There may be differences between this version and the published version. You are advised to consult the publisher's version if you wish to cite from it.http://eprints.gla.ac.uk/118215/
Purpose: M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a monoclonal antibody against programmed death ligand 1 (PD-L1) fused to a transforming growth factor-β (TGF-β) "trap."Experimental Design: In the 3+3 dose-escalation component of this phase 1 study (NCT02517398), eligible patients with advanced solid tumors received M7824 at 1, 3, 10, or 20 mg/kg once-every-2-weeks until confirmed progression, unacceptable toxicity, or trial withdrawal; additionally, a cohort received an initial 0.3 mg/kg dose to evaluate pharmacokinetics/pharmacodynamics (PK/PD), followed by 10 mg/kg dosing. The primary objective is to determine the safety and maximum tolerated dose (MTD); secondary objectives include PK, immunogenicity, and best overall response. Results:Nineteen heavily pretreated patients with ECOG 0-1 have received M7824. Grade ≥3 treatment-related adverse events occurred in 4 patients (skin infection secondary to localized bullous pemphigoid, asymptomatic lipase increase, colitis with associated anemia, and gastroparesis with hypokalemia). The MTD was not reached. M7824 saturated peripheral PD-L1 and sequestered any released plasma TGF-β1, -β2, and -β3 throughout the dosing period at >1 mg/kg. There were signs of efficacy across all dose levels, including 1 ongoing confirmed complete response (cervical cancer), 2 durable confirmed partial responses (PRs; pancreatic cancer; anal cancer), 1 near-PR (cervical cancer), and 2 cases of prolonged stable disease in patients with growing disease at study entry (pancreatic cancer; carcinoid). Conclusions STATEMENT OF TRANSLATIONAL RELEVANCEExcitement surrounding the durable benefits associated with PD-1/PD-L1-targeted therapy has been tempered somewhat by responses being confined to only a subset of patients.To increase the rate of response, many ongoing trials are evaluating anti-PD-1/PD-L1 agents in combination with other immunotherapies; however, these combination strategies have limitations and novel approaches are required. M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a monoclonal antibody against PD-L1 fused to a TGF-β "trap." We report the first clinical data for M7824 -including pharmacokinetics, safety, and efficacy findings -which derive from a phase 1 dose-escalation study in patients with advanced solid tumors. M7824 saturated peripheral PD-L1 and sequestered any released plasma TGF-β throughout the dosing period at a dose >1 mg/kg. M7824 appeared to have a manageable safety profile and early evidence of clinical efficacy -including 1 ongoing confirmed complete response and 2 durable confirmed partial responses -was demonstrated.
Purpose: Regorafenib is a novel oral multikinase inhibitor of angiogenic (VEGFR1-3, TIE2), stromal (PDGFR-b, FGFR), and oncogenic kinases (KIT, RET, and RAF). This first-in-man, phase I dose-escalation study assessed the safety, pharmacokinetic, pharmacodynamic, and efficacy profiles of regorafenib in patients with advanced solid tumors.Patients and Methods: Patients aged 18 years or older with advanced solid tumors refractory to standard treatment were recruited. Regorafenib was administered orally for 21 days on/seven days off in repeating cycles, until discontinuation due to toxicity or tumor progression. Adverse events (AE) were assessed using National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. Pharmacokinetic profiles were measured after a single dose and on day 21. Pharmacodynamic and efficacy evaluations included tumor perfusion assessment using dynamic contrast-enhanced MRI, plasma cytokines, and tumor response using RECIST (v1.0).Results: Fifty-three patients were enrolled into eight cohorts at dose levels from 10 to 220 mg daily. The recommended dose for future studies was determined to be 160 mg daily, with a treatment schedule of 21 days on/seven days off in repeating 28-day cycles. The most common drug-related grade 3 or 4 AEs were dermatologic AEs (hand-foot skin reaction, rash), hypertension, and diarrhea. Pharmacokinetic analysis revealed a similar exposure at steady state for the parent compound and two pharmacologically active metabolites. Tumor perfusion and plasma cytokine analysis showed biologic activity of regorafenib. Three of 47 evaluable patients achieved a partial response (renal cell carcinoma, colorectal carcinoma, and osteosarcoma).Conclusion: Regorafenib showed an acceptable safety profile and preliminary evidence of antitumor activity in patients with solid tumors. Clin Cancer Res; 18(9); 2658-67. Ó2012 AACR.
Background:In a phase I dose-escalation study, regorafenib demonstrated tolerability and antitumour activity in solid tumour patients. The study was expanded to focus on patients with metastatic colorectal cancer (CRC).Methods:Patients received oral regorafenib 60–220 mg daily (160 mg daily in the extension cohort) in cycles of 21 days on, 7 days off treatment. Assessments included toxicity, response, pharmacokinetics and pharmacodynamics.Results:Thirty-eight patients with heavily pretreated CRC (median 4 prior lines of therapy, range 0–7) were enrolled in the dose-escalation and extension phases; 26 patients received regorafenib 160 mg daily. Median treatment duration was 53 days (range 7–280 days). The most common treatment-related toxicities included hand–foot skin reaction, fatigue, voice change and rash. Twenty-seven patients were evaluable for response: 1 achieved partial response and 19 had stable disease. Median progression-free survival was 107 days (95% CI, 66–161). At steady state, regorafenib and its active metabolites had similar systemic exposure. Pharmacodynamic assessment indicated decreased tumour perfusion in most patients.Conclusion:Regorafenib showed tolerability and antitumour activity in patients with metastatic CRC. This expanded-cohort phase I study provided the foundation for further clinical trials of regorafenib in this patient population.
Summary. Multiple myeloma (MM) is characterized by a clonal proliferation of malignant plasma cells in the bone marrow secreting a monoclonal immunoglobulin (paraprotein) with specific antigenic determinants, the idiotype (Id), which can be regarded as a tumour-associated antigen (TAA). In order to analyse the impact of a dendritic cell (DC)-based vaccine, 11 patients with advanced MM were treated with CD34 stem cell-derived dendritic cells that were pulsed with Id peptides. Subsequently, the patients received three boost immunizations every other week with a combination of Id and granulocyte±macrophage colonystimulating factor (GM-CSF) (nine patients) or with Id peptide-pulsed dendritic cells again (two patients). The treatment was well tolerated with no side-effects. The present clinical study was a proof of concept analysis of dendritic cell-based vaccines in MM. The capacity of the dendritic cells to activate idiotype-specific T cells was verified by in vitro stimulation experiments before the vaccination therapy. Immunological effects of the Id vaccination were analysed by monitoring changes in anti-idiotype antibody titres and idiotype-specific T-cell activity. After vaccination, three out of 10 analysed patients showed increased antiidiotype antibody serum titres, indicating the induction of an idiotype-specific humoral immune response. The idiotype-specific T-cell response analysed by ELISpot was increased in four out of 10 analysed patients after vaccination, and one patient had a decreased plasma cell infiltration in the bone marrow. In conclusion, five out of 11 patients showed a biological response after vaccination. Thus, our data indicate that immunotherapy with Id-pulsed DCs in MM patients is feasible and safe. DC generated from CD34 1 progenitor cells can serve as a natural adjuvant for the induction of clinically relevant humoral and cellular idiotype-specific immune responses in patients suffering from advanced MM.
Purpose: Hypertension is a commonly reported side effect in antiangiogenic therapy.We investigated the hypothesis that telatinib, a small molecule angiogenesis inhibitor, impairs vascular function, induces rarefaction, and causes hypertension. Experimental Design: A side-study was done in a phase I trial of telatinib, a small molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptors 2 and 3, platelet-derived growth factor receptor, and c-KIT in patients with advanced solid tumors. Measurements of blood pressure, flow-mediated dilation, nitroglycerin-mediated dilation, aortic pulse wave velocity, skin blood flux with laser Doppler flow, and capillary density with sidestream dark field imaging were done at baseline and after 5 weeks of treatment. Blood pressure and proteinuria were measured weekly. Results: Mean systolic and diastolic blood pressure values increased significantly at +6.6 mm Hg (P = 0.009) and +4.7 mm Hg (P = 0.016), respectively. Mean flow-mediated dilation and mean nitroglycerin-mediated dilation values significantly decreased by -2.1% (P = 0.003) and -5.1% (P = 0.001), respectively. After 5 weeks of treatment, mean pulse wave velocity significantly increased by 1.2 m/s (P = 0.001). A statistically significant reduction of mean skin blood flux of 532.8% arbitrary units was seen (P = 0.015). Capillary density statistically significantly decreased from 20.8 to 16.7 capillary loops (P = 0.015). Proteinuria developed or increased in six patients during telatinib treatment. Conclusion: The increase in blood pressure observed in the treatment with telatinib, an angiogenesis inhibitor, may be caused by functional or structural rarefaction.
Sorafenib 400 mg bid plus doxorubicin 60 mg/m(2) was well tolerated. The increased doxorubicin exposure with sorafenib 400 mg bid did not result in significantly increased toxicity; low patient numbers make the clinical significance of this unclear. These promising efficacy results justify further clinical investigation.
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