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Glasdegib Safety, Tolerability Deemed Manageable in Pretreated Myelofibrosis But Trial Halted Due to Missed Endpoints

Darcy Lewis
Published Online:4:40 PM, Tue May 21, 2019

Aaron T. Gerds, MD, MS

A new report published in Leukemia Research found that results from the lead-in cohort of an open-label phase lb/II trial of glasdegib in patients with primary or secondary myelofibrosis (MF) previously treated with at least one JAK inhibitor indicated acceptable safety and tolerability.

The authors, led by Aaron T. Gerds, MD, MS, of the Cleveland Clinic Taussig Cancer Institute, reported that all 21 patients treated on the study had at least 1 adverse event (AE). Nearly one-fourth of patients (n = 5, 23.8%) had serious AEs. The most common AEs were dysgeusia (61.9%), muscle spasms (57.1%), alopecia (38.1%), fatigue (33.3%), and decreased appetite (33.3%).

Findings that addressed the study’s secondary objectives were varied. At week 12, nearly 10% of patients (n = 2, 9.5%) at least halved their total symptom score (TSS) from baseline. Forty percent of patients had a 20% or more reduction in TSS. No patient met the secondary objective of attaining a spleen volume reduction (SVR) of 35% or more at week 24, and thus the study did not proceed to a randomized phase.

“The safety profile of glasdegib monotherapy was manageable in patients with primary/ secondary MF,” the authors wrote. “Further study of glasdegib in combination with JAK inhibitors in a MF population may be warranted.”

In this trial, 21 patients received open-label oral glasdegib 100 mg once daily for up to 24 weeks. Patients could remain on treatment for as long as they tolerated it and derived clinical benefit. The investigators explored dose reduction to 75 mg or 50 mg or alternative dosing schedules to manage safety and tolerability. Patients were followed for at least 12 weeks following glasdegib discontinuation.

Inclusion factors included severe MF symptoms and spleen volume of at least 5 cm below the inferior left costal margin, measured by manual palpation. Exclusion factors included prior treatment with a licensed or experimental SMO inhibitor and receiving spleen radiation within the 3 months prior to study enrollment.

The study design called for abdominal MRI (or CT, if MRI was not feasible) to measure spleen volume at baseline, every 3 cycles, and when disease progression was confirmed. Blinded independent reviewers assessed imaging for change from baseline in spleen and liver volume.

To assess symptom burden, investigators asked patients to complete the 10-item Myeloproliferative Neoplasm Symptom Assessment Diary (MPN-SAD) daily via a handheld electronic device. After 25 weeks, patients changed to recording their symptoms weekly until treatment discontinuation and then monthly until the study was discontinued.

Of the 21 patients, 15 (71.4%) had received a JAK inhibitor previously. Three patients (14.3%) had received two prior JAK inhibitors, and 3 (14.3%) received 3 or more prior JAK inhibitors. The authors noted that inadequate response or primary resistance was the most common reason for discontinuing prior therapy (n = 11, 52.4%), followed by toxicity and other (n = 8, 38.1 % each).

At the data cut-off in December 2016, 3 patients were still receiving study treatment. Eight patients had completed the study, while the remaining 10 patients had discontinued the study. Of the 18 patients (85. 7%) patients who discontinued treatment, 10 did so due to treatment-related AEs. Other reasons included insufficient clinical response (n = 3), progressive disease (n = 2), global deterioration of health status (n = 1), patient refusal (n = 1), and an unrelated AE (n = 1).

Glasdegib treatment continued for a median duration of 85.0 days (range, 22-512 days). Patients received nearly the planned daily dose of 100 mg, with a median daily dose of 96.0 mg (range, 61-101 mg), for a median relative dose intensity of 97.0% (range, 60%-100%). Nearly one-third of patients (n = 6, 28.6%) required a dose reduction and 5 patients (23.8%) had to delay the start of a treatment cycle. Nearly half the patients (n = 10, 47.6%) had at least one dose interruption; the median duration of the interruption was 15.0 days (range, 8-29 days).

All 21 patients had one or more treatment-emergent AE (TEAE) and 190 TEAEs were reported. Two-thirds of patients (n = 14, 66.7%) had grade 3/4 TEAEs, while 1 patient (4.8%) developed grade 5 respiratory failure. The most common treatment-related TEAEs were dysgeusia (61.9%), muscle spasms (52.4%), alopecia (38.1 %), decreased appetite (33.3%), and fatigue (23.8%).

TEAEs caused 12 patients (57.1 %) to permanently discontinue study treatment, mostly due to muscle spasms (n = 6, including 1 grade 3) and dysgeusia (n = 3). A notable number of discontinuations due to muscle spasms occurred at a single site (n = 5 of 6). Per protocol, patients experiencing muscle spasms or myalgia were advised to consume oral rehydration solutions or salts containing electrolytes. AEs caused 1 patient to reduce the dose, 4 to discontinue treatment temporarily, and 4 patients to do both these things.

One patient died due to disease progression during the follow-up period, but no patient died within 28 days of the last dose of glasdegib. Five patients (23.8%) experienced serious AEs, with 1 patient each experiencing memory impairment and fatigue, gastric varices hemorrhage, portal hypertension, respiratory failure, and esophageal varices, mental status change, failure to thrive, and anemia.

Most serious AEs were grade 2 or 3. Grade 3 hematological toxicities included anemia, lymphopenia, neutropenia, and leukopenia, all in 1 patient each. One patient each had grade 4 lymphopenia and neutropenia. Hyperlipasemia was seen in 5 patients (grade 3) and 1 patient (grade 4).

The trial did not meet its overall SVR secondary endpoint of a 50% or more reduction, with 1 patient achieving this at cycle 4, day 1 and 2 others at treatment’s end. The median change from baseline in spleen size was -28.6% (range, -100% to 0%).

For the 3 patients still on treatment at data cutoff, investigators reported a median decrease from baseline in spleen size based on MRI/CT assessment of 10.6% at 36 weeks and 7.6% at 48 weeks. One patient, who was previously treated with five doses of ruxolitinib, had SVR of 32.9%. A patient with splenomegaly at baseline experienced spleen volume stability on treatment; this patient had previously received 2 doses of ruxolitinib. And a third patient, who had previously treated with 4 doses of the experimental medication INC424, experienced stable spleen volume.

The authors noted that the frequencies of "on target" TEAEs in patients with MF were higher than those reported for glasdegib in patients with other myeloid malignancies like acute myeloid leukemia or myelodysplastic syndrome. “The small number of patients, different nature of the disease under study, and prior exposure to ruxolitinib may have contributed to differences in the frequency and severity of AEs,” they wrote. “Over the course of the study, the investigators became more attuned to recognizing, and better able to address, emerging AEs (ie, electrolyte solution for muscle spasms).”

According to Gerds et al, approximately 40% of patients achieved a 20% to 30% reduction in symptoms. “One potential strategy to increase tolerability of glasdegib in this and similar populations may be to consider alternative dosing schedules,” they wrote. “[P]atient-reported outcome measures and long duration of therapy in select patients, indicative of continued clinical response, suggest glasdegib may improve MF symptoms in this population of pretreated patients.”

Due to secondary efficacy endpoints not being met in the lead-in cohort, the study was terminated early. Accordingly, the authors did not analyze the primary efficacy endpoint of SVR with glasdegib versus placebo.
 
 
Reference:
Gerds AT, Tauchi T, Ritchie E, et al. Phase 1/ 2 trial of glasdegib in patients with primary or secondary myelofibrosis previously treated with ruxolitinib. Leuk Res 2019;79:38-44.


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