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Phase I study of FF-10501-01 in patients with Myelodysplastic Syndrome and continuous administration study

Phase I study of FF-10501-01 in patients with MDS

9

This study enrolled nine patients with myelodysplastic syndrome (MDS) who did not respond to existing treatment, who had recurrent MDS, or who had MDS and could not receive the existing treatment for some reason from an ethical perspective. The mean age of the population was 74.2 years, and the Eastern Cooperative Oncology Group (ECOG) Performance Status scores ranged between 0 and 2.

This study was conducted with the primary objective to evaluate the safety and tolerability of FF‑10501 (oral administration at 400, 600, and 800 mg/day for 14 days/cycle [28 days]). Nine patients, consisting of three patients at each dose, were enrolled in the study. All patients completed Phase I Part (Cycle 1) of the study, and eight of the participants moved on to the Extension Treatment Part of the study from Cycle 2 to investigate dose efficacy.

No deaths occurred in this study, and no dose-limiting toxicity (DLT) occurred during Cycle 1. One patient in the 800 mg/day group discontinued treatment in Cycle 1 owing to a serious adverse event (SAE; neutropenia). SAEs reported during Cycle 2 and subsequent cycles were two cases in two patients treated at 400 mg/day (one case each of pneumonia and anemia in one patient each) and two cases in one patient treated at 600 mg/day (one case each of congestive cardiac failure and cortical cataract). Neutropenia occurred in one patient treated at 800 mg/day, while pneumonia and anemia occurred in one patient each treated at 400 mg/day were adverse events (AEs) of which relationship to the study drug could not be ruled out. Frequently reported AEs (≥ 30%) were anemia, rash, and platelet count decreased in 33.3% (3/9 patients) of the patients each in Cycle 1, and platelet count decreased in 62.5% (5/8 patients) and anemia and back pain in 37.5% (3/8 patients) each in Cycle 2 and subsequent cycles. All AEs, except for those concerning platelet count decreased in one patient in Cycle 2 and the subsequent cycles, were AEs for which the relationship to the study drug could not be ruled out. The incidence of AEs did not increase in a dose- or duration-dependent manner.

As described in the Section “Adverse Events,” the safety and tolerability of FF-10501 of up to 800 mg/day could be demonstrated in MDS patients.

FF-10501 was rapidly absorbed at all doses. The plasma concentration peaked at 2–4 h post-dose and was almost eliminated at 24 h post-dose. The peak plasma FF-10501 concentration was comparable between 400 and 600 mg/day and was higher at 800 mg/day. The plasma concentration of M1, the major metabolite, reached a peak value at 4–8 h post-dose and decreased to 18%-37% of the peak value at 24 h post-dose. The mean cumulative urinary excretion rate up to 24 h post-dose was 25%-45% for FF-10501 and 9%-23% for M1. The best hematological response in the full analysis set (FAS) for efficacy evaluation was that of a stable disease in five patients, consisting of two of the three patients receiving 400 mg/day, two of the three patients receiving 600 mg/day, and one of the two remaining patients receiving 800 mg/day. No patients achieved complete remission (CR), partial remission (PR), or marrow CR at any of these doses. No patients achieved a hematologic improvement (HI‑E, HI‑P, or HI‑N) at any of these doses.

A total of nine MDS patients were enrolled in this study and received FF-10501 orally at doses of 400, 600, and 800 mg/day for 14 days, followed by a 14-day washout as one cycle, up to Cycle 30. None of the patients exhibited DLT. Common AEs included platelet count decreased and anemia. The incidence and grade of AEs did not increase in a dose- or duration-dependent manner. Regarding efficacy, the best response to hematologic remission was that of a stable disease in five of the eight patients. There was no tendency toward recovery in any of the blood cell counts for hematological improvement, and none of the patients showed improvement.

No

FUJIFILM Toyama Chemical Co., Ltd.

https://www.fujifilm.co.jp/form/fftc/en/general/input.php?id=FFTCClinicalEn

Interventional

An open-label, multicenter study

1

Patients diagnosed with MDS (including secondary MDS) according to the FAB classification.
Patients with PS of 0 to 2.
Patients whose organ functions except for bone marrow (cardiac, hepatic, pulmonary, and renal function, etc.) are sufficiently preserved, i.e., patients whose latest laboratory test values within 7 days prior to the first dosing meet all of the followings criteria (within 28 days prior to the first dosing for the resting 12-lead ECG) (ULN, upper limit of normal):
Total bilirubin <= 1.5*ULN
AST <= 2*ULN
ALT <= 2*ULN
Creatinine <= 1.5*ULN
SpO2 >= 93%
Patients with no abnormality requiring treatment on the resting 12-lead ECG
Patients who cannot be expected to have therapeutic effect of existing treatment
Patients with no plan to undergo stem cell transplantation.
Patients who understand the requirements of the study and give consent in writing.

Patients who have been diagnosed with AML.
Patients who have undergone hematopoietic stem cell transplantation.
Patients who have underlying active infection.
Patients who have taken another investigational drug within 90 days prior to the first dosing.

Both

MDS

investigational material(s)
Generic name etc : FF-10501-01
INN of investigational material :
Therapeutic category code : 42- Antineoplastic agents
Dosage and Administration for Investigational material : Oral

safety
safety