- |||||||||| Zarzio (filgrastim biosimilar) / Novartis, Nexavar (sorafenib) / Bayer, Amgen
[VIRTUAL] EHA GUIDELINE: ANTIFUNGAL PROPHYLAXIS IN ACUTE MYELOID LEUKEMIA TREATED WITH NOVEL AGENTS () - May 13, 2021 - Abstract #EHA2021EHA_593;
Results The following novel agents for treatment of AML were identified with not all of them being yet licensed for treatment: Hypomethylating agents (HMA; Azacytidine and decitabine), Midostaurin, Venetoclax (+HMA), Lestaurtinib, Gilteritinib, Sorafenib, Quizartinib, Ivosidenib, Enasidenib, Crenolanib, Glasdegib, Sapacitabine, Custatuzumab, Iomab B, Idanasutlin...Evidence-based recommendations were formulated for HMA, Midostaurin, and Venetoclax/HMA, for all other agents, consensus-based recommendations were given including the patient-specific setting of application of the novel agents (relapsed/refractory AML, single therapy or in combination with chemotherapy, induction treatment or maintenance etc.) into the decision process Antifungal prophylaxis is not recommended or moderately recommended in most settings, and strongly recommended if the novel AML agent is administered with intensive chemotherapy during induction treatment. Dose adaptations of some of the AML agents (midostaurin, venetoclax, quizartinib, sorafenib, gilteritinib) are moderately recommended with limited evidence if antifungal prophylaxis is administered with a strong CYP3A4 inhibitor due to expected increased exposure Conclusion This guideline document to help supporting the decision if to use antifungal prophylaxis in AML patients under treatment with novel agents will soon become available as the first one assessing this specific setting and will complement existing guidelines for antifungal prophylaxis.
- |||||||||| lestaurtinib (CEP-701) / Teva, Kyowa Kirin
Journal: Lestaurtinib potentiates TRAIL-induced apoptosis in glioma via CHOP-dependent DR5 induction. (Pubmed Central) - May 11, 2021
We also demonstrated using a xenograft model of mouse that the tumour growth was absolutely suppressed because of the combined treatment compared to TRAIL or lestaurtinib treatment carried out singly. Our findings reveal a potential new strategy to improve antitumour activity induced by TRAIL in glioma cells using lestaurtinib through a mechanism dependent on CHOP.
- |||||||||| lestaurtinib (CEP-701) / Teva, Kyowa Hakko Kirin
Journal: RET receptor expression and interaction with TRK receptors in neuroblastomas. (Pubmed Central) - Mar 9, 2021
Finally, RET, GFR and TRK expression in primary tumors was investigated and a significant association between RET, its co‑receptors and TRK expression was demonstrated. Thus, the present data support a complex model of interacting neurotrophin receptor pathways in the regulation of cell growth and differentiation in NBs.
- |||||||||| Journal: FLT3 inhibitors in the treatment of Acute Myeloid Leukemia: current status and future perspectives. (Pubmed Central) - Dec 16, 2020
Notwithstandingly, all FLT3 inhibitors face primary and acquired mechanisms of resistance, and therefore the combinations with other drugs (standard chemotherapy, hypomethylating agents, checkpoint inhibitors) and its application in different clinical settings (upfront therapy, maintenance, relapsed or refractory disease) are under study in a myriad of clinical trials. This review focuses on the role of FLT3 mutations in AML, pharmacological features of FLT3 inhibitors, known mechanisms of drug resistance and accumulated evidence for the use of FLT3 inhibitors in different clinical settings.
- |||||||||| fluorouracil topical / Generic mfg.
[VIRTUAL] Metabolic Drug Survey Highlights Cancer Cell Dependencies and Vulnerabilities (Poster Hall (Virtual Meeting)) - Nov 5, 2020 - Abstract #ASH2020ASH_4172;
CLIMET allows for identification of metabolic susceptibilities, grouping of cancer cells based on metabolic dependencies, as well as understanding of context-dependent mechanism of action of drugs. Functional drug testing may provide a rapid and robust approach to identify metabolic vulnerabilities, responding patients, and prioritize compounds for clinical evaluation as illustrated with our study.
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center, Vanflyta (quizartinib) / Daiichi Sankyo
[VIRTUAL] The Combined Treatment with the FLT3-Inhibitor AC220 and the Complex I Inhibitor Iacs-010759 Synergistically Depletes Wt- and FLT3-Mutated Acute Myeloid Leukemia Cells (Poster Hall (Virtual Meeting)) - Nov 5, 2020 - Abstract #ASH2020ASH_2919;
Thus, we investigated more in-depth the synergism between IACS-010759 (10nM) and 13 FLT3 inhibitors, all currently in clinical trials (AC220, sorafenib, gilteritinib, sunitinib, ponatinib, midostaurin, ibrutinib, TP-0903, crenolanib, tandutinib, FF-10101, lestaurtinib, and KW-2449; 0.0128:5x:5000nM), in AML cell lines (FLT3-wt KG-1, U937, OCI-AML2, OCI-AML3; and FLT3-mutant MOLM-13 and MOLM-14)...Influx inhibition of both the two main carbon sources, glucose and glutamine, was observed leading to impairment of the TCA cycle and glycolysis for energy production, as well as pentose phosphate pathway and de novo nucleotide biosynthesis. In conclusion, we identified a novel drug combination AC220 and IACS-010759 which synergistically inhibits AML cell growth regardless of FLT3 mutation at least by metabolism disruption.
- |||||||||| lestaurtinib (CEP-701) / Teva, Kyowa Hakko Kirin
Journal: cDC1 are required for the initiation of collagen-induced arthritis. (Pubmed Central) - Oct 7, 2020
CEP-701 (a Flt3L inhibitor) treatment prevented CIA induction, and reduced dramatically the numbers CD103 cDC1s present in the lymph nodes and synovium. Hence this study identified cDC1 as the main subset orchestrating the initiation of cell-mediated immunity in arthritis.
- |||||||||| Review, Journal: FLT3 inhibitors in acute myeloid leukemia: ten frequently asked questions. (Pubmed Central) - Aug 27, 2020
These diverse FLT3 inhibitors have been evaluated in myriad clinical trials as monotherapy or in combination with conventional chemotherapy or hypomethylating agents and in various settings, including front-line, relapsed or refractory disease, and maintenance therapy after consolidation chemotherapy or allogeneic stem cell transplantation. In this practical question-and-answer-based review, the main issues faced by the leukemia specialists on the use of FLT3 inhibitors in AML are addressed.
- |||||||||| lestaurtinib (CEP-701) / Teva, Kyowa Kirin
Biomarker, Journal: Serum Flt3 ligand is a biomarker of progenitor cell mass and prognosis in acute myeloid leukemia. (Pubmed Central) - Aug 18, 2020
In the UK NCRI AML17 trial, Flt3L was measured at day 26 in a subgroup of 140 patients with Flt3 mutation randomized to the tyrosine kinase inhibitor lestaurtinib or placebo...Serial measurement of Flt3L in patients who had received a hematopoietic stem cell transplant for AML illustrates the potential value of monitoring Flt3L to identify relapse. Measurement of Flt3L is a noninvasive test with the potential to inform clinical decisions in patients with AML.
- |||||||||| cisplatin / Generic mfg.
Journal: Hsp90B enhances MAST1-mediated cisplatin resistance by protecting MAST1 from proteosomal degradation. (Pubmed Central) - Jun 10, 2020
Furthermore, combined treatment with a hsp90 inhibitor and the MAST1 inhibitor lestaurtinib further abrogated MAST1 activity and consequently enhanced cisplatin-induced tumor growth arrest in a patient-derived xenograft model. Our study not only uncovers the regulatory mechanism of MAST1 in tumors but also suggests a promising combinatorial therapy to overcome cisplatin resistance in human cancers.
- |||||||||| Journal: Identification of plicamycin, TG02, panobinostat, lestaurtinib, and GDC-0084 as promising compounds for the treatment of central nervous system infections caused by the free-living amebae Naegleria, Acanthamoeba and Balamuthia. (Pubmed Central) - May 17, 2020
The top five compounds are (i) plicamycin, active against all three free-living amebae and previously U.S. Food and Drug Administration (FDA) approved, (ii) TG02, active against all three amebae, (iii and iv) FDA-approved panobinostat and FDA orphan drug lestaurtinib, both highly potent against Naegleria, and (v) GDC-0084, a CNS penetrant mTOR inhibitor, active against at least two of the three amebae. These results set the stage for further investigation of these clinically advanced compounds for treatment of infections caused by the free-living amebae, including treatment of the highly fatal meningoencephalitis.
- |||||||||| cisplatin / Generic mfg.
Hsp90B protects MAST1 from CHIP-mediated ubiquitination and degradation providing cisplatin resistance (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_788;
Furthermore, a combination of hsp90 inhibitor and MAST1 inhibitor lestaurtinib further inhibited MAST1 activity and consequently potentiated the cisplatin effect in a patient-derived xenograft model. Our study not only reveals the mechanism of MAST1 regulation in tumors but also demonstrates a promising combinatorial therapy to overcome cisplatin resistance in human cancers.
- |||||||||| Journal: Advancing treatment of acute myeloid leukemia: the future of FLT3 inhibitors. (Pubmed Central) - Mar 20, 2020
The failure of these agents to induce durable responses led to the development of second generation FLT3 tyrosine kinase inhibitors (quizartinib, crenolinib, gilteritinib) exhibiting high potency and specificity for mutant FLT3 kinases and sustained in vivo FLT3 inhibition...We provide algorithms for which kinase inhibitor should be utilized for different FLT3 mutations (ITD±TKD) and clinical scenarios (de novo, relapsed/refractory, fit vs. unfit) and discuss novel FLT3 targeted therapeutic approaches. Expert Commentary: Integration of clinically active FLT3 inhibitors into all stages of therapy for all individuals with FLT3 mutant AML promises to significantly improve outcomes for this poor prognosis disease.
- |||||||||| Cabometyx (cabozantinib tablet) / Takeda, Exelixis, Ipsen
Review, Journal: FLT3 inhibitors in acute myeloid leukemia. (Pubmed Central) - Jan 11, 2020
In this review, we summarized the preclinical and clinical studies on new FLT3 inhibitors, including sorafenib, lestaurtinib, sunitinib, tandutinib, quizartinib, midostaurin, gilteritinib, crenolanib, cabozantinib, Sel24-B489, G-749, AMG 925, TTT-3002, and FF-10101. New generation FLT3 inhibitors and combination therapies may overcome resistance to first-generation agents.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, Xospata (gilteritinib) / Astellas
Gilteritinib and Venetoclax Synergize to Eliminate FLT3/ITD+ Leukemia Cells through BIM (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_3733;
These studies provide evidence that the addition of Venetoclax may enhance TKI therapy in the treatment of FLT3/ITD leukemia . Additionally, these findings suggest that enhanced cell death in FLT3/ITD AML cells treated with combination therapy occurs because Venetoclax mitigates unintentded pro-survival effects of the TKI, including an increase in BIM expression and increased association between BIM and BCL-2.
- |||||||||| azacitidine / Generic Mfg.
Consideration of new agents for incorporation into treatment guidelines in AML () - Oct 23, 2019 - Abstract #EHOC2019EHOC_1;
Other inhibitors (quizartinib, crenolinib) are in advanced stage of development...Ivosidenib was approved as monotherapy for relapsed/refractory IDH1+ patients was approved in July 2018, and for first line treatment unfit patients >74 years in May 2019...For older (50–70 years) the liposomal formulation of daunorubicin/ara-C in a fixed 5:1 ratio (Vyxeos), provided a significant survival benefit in high risk patients in a randomised comparison with standard 3+7 treatment, and may represent a step forward for high risk patients and was approved for fist line use in August 2017...A Hedgehog pathway inhibitor (Glasdegib) was approved in November 2018 based on a nonrandomised trial in combination with chemotherapy in untreated older patients and a similar parallel study in combination with low dose Ara-C (LDAC) and a randomised study vs chemotherapy alone are underway...Previous efforts to target this protein in AML have failed, but venetoclax has encouraged much interest initially in older patients in combination with LDAC or azacitidine or dectibine, where it has achieved importantly higher response rates than either LDAC or DMTs alone, and these responses have been more durable, so these unrandomised studies achieved regulatory approval in November 2018 of venetoclax...Thus the current guidelines for the treatment of AML will have to incorporate the new approved drugs but there is a need in every case for further prospective trials to fully explode the potential of these drugs. In addition to these 8 new drugs several new drugs will emerge for similar evaluation.
- |||||||||| azacitidine / Generic Mfg.
Use of FLT3 Inhibitors in AML () - Sep 26, 2019 - Abstract #SOHO2019SOHO_278;
At a median follow-up of 23.5 months, the median OS was 6.2 months (95% CI, 5.3-7.2) for quizartinib compared with 4.7 months (95% CI, 4.0-5.5) with SC (HR, 0.76; 95% CI, 0.58-0.98; stratified log-rank test, 1-sided P=0.0177).Early on, the vulnerability of quizartinib to acquired resistance-causing FLT3 KD mutations at the residue D835, drove the development of Type I FLT3 inhibitors active against these mutations.12,14 Gilteritinib is a potent Type I FLT3 inhibitor with pre-clinical activity against FLT3 D835 mutations, though it has relative vulnerability to the FLT3 gatekeeper F691L mutation.15 In the phase 3 ADMIRAL study, adults with FLT3-mutant (including ITD and D835/I836 mutations) AML refractory to induction chemotherapy or in untreated first relapse were randomized (2:1) to receive 120 mg/day gilteritinib or pre-randomization selected SC: LoDAC, azacytidine (AZA), MEC, or FLAG-IDA...On-target secondary KD mutations in FLT3 are the most common mechanism of acquired resistance in patients responding to type II inhibitors such as quizartinib and sorafenib, which bind only the inactive kinase conformation.17-19 The most common resistance-causing mutations occur at the FLT3 gatekeeper F691 and activation loop D835 residues, but may also involve other residues in the FLT3 KD.14 These mutations directly impair drug binding or result in an active kinase conformation unfavorable to interaction with type II inhibitors.Though gilteritinib has demonstrated pre-clinical and clinical activity against quizartinib resistance-causing FLT3 D835 mutations, it has vulnerability to the FLT3 gatekeeper F691L mutation which has also been implicated in clinical resistance to quizartinib and sorafenib.12,15,19 Additional clinical development of novel FLT3 inhibitors with potential to suppress quizartinib-resistant FLT3 KD mutations is ongoing, including FF-10101, the first irreversible inhibitor in this class.22Recent translational studies in patients reveal KD mutations, including F691L, to be less commonly associated with clinical resistance to gilteritinib.23 Instead, activating mutations in the RAS/MAPK pathway appear to be a particularly common resistance mechanism for gilteritinib.23 Targeted next-generation sequencing at the time of progression on gilteritinib identified treatment-emergent mutations that activate RAS/MAPK pathway signaling in 15/41 (36.6%) patients, mostly in NRAS or KRAS...Given that the current standard of care for newly diagnosed FLT3-ITD+ patients includes midostaurin with induction, patients may not derive the same benefit as those not previously exposed to FLT3 TKI treatment. The currently ongoing Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1506 trial is an international, multi-center, randomized, double-blind placebo-controlled phase 3 trial of gilteritinib maintenance after allogeneic HSCT that seeks to definitively establish whether or not FLT3 TKI maintenance post-HSCT should be considered a true standard of care for patients who go to HSCT in first remission.
- |||||||||| Xospata (gilteritinib) / Astellas
Biomarker, Review, Journal: Gilteritinib: a novel FLT3 inhibitor for acute myeloid leukemia. (Pubmed Central) - Sep 19, 2019
Currently, multiple clinical trials are ongoing to evaluate the combination of gilteritinib with other agents and regimens. This study summarized clinical trials of gilteritinib for AML.
- |||||||||| Review, Journal: What FLT3 inhibitor holds the greatest promise? (Pubmed Central) - Jun 22, 2019
Moreover, as the results of ongoing trials become available, newer agents could supplant former 'best' drugs. This paper reviews FLT3 inhibitors in combination with chemotherapy early in the disease in FLT3 mutant patients, as single agents or in combination in advanced disease, or in the post-transplant setting to provide separate answers to the main question.
- |||||||||| cisplatin / Generic mfg.
Journal: MAST1 Drives Cisplatin Resistance in Human Cancers by Rewiring cRaf-Independent MEK Activation. (Pubmed Central) - Jun 15, 2019
We show clinical evidence that expression of MAST1, both initial and cisplatin-induced, contributes to platinum resistance and worse clinical outcome. Targeting MAST1 with lestaurtinib, a recently identified MAST1 inhibitor, restores cisplatin sensitivity, leading to the synergistic attenuation of cancer cell proliferation and tumor growth in human cancer cells and patient-derived xenograft models.
- |||||||||| lestaurtinib (CEP-701) / Teva
Preclinical, Journal: Lestaurtinib is a potent inhibitor of anaplastic thyroid cancer cell line models. (Pubmed Central) - Apr 17, 2019
In vivo studies using the chick chorioallantoic membrane xenograft models demonstrated that treatment with Lestaurtinib resulted in a significant decrease in endpoint tumor volume and vascularity using power Doppler ultrasound imaging. Overall, this study provides evidence that Lestaurtinib is a potent antiproliferative agent with potential antiangiogenic activity that warrants further investigation as a targeted therapy for ATC.
- |||||||||| lestaurtinib (CEP-701) / Teva, Kyowa Kirin
Trial completion, Trial completion date, Trial primary completion date: AALL0631: Combination Chemotherapy With or Without Lestaurtinib in Treating Younger Patients With Newly Diagnosed Acute Lymphoblastic Leukemia (clinicaltrials.gov) - Jul 17, 2018
P3, N=218, Completed,
Based on this guideline, the sophisticated type-I pan-kinase inhibitor Staurosporine as well as its analogs Midostaurin and Lestaurtinib are identified as potent mutant-selective inhibitors by modeling analysis and kinase assay, which exhibit a moderate or high selectivity for B-Raf over B-Raf (3.7-fold, 6.1-fold and > 3.1-fold, respectively). Active, not recruiting --> Completed | Trial completion date: Sep 2018 --> Dec 2017 | Trial primary completion date: Sep 2018 --> Sep 2017
- |||||||||| Neupogen (filgrastim) / Kyowa Kirin, Amgen, Oncaspar liquid (pegaspargase) / Servier, lestaurtinib (CEP-701) / Teva, Kyowa Kirin
Clinical: Combination Chemotherapy With or Without Lestaurtinib in Treating Younger Patients With Newly Diagnosed Acute Lymphoblastic Leukemia (clinicaltrials.gov) - Aug 21, 2014
P3, N=242, Active, not recruiting,
Active, not recruiting --> Completed N=315 --> 242
- |||||||||| Neupogen (filgrastim) / Kyowa Kirin, Amgen, Oncaspar liquid (pegaspargase) / Servier, lestaurtinib (CEP-701) / Teva, Kyowa Kirin
Clinical: Combination Chemotherapy With or Without Lestaurtinib in Treating Younger Patients With Newly Diagnosed Acute Lymphoblastic Leukemia (clinicaltrials.gov) - Jul 1, 2014
P3, N=315, Active, not recruiting,
N=315 --> 242 Recruiting --> Active, not recruiting
- |||||||||| lestaurtinib (CEP-701) / Teva, Kyowa Kirin
Enrollment closed, Combination therapy: Lestaurtinib, Cytarabine, and Idarubicin in Treating Younger Patients With Relapsed or Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - Dec 22, 2013
P1/2, N=14, Active, not recruiting,
Recruiting --> Completed Completed --> Active, not recruiting
- |||||||||| lestaurtinib (CEP-701) / Teva, Kyowa Kirin
Enrollment closed: CEP-701 (Lestaurtinib) in Myelofibrosis (clinicaltrials.gov) - Jul 17, 2013
P1/2, N=64, Active, not recruiting,
Completed --> Active, not recruiting Recruiting --> Active, not recruiting
- |||||||||| lestaurtinib (CEP-701) / Teva, Kyowa Kirin
Enrollment change, Combination therapy: Lestaurtinib, Cytarabine, and Idarubicin in Treating Younger Patients With Relapsed or Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - May 12, 2013
P1/2, N=14, Active, not recruiting,
Active, not recruiting --> Recruiting N=37 --> 14
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