RESUMO
First-in-human (FIH) dose-escalation trials on oncology should prioritize safety and emphasize efficacy. We reviewed the FIH trials of 67 anti-tumor products approved by the Food and Drug Administration between 2018 and 2023 and found that the "3 + 3" design remains the predominant dose-escalation method (66.2%). The number of patients receiving sub-therapeutic doses is positively correlated with the maximum tolerated dose (MTD) or maximum dose (MD) to starting dose ratio (P = 0.056) and the number of dose levels in trials (P < 0.001). In addition, the proportion of products with a high ratio in antibody drugs is higher than that in small molecules (P < 0.001). The MTD or MD exceeded the label dose by three or more doses in 22.03% of the products. In conclusion, optimizing the starting dose selection method, refining the way of determining doses, and finding alternative indicators to replace toxicity as the endpoints will increase the effectiveness and broaden the beneficiary scope.
Assuntos
Antineoplásicos , Aprovação de Drogas , Neoplasias Hematológicas , Dose Máxima Tolerável , Neoplasias , United States Food and Drug Administration , Humanos , Neoplasias Hematológicas/tratamento farmacológico , Estados Unidos , Neoplasias/tratamento farmacológico , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Relação Dose-Resposta a DrogaRESUMO
Osteoarthritis (OA) is the most common degenerative joint disease. Mesenchymal stromal cells (MSC) are promising cell-based therapy for OA. However, there is still a need for additional randomized, dose-dependent studies to determine the optimal dose and tissue source of MSC for improved clinical outcomes. Here, we performed a dose-dependant evaluation of umbilical cord (UC)-derived MSC (Celllistem) in a murine model and in knee OA patients. For the preclinical study, a classical dose (200.000 cells) and a lower dose (50.000 cells) of Cellistem were intra-articularly injected into the mice knee joints. The results showed a dose efficacy response effect of Cellistem associated with a decreased inflammatory and degenerative response according to the Pritzker OARSI score. Following the same approach, the dose-escalation phase I clinical trial design included 3 sequential cohorts: low-dose group (2â ×â 106 cells), medium-dose group (20â ×â 106), and high-dose group (80â ×â 106). All the doses were safe, and no serious adverse events were reported. Nonetheless, 100% of the patients injected with the high-dose experienced injection-related swelling in the knee joint. According to WOMAC total outcomes, patients treated with all doses reported significant improvements in pain and function compared with baseline after 3 and 6 months. However, the improvements were higher in patients treated with both medium and low dose as compared to high dose. Therefore, our data demonstrate that the intra-articular injection of different doses of Cellistem is both safe and efficient, making it an interesting therapeutic alternative to treat mild and symptomatic knee OA patients. Trial registration ClinicalTrials.gov NCT03810521.
Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Osteoartrite do Joelho , Animais , Humanos , Camundongos , Injeções Intra-Articulares , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Transplante de Células-Tronco Mesenquimais/métodos , Osteoartrite do Joelho/terapia , Resultado do Tratamento , Cordão UmbilicalRESUMO
BACKGROUND: Respiratory syncytial virus (RSV) is responsible for most respiratory tract infections and hospitalizations in infants and represents a significant economic burden for public health. The development of a safe, effective, and affordable vaccine is a priority for the WHO. METHODS: We conducted a double-blinded, escalating-dose phase 1 clinical trial in healthy males aged 18-50 years to evaluate safety, tolerability, and immunogenicity of a recombinant Mycobacterium bovis BCG vaccine expressing the nucleoprotein of RSV (rBCG-N-hRSV). Once inclusion criteria were met, volunteers were enrolled in three cohorts in an open and successive design. Each cohort included six volunteers vaccinated with 5 × 103, 5 × 104, or 1 × 105 CFU, as well as two volunteers vaccinated with the full dose of the standard BCG vaccine. This clinical trial (clinicaltrials.gov NCT03213405) was conducted in Santiago, Chile. FINDINGS: The rBCG-N-RSV vaccine was safe, well-tolerated, and no serious adverse events related to the vaccine were recorded. Serum IgG-antibodies directed against Mycobacterium and the N-protein of RSV increased after vaccination, which were capable of neutralizing RSV in vitro. Additionally, all volunteers displayed increased cellular response consisting of IFN-γ and IL-2 production against PPD and the N-protein, starting at day 14 and 30 post-vaccination respectively. INTERPRETATION: The rBCG-N-hRSV vaccine had a good safety profile and induced specific cellular and humoral responses. FUNDING: This work was supported by Millennium Institute on Immunology and Immunotherapy from Chile (P09/016), FONDECYT 1190830, and FONDEF D11E1098.
RESUMO
OBJECTIVES: Vascular endothelial growth factor (VEGF) is involved in physiological angiogenesis, but also is considered one of the key factors that promotes tumor angiogenesis. CIGB-247 is a VEGF-based vaccine that has been evaluated in phase I clinical trial patients with advanced solid tumors. This specific active immunotherapy is able to reduce platelet VEGF levels; however it is unknown whether this effect leads to a decrease in VEGF below the levels that can be observed in healthy individuals. The objective of the present study is to investigate platelet VEGF levels in cancer patients vaccinated with CIGB-247, and then compare these values with those obtained in healthy individuals. To achieve this, platelet VEGF levels of 62 cancer patients and 93 healthy individuals were compared. Cancer patients were those individuals recruited in CENTAURO and CENTAURO-2 clinical trials. RESULTS: Before vaccination, platelets of cancer patients carried more VEGF than the levels seen in platelet of healthy individuals. However, after vaccination, cancer patients had platelet VEGF values within the range established by healthy individuals, indicating that the antibody response elicited by CIGB-247 is not able to induce a complete suppression of VEGF. Vaccination with CIGB-247 helps to normalize VEGF levels within platelets.
Assuntos
Plaquetas/efeitos dos fármacos , Vacinas Anticâncer/administração & dosagem , Imunoterapia Ativa/métodos , Neoplasias/terapia , Neovascularização Patológica/prevenção & controle , Fator A de Crescimento do Endotélio Vascular/genética , Adjuvantes Imunológicos/administração & dosagem , Adolescente , Adulto , Idoso , Plaquetas/imunologia , Plaquetas/patologia , Estudos de Casos e Controles , Feminino , Expressão Gênica , Humanos , Imunidade Humoral/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , Neovascularização Patológica/genética , Neovascularização Patológica/imunologia , Neovascularização Patológica/patologia , Vacinação/métodos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/imunologiaRESUMO
Preclinical repeated-dose toxicity and efficiency studies developed by our group suggest the potential of FITOPROT in treating mucositis. This serious limiting side effect is observed at a rate of 40-100% in patients under antineoplastic therapy and despite different palliative measures and therapeutic agents have been investigated, still no therapy was completely successful. Therefore, this study aimed to establish the safety and recommended phase II dose of FITOPROT for the prevention and treatment of chemoradiotherapy-induced oral mucositis (OM) in patients with head and neck cancer. Twenty healthy adult participants were randomized into two groups that received pre-established concentrations of the collutory: group 1 (FITOPROT A - mucoadhesive formulation containing 10â¯mg/mL of curcuminoids extract plus 20% v/v of Bidens pilosa L. extract) and group 2 (FITOPROT B - mucoadhesive formulation containing 20â¯mg/mL of curcuminoids extract, plus 40% v/v of Bidens pilosa L. extract). Participants rinsed their mouths with FITOPROT, three times daily, for ten consecutive days. No participant experienced toxicity or unacceptable discomfort and/or adverse reactions (CTCAE v5.0), with laboratory and clinical parameters under normal conditions. Side effects observed were low intensity and temporary mucosa/dental surface pigmentation (nâ¯=â¯7) and tooth sensitivity (nâ¯=â¯4), which disappeared after formulation use ceased. No significant cellular genotoxic effects were observed (pâ¯>â¯0.05), and micronuclei frequencies were not changed (pâ¯>â¯0.05). Biochemical assays reveled no altered levels of myeloperoxidase (pâ¯=â¯0.2268), malondialdehyde (pâ¯=â¯0.1188) nor nitric oxide (pâ¯=â¯0.5709) concentration, and no significant difference were found in the levels of pro-inflammatory cytokines (pâ¯>â¯0.05). Thus, FITOPROT demonstrated to be safe and tolerable in both tested doses and is suitable for evaluation in a phase II trial as treatment against OM.