INCB057643 (BET inhibitor) in Combination with Ruxolitinib for Treatment of Patients with Myelofibrosis

Inclusion Criteria

• Adult (aged ≥ 18 years). Because no dosing or adverse event data are currently available on the use of ruxolitinib in combination with INC057643 in patients < 18 years of age, children are excluded from this study.
• Patients with confirmed diagnosis of MF who meet all of the following criteria: * DIPSS-plus risk category of intermediate-1, intermediate-2, or high * Platelet count ≥ 100 x 10^9/L without the assistance of thrombopoietic factors or transfusions * Absolute neutrophil count (ANC) ≥ 1 x 10^9/L without the assistance of granulocyte growth factors * Spleen volume of ≥ 450 cm^3 by MRI/CT or spleen length ≥ 5 cm below the left costal margin * Peripheral blood blast count < 10% at the screening hematology assessment * At least 2 symptoms that are measurable (each with a score 3) or 1 symptom with a score of 5 or a total symptom score of 10 using the Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0) * No prior treatment with JAK inhibitor (i) or BETi allowed.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
• Life expectancy of > 24 weeks.
• Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN) (total bilirubin > 1.5 x ULN is acceptable if direct bilirubin ≤ 1.2 x ULN or with a diagnosis of Gilbert's syndrome)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN. The AST and /or ALT may be elevated up to 5 x ULN if the elevation can be reasonably ascribed to liver involvement.
• Calculated or measured creatinine clearance (CrCl) ≥ 50 mL/min (either measured or estimated by the Cockcroft- Gault formula) or glomerular filtration rate (GFR) ≥ 50 ml/min/1.73 m^2 calculated by the Modification of Diet in Renal Disease formula.
• Patients must have fully recovered from major surgery and from the acute toxic effects of prior chemotherapy and radiotherapy (residual Common Terminology Criteria for Adverse Events [CTCAE] grade 1 toxicity, e.g., grade 1 peripheral neuropathy, and residual alopecia are allowed).
• Both male and female patients and partners of patients, with reproductive potential, must agree to use at least one highly effective contraceptive method while on study therapy and for 90 days after the last dose of INCB057643 for male patients and male partners of female patients, and for 180 days after the last dose of study drug for female patients and female partners of male patients. NOTE: Patients may consider seeking information from the study investigator regarding donation and cryopreservation of germ cells prior to treatment. Male patients should be informed of the risk of testicular toxicity and provided with adequate advice regarding sperm preservation.
• Patients must give written informed consent to participate in this study before the performance of any study-related procedure.

Exclusion Criteria

• Prior treatment with a BET inhibitor.
• Prior treatment with a JAK inhibitor, including ruxolitinib.
• Patients who have had a prior splenectomy.
• Patients who have had splenic irradiation within 6 months of starting study treatment.
• Current known active or chronic infection with tuberculosis (TB), HIV, hepatitis B, or hepatitis C. Screening of patients with serologic testing for these viruses is not required. However, patients who have a past history of viral hepatitis or in whom there is a current suspicion of viral hepatitis should have deoxyribonucleic acid (DNA)/ribonucleic acid (RNA) testing for hepatitis B and hepatitis C performed to determine whether there is any current evidence for ongoing infection with these viruses. Patients considered to be at risk for HIV infection should have HIV testing performed. Testing for COVID-19 is not mandatory during the screening for this study. However, based on the local epidemiologic situation and each patient’s individual COVID-19 exposure risk and/or vaccination status, investigators should consider testing and in the case of COVID-19 positivity consider delaying the start of the study treatment until the infection is resolved.
• Patients with active clinically significant infection will not be eligible for enrollment until recovery for at least 2 weeks prior to the first dose of study drug.
• Patients with anemia deemed clinically significant by the investigator from iron deficiency, B12 and folate deficiencies, or hemolytic anemia.
• Patient with a major bleeding event causing a decrease in hemoglobin (Hgb) of ≥ 2g/dL or leading to transfusion of ≥ 2 units of packed red cells in the last 6 months prior to enrollment.
• Patients with liver cirrhosis Child-Pugh Class B or C.
• Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption or patients with hypersensitivity to any ingredient in the formulation of ruxolitinib.
• Patients who have or have had progressive multifocal leukoencephalopathy (PML).
• Ongoing uncontrolled hypertension despite maximal antihypertensive treatment.
• Any other concurrent severe and/or uncontrolled concomitant medical condition that in the opinion of the investigator could compromise participation in the study or analysis of study data. This includes but is not limited to clinically significant pulmonary disease or neurological disorders, or active or uncontrolled infections.
• Systemic anticancer treatment other than hydroxyurea (HU) and anagrelide (ANA) less than 2 weeks (or 5 half-lives, whichever is longer) before the first dose of study treatment. NOTE: HU and ANA are permitted to be used up to 72 hours prior to start of study drugs.
• Any investigational agent (whether for cancer treatment or not) less than 2 weeks (or 5 half-lives, whichever is longer) before the first dose of study treatment. < 6 weeks for mitomycin-C or nitrosourea.
• Hematopoietic growth factor (granulocyte growth factor, erythropoiesis stimulating agent, thrombopoietin mimetic) or androgenic steroids less than 4 weeks before the first dose of study drug.
• Platelets < 100 x 10^9/L (at screening).
• Participants unwilling to receive red blood cell transfusion to treat low hemoglobin levels are excluded (at screening).
• ANC < 1 x 10^9/L (at screening).
• ALT > 2.5 x ULN unless due to liver involvement by MF (at screening).
• AST > 2.5 x ULN unless due to liver involvement by MF (at screening).
• Total bilirubin > 1.5 x ULN (total bilirubin > 1.5 x ULN is acceptable if direct bilirubin ≤ 1.2 x ULN or with a diagnosis of Gilbert's syndrome.) (at screening).
• Serum creatinine clearance < 50 mL/minute based on Cockcroft-Gault formula or 24-hour urinalysis, or glomerular filtration rate < 50 mL/min/1.73 m^2 as calculated using the Modification of Diet in Renal Disease formula (at screening).
• International normalized ratio (INR) or prothrombin time (PT) > 1.5 x ULN (at screening). * Note: If the participant is receiving anticoagulant therapy, the participant may be included as long as the INR, PT, and activated partial thromboplastin time (aPTT) are within therapeutic range of intended use of anticoagulants.
• aPTT > 1.5 x ULN (at screening). * Note: Partial thromboplastin time may be used in place of aPTT per institutional standards.
• Hemoglobin (Hb)A1c > 8% (at screening). * Note: All participants will have a HbA1c test at screening.
• Concurrent anticancer therapy (e.g., chemotherapy, radiation therapy, surgery, immunotherapy, biologic therapy, hormonal therapy, investigational therapy, tumor embolization) other than the therapies being tested in this study or with exception to the following: * > Low-dose corticosteroids (prednisone or equivalent ≤ 10 mg per day) may be administered. Use of inhaled or topical steroids and prophylactic corticosteroids for radiographic procedures is permitted. * > Hydroxyurea/anagrelide: Not allowed during the study treatment period.
• Participants who have received allogeneic hematopoietic stem-cell transplant within 6 months of enrollment, or have active graft-versus-host disease (GVHD), or have received immunosuppressive therapy following allogeneic transplant within 2 weeks of the first dose of study treatment.
• Participants may not have received autologous hematopoietic stem-cell transplant within 3 months before the first dose of study treatment.
• Participants who have any unresolved toxicity ≥ grade 2 from previous anticancer therapy except for stable chronic toxicities (≤ grade 2) not expected to resolve, such as stable grade 2 peripheral neuropathy.
• Radiotherapy within the 2 weeks before the first dose of study treatment. Palliative radiation treatment performed less than 2 weeks before treatment initiation may be considered with principal investigator approval.
• Known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer/intraepithelial carcinoma of the cervix, papillary thyroid and follicular thyroid cancers that have undergone potentially curative therapy. Participants with malignancies with indolent behavior such as prostate cancer treated with radiation or surgery may be enrolled as long as they have a reasonable expectation to have been cured with the treatment modality received.
• Significant concurrent, uncontrolled medical condition, including but not limited to the following: * > Gastrointestinal (GI) ** Significant GI disorder, including but not limited to the following adverse events (AEs) ≥ grade 2: large esophageal varices, GI hemorrhage, ulcer (any site except oral), or diarrhea/colitis. ** History of clinically significant GI bleeding, perforation, or fistula. * > Cardiovascular ** History of or current clinically significant or uncontrolled cardiovascular disease or cerebrovascular disease, including stroke, unstable angina, acute myocardial infarction, New York Heart Association Class III or IV clinically significant congestive heart failure, ischemic heart disease, uncontrolled hypertension, or serious cardiac arrhythmias. ** History of arterial or venous thrombosis within the last 6 months. ** History or presence of an abnormal electrocardiogram (ECG) that, in the investigator's opinion, is clinically meaningful. A screening Fridericia’s formula–corrected QT (QTcF) interval > 470 ms is excluded. For participants with an intraventricular conduction delay (QRS interval ≥ 120 ms), the JTc interval may be used in place of the corrected QT (QTc) with sponsor approval. Participants with left bundle branch block are excluded.
• Ejection fraction < 55% (all participants are required to have an ECHO or MUGA during screening and/or baseline assessment in order to meet this criterion). Current use of prohibited medications as described.
• Use of any potent CYP3A4 inhibitors or inducers within 14 days or 5 half-lives (whichever is longer) before the first dose of study treatment. Initiation of treatment of a strong CYP3A4 inhibitor or inducer during study treatment is prohibited.
• Known hypersensitivity or severe reaction to INCB057643 or excipients of INCB057643.
• Inability or unlikeliness of the participant to comply with the dose schedule and study evaluations, in the opinion of the investigator.
• Inadequate recovery from toxicity and/or complications from a major surgery before starting therapy.
• Women who are pregnant or breastfeeding.
• Inability of the participant (or parent, guardian, or legally authorized representative) to comprehend the informed consent form (ICF) or unwillingness to sign the ICF.