A Phase 1 Study of AJ1-11095 in Patients With Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (PPV-MF), or Post-Essential Thrombocythemia Myelofibrosis (PET-MF) Who Have Been Failed by a Type I JAK2 Inhibitor (JAK2i)
- Conditions
- Primary MyelofibrosisPost-Polycythemia Vera MyelofibrosisPMFPPV-MFPost-Essential Thrombocythemia MyelofibrosisPET-MF
- Interventions
- Registration Number
- NCT06343805
- Lead Sponsor
- Ajax Therapeutics, Inc.
- Brief Summary
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 JAK2 inhibitor, AJ1-11095, in subjects 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 AJ1-11095, and establish a Maximally Tolerated Dose (MTD) and/or inform the establishment of a candidate Recommended Phase 2 dose (RP2D). The RP2D may be the maximally tolerated dose (MTD) or may be a dose below the MTD. The candidate RP2D will be based on AE pattern, 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 RP2D 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 76
- 18 years of age or older.
- Diagnosis of PMF, post-PV MF, or post-ET MF.
- DIPSS Intermediate-2 or High-risk MF with ≤10% blasts, regardless of JAK2 mutation status.
- Estimated spleen volume ≥450cm3.
- MFSAF v.4.0 TSS ≥10, or at least 2 of 7 MFSAF-assessed symptoms with scores ≥3.
- 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.
- ANC ≥1.0×10^9/L.
- Platelet count ≥75×10^9/L.
- eGFR ≥45 mL/min/1.73m2.
- Serum total bilirubin ≤2.0 × upper limit of normal (ULN).
- AST and ALT ≤3.0 × ULN.
- QTcF ≤480 msec.
- Prior splenectomy.
- Splenic irradiation within 3 months prior to first dose of study drug.
- Ongoing use of systemic corticosteroids at dose equivalent to >10mg/day of prednisone.
- Uncontrolled intercurrent illness such as an acute infection.
- Chronic active or acute hepatitis B or C infection.
- Chemotherapy in the previous 4 weeks prior to first dose of study drug (Hydrea is permitted until 5 days before starting protocol therapy).
- Use of a JAK2 inhibitor in the previous 10 days.
- Use of erythropoiesis stimulating agents (unless stable for >8 weeks).
- Peripheral neuropathy ≥ Grade 2 (NCI CTCAE v 5.0).
- Unable or unwilling to undergo CT or MRI for spleen size imaging.
- Pregnant or breastfeeding.
- Requirement for therapy with a medication that is a strong CYP3A4 inhibitor as a concomitant medication.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Cohort 3 AJ1-11095 Dose C of AJ1-11095 taken orally by patients. Cohort 4 AJ1-11095 Dose D of AJ1-11095 taken orally by patients. Cohort 5 AJ1-11095 Dose E of AJ1-11095 taken orally by patients. Cohort 1 AJ1-11095 Dose A of AJ1-11095 taken orally by patients. Cohort 2 AJ1-11095 Dose B of AJ1-11095 taken orally by patients. Dose Expansion Cohort 1 AJ1-11095 Candidate RP2D of AJ1-11095 taken orally by patients. Dose Expansion Cohort 2 AJ1-11095 Alternative candidate RP2D of AJ1-11095 taken orally by patients.
- Primary Outcome Measures
Name Time Method 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.
Number of patients with treatment-emergent adverse events as assessed by 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 AJ1-11095.
To establish the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of AJ1-11095 Baseline through study completion, an average of 1 year Safety evaluations will occur consistently for each patient and across patients to assess MTD or RP2D. See description of safety evaluations described in outcomes 1 and 2 mentioned above.
- Secondary Outcome Measures
Name Time Method To assess clinical response to AJ1-11095 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 AJ1-11095 evaluated by spleen length assessments. Baseline through Week 24 Proportion of subjects with ≥50% reduction in length of spleen assessed by palpation.
To evaluate the Tmax of AJ1-11095 Pre dose and post dose Cycle 1 (Day 1, and Day 2 (24hrs post), Day 8, 15, 22, and Cycle 2 (Day 1 and 24 hrs post). The duration of time taken to reach Cmax will be evaluated.
To assess clinical response to AJ1-11095 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 AJ1-11095 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 AJ1-11095 Pre dose and post dose Cycle 1 (Day 1, and Day 2 (24hrs post), Day 8, 15, 22, 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 AJ1-11095 Pre dose and post dose Cycle 1 (Day 1, and Day 2 (24hrs post), Day 8, 15, 22, and Cycle 2 (Day 1 and 24 hrs post). The maximum observed plasma concentration will be evaluated.
To evaluate the half-life of AJ1-11095 Pre dose and post dose Cycle 1 (Day 1, and Day 2 (24hrs post), Day 8, 15, 22, and Cycle 2 (Day 1 and 24 hrs post). The depletion of AJ1-00195 in the body will be observed over time.
Trial Locations
- Locations (12)
Stanford Cancer Institute
🇺🇸Palo Alto, California, United States
Moffitt Cancer Cancer Center
🇺🇸Tampa, Florida, United States
University of Kansas Medical Center
🇺🇸Kansas City, Kansas, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Dana Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
David H. Koch Center for Cancer Care at Memorial Sloan Kettering
🇺🇸New York, New York, United States
Icahn School of Medicine at Mount Sinai
🇺🇸New York, New York, United States
Levine Cancer Institute
🇺🇸Charlotte, North Carolina, United States
University of Cincinnati
🇺🇸Cincinnati, Ohio, United States
The Ohio State University Comprehensive Cancer Center
🇺🇸Columbus, Ohio, United States
MD Anderson Cancer Center
🇺🇸Houston, Texas, United States