Phase I study of olaratumab in Japanese patients with advanced solid tumors.

Olaratumab (IMC-3G3) is a fully human IgG1 monoclonal antibody that selectively binds the external domain of human platelet-derived growth factor receptor-α with high affinity and blocks ligand binding. This was a single-center, dose-escalation, phase I trial of olaratumab in Japanese patients with advanced/refractory solid malignancies. Three to six patients were enrolled into each of three cohorts: Patients received i.v. olaratumab: 10 mg/kg on days 1 and 8 every 3 weeks (cohort 1); 20 mg/kg every 2 weeks (cohort 2); and 15 mg/kg on days 1 and 8 every 3 weeks (cohort 3). Doses were escalated from cohort 1 through cohort 3. The primary objective was to establish the safety and pharmacokinetic profile of olaratumab. Sixteen patients were treated across three cohorts. There were no dose-limiting toxicities, so the maximum tolerated dose was not reached. The most common olaratumab-related treatment-emergent adverse events (TEAEs) were proteinuria (25.0%) and elevated aspartate transaminase (12.5%). One patient (cohort 2) had two olaratumab-related Grade 3 TEAEs (increased aspartate aminotransferase and tumor hemorrhage); otherwise, olaratumab-related TEAEs were Grade 1/2. Seven patients (43.8%) had a best response of stable disease. Based on the pharmacokinetic concentration profile of olaratumab, the trough concentrations following single and multiple doses at 15 mg/kg on days 1 and 8 every 3 weeks (cohort 3) and multiple doses at 20 mg/kg every 2 weeks (cohort 2) were above the 155 µg/mL target. Thus, these two doses could represent an acceptable schedule for future trials in Japanese patients. Olaratumab had an acceptable safety profile and was well tolerated.

Icrucumab, a fully human monoclonal antibody against the vascular endothelial growth factor receptor-1, in the treatment of patients with advanced solid malignancies: a Phase 1 study.

BACKGROUND: IMC-18F1 (icrucumab), a human monoclonal antibody against vascular endothelial growth factor receptor-1 (VEGFR-1), potently inhibits ligand-dependent phosphorylation of VEGFR-1 and downstream signaling, making icrucumab an attractive candidate for antitumor activity. OBJECTIVES: The primary objective was to determine the safety profile and maximum tolerated dose of icrucumab in patients with advanced solid tumors that were previously unresponsive to standard therapy or for which no standard therapy was available. METHODS: In this open-label, dose-escalation, Phase 1 study, patients received icrucumab intravenously weekly at 2, 3, 6, and 12 mg/kg (Cohorts 1-4), every other week (q2w) at 15 mg/kg (Cohort 5), or every third week at 20 mg/kg (Cohort 6). Patients received icrucumab until evidence of progressive disease or other withdrawal criteria were met. RESULTS: Twenty-six patients received icrucumab. The most common adverse events were fatigue, nausea, peripheral edema, anemia, dyspnea, and vomiting. No dose-limiting toxicities (DLTs) were observed in Cohorts 1-5. Two DLTs were observed in Cohort 6 (anemia and hyponatremia), and enrollment was stopped. No patient demonstrated an immunogenic response. Overall, icrucumab exhibited nonlinear pharmacokinetics at doses >6 mg/kg. Six patients (23.1 %) achieved stable disease with median duration of 11.1 weeks (range = 10.3-18.7 weeks); tumor types were thyroid, melanoma, colorectal (3 patients), and small-cell lung cancers. CONCLUSIONS: Icrucumab was safely administered weekly at doses of 2-12 mg/kg and q2w at a dose of 15 mg/kg with no DLTs. Based on achievement of stable disease, icrucumab has potential for antitumor activity against advanced solid tumors.

Dosing Strategies and Quantitative Clinical Pharmacology for Bispecific T-Cell Engagers Development in Oncology.

Bispecific T-cell Engagers (TCEs) are promising anti-cancer treatments that bind to both the CD3 receptors on T cells and an antigen on the surface of tumor cells, creating an immune synapse, leading to killing of malignant tumor cells. These novel therapies have unique development challenges, with specific safety risks of cytokine release syndrome. These on-target adverse events fortunately can be mitigated and deconvoluted from efficacy via innovative dosing strategies, making clinical pharmacology key in the development of these therapies. This review assesses dose selection and the role of quantitative clinical pharmacology in the development of the first eight approved TCEs. Model informed drug development (MIDD) strategies can be used at every stage to guide TCE development. Mechanistic modeling approaches allow for (1) efficacious yet safe first-in-human dose selection as compared with in vitro minimum anticipated biological effect level (MABEL) approach; (2) rapid escalation and reducing number of patients with subtherapeutic doses through model-based adaptive design; (3) virtual testing of different step-up dosing regimens that may not be feasible to be evaluated in the clinic; and (4) selection and justification of the optimal clinical step-up and full treatment doses. As the knowledge base around TCEs continues to grow, the relevance and utilization of MIDD strategies for supporting the development and dose optimization of these molecules are expected to advance, optimizing the benefit-risk profile for cancer patients.

Measurement of surface pH of pharmaceutical solids: a critical evaluation of indicator dye-sorption method and its comparison with slurry pH method.

Two methods for the measurement of surface pH of pharmaceutical solids, namely, the dye-sorption method and the slurry pH method, were compared. High purity drug substances, instead of excipients, were used as model solids, because acidic or basic impurities present in excipients could influence slurry pH. Solid test samples were prepared by sorption of methanol-water solutions of several indicator dyes, and their diffuse reflectance UV-visible spectra were measured. The solid surface pH values were estimated by comparing base-to-acid peak ratios of the diffuse reflectance UV-visible spectra of solid samples to the calibration plots of dye solutions in aqueous standard buffers of known pH. In the slurry pH method, pH values of concentrated slurries of the compounds in water were considered to represent solid surface pH. The agreement between the two methods was mixed and depended on the compound or the indicator used. It was concluded that in many cases calibration plots of indicator dye spectra in aqueous buffers were not applicable to the solid state, and, as a result, the reliability of the method was low. The slurry method provided a simple and reliable measurement of surface pH indicating that concentrated slurry may closely represent solid surface pH.

A phase I study evaluating cixutumumab, a type 1 insulin-like growth factor receptor inhibitor, given every 2 or 3 weeks in Japanese patients with advanced solid tumors.

PURPOSE: The primary objective of this phase I trial was to establish the safety profile and pharmacokinetics of cixutumumab administered every 2 weeks (q2w) or every 3 weeks (q3w) in Japanese patients with advanced solid tumors. Exploratory analyses included preliminary antitumor activity. METHODS: Patients received intravenous cixutumumab q2w or q3w (6-week cycle) in a standard 3 + 3 study design. Safety was evaluated by National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. Patients received treatment until evidence of progressive disease or other withdrawal criteria were met. Pharmacokinetics were described using noncompartmental analyses. Antitumor activity was evaluated using Response Evaluation Criteria in Solid Tumors v1.0. RESULTS: A total of 21 patients were treated in one of four cohorts: 6 mg/kg q2w (n = 4); 10 mg/kg q2w (n = 7); 15 mg/kg q3w (n = 3); or 20 mg/kg q3w (n = 7). No patients experienced dose-limiting toxicity. A majority of patients (61.9 %) experienced one or more drug-related adverse event (AE). Related AEs included impaired glucose tolerance (n = 6 [28.6 %]) and diarrhea, nausea, stomatitis, fatigue, weight decrease, anorexia, rash, and hypertension (n = 2 each [9.5 %]). A best overall response of stable disease was seen in seven patients (33.3 %). The median duration of stable disease was 6.9 months (range 2.8, 6.9) for all cohorts. Although limited, pharmacokinetic results were as expected and were comparable between Japanese and Caucasian patients. CONCLUSION: Cixutumumab was generally well tolerated with no new safety concerns. GOV IDENTIFIER: NCT01007032.

A phase I study of olaratumab, an anti-platelet-derived growth factor receptor alpha (PDGFRα) monoclonal antibody, in patients with advanced solid tumors.

PURPOSE: The platelet-derived growth factor receptor (PDGFR) has an important role in tumorigenesis and tumor progression. Olaratumab (IMC-3G3) is a fully human monoclonal antibody that selectively binds human PDGFRα and blocks ligand binding. This phase I study assessed the safety, maximum tolerated dose (MTD), recommended phase II dose (RP2D), pharmacokinetics, and preliminary antitumor activity of olaratumab in patients with advanced solid tumors. METHODS: Patients were enrolled into five dose-escalating cohorts of 3-6 patients each. Olaratumab was administered intravenously weekly at 4, 8, or 16 mg/kg (cohorts 1-3) or once every other week at 15 or 20 mg/kg (cohorts 4-5), with 4 weeks/cycle. RESULTS: Nineteen patients were treated in five cohorts. There were no dose-limiting toxicities; the MTD was not identified with the doses studied. The most common olaratumab-related adverse events (AE) were fatigue and infusion reactions (10.5 % each). With the exception of 1 patient (20 mg/kg) experiencing two grade 3 drug-related AEs after the dose-limiting toxicity assessment period, all drug-related AEs were grade 1 or 2. The trough concentrations (C min) for 16 mg/kg weekly and 20 mg/kg biweekly were higher than 155 µg/mL, and the concentration found to be efficacious in preclinical xenograft models. Twelve patients (63.2 %) had a best response of stable disease [median duration of 3.9 months (95 % CI 2.3-8.7)]. CONCLUSIONS: Olaratumab was well tolerated and showed preliminary antitumor activity. RP2Ds are 16 mg/kg weekly and 20 mg/kg biweekly. Phase II studies of olaratumab as monotherapy and in combination are ongoing in several tumor types.

A phase I pharmacologic study of necitumumab (IMC-11F8), a fully human IgG1 monoclonal antibody directed against EGFR in patients with advanced solid malignancies.

PURPOSE: This study aimed to determine a maximum tolerated dose (MTD) and recommended dose for disease-directed studies of necitumumab (IMC-11F8), a fully human IgG(1) monoclonal antibody directed at the epidermal growth factor receptor, and to characterize the safety profile, pharmacokinetics, preliminary antitumor activity, and immunogenicity of necitumumab. EXPERIMENTAL DESIGN: Patients with advanced solid malignancies were treated with 100 to 1,000 mg (flat dosing) necitumumab followed by a 2-week pharmacokinetics sampling period, before beginning 6-week cycles of therapy. RESULTS: Sixty patients received necitumumab weekly (29 patients) or every other week (31 patients). Two patients receiving 1,000 mg every 2 weeks experienced dose-limiting toxicities (DLT; grade 3 headache), accompanied by grade 3 nausea and vomiting in one patient. Occurring hours after the initial dose, these DLTs established 800 mg as the MTD. Mild dose-related skin toxicity was the most common drug-related toxicity (80%). One patient in each arm experienced grade 3 acneform rash, which responded to oral antibiotics and topical therapy. Toxicity was similar on both schedules. Necitumumab exhibited saturable elimination and nonlinear pharmacokinetics. At 800 mg (both arms), its half-life was approximately 7 days. All patients treated with >or=600 mg necitumumab achieved target trough concentrations (>or=40 microg/mL). Antibodies against necitumumab were not detected. Partial response and stable disease were experienced by 2 and 16 patients, respectively. CONCLUSION: Well tolerated, necitumumab is associated with preliminary evidence of antitumor activity, and achieves biologically relevant concentrations throughout the dosing period. The recommended dose of necitumumab for further clinical development is 800 mg (flat dose) weekly or every 2 weeks based on the clinical setting.

Randomized, phase II study of the insulin-like growth factor-1 receptor inhibitor IMC-A12, with or without cetuximab, in patients with cetuximab- or panitumumab-refractory metastatic colorectal cancer.

PURPOSE: To evaluate the safety and efficacy of IMC-A12, a human monoclonal antibody (mAb) that blocks insulin-like growth factor receptor-1 (IGF-1R), as monotherapy or in combination with cetuximab in patients with metastatic refractory anti-epidermal growth factor receptor (EGFR) mAb colorectal cancer. METHODS: A randomized, phase II study was performed in which patients in arm A received IMC-A12 10 mg/kg intravenously (IV) every 2 weeks, while patients in arm B received this same dose of IMC-A12 plus cetuximab 500 mg/m(2) IV every 2 weeks. Subsequently, arm C (same combination treatment as arm B) was added to include patients who had disease control on a prior anti-EGFR mAb and wild-type KRAS tumors. Archived pretreatment tumor tissue was obtained when possible for KRAS, PIK3CA, and BRAF genotyping, and immunohistochemistry was obtained for pAKT as well as IGF-1R. RESULTS: Overall, 64 patients were treated (median age, 61 years; range, 40 to 84 years): 23 patients in arm A, 21 in arm B, and 20 in arm C. No antitumor activity was seen in the 23 patients treated with IMC-A12 monotherapy. Of the 21 patients randomly assigned to IMC-A12 plus cetuximab, one patient (with KRAS wild type) achieved a partial response, with disease control lasting 6.5 months. Arm C (all patients with KRAS wild type), however, showed no additional antitumor activity. Serious adverse events thought possibly related to IMC-A12 included a grade 2 infusion-related reaction (2%; one of 64 patients), thrombocytopenia (2%; one of 64 patients), grade 3 hyperglycemia (2%; one of 64 patients), and grade 1 pyrexia (2%, one of 64 patients). CONCLUSION: IMC-A12 alone or in combination with cetuximab was insufficient to warrant additional study in patients with colorectal cancer refractory to EGFR inhibitors.

Effects of trimethoprim on the clearance of apricitabine, a deoxycytidine analog reverse transcriptase inhibitor, and Lamivudine in the isolated perfused rat kidney.

Apricitabine (ATC) is a novel deoxycytidine analog reverse transcriptase inhibitor in development for the treatment of human immunodeficiency virus infection. Studies were performed to characterize the excretion of ATC and its metabolite, BCH-335 (-1-(2-hydroxymethyl-[1,3]oxathiolan-4-yl)-1H-pyrimidine-2,4-dione), in the isolated perfused rat kidney (IPK). A second objective was to investigate the effect of trimethoprim on ATC excretion because trimethoprim inhibits the excretion of lamivudine, structurally similar to ATC, in the IPK. ATC excretion was nonlinear at doses of 80 to 1600 microg. The excretion ratio (ratio of clearance to glomerular filtration rate, assuming negligible protein binding) was greater than 1.0, indicating net tubular secretion. In contrast, the excretion of BCH-335 was independent of the dose of BCH-335. Concomitant administration of ATC and BCH-335 did not affect the excretion of either compound. Trimethoprim significantly inhibited the excretion of both ATC and BCH-335, with IC(50) values of 0.45 and 0.54 microg/ml, respectively. In the presence of trimethoprim, the excretion ratios for both compounds were less than 1.0, indicating tubular reabsorption. Trimethoprim inhibited the excretion of ATC and lamivudine to similar extents. Following concomitant administration of ATC, lamivudine, and trimethoprim, there was no evidence of an interaction between ATC and lamivudine. These results suggest that ATC undergoes active tubular secretion in the kidney. Because the renal excretion of both ATC and lamivudine is inhibited by trimethoprim to similar extents, in clinical practice exposure to ATC, it would be expected to be increased in the presence of therapeutic concentrations of trimethoprim to a similar extent as has been shown previously for lamivudine.