Agree to provide bone marrow biopsies during the study: at baseline or within 12 weeks prior to enrollment, and every 6 months during treatment.
12. Capable of providing signed informed consent as described in Section 10.1 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol
13. Non-fertile or agree to use an adequate method of contraception as described in Section 10.4 while on study and for 6 months following the study, and have a negative pregnancy test (if female of childbearing potential [Section 8.1.7]) and not currently nursing; males agree to use an adequate method of contraception as described in Section 10.4 while on study and for 3 months following the study
14. Splenomegaly during the screening period as demonstrated by splenic length ≥ 5 cm below the costal margin by palpation or spleen volume of ≥ 450 cm3 by magnetic resonance Imaging (MRI) or computerized tomography (CT) scan
15. Show at least 2 symptoms measurable (score ≥ 1) using the Myelofibrosis Symptom Assessment Form (MFSAF), v4.0.
16. Able to take orally administered medication

Exclusion Criteria

Patients meeting any one of these exclusion criteria will be prohibited from participating in this study:

1. Received previous systemic antineoplastic therapy (including unconjugated therapeutic antibodies, toxin immunoconjugates, ESA, and alpha-interferon) or any experimental therapy within 14 days or 5 half-lives, whichever is longer, before the first dose of study treatment
2. Major surgical procedure for any cause within 4 weeks before the first dose of study drug and/or the patient has not recovered adequately from complications of the surgical intervention prior to the first dose of study drug
3. Splenic irradiation within 6 months prior to Screening or prior splenectomy
4. AML, MDS, or peripheral blasts ≥ 10%.
5. Prior autologous or allogeneic stem cell transplant at any time.
6. Eligible for and willing to undergo allogeneic bone marrow or stem cell transplantation. Patients who are not a candidate, who are unwilling to undergo transplantation, or for whom a suitable donor is not available are considered transplant ineligible.
7. Currently receiving treatment with a prohibited medication that cannot be discontinued at least one week prior to the start of treatment (Section 6.6).
8. Experiencing electrolyte abnormalities of NCI CTCAE21 Grade ≥ 2 (eg, serum potassium, magnesium and calcium) unless they can be corrected during screening and are deemed not clinically significant by the Investigator.
9. History of congestive heart failure, myocardial infarction within the past 6 months prior to Cycle 1/Day 1; left ventricular ejection fraction < 45% by echocardiogram, unstable arrhythmia, or evidence of ischemia on electrocardiogram (ECG) within 28 days prior to Cycle 1/Day 1.
10. Corrected QT interval (using Fridericia's correction formula) of > 450 msec in men and > 470 msec in women.
11. Central nervous system (CNS) cancer or metastases, meningeal carcinomatosis, malignant seizures, or a disease that either causes or threatens neurologic compromise (eg, unstable vertebral metastases).
12. Other invasive malignancies within the last 3 years, except non-melanoma skin cancer, and localized cured prostate and cervical cancer
13. Experienced portal hypertension or any of its complications.
14. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic antimicrobial within 14 days.
15. Known bleeding diathesis or signs of uncontrolled active bleeding (hematuria, GI bleeding) other than self-limited causes of benign etiology that have been adequately investigated at the discretion of the Investigator.
16. Requiring anticoagulation with aspirin >100 mg daily, unfractionated heparin, low molecular weight heparin (LMWH), direct anti-thrombin inhibitors, or vitamin K antagonists (eg, warfarin).
17. Severe chronic obstructive pulmonary disease with hypoxemia (defined as resting O2 saturation of < 90% breathing room air).
18. Unwilling or unable to comply with procedures required in this protocol
19. Known infection with human immunodeficiency virus, hepatitis B, or hepatitis C. Patients with history of chronic hepatitis that is currently not active are eligible.
20. Serious nonmalignant disease (eg, hydronephrosis, liver failure, or other conditions) that could compromise protocol objectives in the opinion of the Investigator and/or the Sponsor.
21. Currently receiving any other investigational agent.
22. Exhibited allergic reactions to a similar structural compound, biological agent, or formulation.
23. Medical condition or have undergone significant surgery to the gastrointestinal tract that could impair absorption or that could result in short bowel syndrome with diarrhea due to malabsorption.
24. Used hydroxyurea or anagrelide within 24 hours prior to the first dose
25. Systemic steroid therapy (>10 mg daily prednisone or equivalent) within 7 days prior to the first dose of study treatment (note: topical, inhaled, nasal, and ophthalmic steroids are not prohibited).
26. Unresolved >Grade 1 non-hematological toxicity related to prior treatment (however, stable Grade 2 exceptions may be permitted if discussed in advance with the Sponsor).

A Randomized, Controlled Phase 3 Study of Pacritinib Versus Physician’s Choice in Patients with Primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis, or Post Essential Thrombocythemia Myelofibrosis with Severe Thrombocytopenia (Platelet Counts <50,000/μL) (PAC-303)

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AOU Città della Salute e della Scienza di Torino, SC Ematologia Universitaria - P.O. Molinette

Sindromi MIELOPROLIFERATIVE CRONICHE target: MIELOFIBROSI

Inclusion Criteria

1. PMF (including pre-fibrotic MF), PPV-MF, or PET-MF (as defined by Tefferi and Vardiman 2008; Appendix 1)
2. Platelet count of <50,000/μL at Screening (Day -35 to Day -3) (based on two measurements taken on different days; both measurements must be <50,000/μL)
3. DIPSS Intermediate-1, Intermediate-2, or High-Risk (Passamonti et al 2010; Appendix 2)
4. Palpable splenomegaly ≥5 cm below the lower costal margin (LCM) in the midclavicular line as assessed by physical examination
5. TSS of ≥10 on the MPN-SAF TSS 2.0 or a single symptom score of ≥5 or two symptoms of ≥3, including only the symptoms of left upper quadrant pain, bone pain, itching, or night sweats (Appendix 3). The TSS criteria need only to be met on a single day.
6. If the patient has received prior JAK2 inhibitor treatment, this treatment must meet at least one of the following criteria:
a. Prior treatment with any JAK2 inhibitor, irrespective of dose, with a duration of 90 days or less. The 90-day period starts on the date of first administration of JAK2 inhibitor therapy and continues for 90 calendar days, regardless of whether therapy is administered continuously or intermittently during that interval.
b. Prior treatment with ruxolitinib, at no more than 10 mg total daily dose on any day, with a duration of 270 days or less. The 270-day period starts on the date of first ruxolitinib administration and continues for 270 calendar days, regardless of whether therapy is administered continuously or intermittently. The patient may not have received >10 mg of ruxolitinib on any day during that interval. The 90- or 270-day period may overlap with the Screening period but may not extend into the washout period (14 days prior to treatment Day 1).
7. Age ≥18 years
8. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 (Appendix 4)
9. Peripheral blast count of <10% throughout the Screening period and prior to randomization
10. Absolute neutrophil count of ≥500/μL
11.Left ventricular cardiac ejection fraction of ≥50% by echocardiogram or multigated acquisition (MUGA) scan
12.Adequate liver and renal function, defined by liver transaminases (aspartate aminotransferase [AST]/serum glutamic-oxaloacetic transaminase [SGOT] and alanine aminotransferase [ALT]/serum glutamic pyruvic transaminase [SGPT]) ≤3 × the upper limit of normal (ULN) (AST/ALT ≤5 × ULN if transaminase elevation is related to MF), total bilirubin ≤4 × ULN (in cases where total bilirubin is elevated, direct bilirubin ≤4 × ULN is required), and creatinine ≤2.5 mg/dL
13. Adequate coagulation defined by prothrombin time (PT)/international normalized ratio (INR) and PTT ≤1.5 × ULN
14. If fertile, willing to use effective birth control methods during the study
15. Willing to undergo and able to tolerate frequent MRI or CT scan assessments during the study
16. Able to understand and willing to complete symptom assessments using a patient-reported outcome instrument
17. Provision of informed consent

Exclusion Criteria

1. Life expectancy <6 months
2. Completed allogeneic SCT, or are eligible for and willing to complete other approved available therapy including allogeneic SCT
3. History of splenectomy or planning to undergo splenectomy
4. Splenic irradiation within the last 6 months
5. Previously treated with pacritinib
6. Treatment with any MF-directed therapy within 14 days prior to treatment Day 1
7. Prior treatment with more than one JAK2 inhibitor
8. Treatment with an experimental therapy within 28 days prior to treatment Day 1
9. Systemic treatment with a strong CYP3A4 inhibitor or a strong CYP450 inducer within 14 days prior to treatment Day 1 (Appendix 5 and Appendix 6, respectively). Shorter washout periods may be permitted with approval of the Medical Monitor, provided that the washout period is at least five half-lives of the drug prior to treatment Day 1.
10.Significant recent bleeding history defined as NCI CTCAE grade ≥2 within 3 months prior to treatment Day 1, unless precipitated by an inciting event (eg, surgery, trauma, or injury)
11.Systemic treatment with medications that increase the risk of bleeding, including anticoagulants, antiplatelet agents (except for aspirin dosages of ≤100 mg per day), anti-vascular endothelial growth factor (anti-VEGF) agents, and daily use of COX-1 inhibiting Non-steroidal anti-inflammatory drugs (NSAIDs) within 14 days prior to treatment Day 1
12.Systemic treatment with medications that can prolong the QT interval within 14 days prior to treatment Day 1. Shorter washout periods may be permitted with approval of the Medical Monitor, provided that the washout period is at least five half-lives of the drug prior to treatment Day 1 (Appendix 8)
13.Any history of CTCAE grade ≥2 non-dysrhythmia cardiac conditions within 6 months prior to treatment Day 1. Patients with asymptomatic grade 2 non-dysrhythmia cardiovascular conditions may be considered for inclusion, with the approval of the Medical Monitor, if stable and unlikely to affect patient safety.
14.Any history of CTCAE grade ≥2 cardiac dysrhythmias within 6 months prior to treatment Day 1. Patients with non-QTc CTCAE grade 2 cardiac dysrhythmias may be considered for inclusion, with the approval of the Medical Monitor, if the dysrhythmias are stable, asymptomatic, and unlikely to affect patient safety
15.QT corrected by the Fridericia method (QTcF) prolongation >450 ms or other factors that increase the risk for QT interval prolongation (eg, hypokalemia [defined as serum potassium <3.0 mEq/L that is persistent and refractory to correction], or history of long QT interval syndrome)
16.New York Heart Association Class II, III, or IV congestive heart failure (Appendix 7)
17.Any active GI or metabolic condition that could interfere with absorption of oral medication
18.Active or uncontrolled inflammatory or chronic functional bowel disorder such as Crohn’s disease, inflammatory bowel disease, chronic diarrhea, or chronic constipation
19.Other malignancy within 3 years prior to treatment Day 1. The following patients may be eligible despite having had a malignancy within the prior 3 years: patients with curatively treated squamous or basal cell carcinoma of the skin; patients with curatively treated non-invasive cancers; patients with organ-confined prostate cancer with prostate-specific antigen (PSA) <20 ng/mL and National Comprehensive Cancer Network risk of Very Low, Low, or Favorable Intermediate; and patients with curatively treated non-metastatic prostate cancer with negative PSA.
20.Uncontrolled intercurrent illness, including, but not limited to, ongoing active infection, psychiatric illness, or social situation that, in the judgment of the treating physician, would limit compliance with study requirements
21.Active hepatitis B or C virus infection or known active hepatitis A virus infection
22.Human immunodeficiency virus (HIV) infection
23.Women who are pregnant or lactating
24.Concurrent enrollment in another interventional trial
25.Severe thrombocytopenia due to vitamin B12 deficiency, folate deficiency, or viral infection in the opinion of the investigator
26.Known hypersensitivity to pacritinib or any of the following inactive ingredients: microcrystalline cellulose, polyethylene glycol, and magnesium stearate; any contraindication to the “physician’s choice” medicinal product selected by the investigator to be used as the comparator or to loperamide or equivalent antidiarrheal medication.

A Phase 3, Randomized, Double-blind, Add-on Study Evaluating the Safety and Efficacy of Navtemadlin Plus Ruxolitinib vs Placebo Plus Ruxolitinib in JAK Inhibitor-Naïve Patients with Myelofibrosis Who Have a Suboptimal Response to Ruxolitinib (KRT-232-115).

Attivazione Dicembre 2024.

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AOU Città della Salute e della Scienza di Torino, SC Ematologia Universitaria - P.O. Molinette

Sindromi MIELOPROLIFERATIVE CRONICHE target: MIELOFIBROSI

Inclusion Criteria

• 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 (Appendix 2).
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 (as per protocol definition and within 28 days prior to the first dose of ruxolitinib monotherapy):
a. Hematologic:
i. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L in the absence of myeloid growth factors during the prior 28 days.
ii. Platelet count ≥ 100 × 109/L.
iii. White blood cell count ≤ 50 × 109/L.
b. Hepatic:
i. Total serum bilirubin within normal limits. If total bilirubin is > upper limit of normal (ULN), subjects are eligible if direct bilirubin ≤ 2.0 ULN, unless documented Gilbert’s Syndrome.
ii. Aspartate transaminase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine transaminase/serum glutamic pyruvic transaminase (ALT/SGPT) ≤ 2.5 ULN.
c. Renal: estimated creatinine clearance ≥ 30 mL/min by the Cockcroft Gault equation.
8. Female subjects of childbearing potential and their male partners, or male subjects who have female partners of childbearing potential must both use a highly effective contraception method during the study. In addition, after the last dose of study drug, female subjects must continue to use a highly effective method of contraception for one month and one week, and male subjects must continue to use a highly effective method of contraception for three months and one week. A woman is considered of childbearing potential (ie, fertile) following menarche and until becoming post-menopausal unless permanently sterile.

• Randomized Period

1. PMF, post-PV MF, or post-ET MF that is TP53WT as assessed by central testing.
2. ECOG performance status of 0 to 2.
3. 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.
a. A stable dose is defined as a ruxolitinib dose that did not require a treatment hold or dose adjustment.
b. Subjects must be taking a stable dose of ruxolitinib of ≥ 5 mg BID.
4. 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.
5. Adequate hematological, hepatic, and renal organ function (as per protocol definition and within 14 days prior to the first dose of study treatment):
a. Hematologic:
i. ANC ≥ 1.5 × 109/L in the absence of myeloid growth factors during the prior 28 days.
ii. Platelet count ≥ 100 × 109/L.
b. Hepatic:
i. Total serum bilirubin within normal limits. If total bilirubin is > ULN, subjects are eligible if direct bilirubin ≤ 2.0 ULN, unless documented Gilbert’s Syndrome.
ii. AST/SGOT and ALT/SGPT ≤ 2.5 ULN.
c. Renal: estimated creatinine clearance ≥ 30 mL/min by the Cockcroft Gault equation.
6. Female subjects of childbearing potential and their male partners, or male subjects who have female partners of childbearing potential must both use a highly effective contraception method during the study. In addition, after the last dose of study drug, female subjects must continue to use a highly effective method of contraception for one month and one week, and male subjects must continue to use a highly effective method of contraception for three months and one week. A woman is considered of childbearing potential (ie, fertile) following menarche and until becoming post-menopausal unless permanently sterile.

Exclusion Criteria

• 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.
9. Women who are pregnant or breastfeeding.
10. History of solid organ transplant.
11. Known infection with human immunodeficiency virus (HIV).
12. Known active hepatitis B or C infection.
13. Active serious viral, mycobacterial, parasitic, fungal, and bacterial infections, including acute hepatitis A, herpes zoster, and progressive multifocal leukoencephalopathy (PML). Active serious infections must be resolved before enrollment. Subjects with acute infections requiring systemic antibiotic use should delay enrollment until the course of antibiotic therapy has been completed.
14. Subjects with uncontrolled intercurrent illness including, but not limited to; clinically significant cardiac disease (New York Heart Association Class III or IV); symptomatic congestive heart failure; unstable angina pectoris; ventricular arrhythmia; or subjects with psychiatric illness/social situations that would limit compliance with study requirements; or subjects who have been committed to an institution by judicial or administrative authority.
15. Active or chronic bleeding within 28 days prior to the first dose of ruxolitinib monotherapy.
16. Subjects with active fever (temperature higher than 38.2°C [100.8°F]) within 14 days prior to the first dose of ruxolitinib monotherapy.
17. Other malignancy within the last three years, other than curatively treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, organ-confined or treated non- metastatic prostate cancer with normal prostate-specific antigen, in situ breast carcinoma after complete surgical resection, or superficial/non-invasive transitional cell bladder carcinoma.
18. Grade 2 or higher QTc prolongation (> 480 milliseconds per NCI-CTCAE criteria, version 5.0).
19. History of difficulty swallowing, gastric or small bowel surgery with history of malabsorption or other chronic gastrointestinal disease conditions that may hamper compliance and / or absorption of the study treatment.
20. History of severe hypersensitivity reaction to any component of navtemadlin or ruxolitinib, any of their excipients, or to required prophylaxis.
21. History of stroke, reversible ischemic neurological defect, or transient ischemic attack within six months prior to first dose of ruxolitinib monotherapy.
22. Subjects with indwelling surgical drains (eg, peritoneal, CNS, or pleural).
23. Subjects with symptomatic ascites or requiring paracentesis.
24. Subjects with any open wound or ulcer.

• 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.
3. Splenic irradiation within three months prior to the first dose of study treatment.
4. Non-spleen-directed radiation therapy for MF or major surgery or planned major surgery within 28 days prior to the first dose of study treatment.
5. Eligible for allogeneic stem cell transplantation. Subjects who are eligible for stem cell transplant but refuse transplant are not excluded.
6. Peripheral blood or bone marrow blast count ≥ 10% at any time within 28 days prior to the first dose of study treatment.
7. Women who are pregnant or breastfeeding.
8. History of solid organ transplant.
9. Known infection with HIV.
10. Known active hepatitis B or C infection.
11. Active serious viral, mycobacterial, parasitic, fungal, and bacterial infections, including acute hepatitis A, herpes zoster, and progressive multifocal leukoencephalopathy (PML).

XPORT-MF-034: a phase 1/3 study to evaluate the efficacy and safety of selinexor, a selective inhibitor of nuclear export, in combination with ruxolitinib in treatment-naïve patients with myelofibrosis

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S.C. Ematologia U - PO Molinette

Sindromi MIELOPROLIFERATIVE CRONICHE target: MIELOFIBROSI

Inclusion Criteria

• A diagnosis of primary MF, post-essential thrombocythemia (ET), or postpolycythemia vera (PV) MF according to the 2016 World Health Organization (WHO) classification of MPN, confirmed by the most recent local pathology report.
• Measurable splenomegaly during the screening period as demonstrated by spleen volume of ≥450 cm3 by MRI or CT scan (results from MRI or CT imaging performed within 28 days prior to screening are acceptable).
• Patients with DIPSS risk category of intermediate-1, or intermediate-2, or high-risk.
• Patients ≥18 years of age.§
• ECOG performance status ≤2
• Platelet count ≥100 × 109/L without platelet transfusion.
• Absolute neutrophil count (ANC) ≥1.0 × 109/L without need for growth factors within 7 day prior to C1D1
• Adequate liver function as defined by the following: aspartate transaminase (AST) and alanine aminotransferase (ALT) ≤2.5 × upper limit normal (ULN) and serum total bilirubin ≤2 × ULN.
• Calculated creatinine clearance (CrCl) >15 mL/min based on the Cockcroft and Gault formula.

• Patients with active hepatitis B virus (HBV) are eligible if antiviral therapy for hepatitis B has been given for >8 weeks and the viral load is <100 IU/mL.

• Patients with history of hepatitis C virus (HCV) are eligible if they have received adequate curative anti-HCV treatment and HCV viral load is below the limit of quantification.

• Patients with history of human immunodeficiency virus (HIV) are eligible if they have CD4+ T-cell counts ≥350 cells/μL, negative viral load, and no history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections in the last year and should be on established antiretroviral therapy (ART) for at least 4 weeks.

• Female patients of childbearing potential must have a negative serum pregnancy test at screening and within 3 days prior to first dose on C1D1 and agree to use highly effective methods of contraception throughout the selinexor treatment period and for 90 days following the last dose of selinexor treatment. A woman is considered of childbearing potential, i.e., fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.

• Male patients who are sexually active must use a barrier method in addition to highly effective methods of contraception throughout the study treatment period and for 90 days following the last dose of selinexor treatment. Male patients must agree not to donate sperm during the study treatment period and for at least 90 days after the last dose of selinexor treatment. Patients must sign written informed consent in accordance with federal, local, and institutional guidelines.

• Active symptoms of MF as determined by presence of at least 2 symptoms with a score ≥3 or total score of ≥10 at screening using the MFSAF v4.0.

• Patient currently not eligible for stem cell transplantation.

• Patients must provide bone marrow biopsy samples (samples obtained up to 3 months prior to C1D1 are permitted) at screening and during the study.

• Life expectancy of greater than 6 months in the opinion of the Investigator.

• Patients with no other concomitant malignancies or history of another malignancy within 2 years prior to C1D1 except for adequately treated early-stage basal cell or squamous cell carcinoma of skin, adequately treated carcinoma in situ of breast or cervix or organ confined prostate cancer, or PV or ET.

• Subjects must be able to voluntarily provide informed consent per all relevant rules and institutional policies before any study procedures are performed. No incapacitated subjects will be recruited for participation. Where the subject cannot sign the ICF due to a physical disability, an impartial witness will be appointed.

Exclusion Criteria

1.More than 10% blasts in peripheral blood or bone marrow (accelerated or blast phase).
2. Previous treatment with JAK inhibitors for MF.
3. Previous treatment with selinexor or other XPO1 inhibitors.
4. Impairment of gastrointestinal (GI) function or GI disease that could significantly alter the absorption of selinexor (e.g., vomiting or diarrhea CTCAE v5.0 Grade 2 or higher), Grade 3 or higher hyponatremia, Grade 3 or higher fatigue, or Grade 2 or higher ocular toxicity.
5. Received strong cytochrome P450 3A (CYP3A) inhibitors ≤7 days prior to selinexor dosing OR strong CYP3A inducers ≤14 days prior to selinexor dosing (Phase 1 patients only)
6. Major surgery <28 days prior to C1D1.
7. Uncontrolled (i.e., clinically unstable) infection requiring parenteral antibiotics, antivirals, or antifungals within 7 days prior to C1D1; however, prophylactic use of these agents is acceptable (including parenteral).
8. Any life-threatening illness, medical condition, or organ system dysfunction which, in the Investigator’s opinion, could compromise the patient’s safety, prevent the patient from giving informed consent, or being compliant with the study procedures, or confound the ability to interpret study results.
9. Female patients who are pregnant or lactating.
10. Prior splenectomy, or splenic radiation within 6 months prior to C1D1.
11. Unable or unwilling to undergo CT scan or MRI per protocol.
12. Patients with contraindications or known hypersensitivity to selinexor or ruxolitinib or excipients.
13. History of pulmonary hypertension.
14. History of myocardial infarction, unstable angina, percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass graft (CABG), cerebrovascular accident (stroke or transient ischemic attack [TIA]), ventricular arrhythmias, congestive heart failure New York Heart Association (NYHA) class >2 within 6 months of C1D1.
15. Patients unable to tolerate 2 forms of antiemetics prior to each dose for at least 2 cycles

XPORT-MF-044: a phase 2 study to evaluate the efficacy and safety of selinexor monotherapy in subjects with jak inhibitor-naïve myelofibrosis and moderate thrombocytopenia

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S.C. Ematologia U - PO Molinette

Inclusion Criteria

1. A diagnosis of MF or post-ET or post-PV MF according to the 2016 World Health Organization (WHO) classification of MPN, confirmed by the most recent local pathology report.
2. Measurable splenomegaly during the screening period as demonstrated by spleen volume of ≥450 cm3 by MRI or CT scan (results from MRI or CT imaging performed within 28 days prior to screening are acceptable).
3. Subjects with DIPSS risk category of intermediate-1 with symptoms, or intermediate-2, or highrisk.
4. Subjects ≥18 years of age.
5. ECOG Performance Status ≤2,
6. Platelet count of 50 to <100 x 109 /L without platelet transfusion within 7 days prior to the first dose of selinexor.
7. Absolute neutrophil count (ANC) ≥1.0 × 109 /L without need for growth factors within 7 days prior to the first dose of selinexor.
8. Adequate liver function as defined by the following: aspartate transaminase (AST) and alanine aminotransferase (ALT) ≤2.5 × upper limit normal (ULN) and serum total bilirubin ≤3× ULN.
9. Calculated creatinine clearance (CrCl) >15 mL/min based on the Cockcroft and Gault formula.
10. Subjects with active hepatitis B virus (HBV) are eligible if antiviral therapy for hepatitis B has been given for >8 weeks and the viral load is <100 IU/mL.
11. Subjects with history of hepatitis C virus (HCV) are eligible if they have received adequate curative anti-HCV treatment and HCV viral load is below the limit of quantification.
12. Subjects with history of human immunodeficiency virus (HIV) are eligible if they have cluster of differentiation 4 (CD4) + T-cell counts ≥350 cells/μL, negative viral load, and no history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections in the last year and should be on established antiretroviral therapy (ART) for at least 4 weeks.
13. Female subjects of childbearing potential must have a negative serum pregnancy test at screening and within 3 days prior to first dose on C1D1 and agree to use highly effective methods of contraception throughout the selinexor treatment period and for 90 days following the last dose of selinexor treatment. A woman is considered of childbearing potential, i.e., fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.
14. Male subjects who are sexually active must use a barrier method in addition to highly effective methods of contraception throughout the study treatment period and for 90 days following the last dose of selinexor treatment. Male subjects must agree not to donate sperm during the study treatment period and for at least 90 days after the last dose of selinexor treatment.
15. Subjects must sign written informed consent in accordance with federal, local, and institutional guidelines.
16. Active symptoms of MF as determined by presence of at least 2 symptoms with a score ≥3 or total score of ≥10 at screening using the MFSAF V4.0.
17. Subjects must provide bone marrow biopsy samples (samples obtained up to 3 months prior to C1D1 are permitted) at screening and during the study.
18. Life expectancy of greater than 6 months in the opinion of the Investigator.
19. Subjects with no other concomitant malignancies or history of another malignancy within 2 years prior to C1D1 except for adequately treated early-stage basal cell or squamous cell carcinoma of skin, adequately treated carcinoma in situ of breast or cervix or organ confined prostate cancer, or PV or ET.
20. Subject is currently not a candidate for stem cell transplantation.
21. Subjects must be willing to complete the MFSAF) V4.0 daily during the study for evaluating the symptom response (i.e., TSS50).
22. Subjects must be able to voluntarily provide informed consent per all relevant rules and institutional policies before any study procedures are performed. No incapacitated subjects will be recruited for participation.

Exclusion Criteria

1. More than 10% blasts in peripheral blood or bone marrow (accelerated or blast phase).
2. Previous treatment with JAK inhibitors for MF.
3. Previous treatment with selinexor or other XPO1 inhibitors.
4. Impairment of gastrointestinal (GI) function or GI disease that could significantly alter the absorption of selinexor (e.g., vomiting or diarrhea > Common Terminology Criteria for Adverse Events [CTCAE] v5.0 Grade 2 or higher), Grade 3 or higher hyponatremia, Grade 3 or higher fatigue, or Grade 2 or higher ocular toxicity.
5. Major surgery <28 days prior to C1D1.
6. Uncontrolled (i.e., clinically unstable) infection requiring parenteral antibiotics, antivirals, or antifungals within 7 days prior to C1D1; however, prophylactic use of these agents is acceptable (including parenteral).
7. Any life-threatening illness, medical condition, or organ system dysfunction which, in the Investigator’s opinion, could compromise the subject’s safety, prevent the subject from giving informed consent, or being compliant with the study procedures, or confound the ability to interpret study results.
8. Female subjects who are pregnant or lactating.
9. Prior splenectomy, or splenic radiation/splenic embolization within 6 months prior to C1D1.
10. Unable or unwilling to undergo CT/ MRI or bone marrow biopsy per protocol.
11. Subjects with contraindications or known hypersensitivity to selinexor or excipients.
12. History of myocardial infarction, unstable angina, percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass graft (CABG), cerebrovascular accident (stroke or transient ischemic attack [TIA]), ventricular arrhythmias, congestive heart failure New York Heart Association (NYHA) class >2 within 6 months of C1D1.
13. Subjects unable to tolerate two forms of antiemetics prior to each dose for the first two cycles.

ITALY-TFR: Studio osservazionale in pazienti adulti con leucemia mieloide cronica (LMC) che hanno discontinuato inibitori di tirosin-kinasi (TKI) in Italia

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Sindromi MIELOPROLIFERATIVE CRONICHE target: LEUCEMIA MIELOIDE CRONICA

Inclusion Criteria

1) Patients with CP-CML, treated with TKI monotherapy or TKI in association with other drugs (such as interferon, BCR-ABL1 peptidic vaccine and others)
2) Treatment with TKI discontinued for any reason
3) Deep Molecular Response (DMR), defined as MR4, or MR4.5, or MR5 confirmed at least three times before TKI discontinuation In patients who discontinued TKIs before the establishment of molecular standardization, DMR will be defined as a level of BCR-ABL1 transcript undetectable by qPCR or by qualitative PCR, confirmed in at least two controls

Exclusion Criteria

Patients who were diagnosed with accelerated or blastic phase CML will be excluded

REGISTRO LMC: Studio osservazionale multicentrico retrospettivo e prospettico su pazienti affetti da leucemia mieloide cronica: raccolta di dati epidemiologici e clinici nella pratica clinica reale

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Sindromi MIELOPROLIFERATIVE CRONICHE target: LEUCEMIA MIELOIDE CRONICA

Inclusion Criteria

Pazienti con LMC Ph+ in qualsiasi fase della malattia

REAL: Observational study protocol REALFed – REAL world evidence of fedratinib effectiveness in myelofibrosis

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Sindromi MIELOPROLIFERATIVE CRONICHE target: MIELOFIBROSI

Inclusion Criteria

Mielofibrosi

CABL: Studio di fase IIIb, multicentrico, in aperto, randomizzato, per valutare la tollerabilità e l’efficacia di asciminib per via orale versus nilotinib in pazienti con leucemia mieloide cronica cromosoma Philadelphia positiva in fase cronica

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Sindromi MIELOPROLIFERATIVE CRONICHE target: LEUCEMIA MIELOIDE CRONICA

Inclusion Criteria

Nuove diagnosi di LMC