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Anti-Leukemic Activity and Safety Data for Gilteritinib in Relapsed/Refractory Acute Myeloid Leukemia Supported Initiation Phase III ADMIRAL Trial

Published on 23rd June

As published in The Lancet Oncology this week, investigational data from the Phase I/II CHRYSALIS trial studying anti-leukemic activity and tolerability of gilteritinib, also known as ASP2215 (Astellas), supports the initiation of currently enrolling pivotal phase III ADMIRAL Trial.[1]

Gilteritinib is a novel, highly selective, potent oral FLT3/AXL inhibitor with preclinical activity against FLT3-ITD activating and FLT3-D835 resistance mutations. [2] The investigational agent is being used in the treatment of  patients with FLT3 mutation-positive relapsed or refractory (R/R) acute myeloid leukemia (AML).

Adult acute myeloid leukemia (AML) is a cancer of the blood and bone marrow. Generally, AML is a type of cancer that usually gets worse quickly if it is not treated. It is the most common type of acute leukemia in adults.[3]

Illustration: The CHRYSALIS study (NCT02014558), an international, multi-center, open-label, Phase I/II dose-escalation/ dose-expansion study, designed to determine the safety, tolerability, pharmacokinetic profile, and anti-leukemic activity of gilteritinib (ASP2215).

“Although AML is an uncommon blood cancer, approximately one third of patients have FLT3 tyrosine kinase mutations, which are associated with high relapse rates and poor survival. Once relapsed, FLT3 mutated AML is extremely difficult to treat with current therapies and rarely curable. Targeting FLT3 in the clinic has long been a therapeutic goal, but historically this has proven challenging,” explained Alexander E. Perl, M.D., University of Pennsylvania-Abramson Comprehensive Cancer Center.

Unmet Medical Need
Over the last decade, advances in the treatment of AML have resulted in substantially improved complete remission (CR) rates. [3] But there remains a major unmet medical need.

“There is a need for new agents to treat relapsed FLT3 mutated disease and it is exciting that these data for gilteritinib have been published in The Lancet Oncology,” added Jessica K. Altman, M.D., Robert H. Laurie Cancer Center of Northwestern University.

Internal tandem duplications
Mutations of the FLT3 gene in AML, including internal tandem duplications (ITD), are present in approximately one third of AML patients. These mutations lead to constitutive activation of the tyrosine kinase receptor, thereby promoting proliferation and survival of leukemia cells and contributing to a higher relapse rate and a poor prognosis to treatment. FLT3 tyrosine kinase domain (FLT3-TKD) mutations and AXL receptor tyrosine kinase domain mutations have been associated with resistance to early generation FLT3 inhibitors.

CHRYSALIS
The CHRYSALIS study (NCT02014558), an international, multi-center, open-label, Phase I/II dose-escalation/ dose-expansion study, designed to determine the safety, tolerability, pharmacokinetic profile, and anti-leukemic activity of gilteritinib, enrolled a total of 252 adults (N=252; 129M:123F, median age 62 yr [range: 21–90]) with R/R AML, including 58 with wild-type FLT3 and 191 with FLT3 mutations (FLT3-ITD, n=162; FLT3-D835, n=16; FLT3-ITD and -D835, n=13). The participating patients received oral gilteritinib (20 – 450 mg) once daily in one of seven dose-escalation (n=23) or dose-expansion (n=229) cohorts.[2][4]

In addition to assessing the safety and tolerability and pharmacokinetics of gilteritinib, the researchers were interested in assessing anti-leukemic activity and drug-drug interactions.

The study confirmed showed FLT3 inhibition at doses ≥80 mg/day. A 52% overall response rate (ORR) was demonstrated regardless of prior therapy. Additionally, a 55% ORR was observed in patients who had a FLT3-ITD and 37% ORR was observed in patients who were treated with a tyrosine kinase inhibitor prior to the study. Median OS in the full analysis set was approximately 25 weeks (95% CI: 20–30), and 31 weeks (95% CI: 24-59) in FLT3+ patients receiving ≥80mg of gilteritinib.

Adverse events
The most commonly reported Grade 3/4 adverse events were febrile neutropenia (39%; n=98/252), anemia (24%; n=61/252), thrombocytopenia (13%; n=33/252), sepsis (11%; n=28/252), and pneumonia (11%; n=27/252).

Furthermore, most commonly reported adverse events were judged to be related to gilteritinib were typical of those associated with acute myeloid leukemia drugs: diarrhea, fatigue, elevated aspartate aminotransferase, and increased alanine aminotransferase. A maximum post-baseline QTcF interval prolongation longer than 500 ms. was reported in 4% of subjects.


Clinical Response FLT3+ Mutated
80  mg

(n=12)

120 mg

(n=56)

200 mg

(n=89)

300 mg

(n=10)

450 mg

(n=2)

Total

(N=169)

CR 2 (17) 7 (13) 8 (9) 1 (10) 0 18 (11)
CRp 0 2 (4) 7 (8) 1 (10) 0 10 (6)
CRi 3 (25) 17 (30) 20 (22) 1 (10) 0 41 (24)
PR 3 (25) 5 (9) 7 (8) 3 (30) 1 (50) 19 (11)
CRc 5 (42) 26 (46) 35 (39) 3 (30) 0 69 (41)
ORR 8 (67) 31 (55) 42 (47) 6 (60) 1 (50) 88 (52)
Data are presented as n (%) and includes all patients with FLT3-ITD, -D835, -ITD-D835, or unknown FLT3 mutations. CR = Complete Response; CRc = Composite Complete Response (CR + CRi + CRp); CRi = Complete Response with incomplete hematological recovery; CRp = Complete Response with incomplete platelet recovery; ORR = Overall Response Rate; PR = Partial Response. Adapted from [2]

Gilteritinib demonstrated inhibition of FLT3 phosphorylation at doses >80 mg/d in correlative assays. While responses were observed across all dose levels, regardless of FLT3 mutation status (overall response rate (ORR)=40%), response rate was enhanced in FLT3 mutation-positive patients at doses ≥80 mg/d (ORR=52%). Among patients with FLT3-ITD, the additional presence of FLT3-D835 did not alter response rate; patients with only FLT3-D835 responded less frequently.

Based on the study resulrs, researchers at Astellas are further investigating the potential benefit of gilteritinib in various AML patient populations through several planned and already initiated trials, including the Phase III ADMIRAL study in R/R AML.

“AML is a disease that represents a high unmet clinical need and we continue to be encouraged by the results achieved thus far with gilteritinib,” noted Steven Benner, M.D., senior vice president and global therapeutic area head, oncology development, Astellas.

“We look forward to further investigating this potential treatment in hopes of bringing new options to patients,” Benner added.


Last editorial review: June 22, 2017

Featured Image: Blood testing in laboratory Courtesy: © 2017 Fotolia. Used with permission.

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