Title A Phase 2 Study of LY2784544 in Patients with Myeloproliferative Neoplasms
IRB LILY 1Z11
Hospital Main Campus
Disease Myeloproliferative Neoplasms
- The primary objective of the study is to assess the activity of LY2784544 therapy administered once daily, as measured by objective response rate in patients with the myeloproliferative neoplasms: PV, ET, and MF, including those who have demonstrated an intolerance to, failure of primary response to, or have demonstrated disease progression while on ruxolitinib.
- To characterize the safety and toxicity profile of LY2784544 by MPN subtype
- To assess the individual components of response criteria including changes in spleen and liver measurement, changes in JAK2 V617F mutant allele burden, changes in blood counts, changes in bone marrow histology, and changes in transfusion or phlebotomy requirements by MPN subtype and by prior JAK2 inhibitor treatment status.
- To document any change in patient-reported or physician assessment of symptom burden by MPN subtype
- To examine JHTB PK data at 120 mg and explore for potential relationship with response for each MPN subtype
- To document any change in frequency of thrombotic/hemorrhagic events after treatment with LY2784544 by MPN subtype
- To assess time-to-event measures, including time to best response, duration of response for each MPN subtype, and progression-free survival.
- To describe response to LY2784544 in patients with wild-type JAK2
- Have a diagnosis of polycythemia vera (PV), essential thrombocythemia (ET), or myelofibrosis (MF) as defined by the World Health Organization (WHO) diagnostic criteria for myeloproliferative neoplasms (Swerdlow et al. 2008; see Attachment 8) and meet the following additional subtype specific criteria: a) PV: have failed or is intolerant, b) ET: have failed or is intolerant of standard therapies or refuses to take standard medications, c) MF (patients with MF must meet at least 1 of the following): i) have intermediate 1, intermediate 2, or high-risk MF according to the Dynamic International Prognostic Scoring System (DIPPS Plus) for Primary Myelofibrosis (Gangat et al. 2011); or ii) have symptomatic MF with spleen greater than 10 cm below left costal margin; or iii) have post-polycythemic MF; or iv) have post-ET MF All PV, ET, and MF patients must meet the following criteria:
- Have a quantifiable JAK2 V617F mutation. This inclusion criterion will not apply to the subset of patients in Cohorts 10 and 11 that must be negative for the JAK2 V617F mutation.
- Are ≥ 18 years of age.
- Have given written informed consent prior to any study-specific procedures.
- Have adequate organ function, including:
- Hepatic: Direct bilirubin ≤ 1.5 times upper limits of normal (ULN), alanine transaminase (ALT), and aspartate transaminase (AST) ≤ 2.5 times ULN
- Renal: Serum creatinine ≤ 1.5 times ULN.
- Bone Marrow Reserve: Absolute neutrophil count (ANC) ≥ 1000/mcl, platelets ≥ 50,000/mcL for patients with ET or PT and ≥ 25,000/mcL for patients with MF.
- Have a performance status of 0, 1, or 2 on the Eastern Cooperative Oncology Group (ECOG) scale (refer to Attachment 4).
- Have discontinued all previous approved therapies for MPNs, including any chemotherapy, immunomodulating therapy (for example, thalidomide,interferon-alpha), immunosuppressive therapy (for example, corticosteroids > 10 mg/day prednisone or equivalent), radiotherapy, and erythropoietin, thrombopoietin, or granulocyte colony stimulating factor or at least 14 days and recovered from the acute effects of therapy. Hydroxyurea used to control blood cell counts is permitted at study entry if the subject has been maintained on a stable dose for at least 4 weeks. Low-dose acetylsalicylic acid (aspirin; 81 or 100 mg) is permitted as well.
- Are reliable and willing to make themselves available for the duration of the study and are willing to follow study procedures.
- Males and females with reproductive potential must agree to use medically approved contraceptive precautions during the study and for 3 months following the last dose of study drug.
- Females with child-bearing potential must have had a negative urine pregnancy test ≤ 7 days before the first dose of study drug and must also not be breastfeeding.
- Are able to swallow capsules.
- For patients who have undergone recent major surgery, at least 28 days must have elapsed between surgery and study participation and the subject must have achieved, in the opinion of the treating physician, at least a good recovery from the surgical procedure
- Enrollment into Cohort 12 is limited to MF, PV, or ET patients, regardless of mutational status, who, in addition to all other criteria, have demonstrated intolerance to ruxolitinib, failure of primary response to ruxolitinib, or have demonstrated disease progression while on ruxolitinib.
- Are currently enrolled in, or discontinued within the last 14 days from a clinical trial involving an investigational product or non-approved use of a drug or device, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study.
- Have a corrected QT (QTc) interval > 470 msec using Bazett's formula.
- Have serious preexisting medical conditions that, in the opinion of the investigator would preclude participation in the study (for example a gastrointestinal disorder causing clinically significant symptoms such as nausea, vomiting, and diarrhea, or malabsorption syndrome).
- Are currently being treated with agents that are metabolized by CYP3A4 with a narrow therapeutic margin (for example, alfentanil, cyclosporine, diergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus) or CYP2B6 (for example, cyclophosphamide, ifosfamide, tamoxifen, efavirenz, propofol, methadone, and bupropion).
- Are currently being treated with warfarin or 1 of its derivatives which is known to alter levels of protein C or protein S. An exception to this criterion will be allowed for patients with a prior history of Budd-Chiari Syndrome who are being treated with warfarin or 1 of its derivatives.
- Have received a hematopoietic stem cell transplant.
- Have a second primary malignancy that in the judgment of the Investigator and Sponsor may affect the interpretation of results.
- Have an active fungal, bacterial, and/or known viral infection including human immunodeficiency virus (HIV) or viral (A, B, or C) hepatitis (screening is not required).
- Have a history of congestive heart failure with New York Heart Association Class > 2 (NYHA Class 1 and 2 are eligible), unstable angina, recent myocardial infarction (within 6 months prior to administration of study drug), or documented history of ventricular arrhythmia.