Myelofibrosis, Post-PV MF, Post-ET Myelofibrosis, Primary Myelofibrosis
Conditions
Keywords
Relapsed/Refractory Myelofibrosis, Janus associated Kinase Inhibitor-Intolerant Myelofibrosis, MDM2, navtemadlin
Brief summary
This study evaluates KRT-232 in Combination With TL-895 for the Treatment of Relapsed or Refractory Myelofibrosis and KRT-232 for the Treatment of JAK Inhibitor Intolerant Myelofibrosis.
Detailed description
Cohorts 1 and 2 will undergo dose finding and dose expansion. Eligible patients will be randomly assigned to an open cohort, either Cohort 1 or Cohort 2. Cohort 3 will be conducted as a dose expansion, independent of Cohorts 1 and 2. Cohort 1 will follow a 3+3 dose escalation design to determine the maximum tolerated dose (MTD)/maximum administered dose (MAD) and recommended Phase 2 dose (RP2D) of TL-895 administered QD in combination with KRT-232. A Safety Review Committee (SRC) will review the safety data during the dose escalation to decide on dose escalation and/or exploration of intermediate doses. Cohort 2 will follow a 3+3 dose escalation design to determine the MTD/MAD and recommended RP2D of TL-895 administered BID in combination with KRT-232. An SRC will review the safety data during the dose escalation to decide on dose escalation and/or exploration of intermediate doses. Cohort 3 will be conducted a 2-stage design. In stage 1, enrollment will continue until 15 evaluable patients have been enrolled. An SRC will review the data during the study and if there are ≥4 responders based on the futility criteria and safety data from Stage 1, Cohort 3 expansion will commence. If there are ≤3 patients responding to therapy, Cohort 3 will be terminated. Once expansion criteria have been met, Cohort 3 will be expanded to a total of 46 evaluable patients for Stage 2 analyses.
Sponsors
Telios Pharma, Inc.
Kartos Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Confirmed diagnosis of primary MF, post-PV MF, or post-ET MF, (WHO 2016) * ECOG ≤ 2 * Cohort 1 and Cohort 2: R/R following JAK inhibitor treatment * Cohort 3: patients who are intolerant to JAK inhibitor treatment
Exclusion criteria
* Prior treatment with MDM2 inhibitors or p53-directed therapies * Prior treatment with a BCR-ABL, phosphoinositide 3-kinase (PI3k), mammalian target of rapamycin (mTOR), bromodomain and extraterminal domain (BET), histone deacetylase (HDAC), or spleen tyrosine kinase (Syk) inhibitor * Prior splenectomy * Splenic irradiation within 3 months prior to the first dose of study treatment * Clinically significant thrombosis within 3 months of screening * Grade 2 or higher QTc prolongation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b - The MTD/MAD and RP2D of TL-895 in combination with KRT-232 in patients with R/R MF (Cohort 1 and Cohort 2) | 56 Days | DLTs will be used to establish the MTD. RP2D will be determined by the SRC based on safety data from the combination of TL-895 and KRT-232. |
| Phase 2 - Spleen response rate for each cohort | 24 Weeks | A reduction in spleen volume as assessed by MRI (or CT) ≥ 35% from baseline at Week 24 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Symptom Score (TSS) | 24 Weeks | The change in TSS based Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0) |
Countries
Austria, Bulgaria, France, Germany, Hungary, Italy, Poland, Serbia, Spain, United States
Contacts
Primary ContactJohn Mei
Backup ContactIrene Dea
Outcome results
None listed