The PIM1 kinase inhibitor TP-3654 was well tolerated, with spleen volume reduction (SVR), symptomatic improvement, and extensive showed preliminary signs of activity such as cytokine reduction. According to results from the dose escalation portion of a phase 1/2 trial (NCT04176198).
Data presented at the 2022 ASH Annual Meeting showed that of eight evaluable patients who had been on treatment for at least 12 weeks, six experienced SVR. The median SVR was 11%. He had 5 patients with SVR >10% and he had 2 patients with SVR >35%. In addition, 7 of her 8 patients experienced improvement in Total Symptom Score (TSS). Median TSS improvement was 66%, with five patients experiencing at least 50% improvement in her TSS.
“Dose escalation is ongoing and TP-3654 appears to be well tolerated. [with] No Dose Limiting Toxicity [DLTs] Firas El Chaer, M.D., Ph.D., associate professor in the Department of Hematology/Oncology, University of Virginia Health System, Charlottesville, Virginia, and principal study author, said in a presentation of the data. Grade 1 gastrointestinal toxicity that resolves in ~2 weeks.”
PIM1 is a proto-oncogene that is partially regulated through the JAK/STAT pathway, and PIM1 kinase plays a key role in cytokine-induced signaling by regulating transcription factors. Upregulation of PIM1 kinase increases cytokines associated with immune activation and fibrosis. A significant increase in PIM1 expression has been observed in bone marrow and peripheral blood mononuclear cell samples taken from patients with myelofibrosis. The researchers hypothesized that new therapeutics that selectively inhibit PIM1 might have disease-modifying effects and avoid cytopenic cases.
“In an aggressive mouse MLP myelofibrosis mouse model, PIM1 inhibition reduced myelofibrosis. [reduced] Splenomegaly, and increase [overall] survival [OS]” added El Chaer.
Relapsed, refractory, intolerant, or ineligible for treatment with a JAK inhibitor, primary, postpolycythemia vera (PV), or essential thrombocythemia (ET) in phase 1/2 trials TP-3654 is being evaluated in post-myelofibrosis patients. .
To participate in the study, patients must have a Dynamic International Prognostic Scoring System (DIPSS) score of Intermediate-1, Intermediate-2, or High Risk. platelet count of at least 25 x 109 cells/L; ECOG performance status of 0-2; splenomegaly with a volume of at least 450 cm3; and at least 2 symptoms according to the Myelofibrosis Symptom Assessment Form v. 4.0.
In the dose escalation portion of the previous study, patients were treated with single-agent TP-3654 across five dose levels. 720 mg he twice a day. Dose escalation is underway, and the researchers plan to explore doses up to 1440 mg twice daily. The study will determine the maximum tolerated dose (MTD) and recommended Phase 2 dose of the drug before proceeding to Phase 2 dose escalation.
The primary endpoints of the trial are safety and tolerability. Secondary endpoints consisted of SVR, TSS reduction, OS, changes in myelofibrosis, and pharmacokinetics.
Of the 9 patients enrolled in the dose escalation portion of the study, the median age was 71 years (range, 61-77 years). Median spleen length was 12 cm (range, 0-25), median spleen volume was 2231 cm3 (range, 857-4407), and median TSS was 18 (range, 4-62). In addition, the median platelet count was 120 x 109 cells/L (range, 68-237), and six patients had platelet counts of at least 100 x 109 cells/L. Median hemoglobin was 10.1 g/dL (range, 5.9–13.7), and five patients had hemoglobin levels of at least 10 g/dL. Notably, two patients were transfusion dependent.
The myelofibrosis subtypes of patients enrolled in the trial were primary (n = 4), post-PV (n = 4) and post-ET (n = 1). They had his DIPSS scores of intermediate -1 (n = 3), intermediate -2 (n = 4), or high risk (n = 2). In addition, 7 patients had tumors. JAK2 V617F mutation, and 2 patients CALR mutation.
All 9 patients were pretreated with ruxolitinib (Jakafi) for a median of 33 weeks (range, 10–268), and 2 patients were previously treated with fedratinib (Inrebic) for a median of 36 weeks (range, 10–268). , 36–49). Three patients were primary refractory to her JAK inhibitors, four experienced loss of response, and two were intolerant to these agents.
As of the data cutoff date of 11 October 2022, 4 patients were still receiving treatment. This included 2 patients receiving TP-3654 480 mg bid, 1 patient receiving 720 mg bid, and 1 patient receiving 720 mg bid. patients were included. Reasons for discontinuation included physician discontinuation (n = 2), disease progression (n = 2), and patient discontinuation (n = 1). Notably, no patients discontinued due to side effects (AEs).
Additional data showed that a decrease in cytokines was observed as early as week 4 in the first-dose cohort, and this decrease correlated with a decrease in TSS. Cytokines associated with myelofibrosis—IL-6, IL-10, IL-12, IL-18, TGF-b, EGFR, ferritin, GRO-a, IL-1RA, MMP-9, PAI-1, RANTES, TIMP-containing 1, TNFR-2, and VCAM-1 showed a decrease after treatment.
Regarding safety, no DLTs or treatment-related serious AEs were reported. The most common grade 1 or 2 treatment-emergent AEs (TEAEs) included diarrhea (n = 7), nausea (n = 5), vomiting (n = 4), bloating (n = 2), Urinary tract infection (n = 2), muscle cramps (n = 2), insomnia (n = 2), fatigue (n = 2), dyspnea (n = 2), abdominal pain (n = 1), elevated bilirubin ( n = 1) . Grade 3 vomiting, abdominal pain, and elevated bilirubin were each experienced by one patient.
Grade 1/2 hematologic TEAEs included decreased platelet count (n = 2), anemia (n = 1), and leukocytosis (n = 1). Grade 3 platelet count decrease, anemia, and leukocytosis were observed in 1 patient each. No patients required dose reduction or treatment discontinuation due to adverse events.
“Registration will continue [TP-3654] monotherapy to identify MTD, and [data] We support the development of TP-3654 in combination with JAK inhibitors,” concluded El Chaer.
reference
Preliminary data from a phase I/II trial of TP-3654, a selective oral PIM1 kinase inhibitor, by El Chaer F, McCloskey J, Rein LAM et al. Intended for fibrosis patients. blood. 2022;140(suppl 1):594-595.doi:10.1182/blood-2022-159086