A phase Ib, multi-center, open-label, dose-escalation study of PIM447 in combination with ruxolitinib (INC424) and LEE011 administered orally in patients with myelofibrosis (CPIM447X2104C)
- Conditions
- myelofibrosis10018849
- Registration Number
- NL-OMON44750
- Lead Sponsor
- ovartis
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 4
* ECOG performance status 0, 1, 2.
* JAK2V617F-positive primary or secondary myelofibrosis.
* < 35% reduction in spleen volume by MRI/CT or < 50% reduction in spleen size by physical exam, with or without corresponding symptomatic improvement, after at least 6 months of treatment with single agent ruxolitinib at an optimal dose level in line with label recommendations.
* Expansion parts only: Ruxolitinib-naive patients and patients who have been previously treated with single agent ruxolitinib and are relapsed and/or refractory.
* Splenomegaly measuring at least 5 cm by MRI at baseline.
* Adequate bone marrow function (Platelets * 100 x 10 9/L - Absolute Neutrophil Count * 1.5 x 109/L - Hb * 9 g/dL <= 5,58 mmol/L).
* Systemic antineoplastic therapy or any experimental therapy within 14 days or 5 half-lives before the first dose of study treatment
* Major surgery within 2 weeks before the first dose of study drug.
* Splenic irradiation within 2 weeks prior to Screening or splenectomy.
* AML, MDS, or peripheral blasts > 5 %.
* Prior autologous or allogeneic stem cell transplant.
* Treatment with a prohibited medication that cannot be discontinued at least one week prior to the start of treatment (Appendix 1), including agents that are:
- substrates of CYP3A4/5, CYP2B6 or CYP2D6 that have a narrow therapeutic window
- strong inhibitors of CYP3A4/5 or CYP2D6
- potent inducers of CYP3A4/5 or CYP2D6
* Medication with a known risk of prolonging the QT interval or inducing Torsades de Pointes (protocol appendix 2).
* History of (or predisposition to) clinically significant bleeding, history of platelet dysfunction and/or bleeding diathesis, and/or regular use of drugs that interfere with coagulation or inhibit PLT function (Appendix 3). NOTE: low doses of aspirin * 125 mg/day are allowed.
* Total bilirubin > 1.5 x upper limit of normal (ULN), AST (SGOT) or ALT (SGPT) > 3 x ULN, except with liver involvement AST or ALT > 5 x ULN.
* Creatinine > 1.5 x ULN or calculated creatinine clearance < 60 ml/min according to Cockcroft-Gault equation.
* Electrolyte abnormalities CTCAE grade * 2
* Patients with impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study treatments
* Unresolved nausea, vomiting, or diarrhea of CTCAE grade * 2.
* Active infection requiring systemic therapy or other severe infection within 2 weeks before the first dose of either study drug.
* Impaired cardiac function or clinically significant cardiac diseases (refer to exclusion criterion #19)
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>Incidence of DLTs in Cycle 1</p><br>
- Secondary Outcome Measures
Name Time Method <p>Frequency and severity of Adverse events<br /><br>% of patients achieving *35% reduction in spleen volume<br /><br>Changes in allele burden<br /><br>Change in platelets, neutrophils and hemoglobin<br /><br>Changes in bone marrow fibrosis and histomorphology<br /><br>Plasma concentration of PIM447, Ribociclib (LEE011) and ruxolitinib. Pk<br /><br>parameters</p><br>