Daurismo (glasdegib)

P1, N=73, Completed, Pfizer | Phase classification: P1b --> P1

P1, N=48, Completed, Pfizer | Active, not recruiting --> Completed

This study is partially supported by Astellas Pharma Global Development, Inc. The study population will include patients with AML with dual FLT3 and IDH1/IDH2 mutations R/R to initial intensive induction therapy, or for patients treated with low intensity therapy, the patient must be refractory to treatment with a single agent hypomethylating agent (HMA) or low dose cytarabine (LDAC) (at least two cycles) or an HMA/LDAC in combination with venetoclax (at least one cycle) or another standard of care therapy (e. g. gemtuzumab ozogamicin, glasdegib/LDAC). Patients with a history of autologous or allogeneic stem cell transplant for AML are permitted to participate in the study.

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.

We used patient-derived xenografts (PDX) of human ML-DS and relapsed ML-DS blasts in immunodeficient mice (NSG and NSG-W41) to determine in vivo responses to standard chemotherapeutic agents (cytarabine, vincristine) and novel approaches such as demethylating agents (azacytidine), inhibition of histone deacetylation (panobinostat), mTOR (rapamycin), PARP (olaparib), and sonic hedgehog signaling (glasdegib) alone or in combination (glasdegib + cytarabine; panobinostast + azacytidine). Patient-specific molecular mechanisms underlying relapsed ML-DS are likely to have an impact on drug sensitivity. They should be determined for all patients with relapsed ML-DS to assist identification of targets and selection of drugs in order to establish urgently needed but currently still lacking efficacious treatment for relapsed ML-DS.

Some SMO inhibitors have been tested in clinical trial and Glasdegib is FDA approved in combination with low dose cytarabine in elderly patients. Given the success of generating these two point mutations, we are currently generating more RAS pathway mutations, including other KRAS mutations, PNTP11 and NF1 mutations. Conclusion These experiments showed: 1) It is possible to induce 2 oncogenic hits in human primary cells and get leukemia in vivo; 2) the KRAS G13D and NRAS G12D mutations shorten the latency of the disease and 3) increase the LSC frequency in secondary mice; 4) a possible involvement of the Hh pathway on stemness/LSC in RAS mutated cells; 5) our experimental approach is robust and very promising to decipher the RAS pathway in human MLL leukemias.

Indeed, the landscape of AML therapy has evolved substantially in recent years, mainly due to the introduction of hypomethylating agents and small molecules.Bcl2 inhibitor venetoclax, Fms-like tyrosine kinase 3 (FLT3) inhibitors such as midostaurin and gilteritinib, and isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) inhibitors ivosidenib and enasidenib, as well as hedgehog (HH) pathway inhibitor glasdegib represented a significant step forward in AML therapeutic armamentarium. Smoothened (SMO) inhibitor in combination with low-dose cytarabine marks a recent milestone...The identified ivosidenib's strengths, including its remarkable safety record and ability to yield positive therapeutic outcomes, position it as an ideal partner for both classic chemotherapy and biological treatments, i.e. hypometilant agents and/or venetoclax. Further studies are warranted to explore strategies for overcoming the occurrence of ivosidenib resistance.

The role of CYP3A4 in the clearance of glasdegib has been confirmed with clinical drug-drug interaction (DDI) studies following co-administration of glasdegib with strong CYP3A4 inhibitor ketoconazole and strong inducer rifampin. To evaluate the potential drug interactions with CYP3A4 modulators, co-administration of glasdegib with a moderate CYP3A4 inducer, efavirenz, was evaluated using physiologically based pharmacokinetic (PBPK) modeling using the Simcyp simulator...PBPK modeling predicted a glasdegib area under the concentration-time curve ratio of 0.45 and maximum plasma concentration ratio of 0.75 following co-administration with efavirenz. The PBPK results, in lieu of a formal clinical study, informed the drug label with the recommendation to double the clinical dose of glasdegib when administered in conjunction with a moderate CYP3A4 inducer, followed by resumption of the original dose 7 days post discontinuation.

Our study provides a new perspective on the potential clinical application of PF-04449913 in the treatment of colorectal cancer.

The addition of glasdegib to either cytarabine and daunorubicin or azacitidine did not significantly improve overall survival and the primary efficacy endpoint for the BRIGHT AML 1019 phase 3 trial was not met. Clinical trial registration: ClinicalTrials.gov: NCT03416179.

Long-term survival will be updated. No new safety alerts were reported.

The first changes in the management of AML date back to last 2000s with the advent of hypometilant agents, later with Bcl2 inhibitor venetoclax, and Fms-like tyrosine kinase 3 (FLT3) inhibitors (midostaurin and gilteritinb), and more recently with IDH1/2 inhibitors (ivosidenib and enasidenib) and the hedgehog (HH) pathway inhibitor glasdegib. Glasdegid, formerly PF-04449913 or PF-913, acts as a smoothened (SMO) inhibitor and has been recently approved in combination with low-dose cytarabine (LDAC) by FDA and EMA for the treatment of naïve AML patients unfit for intensive chemotherapy.Several studies have explored the efficacy and safety of glasdegib, as single agent or in combination with other drugs, in both the setting of relapsed/refractory and naïve AML patients, confirming its efficacy in controlling disease and safety profile. All these trials suggest that glasdegib seems to be an ideal partner for both classic chemotherapy and biological treatments (such as therapy with FLT3 inhibitors). Further studies are needed to better understand which patients are more likely to respond to glasdegib.

P2, N=30, Recruiting, University of California, Irvine | Trial completion date: Sep 2023 --> Sep 2025 | Trial primary completion date: Mar 2023 --> Mar 2024

P1/2, N=50, Completed, M.D. Anderson Cancer Center | Active, not recruiting --> Completed | N=138 --> 50

Any attempt to prevent or treat Aspergillus or Mucor infections requires the administration of some drugs in the azole group, which include voriconazole, posaconazole and isavuconazole, noted for their activity against these pathogens. One very relevant aspect is the potential risk of interaction when associated with one of the antineoplastic drugs used to treat hematologic tumors, with serious complications. In this regard, acalabrutinib, bortezomib, bosutinib, carfilzomib, cyclophosphamide, cyclosporine A, dasatinib, duvelisib, gilteritinib, glasdegib, ibrutinib, imatinib, nilotinib, ponatinib, prednisone, ruxolitinib, tacrolimus, all-transretinoic acid, arsenic trioxide, venetoclax, or any of the vinca alkaloids, are very clear examples of risk, in some cases because their clearance is reduced and in others because of increased risk of QTc prolongation, which is particularly evident when the drug of choice is voriconazole or posaconazole.

Aims: The primary outcome measures of AML1819 are to determine (1) the percentage of MRD negativity after consolidation in patients treated in induction and consolidation with GO; (2) the efficacy of a post-transplant maintenance with glasdegib vs clinical observation in terms of disease free survival improvement. I n the AML1819 trial, the preliminary analysis of the MRD status after consolidation indicates that a remarkable proportion of patients become negative when GO is added to intensive chemotherapy. With all the limits of such a comparison, we also found that the proportion of patients being MRD negative after consolidation was higher inAML1819 trial than in AML1310 one, in which no GO was added to chemotherapy. Such a finding has practical implications since, in AML1819 trial, a lower fraction of patients is submitted to ASCT.

Although HH inhibitor Glasdegib in combo with low-dose cytarabine achieved FDA approval for AML, Venetoclax (BCL-2 inhibitor/ABT-199) plus a hypomethylating agent (HMA) have been dominating the regimens in AML recently...Furthermore, ABT+Aza (Azacidine/HMA drug) induced more MCL-1 expression than ABT-199...GT1708 has been shown to reduce blast counts in three of 13 AML patients treated with higher doses and demonstrated favorite PK and safety profiles. In brief, these results support the clinical development of GT1708 in combination with ABT-199 in AML patients.

Here, we report the biological activities, the efficacy and toxicities of humanized antibodies and antibody-drug conjugates that targets surface antigens as CD33 (gemtuzumab ozogamicine) or CD123 (pivekimab sunirine). We further explore mechanisms and effectiveness of medications that modify the microenvironment, such as glasdegib, or that harness the immune system against leukemia, such as CD47 antibody magrolimab, PD1/PDL1 inhibitors pembrolizumab and nivolumab, TIM3 inhibitor sabatolimab, T-cell and NK-cell engagers...In this scenario, a brief overview of the mechanism of action of target agents is provided, particularly with respect to their biological mechanisms. Overall, this therapeutic armamentarium will constitute the basis for multimodal and personalized combinations that, in the idea of precision medicine, will enormously benefit elderly AML patients.

P2, N=30, Recruiting, University of California, Irvine | Trial completion date: Sep 2022 --> Sep 2023 | Trial primary completion date: Sep 2021 --> Mar 2023

This study aimed to compare AML induction regimen treatment patterns based on patient characteristics and outcomes based on the following 3 different therapies; IC; a VEN-based therapy (eg, VEN monotherapy or VEN + decitabine, azacitidine, or low-dose cytarabine [LDAC]); or a non-VEN-based low-intensity therapy (ie, single-agent HMAs, glasdegib + LDAC, or HMA + LDAC [excluding single-agent LDAC or hydroxyurea]). Additionally, patients who received 1L IC had the lowest rate of refractory disease across all the treatment cohorts assessed. Further research is warranted to determine appropriate treatment approaches for patients with AML based on treatment effectiveness, patient medical history, and IC eligibility.

ARA-C (69.6%) backbone and Azacitidine alone (6.9%) were the most commonly used regimens and 13.2% underwent allo-HCT at first remission... 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.

Venetoclax was combined with azacitidine in 35.2% and LDAC in 64.7%, 11.7% received additional midostaurin. Venetoclax dose was 100 mg/day in combination with strong CYP3A4 inhibitors (mainly itraconazole) in all patients... the Q-TWiST in our unselected population was better than the Q-TWiST described for LDAC arm in the glasdegib trial, this is striking considering the comparison between real world data in a low-income setting with clinical trial population. This suggests that venetoclax-based non intensive chemotherapy not only offers longer OS but also longer quality-adjusted time compared to previous standard to this vulnerable population. When compared to 7+3 regimens the Q-TWiST was slightly shorter in our cohort, probably associated with the inclusion criteria of the trial, including ability to tolerate 7+3 regimen and an age limit of 75 years, which different from our population.

Glasdegib, an oral inhibitor of the transmembrane protein Smoothened (SMO) involved in the Hedgehog (Hh) signaling pathway, was approved in 2018 for older or unfit adults with AML and attained a role in clinical practice after showing an overall survival (OS) advantage when combined with the established agent low-dose cytarabine (LDAC). Since that time, however, several other highly active lower intensity therapies such as venetoclax plus a hypomethylating agent (HMA) have garnered a dominant role in the treatment of this patient population. In this review, we summarize the role of glasdegib in the current treatment landscape of newly diagnosed AML and discuss ongoing investigations into its role in novel combination therapies.

P1b, N=0, Withdrawn, City of Hope Medical Center | N=36 --> 0 | Not yet recruiting --> Withdrawn

The addition of venetoclax, targeted therapy with IDH1/2 and FLT3 inhibitors, and enhanced formulas of existing drugs like CPX-351 and oral azacitidine have improved responses and outcomes. New drugs and combination therapies have increased the therapeutic options for elderly AML patients but determination of fitness and disease biology is essential to select patient-tailored treatments.

Consensus OTar/OTr drug prediction analysis on both scRNASeq tumor cells and bulk RNA-Seq of an engrafted PDX model from resected tumor at the time of biopsy ranked Glasdegib, Plicamycin, Flavopiridol, AT9283, and Dacinostat as the top 5 drugs with best overall tumor cell coverage. Both of these drugs significantly extended survival time by Kaplan-Meier regression (p=0.001 and p=0.03, respectively). Furthermore, scRNASeq data of drug-treated PDXs showed that Dacinostat uniformly depleted all three tumor sub-populations compared to Vehicle control, whereas one of the tumor sub-clusters was resistant to Plicamycin, consistent with single-cell drug sensitivity predicted by OTr.Given the in vivo activity of these two drugs in inhibiting tumor growth, and the effectiveness of Dacinostat across observed tumor cell phenotypes, as well as the high immune infiltration of this CCA sample, these drugs may be translated into pre-clinical and clinical trials alone and in combination with checkpoint immunotherapy.

Midostaurin in combination with intensive chemotherapy is the standard of care as upfront therapy in younger AML patients with mutated fms-related tyrosine kinase 3 (FLT3). Gilteritinib, a second- generation FLT3 inhibitor, represents a key drug for relapsed/refractory (R/R) FLT3-mutated AML patients...The US Food and Drug Administration (FDA) approved ivosidenib as a monotherapy for newly diagnosed older adult IDH1-mutated patients and enasidenib for R/R IDH2-mutated AML patients...The antibody drug conjugate gemtuzumab ozogamicin was approved in combination with intensive therapy for patients with newly diagnosed (FDA/European Medicines Agency [EMA]) as well as R/R CD33+ AML. The combination of venetoclax, an oral selective B-cell leukemia/lymphoma-2 inhibitor, with hypomethylating agents or low-dose AraC (LDAC) has changed the treatment landscape and prognosis for older adult patients very favorably. The addition of glasdegib, a small-molecule hedgehog inhibitor, to LDAC is another example of novel options in older patients. Further substances have shown promising results in early clinical trials.

The authors review the value-for-cost of targeted drugs such as gemtuzumab ozogamycin, CPX-351, midostaurin, gilteritinib, glasdegib, venetoclax, oral azacytidine and enasidenib used to treat adult AML...The cost of most targeted therapies for AML in unfit patients seems unfair in comparison to the absolute survival advantage provided in fit patients. Point of cure and transplant outcomes should be standardized to allow comparability among the models.

P1/2, N=138, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

Chemotherapy backbone for induction therapy consists of standard 7 + 3 schedule with cytarabine 200 mg/m continuously days 1 to 7, daunorubicin 60 mg/m days 1, 2, and 3 and high-dose cytarabine (1 g/m, bi-daily, days 1, 2, and 3) for consolidation therapy. ClinicalTrials.gov NCT04093505 ; EudraCT 2019-003913-32. Registered on October 30, 2018.

Extensive research has led to recent approval of novel therapies such as mylotarg, venetoclax, glasdegib and CC486, and small molecule inhibitors against actionable mutations such as ivosidenib (IDH1), enasidenib (IDH2), gliteritinib and midostaurin (FLT3) in AML...Taken together, our studies suggest that the LAIR-1 mAb we generated is a novel AML immunomedicine that preferentially eradicates AML LSCs and blasts while preserving healthy HSCs through disruption of AML survival signals and clearance of AML through ADCP and ADCC. Additional studies are currently evaluating if this novel LAIR-1 mAb has other mechanisms of action that contribute to overall in vivo activity, including reduction of AML niche implantation, regulation of bone marrow homing and regulation of anti-tumor immunity.

P2, N=1, Terminated, Yale University | Active, not recruiting --> Terminated; Unable to accrue patients following COVID-19 study pause.

The Hedgehog (HH) signaling pathway is aberrantly activated in many of these diseases, and glasdegib, a Smoothened (SMO) antagonist and HH pathway inhibitor, has recently been approved for the treatment of acute myeloid leukemia (AML)...We will discuss the biological role of the HH pathway in normal hematopoiesis and myeloid malignancies and review clinical studies targeting HH signaling in these diseases. In addition, we will examine SMO-independent pathway activation and highlight potential strategies that may expand the clinical utility of HH pathway antagonists.

P1b, N=36, Not yet recruiting, City of Hope Medical Center | Trial completion date: Dec 2022 --> Dec 2023 | Initiation date: Feb 2021 --> Oct 2021 | Trial primary completion date: Dec 2022 --> Dec 2023

P1, N=48, Active, not recruiting, Pfizer | Trial completion date: May 2021 --> Nov 2021

P1, N=48, Active, not recruiting, Pfizer | Trial completion date: Jan 2021 --> May 2021 | Trial primary completion date: Nov 2020 --> Feb 2021

The MEDLINE database, ClinicalTrials.gov and conference proceedings were reviewed for the most salient literature concerning FDA-approved drugs for AML beyond standard chemotherapy: gemtuzumab ozogamicin, hypomethylating agents, Fms-like tyrosine kinase 3 (FLT3) inhibitors, isocitrate dehydrogenase (IDH) inhibitors, venetoclax, liposomal cytarabine and daunorubicin (CPX-351), and hedgehog pathway inhibitors...In parallel, advances in low-intensity therapies have allowed patients unfit for standard induction chemotherapy to achieve meaningful disease control. Further work is ongoing to identify synergistic drug combinations as well as optimal treatment selection guided by individual patient and disease features.

P2, N=1, Active, not recruiting, Yale University | Recruiting --> Active, not recruiting | N=46 --> 1