Showing papers by "Elizabeth Ferreira Martinez published in 2022"

Phase 1/2a study of the IRAK4 inhibitor CA-4948 as monotherapy or in combination with azacitidine or venetoclax in patients with relapsed/refractory (R/R) acute myeloid leukemia or lyelodysplastic syndrome.

Abstract: 7016 Background: CA-4948 is a novel oral inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4) and FLT3. IRAK4 is critical in triggering inflammation, oncogenesis, and survival of cancer cells. Genetic mutations in the splicing factors SF3B1 and U2AF1 drive overexpression of a highly active long isoform of IRAK4 and have been associated with disease progression and poor prognosis of high-risk myelodysplastic syndrome (HR-MDS) and acute myeloid leukemia (AML). Methods: This is an open-label, phase 1/2a dose escalation and cohort expansion trial (NCT04278768). In phase 1 Dose Escalation, patients with R/R AML or HR-MDS are treated with CA-4948 monotherapy. Phase 1b includes 2 arms of combination therapy: CA-4948 + azacitidine (AZA) and CA-4948 + venetoclax (VEN). The primary objectives of this study are to assess the safety, clinical activity, and identify the Recommended Phase 2 Dose (RP2D) of CA-4948 as monotherapy or in combination with AZA or VEN in R/R AML or HR-MDS. The Phase 2a Dose Expansion includes patients for CA-4948 monotherapy: R/R AML with FLT3 mutation, or AML and HR-MDS R/R to HMA with U2AF1 or SF3B1 mutations. Results: As of December 16th, 2021, 49 patients have been treated in the phase 1 portion, of whom 43 started by September 30th, allowing 2 on-study disease assessments. The median number of prior therapies was 2 (range 1-5). Four monotherapy dose levels of CA-4948 were tested (200 to 500 mg orally BID). No dose-limiting toxicities were observed at 200 mg and 300 mg BID. No Grade 4 or 5 treatment-related AEs (TRAEs) were reported, and all the TRAEs were manageable. Reversible, manageable Grade 3 rhabdomyolysis occurred in 1/26 (4%) patients at 300 mg BID, 2/17 (12%) at 400 mg BID, and 1/3 (33%) at 500 mg BID. RP2D was determined as 300 mg BID. Of 43 patients starting before Sept 30th, 2021, 14 had SF3B1, U2AF1 or FLT3 mutations and demonstrated more promising efficacy. In the 5 evaluable AML patients with spliceosome mutations, 40% reached CR/CRh (1 CR, 1 CRh), both with study duration >6 months. In the 7 spliceosome-mutated HR-MDS patients, 57% reached marrow CR, including 1 with RBC transfusion independence and 1 proceeding to HSCT. One of the three FLT3-mutated AML reached CR, and 2 became FLT3-negative. Among the 29 patients without SF3B1/U2AF1/FLT3 mutations, 1 reached CR and 2 PR. Phase 1b and Phase 2a are ongoing. RNA-seq on selected samples showed decrease in relative expression of IRAK4-long isoforms with response to CA-4948. Conclusions: CA-4948 is well tolerated and effective in heavily pretreated AML and HR-MDS patients, especially in those with U2AF1/SF3B1/FLT3 mutations. No dose-limiting myelosuppression was reported, suggesting CA-4948 may be a candidate for combination therapy. Accrual of Phases 1b and 2a is ongoing. Clinical trial information: 04278768.

S129: takeaim leukemia- a phase 1/2a study of the irak4 inhibitor emavusertib (ca-4948) as monotherapy or in combination with azacitidine or venetoclax in relapsed/refractory aml or mds

Abstract: Background: Emavusertib (CA-4948) is a novel oral inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4) and FLT3. IRAK4 is critical in triggering inflammation, oncogenesis, and survival of cancer cells. Genetic mutations in the splicing factors SF3B1 and U2AF1 drive overexpression of a highly active long isoform of IRAK4 and have been associated with disease progression and poor prognosis of high-risk myelodysplastic syndrome (HR-MDS) and acute myeloid leukemia (AML). Aims: Assessment of safety, clinical activity, and Recommended Phase 2 Dose (RP2D) of emavusertib as monotherapy or in combination with azacitidine (AZA) or venetoclax (VEN). Methods: This is an open-label, phase 1/2a dose escalation and cohort expansion trial (NCT04278768). In phase 1 Dose Escalation, patients with R/R AML or HR-MDS are treated with emavusertib monotherapy. Phase 1b includes 2 arms of combination therapy: emavusertib + AZA and emavusertib + VEN. The primary objectives of this study are to assess the safety, clinical activity, and identify the RP2D of emavusertib as monotherapy or in combination with AZA or VEN in R/R AML or HR-MDS. The Phase 2a Dose Expansion includes patients for emavusertib monotherapy: R/R AML with FLT3 mutation, or AML and HR-MDS R/R to HMA with U2AF1 or SF3B1 mutations. Results: As of December 16th, 2021, 49 patients have been treated in the phase 1 portion, of whom 43 started by September 30th, allowing 2 on-study disease assessments. The median number of prior therapies was 2 (range 1-5). Four monotherapy dose levels of emavusertib were tested (200 to 500 mg orally BID). No dose-limiting toxicities were observed at 200 mg and 300 mg BID. No Grade 4 or 5 treatment-related AEs (TRAEs) were reported, and all the TRAEs were manageable. Reversible, manageable Grade 3 rhabdomyolysis occurred in 1/26 (4%) patients at 300 mg BID, 2/17 (12%) at 400 mg BID, and 1/3 (33%) at 500 mg BID. RP2D was determined as 300 mg BID. Of 43 patients starting before Sept 30th, 2021, 14 had SF3B1, U2AF1 or FLT3 mutations and demonstrated more promising efficacy. In the 5 evaluable AML patients with spliceosome mutations, 40% reached CR/CRh (1 CR, 1 CRh), both with study duration >6 months. In the 7 spliceosome-mutated HR-MDS patients, 57% reached marrow CR, including 1 with RBC transfusion independence and 1 proceeding to HSCT. One of the three FLT3-mutated AML reached CR, and 2 became FLT3-negative. Among the 29 patients without SF3B1/U2AF1/FLT3 mutations, 1 reached CR and 2 PR. Phase 1b and Phase 2a are ongoing. RNA-seq on selected samples showed decrease in relative expression of IRAK4-long isoforms with response to emavusertib. Summary/Conclusion: Emavusertib is well tolerated and effective in heavily pretreated AML and HR-MDS patients, especially in those with U2AF1/SF3B1/FLT3 mutations. No dose-limiting myelosuppression was reported, suggesting emavusertib may be a candidate for combination therapy. Accrual of Phases 1b and 2a is ongoing.

Dose escalation study of OMO-103, a first in class Pan-MYC-Inhibitor in patients (pts) with advanced solid tumors

Abstract: Background: MYC has a key role in driving and maintaining human tumors. However, MYC has long been perceived as an “undruggable” target and, to date, there is still no MYC inhibitor approved for clinical use. Omomyc is a MYC dominant negative mini-protein, previously used to inhibit MYC function both in vitro and in vivo, demonstrating a potent therapeutic impact in various mouse models of cancer. Here we present the dose escalation results of a Phase 1 study testing OMO-103, an Omomyc-based mini-protein developed by Peptomyc S.L. Material and Methods: Phase I dose escalation study used the conventional 3 + 3 design, with 6 dose levels ranging from 0.48 to 9.72 mg/kg, as a weekly 30-min i.v. infusion. The primary objectives were safety and tolerability, while secondary ones were preliminary efficacy according to RECIST 1.1, PK and RP2D. Tumor biopsies were collected at screening and at the end of the dose limiting toxicity (DLT) period (3 weeks) to assess MYC-levels, Ki67, CC3 and transcriptomics, among other indicators. Results: 22 patients with advanced solid tumors were included. 50% women and men, pts had a range of 3–13 prior treatment lines. ECOG 0 and 1 were equally distributed. The most common treatment related adverse events (TRAE) were mainly grade 1 infusion related reactions (IRR) like chills, fever, nausea, rash, hypotension. 58 TRAEs (80.5%) were grade 1, 12 (16.6%) grade 2 and 1 (1.4%) grade 3. Higher dose levels were associated with more IRRs but easily treated with (pre)medication. 1 DLT was observed: grade 2 pancreatitis (DL 5). 18 SAE, only one considered related. At the time of data cut-off (June22) 4 patients where non evaluable for response. 7 patients achieved SD. 2 pts with PDAC, 2 CRC, 1 NSCLC, 1 Sarcoma, 1 Salivary Gland Carcinoma. Remarkably, 1 PDAC patient stayed in the study for more than 6 months with tumor shrinkage of 8% of target lesions and a reduction of ctDNA. A sarcoma patient was on treatment for more than 7 months and the salivary gland carcinoma patient is still ongoing after 11 months. The PK analysis revealed a plasma half-life of approximately 50 h. No ADAs were detected in any of the patients, even after long term treatment. Drug activity is supported by a strong association of stable disease with a distinctive dose-dependent cytokine signature. Moreover, patients responding to the drug display modulation of the bona fide MYC target CD47 as well as of anti-tumor immune related markers such as calprotectin and OX-40. Further intratumoral PK data and target engagement evidence will be presented. Conclusion: OMO-103 demonstrates a favorable safety profile, with early signs of activity that merit further investigation. RP2D has been determined to be DL5 with 6.48 mg/kg. Dose expansion cohorts (Phase 2a) are already planned. Conflict of interest: Ownership: M. Niewel: Peptomyc S.L. L. Soucek: Peptomyc S.L. E.Calvo: START and OnCoart Associated. Advisory Board: E.Garralda has Consulting fees from: Roche/Genentech - F. Hoffmann/La Roche, Ellipses Pharma, Neomed Therapeutics1 Inc, Boehringer Ingelheim, Janssen Global Services, SeaGen, Alkermes, Thermo Fisher, Bristol-Mayers Squibb, MabDiscovery, Anaveon, F-Star Therapeutics, Hengrui, Lilly and Novartis. V.Moreno from: Roche, Bayer, BMS, Janssen and Basilea. E.Calvo from: Nanobiotix, anssen-Cilag, Roche/ Genentech, TargImmune Therapeutics, Servier, Bristol-Myers Squibb, Amunix, Adcendo, Anaveon, AstraZeneca/MedImmune, Chugai Pharma, MonTa, MSD Oncology, Nouscom, Novartis, OncoDNA, T-Knife, Elevation Oncology, PharmaMar, Ellipses Pharma. Board of Directors: E.Calvo: START, PharmaMar, EORTC, Sanofi, BeiGene, Novartis. Corporate-sponsored Research: E.Garralda has institutional research funding from: Novartis/Roche/Thermo Fisher/AstraZeneca/Taiho/BeiGene. E.Calvo has personal research funding from: START. Other Substantive Relationships: PI or Co-PI, institutional. E.Garralda: Novartis/Roche/Thermo Fisher/AstraZeneca/Taiho/BeiGene. V.Moreno: AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca Bayer Beigene BioInvent International AB, BMS, Boehringer, Boheringer, Boston, Celgene, Daichii Sankyo, DEBIOPHARM, Eisai, e-Terapeutics, Exelisis, Forma Therapeutics, Genmab, GSK, Harpoon, Hutchison, Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa Kirin, Lilly, Loxo, MedSir, Menarini, Merck, Merus, Millennium, MSD, Nanobiotix, Nektar, Novartis, Odonate Therapeutics, Pfizer, Pharma Mar, PharmaMar, Principia, PsiOxus, Puma, Regeneron, Rigontec, Roche, Sanofi, Sierra Oncology, Synthon, Taiho, Takeda, Tesaro, Transgene, Turning Point Therapeutics, Upshersmith.

Open-label, dose-escalation, and expansion trial of CA-4948 in combination with ibrutinib in patients with relapsed or refractory hematologic malignancies.

Abstract: 7575 Background: CA-4948 is a novel oral inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4), which is essential for toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling in B cell proliferation. IRAK4 forms a Myddosome complex with MYD88 adaptor protein and drives overactivation of nuclear factor-kappa B (NF-κB), causing inflammation and tumor growth. CA-4948 has been reported to be well tolerated and active as monotherapy in heavily pretreated patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL). Preclinical studies demonstrated that tumor resistance and survival via IRAK4 activation could be delayed or reversed. CA-4948 crossed the blood-brain barrier in a murine PDX model of pCNS lymphoma, resulting in tumor response and prolonged survival. In combination with Bruton tyrosine kinase (BTK) inhibitors, CA-4948 showed in vivo synergy in B-cell NHL. Here we will present an update on the preliminary efficacy data of CA-4948+ibrutinib in R/R hematologic malignancies. Methods: This is an ongoing open-label trial (NCT03328078) of CA-4948 as monotherapy and in combination with ibrutinib. Part A1 (completed) dose escalation of CA-4948 as monotherapy; the recommended phase 2 dose (RP2D) is 300 mg BID with continuous oral dosing. Part A2 (dose escalation in combination with ibrutinib), and Part B (a basket design of 4 expansion cohorts of CA-4948 and ibrutinib: BTK-naïve MZL, DLBCL, or PCNSL and NHL with adaptive resistance to ibrutinib). The primary endpoints of Parts A1 and A2 include safety, tolerability, and RP2D. The primary endpoints of Part B include CR or ORR, with key secondary endpoints of DOR, DCR, PFS and OS following treatment of CA-4948 at dose levels of 200 (DL1) or 300 mg BID (DL2) with ibrutinib at full prescribed dose. Results: As of December 7th, 2021, 35 heavily pretreated NHL patients have received CA-4948 monotherapy (median age 66 years, range 50-87), of which six patients have been on CA-4948 for approximately 1 year or longer, suggesting CA-4948 has a long-term acceptable safety and tolerability profile at RP2D (dose level of 300 mg BID). In Part A2, 10 patients are treated with CA-4948+ibrutinib (median age 65 years, range 56-82). Median number of prior lines of anti-cancer therapies is 3 (range 1-8). No DLTs were observed at 200 or 300 mg dose levels to date. The preliminary efficacy data of seven evaluable patients with combination therapy showed 1 CR (MCL), 2 PR (MCL and MZL), 3 SD, and 1 PD, 3 of whom had failed prior ibrutinib. The preliminary data indicate the combination therapy may overcome ibrutinib resistance. Conclusions: CA-4948 as a monotherapy and in combination with ibrutinib is well tolerated with an acceptable long term safety profile and promising efficacy. Part A2 is transitioning to Part B basket cohorts of MZL, ABC-DLBCL, PCNSL and NHL with adaptive resistance to ibrutinib. Clinical trial information: 03328078.

Analysis of the Viability and Morphology of Gingival Cells on Materials Used in Novel Prosthetic Components: In Vitro Study.

Abstract: AIM The objective of this in vitro study was to evaluate the viability and morphology of human fibroblasts and keratinocytes cells, both grown on stainless steel (steel) (18Cr14Ni2.5Mo), and polyether-ether-ketone (PEEK) surfaces, hypothesizing the use of these surfaces as novel materials for prosthetic components. MATERIALS AND METHODS Gingival human keratinocytes and gingival human fibroblasts lines were grown on discs made by steel (n = 36), PEEK (n = 36), and titanium (Ti) (Ti6A14V) (n = 36)-control. For viability assay, cultures were grown at 24 hours (TV1), 48 hours (TV2), and 72 hours (TV3) times and evaluated by the colorimetric tetrazolium assay (MTT). For morphology and cell adhesion assays, after 24 hours (TM1), 48 hours (TM2), and 96 hours (TM3) of cell culture, cells were examined by scanning electron microscopy (SEM) and analyzed at magnifications with 500×, 1,000×, and 2,500×. RESULTS Regarding the viability, the keratinocytes did not present statistical difference on the different materials, in TV1 and TV3 times of culture. Their growth rate increased on all materials, being more expressive in steel; the fibroblasts did not present statistical difference on the different materials, in TV2 and TV3 times of culture. The growth rate of these decreased on all materials, being more expressive in PEEK. The morphology analyses show increase in cell numbers, adequate spreading, and adhesion at all cultivation times (TM1, TM2, and TM3) in both cell lines, on all materials. CONCLUSION All materials tested are suitable for use in the manufacture of prosthetic components for implant-supported rehabilitations, considering the limitations of this study. CLINICAL SIGNIFICANCE This work analyzes the cellular response of cells present in the human gingiva, as a way to simulate the peri-implant tissue response around novel angular prosthetic components made of stainless steel and PEEK.

Ctim-34. preliminary safety and efficacy data on two patients with relapsed/refractory cns lymphoma treated with emavusertib (ca-4948) and ibrutinib combination: a subset analysis of takeaim lymphoma trial

Abstract: Emavusertib, an oral interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor, targets toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathway in B-cell proliferation. IRAK4 forms a Myddosome complex with MYD88 adaptor protein and drives overactivation of NF-κB, causing inflammation and tumor growth. Emavusertib has been reported to be well tolerated and active as monotherapy in heavily pretreated relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL). In a murine PDX model of primary CNS lymphoma (PCNSL), emavusertib crossed the blood-brain barrier, resulting in tumor response and prolonged survival. In combination with Bruton tyrosine kinase (BTK) inhibitors, emavusertib showed in vivo anti-cancer synergy in B-cell NHL. This is an ongoing open-label trial (NCT03328078) in patients with R/R NHL. Currently, we are in the dose escalation portion of combination therapy to evaluate safety and efficacy following treatment of emavusertib at dose levels of 200 or 300mg BID with ibrutinib at full prescribed dose. As of May 6th, 2022, 13 patients have been treated with emavusertib+ibrutinib combination therapy. Among the 13 patients, two were diagnosed with R/R PCNSL and had several prior lines of anti-cancer therapy. Emavusertib in combination with ibrutinib (560 mg daily) appeared to be well tolerated in these two subjects. One patient experienced Gr3 treatment-related adverse events (thrombocytopenia, muscle weakness, pain). The preliminary efficacy data demonstrated one CR and one SD. The patient who achieved CR after the combination therapy was originally intolerant to high-dose methotrexate based chemoimmunotherapy and did not achieve complete remission after switching to ibrutinib, providing early clinical evidence of CNS penetration and anti-tumor activity of emavusertib. In R/R PCNSL, these preliminary data suggest that combination therapy has a tolerable safety profile with promising anti-cancer activity and may overcome ibrutinib resistance.

Exth-93. the irak-4 inhibitor emavusertib (ca-4948) for the treatment of primary cns lymphoma

Abstract: PCNSL is an aggressive brain tumor accounting for 3% of all CNS malignancies and is associated with poor prognosis. Standard of care treatment includes induction with high-dose methotrexate based chemoimmunotherapy followed by consolidation with autologous stem cell transplant or whole brain radiation. However, more than half of PCNSL patients cannot tolerate this intensive therapeutic intervention. Novel treatments are urgently needed. Toll-like receptor signaling pathway via MyD88/IRAK-4 signalosome is constitutively active in PCNSL secondary to MYD88 L265P mutation and represents an excellent therapeutic target. Emavusertib (CA-4948) is an oral first-in-class small molecule inhibitor of IRAK-4 that demonstrates clinical activity in patients with systemic Non-Hodgkin’s Lymphoma, however it has not been evaluated in the CNS space. HYPOTHESIS: Emavusertib has anti-tumor activity against preclinical PCNSL. Using multiparameter immunohistochemistry (IHC) and proteomics analysis, IRAK-1, IRAK-4, and NF-κB pathway activation were examined in patient PCNSL tissues as compared to normal controls. Plasma, cerebrospinal fluid, and brain tissue were assessed via UPLC-MS/MS for emavusertib drug concentration following single oral high dose in a murine model. Survival responses in preclinical PCNSL models were measured in response emavusertib treatment, along with in vivo tumor proliferation and downstream biomarker expression by multi-parameter IHC. Our data confirm elevated IRAK-1, IRAK-4, and NF-κB signaling in patient PCNSL. We show that emavusertib can achieve therapeutically relevant concentrations in the brain and CSF. Emavusertib impairs tumor cell proliferation in vitro and in vivo, and shows dose-dependent single-agent activity in preclinical PCNSL models. We confirm decreased ERK1/2, MAPK and NF-κB activation, indicative of downstream IRAK-4 inhibition. Our data supports that emavusertib demonstrates anti-tumor activity in the CNS space, warranting further preclinical and clinical evaluation of this agent for the treatment of PCNSL.

Evaluation of the dosimetry and centralization of scout-view function in CBCT

Abstract: Abstract This study evaluated the centralization of the region of interest (ROI) in acquisition of the CBCT images, when the freely positionable scout-view (SV) function is applied. Additionally, the dosimetry of the acquired images was assessed in the SV function alone as well as in complete tomographic image in two different fields of view (FOV) (50x50 and 78x150mm). A three-location device was created to accommodate the dosimeters and the specimens, in the right, middle and left location during image acquisition. For dose assessment, thermoluminescent dosimeters were irradiated within the FOV and analyzed in a portable reader. For ROI evaluation, three specimens of gutta-percha stick were placed on the same device and the CT scans were acquired (CBCT OP 300 Maxio device, 90kV, 13mA, 85 µm voxel size, FOV of 50X50mm), with and without the SV, in three positions (3-9, 1-7 and 5-11 o’clock), simulating different regions of the mouth. Two image evaluations were performed, an objective and subjective. There was a slight percentage increase (1.36% to 1.40%) of the radiation dose with the use of SV. The distances were significantly greater in the images acquired without SV (p < 0.05). Every image obtained with SV was classified as being at the FOV’s center. In conclusion, the results demonstrated that SVs function is effective to centralize the ROI in the FOV, increasing the scan precision and avoiding repetitions due to positioning errors.

The role of extracellular microvesicles in carcinoma ex-pleomorphic adenoma tumorigenesis.

Abstract: The authors declare that they have no competing interests. The peer review history for this article is available at https://publons.com/publon/10.1111/odi.14274.