P=N/A, N=3087, Completed, University of Washington | Active, not recruiting --> Completed | Trial completion date: May 2024 --> Aug 2023

P1/2, N=47, Recruiting, Ohio State University Comprehensive Cancer Center | Suspended --> Recruiting

P=N/A, N=100, Recruiting, Centre Hospitalier Universitaire de Nice

P4, N=82, Recruiting, Dow University of Health Sciences

P1/2, N=49, Completed, Hektoen Institute for Medical Research | Unknown status --> Completed | Trial completion date: Nov 2020 --> Nov 2023 | Trial primary completion date: May 2020 --> Nov 2023

Urinary EBV was undetectable in any sample after valacyclovir treatment, and the decreases in urinary interleukin (IL)-1β (from 0.66 [0.55-0.82] pg/mL to 0.58 [0.55-0.64] pg/mL, p = 0.0034), IL-8 (from 6.81 [2.38 to 29.1] pg/mL to 4.33 [1.53-11.04] pg/mL, p = 0.0361), IL-10 (from 1.06 [0.94-1.18] pg/mL to 0.92 [0.88-1.02], p = 0.0086), and tumor necrosis factor-α (from 1.61 [1.50-1.72] pg/mL to 1.50 [1.44-1.55] pg/mL, p = 0.0079) were significant. Valacyclovir could relieve bladder pain, eliminate urinary EBV, and reduce bladder inflammation.

P2, N=60, Recruiting, Bateman Horne Center

P2, N=30, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Jun 2024 --> Jun 2025

P3, N=36, Active, not recruiting, Brigham and Women's Hospital | Recruiting --> Active, not recruiting | N=60 --> 36

P2, N=390, Completed, National Institute of Allergy and Infectious Diseases (NIAID) | Active, not recruiting --> Completed

P3, N=1400, Active, not recruiting, Children's Oncology Group | Recruiting --> Active, not recruiting

P1, N=38, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

P2, N=30, Completed, Weill Medical College of Cornell University | Active, not recruiting --> Completed

P1/2, N=47, Suspended, Ohio State University Comprehensive Cancer Center | Recruiting --> Suspended | Trial primary completion date: Dec 2023 --> Dec 2024

P2, N=32, Active, not recruiting, Acurx Pharmaceuticals Inc. | Phase classification: P2b --> P2

P3, N=142, Recruiting, Centre Hospitalier Universitaire de Nice | Not yet recruiting --> Recruiting

P=N/A, N=96, Active, not recruiting, Population Council | Recruiting --> Active, not recruiting

P1, N=14, Completed, Eastern Virginia Medical School | Trial completion date: Aug 2021 --> Jan 2023 | Trial primary completion date: Aug 2021 --> Jan 2023

Mechanistically, the protective effect of CPX-351 occurred through pathways involving both the host and the intestinal microbiota, namely via the activation of the aryl hydrocarbon receptor-IL-22-IL-10 host pathway and the production of immunomodulatory metabolites by anaerobes. This study reveals how the gut microbiota may contribute to the good safety profile, with a low infection-related mortality, of CPX-351 and highlights how a better understanding of the host-microbiota dialogue may contribute to pave the way for precision medicine in AML.

P2, N=120, Recruiting, Fujifilm Pharmaceuticals U.S.A., Inc. | N=10 --> 120

P1, N=30, Recruiting, Delta-Fly Pharma, Inc. | Trial completion date: Apr 2022 --> Dec 2024 | Trial primary completion date: Dec 2021 --> Sep 2024

P1, N=20, Recruiting, Johns Hopkins University | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Mar 2024 --> Mar 2025

P1, N=16, Recruiting, National Institute of Allergy and Infectious Diseases (NIAID) | Trial completion date: Apr 2024 --> Nov 2024 | Trial primary completion date: Apr 2024 --> Nov 2024

P2, N=12, Recruiting, Roswell Park Cancer Institute | N=46 --> 12

P2, N=78, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

P3, N=882, Recruiting, University of Ulm

P3, N=142, Not yet recruiting, Centre Hospitalier Universitaire de Nice

P2, N=50, Completed, Shanghai Institute Of Biological Products | Not yet recruiting --> Completed | N=240 --> 50 | Trial primary completion date: Mar 2023 --> Jul 2023

P=N/A, N=108, Recruiting, Jazz Pharmaceuticals | Not yet recruiting --> Recruiting

P3, N=3, Terminated, Bristol-Myers Squibb | Phase classification: P3b --> P3

P=N/A, N=30, Completed, Population Council | Recruiting --> Completed

P2, N=72, Active, not recruiting, University of Washington | Enrolling by invitation --> Active, not recruiting

P2, N=10, Recruiting, Fujifilm Pharmaceuticals U.S.A., Inc. | Phase classification: P2a --> P2

Here, we review the current in vitro, clinical, and real-world evidence on the use of CPX-351 in patients with AML and mutations in FLT3. Additionally, we review preliminary data from clinical trials and patient case reports that suggest the combination of CPX-351 with FLT3 inhibitors may represent another treatment option for patients with FLT3 mutation-positive AML.

As in AML, FL kinetic profile predicts response and survival in HR-MDS/CMML. A FLD kinetic profile was the only factor independently associated with higher CR/CRi rates and better EFS. These results have to be confirmed on larger cohorts.

CPX-351 is able to induce good quality remission with high CR rate and MRD negativity, regardless of mutational burden, allowing a high number of elderly AML patients to undergo to HSCT. MRD evaluation has proven to be a strong prognostic tool also in the setting of elderly s-AML and t-AML patients receiving CPX-351. The prognostic value of high risk mutation seems to be less relevant in CPX-351 treated patients.

Concomitant midostaurin (days 8-21) was allowed for patients with FLT3 mutations (Patients #1 and #8)...ConclusionThis ongoing phase 1b/2 trial of CPX-351 (liposomal cytarabine and daunorubicin) as re-induction treatment for intermediate and high-risk AML has been safe and tolerable with early treatment outcomes that appear to be much better than reported historical controls. Correlative studies by mass cytometry will further establish the mechanistic reasons for the observed responses.

Among patients with AML treated with CPX-351, PTPN11 and IDH2 mutations were independently associated with inferior overall survival compared to those without these mutations. The PTPN11 gene is involved in RAS pathway regulation and has also been associated with shorter survival in AML in other studies. Here, mutated SRSF2 was associated with improved survival after CPX-351 induction.

The use of CPX-351 demonstrated efficacy across subgroups, especially in t-AML and pts without prior HMA exposure, as shown in larger studies. In pts <60 years, even though CRc rates were lower, CPX-351 led to longer mOS in those who achieved CRc and in those who underwent alloSCT compared to pts ≥60 years, although it didn't reach statistical significance in this small cohort. Induction therapy outcomes and treatment-related complications in our study corroborate the data for prior CPX-351 studies.

Four pts (33%) were refractory to venetoclax (VEN)-based therapy and 3 pts (25%) had previous alloHCT (Table 1)... Combination of cladribine with standard dose of CPX-351 is well tolerated. Cladribine dose 5 mg/m 2 was selected as RP2D. Safety profile does not indicate any significant additional myelosuppression.

7%) backbone and Azacitidine alone (13... Progression free survival obtained after induction therapy and overall survival were relatively shorter than the ones which were presented by other real-world registries. Lack of early access to the targeted and novel agents, like Flt3 inhibitors, Venetoclax, IDH1 and 2 inhibitors, CPX351 and Glasdegib should be a potential explanation to this relatively short PFS and OS. We have also been aware of un-ideal access to well established and nation wide cytogenetic laboratory service to induce early integration of targeted agents to the treatment and better risk stratification to determine the patients who should obtain the best prolonged survival via allo-HCT.

Traditionally, patients who are eligible for allogenic stem cell transplant (SCT) with AML-MRC/AML-MR are given high intensity chemotherapy (IC), such as daunorubicin and cytarabine (“7+3”), liposomal 7+3 or fludarabine+cytarabine+idarubicin (FLAG-IDA) whereas patients who are not transplant-eligible were treated with hypomethylating agents (i...Treatment with a “7+3” backbone or FLAG-IDA were considered ‘intensive’ regimens; treatment with azacitidine with or without venetoclax, and low dose cytarabine (LDAC), with or without venetoclax were considered ‘non-intensive... Aza/Ven is an effective treatment regimen for AML-MRC/AML-MR, with 14/21 patients achieving CR/CRi after firstline treatment compared to 6/14 patients after IC. 4/4 patients achieved CR/CRi with salvage aza/ven after failing to respond to IC. Our study suggests that aza/ven should be considered as a firstline treatment option even in patients who are fit for intensive therapy as a means to achieve adequate responses to bridge to allogenic stem cell transplant without attendant toxicities associated with IC.