dolastatin-15 and Neoplasms

To determine the safety, tolerability, and pharmacokinetics and to seek preliminary evidence of anticancer activity of tasidotin (ILX651), a novel dolastatin analogue, when administered as a 30-minute i.v. infusion weekly for 3 weeks every 4 weeks.. Thirty patients with advanced solid malignancies were treated with 82 courses at six dose levels ranging from 7.8 to 62.2 mg/m2 weekly, initially according to an accelerated dose-escalation scheme, which evolved into a Fibonacci scheme as a relevant degree of toxicity was observed. Plasma and urine were sampled to characterize the pharmacokinetic behavior of tasidotin.. A high incidence of neutropenia complicated by fever (one patient), or precluding treatment on day 15 (three patients), was the principal toxicity of tasidotin, at doses above 46.8 mg/m2. At all dose levels, nonhematologic toxicities were generally mild to moderate and manageable. Grade 3 toxicities included diarrhea and vomiting (one patient each). Drug-induced neurosensory symptoms were mild and there was no evidence of cardiovascular toxicity, which has been previously associated with other dolastatins. Tasidotin pharmacokinetics were mildly nonlinear, whereas metabolite kinetics were linear. A patient with non-small cell lung carcinoma experienced a minor response, and a patient with hepatocellular carcinoma had stable disease lasting 11 months.. The recommended dose for phase II studies of tasidotin administered on this schedule is 46.8 mg/m2. The mild myelosuppression and manageable nonhematologic toxicities at the recommended dose, the evidence of antitumor activity, and the unique mechanistic aspects of tasidotin warrant further disease-directed evaluations on this and alternative schedules.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Depsipeptides; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Middle Aged; Molecular Structure; Neoplasms; Oligopeptides; Time Factors; Treatment Outcome

To determine the maximum tolerated dose, dose-limiting toxicity, and pharmacokinetics of the dolastatin-15 analogue, tasidotin (ILX651), when administered i.v. daily for 5 days every 3 weeks.. Thirty-six patients with advanced solid tumors received a total of 114 courses through eight dose levels ranging from 2.3 to 36.3 mg/m(2). Pharmacokinetic samples were collected in cycle 1.. Neutropenia was the principal dose-limiting toxicity at 36.3 mg/m(2)/d along with grade 3 ileus and elevated aspartate amino transaminase/alanine amino transaminase (n = 1). At the maximum tolerated dose, 27.3 mg/m(2), 4 of 14 patients experienced dose-limiting grade 4 neutropenia. The other principal toxicities consisted of mild-to-moderate elevated transaminases, alopecia, fatigue, and nausea. One patient with melanoma metastatic to liver and bone treated at 15.4 mg/m(2)/d experienced a complete response and received 20 courses of tasidotin. Two other patients with melanoma had mixed responses of cutaneous metastases at 27.3 mg/m(2)/d associated with either stable or progressive visceral disease. In addition, nine patients had stable disease. There was no accumulation of tasidotin following repeated daily dosing. Tasidotin decayed from plasma in a biphasic fashion with a half-life of <45 minutes in most cases.. The maximum tolerated dose and recommended phase II dose for tasidotin when administered on this schedule was 27.3 mg/m(2)/d. The favorable toxicity profile of tasidotin compared with other antitubulin agents (particularly the lack of severe cumulative neuropathy, peripheral edema, and fatigue), the observed antitumor activity of tasidotin, and its novel mechanism of action support further disease-directed evaluations of this agent on this 5-day schedule every 3 weeks.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Area Under Curve; Depsipeptides; Dose-Response Relationship, Drug; Female; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Melanoma; Middle Aged; Neoplasm Metastasis; Neoplasms; Oligopeptides; Time Factors; Tomography, X-Ray Computed

A highly sensitive and specific assay for the quantitation of the anticancer agent dolastatin-10 (DOL-10) in human plasma is described. The method was based on the use of electrospray ionization-high-performance liquid chromatography/mass spectrometry (ESP-LC/MS). The analytical procedure involved extraction of plasma samples containing DOL-10 and the internal standard (DOL-15) with n-butyl chloride, which was then evaporated under nitrogen. The residue was dissolved in 50 microl mobile phase and 10 microl was subjected to ESP-LC/MS analysis using a C18 microbore column. A linear gradient using water/acetonitrile was used to keep the retention times of the analytes of interest under 5 min. The method exhibited a linear range from 0.005 to 50 ng/ml with a lower limit of quantitation (LLQ) at 0.005 ng/ml. Absolute recoveries of extracted samples in the 85-90% range were obtained. The method's accuracy (< or =5% relative error) and precision (< or =10% CV) were well within industry standards. The analytical procedure was applied to extract DOL-10 metabolites from samples obtained following incubation of the drug with an activated S9 rat liver preparation. Two metabolic products were detected and were tentatively identified as a N-demethyl-DOL-10 and hydroxy-DOL-10. Structural assignments were made based on the fragmentation patterns obtained using the electrospray source to produce collision-induced dissociation (CID). The method was also applied to the measurement of DOL-10 in the plasma of patients treated with this drug. Preliminary investigation of the pharmacokinetics suggested that drug distribution and elimination may be best described by a three-compartment model with t1/2alpha = 0.087 h, t1/2beta = 0.69 h and t1/2gamma = 8.0 h. Plasma clearance was 3.7 l/h per m2.

Topics: Antineoplastic Agents; Atmospheric Pressure; Chromatography, High Pressure Liquid; Depsipeptides; Humans; Mass Spectrometry; Neoplasms; Oligopeptides; Reference Standards; Tissue Distribution

Antibody-drug conjugates (ADC) are emerging as powerful treatment strategies with outstanding target-specificity and high therapeutic activity in patients with cancer. Brentuximab vedotin represents a first-in-class ADC directed against CD30(+) malignancies. We hypothesized that its sustained clinical responses could be related to the stimulation of an anticancer immune response. In this study, we demonstrate that the dolastatin family of microtubule inhibitors, from which the cytotoxic component of brentuximab vedotin is derived, comprises potent inducers of phenotypic and functional dendritic cell (DC) maturation. In addition to the direct cytotoxic effect on tumor cells, dolastatins efficiently promoted antigen uptake and migration of tumor-resident DCs to the tumor-draining lymph nodes. Exposure of murine and human DCs to dolastatins significantly increased their capacity to prime T cells. Underlining the requirement of an intact host immune system for the full therapeutic benefit of dolastatins, the antitumor effect was far less pronounced in immunocompromised mice. We observed substantial therapeutic synergies when combining dolastatins with tumor antigen-specific vaccination or blockade of the PD-1-PD-L1 and CTLA-4 coinhibitory pathways. Ultimately, treatment with ADCs using dolastatins induces DC homing and activates cellular antitumor immune responses in patients. Our data reveal a novel mechanism of action for dolastatins and provide a strong rationale for clinical treatment regimens combining dolastatin-based therapies, such as brentuximab vedotin, with immune-based therapies.

Topics: Animals; Antibodies; Antigens; Brentuximab Vedotin; Cancer Vaccines; Cell Line; Cells, Cultured; CTLA-4 Antigen; Cytokines; Dendritic Cells; Depsipeptides; Humans; Immunoconjugates; Mice, Inbred C57BL; Mice, Transgenic; Neoplasms; Ovalbumin; Programmed Cell Death 1 Receptor; T-Lymphocytes; Tubulin Modulators; Tumor Burden