P2, N=41, Completed, Endeavor Biomedicines, Inc. | Active, not recruiting --> Completed

P3, N=140, Recruiting, Sol-Gel Technologies, Ltd. | Not yet recruiting --> Recruiting

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

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

P2, N=44, Active, not recruiting, Endeavor Biomedicines, Inc. | Recruiting --> Active, not recruiting

P2, N=40, Active, not recruiting, Endeavor Biomedicines, Inc. | Recruiting --> Active, not recruiting

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.

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.

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.

P3, N=140, Not yet recruiting, Sol-Gel Technologies, Ltd.

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.

Patient was further treated by vismodegib for 12 months followed by Cemiplimab. For the first time we report here that mBCC patients who were refractory to current standard of care treatments responded to taladegib with a duration of response of around one year with fewer and manageable adverse effects.

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.

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

Glucuronidation is a common mechanism of drug inactivation impacting many AML therapies e.g. cytarabine, decitabine, azacytidine and venetoclax. In all, our studies are the first to demonstrate that UGT1A protein, and thus glucuronidation, are targetable in humans. These studies pave the way for the development of therapies that impair glucuronidation, one of the most common drug deactivation modalities.

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.

In a Sonic hedgehog medulloblastoma animal model, fucoidan-based nanoparticles encapsulating vismodegib exhibit a striking efficacy and marked reduced bone toxicity and drug exposure to healthy brain tissue. Overall, these findings demonstrate a potent strategy for targeted intracranial pharmacodelivery that overcomes the restrictive blood-brain barrier to achieve enhanced tumour-selective penetration and has therapeutic implications for diseases within the central nervous system.

In recent years, the combination therapy of nivolumab plus ipilimumab has gained ground in studies for its survival and response rate benefits in patients with advanced melanoma...On the contrary, in advanced and metastatic BCC, successful therapeutic strategies, such as vismodegib and sonidegib, are based on the inhibition of aberrant activation of the Hedgehog signaling pathway...In patients with locally advanced or metastatic SCC, who are not candidates for surgery or radiotherapy, anti-PD1 agents such as cemiplimab, pembrolizumab, and cosibelimab (CK-301) have shown significant results in terms of response rate. PD-1/PD-L1 inhibitors, such as avelumab, have also been used in Merkel carcinoma, achieving responses in half of the patients with advanced disease...Two of the most promising molecules used in combination with immunotherapy are cavrotolimod (a Toll-like receptor 9 agonist) and a Toll-like receptor 7/8 agonist...Neoadjuvant treatment with cemiplimab in CSCCs and nivolumab in MCCs has shown promising results. Despite the successes of these new drugs, the new challenges ahead will be to select patients who will benefit from these treatments based on biomarkers and parameters of the tumor microenvironment.

Our study also pioneers an investigation of the dynamic effects of an orally delivered Hh inhibitor on the gut microbiome and the gut-associated immune-regulatory adaptive effector CD8 T cells. These findings inform future comprehensive studies on the consortium of altered microbes that can impact potential systemic immunomodulatory roles of Vismodegib.

This work demonstrates that AMPK functions through two signaling pathways, SHH-GLI1 and NF-κB. AMPK-NF-κB axis is a potential target for molecular therapy of SHH-MB, and the combinational blockade of NF-κB and Shh pathways confers synergy for SHH-MB therapy.

P2, N=720, Recruiting, Canadian Cancer Trials Group | Trial completion date: Sep 2023 --> Jan 2027 | Trial primary completion date: Jun 2023 --> Jan 2026

GDC-0449 was well tolerated, reached tumor, and inhibited CD133 neurosphere formation, but had little clinical efficacy as a single agent in rGBM. This suggests growth and maintenance of rGBM is not solely dependent on the SHH pathway thus targeting SMO may require combined approaches.

P2a, N=670, Active, not recruiting, Genentech, Inc. | Trial completion date: Jan 2023 --> Sep 2023 | Trial primary completion date: Jan 2023 --> Sep 2023

P1, N=68, Active, not recruiting, St. Jude Children's Research Hospital | Recruiting --> Active, not recruiting | N=108 --> 68 | Trial primary completion date: Feb 2025 --> Sep 2022

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

Our recent clinical trial highlighted the utility of vismodegib for preserving visual organs in opBCC patients: 67% of patients displayed a complete response histologically...In the age of targeted therapies, linking molecular genetic analysis to prospective clinical trials may be necessary to provide mechanistic understanding of clinical outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT02436408.

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.

P2, N=205, Recruiting, European Organisation for Research and Treatment of Cancer - EORTC | Not yet recruiting --> Recruiting

P2, N=720, Recruiting, Canadian Cancer Trials Group | Trial primary completion date: Sep 2022 --> Jun 2023

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.

Our patient attained stable disease in advanced basal cell carcinoma and complete remission in metastatic muscle-invasive urothelial cancer after receiving programmed death-ligand 1 inhibitor, atezolizumab, therapy. To our knowledge, this is the first paper to report the use of programmed death-ligand 1 inhibitor, atezolizumab, as treatment for advanced basal cell carcinoma. This case may also be of interest for clinicians when treating patients with two synchronous cancers.

Sonidegib and vismodegib are registered based on their efficacy in clinical trials. However, despite this success, limitations might occur during the therapy, as some patients show resistance to these molecules. This review aims to summarize novel options of targeted therapies in BCC and debate the mechanisms and clinical implications of tumor resistance.

Our study also pioneers an investigation of the dynamic effects of an orally delivered Hh inhibitor on the gut microbiome and the gut-associated immune-regulatory adaptive effector CD8 T cells. These findings inform future comprehensive studies on the consortium of altered microbes that can impact potential systemic immunomodulatory roles of Vismodegib.

However, it is still unknown whether vismodegib will has adverse effects on the patient or animal model of IVDs cartilage homeostasis. Based on our study, systemic administration of vismodegib damages IVDs homeostasis via inhibition of Ihh signaling in adult mice and special attention should be paid to the clinical application of vismodegib.

We report the rare case of a man with multiple bony metastasis, with a resistance to vismodegib, and we evaluated all manuscripts in literature reporting bone metastasis. Moreover, we review all the manuscripts in literature reporting bone metastasis, and we summarize the main therapeutic strategies, and the further perspectives.

Our study indicates that overexpression of BDNF in taste buds plays a role in preventing degeneration of taste buds. Counteracting the negative side effects of vismodegib treatment might improve compliance and achieve better outcome in patients suffering from advanced BCC.