Primary Myelofibrosis
Conditions
Keywords
Post-Essential Thrombocythemia Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, PMF, PPV-MF, PET-MF
Brief summary
J8G-MC-JDIA (AJX-101) is a first-in-human (FIH), phase 1, non-randomized, multi-center, open-label clinical trial designed to investigate the safety, tolerability, pharmacokinetics (PK), clinical activity and changes in biomarkers of an orally administered type II Janus Kinase 2 (JAK2) inhibitor, LY5830966, in participants with primary or secondary myelofibrosis previously treated with at least one type I JAK2 inhibitor.
Detailed description
This is a phase 1, non-randomized, open-label study utilizing a 3+3 sequential dose escalation design followed by an expansion phase. The primary objective will be to evaluate the safety and tolerability of LY5830966 and establish a Maximally Tolerated Dose (MTD) and/or inform the establishment of a candidate Recommended Phase 3 dose (RP3D). The RP3D may be the maximally tolerated dose (MTD) or may be a dose below the MTD. The candidate RP3D will be based on adverse event (AE) pattern, pharmacokinetics (PK) and biomarker information, in addition to all available safety and efficacy data. Expansion cohorts will be enrolled to gather additional safety and efficacy information and to further refine input for future RP3D discussions. Eligible participants will have PMF, PPV-MF or PET-MF and will have either have relapsed after a response, or be refractory to, at least one prior type I JAK2 inhibitor therapy, either administered as monotherapy or in combination with another drug.
Interventions
DRUGLY5830966
Type II JAK2 Inhibitor
Sponsors
Ajax Therapeutics, Inc., a wholly owned subsidiary of Eli Lilly and Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This dose escalation study will follow a 3+3 cohort design until the RP3D and/or MTD is determined.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of PMF, post-PV MF, or post-ET MF. * Dynamic International Prognostic Scoring System (DIPSS) Intermediate-1, Intermediate-2 or High-risk MF with less than or equal to (≤)10% blasts, regardless of JAK2 mutation status. * Estimated spleen volume greater than or equal to (≥)450 cubic centimeter (cm ³) * Myelofibrosis Symptom Assessment Form, version 4.0 (MFSAF v.4.0) TSS ≥10, or at least 2 of 7 MFSAF-assessed symptoms with scores ≥3. * Eastern Cooperative Oncology Group performance score (ECOG PS) of 0, 1, 2, or 3. * Prior therapy with at least 1 type I JAK2 inhibitor, and either failed to achieve a response or relapsed after achieving a response. * Absolute neutrophil count greater than or equal to 1,000 per microliter of blood (ANC ≥1.0×10\^9/L). * Platelet count ≥75×10\^9/L. * Estimated glomerular filtration rate greater than or equal to 45 milliliters per minute per 1.73 square meters (eGFR ≥45 mL/min/1.73m²). * Serum total bilirubin ≤2.0 × upper limit of normal (ULN). * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0 × upper limit normal (ULN). * QTcF ≤470 msec. Polycythemia vera (PV) Only * Confirmed diagnosis of PV * Participants must have high-risk disease as defined by 60 years of age or older and/or have prior history of thrombotic event * R/R or intolerant to at least one line of prior therapy including but not limited to interferon-based therapies, ruxolitinib, or hydroxyurea (HU) as defined by European LeukemiaNet (ELN) criteria
Exclusion criteria
* Prior splenectomy or splenic irradiation within 3 months. * Ongoing use of systemic corticosteroids at dose equivalent to greater than (\>) 20 milligrams per day (mg/day) of prednisone. * Active, uncontrolled systemic infection or active Hepatitis B or C * Chemotherapy in the previous 4 weeks or prior JAK2 inhibitor not discontinued per required washout prior to first dose * Peripheral neuropathy ≥ Grade 2 (NCI CTCAE v 5.0). * Pregnant or breastfeeding: males planning to father a child during treatment and for 3 months after last dose. * Requirement for therapy with a medication that is a strong Cytochrome P450 3A4 CYP3A4 inhibitor as a concomitant medication. * Currently on an interventional therapeutic trial in the treatment phase. * Significant cardiovascular disease * Active second primary malignancy (or diagnosed within 2 years) at high risk of progression, with standard exceptions (treated skin cancer, in situ cervical cancer, curatively treated localized breast/prostate cancer) * Prolongation of the corrected QTcF ≥470 millisecond during screening * Individual with a history of (noninfectious) pneumonitis/interstitial lung disease. First line (1L) MF only: * Prior treatment with JAK2 inhibitors High-risk R/R PV only: * Prior PV-directed therapy without required washout * Active or chronic bleeding within 2 months prior to enrollment * Clinically significant thrombosis (e.g., pulmonary embolism, deep vein thrombosis, or splenic vein thrombosis) within 2 months prior to enrollment * Requires phlebotomy at hematocrit levels \<45%.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of patients with treatment-emergent adverse events (TEAEs) as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v 5.0). | Baseline through study completion, an average of 1 year | Treatment Emergent AEs will be assessed during routine study visits and compared to Baseline to continuously evaluate safety and tolerability of LY5830966. |
| Number of patients with Dose Limiting Toxicities (DLTs) | Baseline through study completion, an average of 1 year | Protocol-defined potential DLTs will be assessed by the Safety Review Committee at routine intervals. |
| To establish the maximum tolerated dose (MTD) and/or recommended phase 3 dose (RP3D) of LY5830966 | Baseline through study completion, an average of 1 year | Safety evaluations will occur consistently for each patient and across patients to assess MTD or RP3D. See description of safety evaluations described in outcomes 1 and 2 mentioned above. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To assess clinical response to LY5830966 evaluated by the Total Symptom Score (TSS). | Baseline through Week 24 | Number and proportion of patients with an improvement of ≥50% from Baseline in Total TSS as well as time to TSS response and duration of TSS response using the Myelofibrosis Symptom Assessment Form (MFSAF) v4.0. The TSS is a 7 question assessment form with lower scores indicating better outcomes. |
| To assess clinical response to LY5830966 evaluated by spleen volume assessments. | Baseline through Week 24 | Spleen volume reduction (SVR) of ≥35% from Baseline measured by magnetic resonance imaging (MRI) or computed tomography (CT). |
| To assess clinical response to LY5830966 evaluated by spleen length assessments. | Baseline through Week 24 | Proportion of subjects with ≥50% reduction in length of spleen assessed by palpation. |
| To assess clinical response to LY5830966 evaluated through spleen size improvement. | Baseline through Week 24 | Time to spleen size improvement response measured by patient and across all patients. |
| To evaluate the Area Under the Curve (AUC) of LY5830966 | Pre dose and post dose Cycle 1 (Day 1, and Day 2 (24hrs post), and Cycle 2 (Day 1 and 24 hrs post). | AUC time curve from 0 to 24 hrs post dose and percent difference between intervals will be evaluated. |
| To evaluate the Cmax of LY5830966 | Pre dose and post dose Cycle 1 (Day 1, and Day 2 (24hrs post), and Cycle 2 (Day 1 and 24 hrs post). | The maximum observed plasma concentration will be evaluated. |
| To evaluate the Tmax of LY5830966 | Pre dose and post dose Cycle 1 (Day 1, and Day 2 (24hrs post), and Cycle 2 (Day 1 and 24 hrs post). | The duration of time taken to reach Cmax will be evaluated. |
| To evaluate the half-life of LY5830966 | Pre dose and post dose Cycle 1 (Day 1, and Day 2 (24hrs post), and Cycle 2 (Day 1 and 24 hrs post). | The depletion of AJ1-00195 in the body will be observed over time. |
Countries
France, Italy, Spain, United Kingdom, United States
Contacts
CONTACTDavid Steensma, M.D.
PRINCIPAL_INVESTIGATORJohn Mascarenhas, M.D.
Mt. Sinai
Outcome results
None listed