A Phase 2 Study of the Safety, Tolerability, and Efficacy of INCB050465 in Combination with Ruxolitinib in Subjects with Myelofibrosis
The goal of this clinical research study is to find the highest tolerable dose of INCB050465 that can be given in combination with ruxolitinib to patients with myelofibrosis. Researchers also want to learn more about the effects of INCB050465 in combination with ruxolitinib on spleen size and/or symptoms of myelofibrosis.
Disease Group: Malignant neoplasms stated as primary lymphoid haematopoietic
Treatment Agent: INCB050465,Ruxolitinib
Treatment Location: Both at MD Anderson & Other Sites
Primary Objectives: Part 1: To evaluate the safety and tolerability of INCB050465 in combination with ruxolitinib in subjects with MF (primary myelofibrosis [PMF], post–polycythemia vera myelofibrosis [PPV-MF] or post–essential thrombocythemia myelofibrosis [PET-MF]) and select a dose for further evaluation. Part 2: To evaluate the efficacy of INCB050465 in combination with ruxolitinib on spleen volume reduction in subjects with PMF, PPV-MF, or PET-MF. Secondary Objectives: To evaluate the efficacy of INCB050465 in combination with ruxolitinib on subject reports of MF symptoms. To evaluate the efficacy of INCB050465 in combination with ruxolitinib on response using International Working Group (IWG)–Myeloproliferative Neoplasms Research and Treatment criteria. To assess the pharmacokinetics (PK) of INCB050465 and ruxolitinib alone and when given in combination in subjects with MF. To evaluate the safety and tolerability of INCB050465 when combined with ruxolitinib in subjects with MF. Exploratory Objectives: To evaluate the relationship between biomarkers and clinical activity in subjects with MF when treated with INCB050465 in combination with ruxolitinib. To evaluate the effects of INCB050465 in combination with ruxolitinib on gene expression in peripheral CD34+ cells. To evaluate the efficacy of INCB050465 in combination with ruxolitinib on transfusion rates. To evaluate the effects of INCB050465 in combination with ruxolitinib on bone marrow fibrosis grade, cytogenetics, and JAK2 allele burden, when available. Primary Endpoints: Part 1: Determination of doses of INCB050465 that are safe and tolerable in combination with ruxolitinib. Part 2: Change and percentage change in spleen volume from baseline through Week 12 as measured by magnetic resonance imaging (MRI or computed tomography [CT] scan in applicable subjects). Secondary Endpoints: Change and percentage change in spleen volume from baseline through Week 24 as measured by MRI (or CT scan in applicable subjects). Change and percentage change in total symptom score from baseline through Week 12 or Week 24 as measured by the Myelofibrosis Symptom Assessment Form version 3.0 (MFSAF v3.0) symptom diary and by the Myeloproliferative Neoplasms Symptom Assessment Form (MPN-SAF). Number of subjects with responses according to the 2013 IWG consensus criteria for treatment response in PMF, PPV-MF, and PET-MF. Patient Global Impression of Change score at each visit where the variable is measured. Population PK parameters of INCB050465 and ruxolitinib alone and in combination (eg, AUC, Cmax) will be summarized. Safety and tolerability of the treatment regimens through assessment of adverse events (AEs) and changes in safety assessments including laboratory parameters. Exploratory Endpoints: Change in cytokine and other tumor marker levels from baseline to each visit where the variable is measured. Markers may include, but are not limited to interleukin (IL)-6, IL-1â, tumor necrosis factor (TNF), and TNFRII. Comparison of reductions in spleen volume and total symptom score reductions between subjects with at least 1 mutation in the HMR genes (ASXL1, EZH2, SRSF2, and IDH1/2) and those with no HMR gene mutations. Change in allele burden of JAK2 V617F, MPL W515 and S505, and calreticulin exon 9 from baseline through Week 24. Change and percentage change in frequency of red blood cell (RBC) transfusions during any consecutive 8-week period. Change in bone marrow fibrosis grade and cytogenetics from baseline through Week 24. Change in gene expression in peripheral CD34+ cells including, but not limited to, phosphatidylinositol 3-kinase (PI3K) isoforms.
IRB Review and Approval Date: 11/18/2016
Recruitment Status: Open
Projected Accrual: 66-78
1) Men and women, aged 18 years or older.
2) Diagnosis of PMF, PPV-MF, or PET-MF.
3) Treated with ruxolitinib for >/= 6 months with stable dose for >/= 8 weeks (acceptable doses are 5 mg BID to 25 mg BID).
4) Evidence of inadequate response to ruxolitinib: Palpable spleen of > 10 cm below the left subcostal margin on physical examination at the screening visit OR Palpable splenomegaly of 5 to 10 cm below left subcostal margin on physical exam AND active symptoms of MF at the screening visit as demonstrated by presence of 1 symptom score >/= 5 or 2 symptom scores >/= 3 using the Screening Symptom Form.
5) Subjects with an ECOG performance status of 0, 1, or 2.
6) Screening bone marrow biopsy specimen available or willingness to undergo a bone marrow biopsy at screening/baseline; willingness to undergo bone marrow biopsy at Week 24.
7) Life expectancy of at least 24 weeks.
8) Willingness to avoid pregnancy or fathering children based on the criteria below: Woman of non-childbearing potential (ie, surgically sterile with a hysterectomy and/or bilateral oophorectomy OR >/= 12 months of amenorrhea and at least 50 years of age). Woman of childbearing potential who has a negative serum pregnancy test at screening and before the first dose on Day 1 and who agrees to take appropriate precautions to avoid pregnancy (with at least 99% certainty) from screening through safety follow-up. Permitted methods that are at least 99% effective in preventing pregnancy should be communicated to the subject and their understanding confirmed. Man who agrees to take appropriate precautions to avoid fathering children (with at least 99% certainty) from screening through safety follow-up. Permitted methods that are at least 99% effective in preventing pregnancy should be communicated to the subject and their understanding confirmed.
9) (Continued from #8): The safety follow-up period is the interval between the EOT visit and the scheduled follow-up visit, which should occur 30 to 35 days after the EOT visit (or after the last dose of study drug if the EOT visit was not performed).
1) Use of experimental drug therapy for MF, or any other standard drug
(eg, danazol, hydroxyurea, etc) with the exception of ruxolitinib within
6 months of starting study (combination) therapy and/or lack of recovery
from all toxicities from previous therapy (except ruxolitinib) to Grade
1 or better.
2) Inability to swallow food or any condition of the upper gastrointestinal tract that precludes administration of oral medications.
3) Unwillingness to be transfused with blood components.
4) Recent history of inadequate bone marrow reserve as demonstrated by the following: Platelet count < 50 × 10^9/L in the 4 weeks before screening or platelet transfusion(s) within 8 weeks before screening. Absolute neutrophil count levels < 0.5 × 10^9/L in the 4 weeks before screening. Subjects with peripheral blood blast count of > 10% at the screening or baseline hematology assessments. Subjects who are not willing to receive RBC transfusions to treat low hemoglobin levels.
5) Inadequate liver function at screening and baseline visits as demonstrated by the following: Direct bilirubin >/= 2.0 × the upper limit of laboratory normal (ULN). (NOTE: direct bilirubin will only be determined if total bilirubin is = 2.0 × ULN). ALT or AST > 2.5 × ULN.
6) Inadequate renal function at screening and baseline visits as demonstrated by creatinine clearance < 50 mL/min measured or calculated by Cockroft-Gault equation, or glomerular filtration rate < 50 mL/min/1.73 m^2 as calculated using the Modification of Diet in Renal Disease formula.
7) Active bacterial, fungal, parasitic, or viral infection that requires therapy. Subjects with acute infections requiring treatment should delay screening/enrollment until the course of therapy has been completed and the event is considered resolved. Prophylactic antibiotics will be permitted.
8) Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection that requires treatment or at risk for HBV reactivation. Hepatitis B virus DNA and HCV RNA must be undetectable upon testing. At risk for HBV reactivation is defined as hepatitis B surface antigen positive or anti–hepatitis B core antibody positive.
9) Known human immunodeficiency virus infection.
10) Uncontrolled, severe, or unstable cardiac disease that in the investigator's opinion may jeopardize the safety of the subject or the compliance with the Protocol.
11) Active invasive malignancy over the previous 2 years except treated basal or squamous carcinomas of the skin, completely resected intraepithelial carcinoma of the cervix, and completely resected papillary thyroid and follicular thyroid cancers. Subjects 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.
12) Splenic irradiation within 6 months before receiving the first dose of INCB050465.
13) Concurrent use of any prohibited medications.
14) Active alcohol or drug addiction that would interfere with their ability to comply with the study requirements.
15) Prior therapy with any drug that inhibits PI3K (examples of drugs targeting this pathway include but are not limited to INCB040093, idelalisib, duvelisib, and TGR-1202).
16) Use of any potent cytochrome P450 3A4 inhibitors or inducers within 14 days or 5 half-lives (whichever is longer) before the first dose of INCB050465 or anticipated during the study.
17) Inadequate recovery from toxicity and/or complications from a major surgery before starting therapy.
18) Currently breastfeeding or pregnant.
19) Any medical, psychological, or social condition that would interfere with full participation in the study, including administration of study drug and attending required study visits; pose a significant risk to the subject; or interfere with interpretation of study data.
20) Inability to comprehend or unwilling to sign the informed consent form.
21) History of Grade 3 or 4 immune-related AEs from prior immunotherapy. - Any immune-related AEs of Grade 1 or 2 must be resolved before receiving the first dose of INCB050465.
22) History of immune-related ocular AEs of any toxicity grade.
Information and next steps
Malignant neoplasms stated as primary lymphoid haematopoietic
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