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Phase 1/2 trial of glasdegib in patients with primary or secondary myelofibrosis previously treated with ruxolitinib.

ABSTRACT: Glasdegib is a potent and selective oral inhibitor of the Hedgehog pathway. We report data from the single-arm, lead-in cohort of an open-label phase 1b/2 trial of glasdegib in patients with primary/secondary myelofibrosis (MF) previously treated with at least one Janus kinase inhibitor (JAKi). Patients received glasdegib 100 mg orally once daily until there was no further clinical benefit. Primary endpoints included adverse events (AEs). Secondary endpoints included patients with spleen volume reduction (SVR) ≥35% at week 24, patients with ≥50% total symptom score (TSS) reduction, and pharmacokinetics. All 21 treated patients had one or more AE and five (23.8%) had serious AEs. Most common (>30%) AEs were dysgeusia (61.9%), muscle spasms (57.1%), alopecia (38.1%), fatigue (33.3%), and decreased appetite (33.3%). Although no patient had ≥35% SVR at week 24, one patient previously treated with ruxolitinib had an SVR of 32.9%. At week 12, two (9.5%) patients had ≥50% reduction in TSS from baseline and ˜40% had ≥20% reduction. One patient had an anaemia response. Following administration of glasdegib 100 mg once daily, the median time to peak plasma concentrations at steady-state generally occurred at 1 h post-dose. The safety profile of glasdegib monotherapy was manageable in patients with primary/secondary MF. Further study of glasdegib in combination with JAKi in a MF population may be warranted.

SUBMITTER: Gerds AT

PROVIDER: S-EPMC8148985 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundMyelofibrosis is a chronic myeloproliferative neoplasm characterised by splenomegaly, cytopenias, bone marrow fibrosis, and debilitating symptoms including fatigue, weight loss, and bone pain. Mutations in Janus kinase-2 (JAK2) occur in approximately 50% of patients. The only approved JAK2 inhibitor for myelofibrosis is the dual JAK1 and JAK2 inhibitor, ruxolitinib. 58-71% of patients treated with ruxolitinib in clinical trials so far have not achieved the primary endpoint of 35% or more reduction in spleen volume from baseline assessed by MRI or CT. Furthermore, more than 50% of patients discontinue ruxolitinib treatment after 3-5 years. On the basis of this unmet need, we investigated the efficacy and safety of fedratinib, a JAK2-selective inhibitor, in patients with ruxolitinib-resistant or ruxolitinib-intolerant myelofibrosis.MethodsThis single-arm, open-label, non-randomised, phase 2, multicentre study, done at 31 sites in nine countries, enrolled adult patients with a current diagnosis of intermediate or high-risk primary myelofibrosis, post-polycythaemia vera myelofibrosis, or post-essential thrombocythaemia myelofibrosis, found to be ruxolitinib resistant or intolerant after at least 14 days of treatment. Other main inclusion criteria were palpable splenomegaly (≥5 cm below the left costal margin), Eastern Cooperative Oncology Group performance status of 2 or less, and life expectancy of 6 months or less. Patients received oral fedratinib at a starting dose of 400 mg once per day, for six consecutive 28-day cycles. The primary endpoint was spleen response (defined as the proportion of patients with a ≥35% reduction in spleen volume as determined by blinded CT and MRI at a central imaging laboratory). We did the primary analysis in the per-protocol population only (patients treated with fedratinib, for whom a baseline and at least one post-baseline spleen volume measurement was available) and the safety analysis in all patients receiving at least one dose of fedratinib. This trial was registered with ClinicalTrials.gov, number NCT01523171.FindingsBetween May 8, 2012, and Aug 29, 2013, 97 patients were enrolled and received at least one dose of fedratinib. Of 83 assessable patients, 46 (55%, 95% CI 44-66) achieved a spleen response. Common grade 3-4 adverse events included anaemia (37 [38%] of 97 patients) and thrombocytopenia (21 [22%] of 97), with 18 (19%) patients discontinuing due to adverse events. Seven (7%) patients died during the study, but none of the deaths was drug related. Suspected cases of Wernicke's encephalopathy in other fedratinib trials led to study termination.InterpretationThis phase 2 study met its primary endpoint, suggesting that patients with ruxolitinib-resistant or ruxolitinib-intolerant myelofibrosis might achieve significant clinical benefit with fedratinib, albeit at the cost of some potential toxicity, which requires further evaluation. Fedratinib development in this setting is currently being assessed.FundingSanofi.

Project description:BACKGROUND:Myelofibrosis (MF) is associated with a variety of burdensome symptoms and reduced survival compared with age-/sex-matched controls. This analysis evaluated the long-term survival benefit with ruxolitinib, a Janus kinase (JAK)1/JAK2 inhibitor, in patients with intermediate-2 (int-2) or high-risk MF. METHODS:This was an exploratory analysis of 5-year data pooled from the phase 3 COMFORT-I and -II trials. In both trials, patients could cross over to ruxolitinib from the control group (COMFORT-I, placebo; COMFORT-II, best available therapy). All continuing patients in the control groups crossed over to ruxolitinib by the 3-year follow-up. Overall survival (OS; a secondary endpoint in both trials) was evaluated using pooled intent-to-treat data from patients randomized to ruxolitinib or the control groups. OS was also evaluated in subgroups stratified by baseline anemia and transfusion status at week 24. RESULTS:A total of 528 patients were included in this analysis; 301 were originally randomized to ruxolitinib (COMFORT-I, n?=?155; COMFORT-II, n?=?146) and 227 to control (n?=?154 and n?=?73, respectively). The risk of death was reduced by 30% among patients randomized to ruxolitinib compared with patients in the control group (median OS, 5.3 vs 3.8 years, respectively; hazard ratio [HR], 0.70 [95% CI, 0.54-0.91]; P?=?0.0065). After correcting for crossover using a rank-preserving structural failure time (RPSFT) method, the OS advantage was more pronounced for patients who were originally randomized to ruxolitinib compared with patients who crossed over from control to ruxolitinib (median OS, 5.3 vs 2.3 years; HR [ruxolitinib vs RPSFT], 0.35 [95% CI, 0.23-0.59]). An analysis of OS censoring patients at the time of crossover also demonstrated that ruxolitinib prolonged OS compared with control (median OS, 5.3 vs 2.4 years; HR [ruxolitinib vs censored at crossover], 0.53 [95% CI, 0.36-0.78]; P?=?0.0013). The survival benefit with ruxolitinib was observed irrespective of baseline anemia status or transfusion requirements at week 24. CONCLUSIONS:These findings support ruxolitinib treatment for patients with int-2 or high-risk MF, regardless of anemia or transfusion status. Further analyses will be important for exploring ruxolitinib earlier in the disease course to assess the effect on the natural history of MF. TRIAL REGISTRATION:ClinicalTrials.gov identifiers, NCT00952289 and NCT00934544 .

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Phase 1/2 trial of glasdegib in patients with primary or secondary myelofibrosis previously treated with ruxolitinib.

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