Novel dual GIP and GLP-1 receptor agonist, tirzepatide (TZP), is being developed as a potential weekly treatment for type 2 diabetes (T2DM), weight management and nonalcoholic steatohepatitis. The ...absorption, metabolism and excretion of a single subcutaneous (SC) dose of 14C-tirzepatide was investigated in Sprague Dawley rat and cynomolgus monkey. In addition, tissue distribution of 14C-tirzepatide was assessed in quantitative whole-body autoradiography (QWBA) study in pigmented Long Evans rat following a single SC dose.
14C-Tirzepatide was prepared by incorporating four 14C’s in the mini-PEG linker between the peptide backbone and the di-acid chain to provide a specific activity of ∼ 40 µCi/mg. Following a single SC dose of 14C-tirzepatide in rat (3 mg/kg) and monkey (0.5 mg/kg), total radioactivity recovery was > 97% over the course of study (336 hours for rat and 672 hours for monkey). The dosed radioactivity was similarly excreted via urine and feces in rats and monkeys. Metabolism of 14C-tirzepatide was characterized in plasma and excreta. Parent drug was the major component in circulation accounting for approximately 87% of total radioactivity in rat and 84% in monkey. Tirzepatide was primarily metabolized via catabolism of the peptide backbone and β-oxidation of the di-acid chain.
Following a single SC dose of 14C-tirzepatide in rats (3 mg/kg), radioactivity was distributed to tissues as early as the first collection time point at 1-hour post dose. The tissues with the highest radioactivity concentrations were observed in the dose site, kidney, cecum, urinary bladder, intervertebral ligaments, arterial wall, lungs, and liver, generally at 12 to 48 hours post dose.
Disclosure
J. Martin: Employee; Self; Eli Lilly and Company. K. Cassidy: Employee; Self; Eli Lilly and Company. B. Czeskis: None. J. Alberts: Employee; Self; Eli Lilly and Company. Y. Lao: Employee; Spouse/Partner; Eli Lilly and Company. J. Gluff: None. A.M. Niedenthal: None.
Cumulative sensory neurotoxicity (sNT) is the dose-limiting toxicity of oxaliplatin, which commonly leads to early discontinuation of oxaliplatin-based therapy in the palliative and adjuvant ...settings. In a nonrandomized, retrospective study, intravenous (IV) calcium/magnesium (Ca/Mg) was associated with reduced oxaliplatin-induced sNT.
Patients with colon cancer undergoing adjuvant therapy with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) were randomly assigned to Ca/Mg (1g calcium gluconate plus 1g magnesium sulfate pre- and post-oxaliplatin) or placebo, in a double-blinded manner. The primary end point was the percentage of patients with grade 2 or greater sNT at any time during or after oxaliplatin-based therapy by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; version 3) criteria. An oxaliplatin-specific sNT scale and patient questionnaires were also used to assess sNT. After 104 of 300 planned patients were enrolled, the study was closed. This was due to preliminary reports from another trial that suggested that Ca/Mg decreased treatment efficacy; these data were subsequently found to be incorrect.
Overall, 102 patients were available for analysis. Ca/Mg decreased the incidence of chronic, cumulative, grade 2 or greater sNT, as measured by NCI CTCAE (P = .038) and also by the oxaliplatin-specific sNT scale (P = .018). In addition, acute muscle spasms associated with oxaliplatin were significantly reduced (P = .01) No effect on acute, cold-induced sNT was found. No substantial differences in adverse effects were noted between Ca/Mg and placebo.
Despite early termination and decreased statistical power, this study supports IV Ca/Mg as an effective neuroprotectant against oxaliplatin-induced cumulative sNT in adjuvant colon cancer.
Abstract Context Many patients with potentially curable cancer do not complete their prescribed treatment regimens because of the toxicity. There is evidence that the common endpoints of many of ...these toxicities are amenable to quality of life (QOL)-directed interventions. Objectives This study was conducted to determine the effect of a multidisciplinary QOL-directed intervention on patients' adherence to planned chemoradiation (CR) regimens. Methods The results of two randomized controlled trials that used the same QOL intervention were pooled to form a cohort of 61 patients with advanced localized gastrointestinal cancer. Of these 61 subjects, 29 participated in six to eight bi- to triweekly sessions that included exercise, education, and relaxation, and 32 received usual medical care. The primary endpoint was completion of their prescribed CR regimens. Secondary outcomes included hospitalization during CR, rates of adverse postoperative events, and complete pathological response in those undergoing neoadjuvant therapy. Results Significantly, more members of the intervention than the control group completed their planned CR regimens (77.8 vs. 38.2%, P = 0.003). More participants in the control ( n = 14) than the intervention ( n = 5) group ( P = 0.063) required hospitalization. Among those undergoing neoadjuvant CR, those in the intervention group were significantly more likely to complete CR as planned (81.0% vs. 37.5%, P = 0.005) and less likely to be hospitalized (14.3% vs. 50.0%, P = 0.011). Conclusion A structured multidisciplinary QOL-directed intervention delivered to patients undergoing CR may increase the proportion of patients who complete CR as planned and reduce unplanned hospitalizations. Utilization is an important outcome in QOL-directed intervention trials.
Background
Previous studies have established that higher baseline quality of life (QOL) scores are associated with improved survival in patients with metastatic colorectal cancer (mCRC). We examined ...the relationship between overall survival (OS) and baseline QOL.
Patients and Methods
A total of 1 247 patients with mCRC participating in N9741 (comparing bolus 5-FU/LV, irinotecan IFL vs infusional 5-FU/leucovorin LV/oxaliplatin FOLFOX vs. irinotecan/oxaliplatin IROX) provided data at baseline on overall QOL using a single-item linear analogue self-assessment (LASA) 0–100 point scale. The association of OS according to clinically deficient (defined as CD-QOL, score 0–50) vs not clinically deficient (nCD-QOL, score 51–100) baseline QOL scores was tested. A multivariable analysis using Cox proportional hazards modeling was performed to adjust for the effects of multiple baseline factors. An exploratory analysis was performed evaluating OS according to baseline QOL status among patients who did or did not receive second-line therapy.
Results
Baseline QOL was a strong predictor of OS for the whole cohort (CD-QOL vs nCD-QOL: 11.2 months vs 18.4 months, P < .0001), and in each arm IFL 12.4 vs 15.1 months, FOLFOX 11.1 months vs 20.6 months, and IROX 8.9 months vs 18.1 months. Baseline QOL was associated with baseline performance status (PS) (P < .0001). After adjusting for PS and treatment arm, baseline QOL was still associated with OS (P = .017).
Conclusions
Baseline QOL is an independent prognostic factor for OS in patients with mCRC. The demonstration that patient-assessed QOL and PS are independent prognostic indicators suggests that these assessments provide important complementary prognostic information.
To determine whether weekly epoetin alfa could improve hemoglobin (HgB) levels, reduce RBC transfusions, and improve quality of life (QOL) in patients with advanced cancer and with anemia after ...receiving myelosuppressive chemotherapy.
This double-blind, placebo-controlled study randomly assigned patients to placebo or epoetin alfa (Ortho Biotech, Bridgewater, NJ) 40,000 U subcutaneous weekly for 16 weeks. QOL, HgB, and RBC transfusions were measured pretreatment and monthly.
The study accrued 344 patients; 330 were assessable for efficacy and 305 were assessable for QOL. Placebo-treated patients had a mean increase in HgB of 0.9 g/dL (range, -3.8 to +5.3) compared with 2.8 g/dL (range, -2.2 to +7.5) for epoetin-treated patients (P < .0001). During the study, 31.7% of placebo-treated patients achieved a > or = 2 g/dL HgB increase compared with 72.7% of epoetin-treated patients (P < .0001). The incidence of RBC transfusion for placebo and epoetin treatment arms was 39.6% and 25.3% (P = .005), respectively. The placebo group received 256 units of RBCs compared with 127 units in the epoetin group (P < .0001). The incidence of toxicity in the groups was similar. Changes in the average QOL scores from baseline to the end of the study were similar in the two groups (P = not significant). The HgB responders (irrespective of treatment arm) had a mean change in Functional Assessment of Cancer Therapy (FACT) fatigue score from a baseline of +5.1 compared with -2.1 for the nonresponders (P = .006).
Epoetin alfa significantly improved HgB and reduced transfusions in this patient population. These results support the use of weekly epoetin alfa as an ameliorative agent for cancer-related anemia.
Abstract Objectives Interferon gamma (IFN-γ) is a pleiotropic cytokine with antiproliferative, immunostimulatory, and chemosensitization properties. This trial was designed to evaluate IFN-γ 1b plus ...carboplatin and paclitaxel in treatment-naive ovarian cancer (OC) and primary peritoneal carcinoma (PPC) patients. Methods Eligible patients were randomized to 6 cycles of carboplatin/paclitaxel every 3 weeks or the same in combination with IFN-γ 1b (100 µg 3×/wk subcutaneously). The primary endpoint was overall survival (OS) time (target hazard ratio (HR) = 0.77). Secondary endpoints included progression-free survival (target HR = 0.7), based on blinded review of serial imaging scans, physical exams, and CA-125 levels. Results 847 patients were enrolled (OC 774, PPC 73) in Europe ( n = 539) and North/South America ( n = 308) from January 29, 2002 to March 31, 2004 and stratified according to: optimal debulking ( n = 271) versus suboptimal debulking with plans for interval debulking (PID) ( n = 238) or no PID ( n = 338). The study stopped early following a protocol-defined second interim analysis which revealed significantly shorter OS time in patients receiving IFN-γ 1b plus chemotherapy compared to chemotherapy alone (1138 days vs. not estimable, HR = 1.45, 95% CI = 1.15–1.83). At the time of the analysis, 169 of 426 (39.7%) patients in the IFN-γ 1b plus chemotherapy group had died compared to 128 of 421 (30.4%) in the chemotherapy alone group. Serious adverse events were more common in the IFN-γ 1b plus chemotherapy group (48.5% vs. 35.4%), primarily due to a higher incidence of serious hematological toxicities (34.5% vs. 22.7%). Conclusions Treatment with IFN-γ 1b in combination with carboplatin/paclitaxel does not have a role in the first-line treatment of advanced ovarian cancer.
To prospectively assess whether low-molecular-weight heparin (LMWH) provides a survival benefit in patients with advanced cancer.
Between December 1998 and June 2001, we performed a randomized ...controlled study of patients with advanced cancer. Initially, the study was double blinded and placebo controlled, with the patients receiving daily injections of 5000 U of LMWH or saline. However, because of low accrual midway through the study, the placebo injection arm was eliminated, and the study became open labeled, with patients receiving either LMWH injections plus standard clinical care or standard clinical care alone. The primary study end point was overall survival.
Of 141 patients randomized to this clinical trial, 3 dropped out, leaving 138 patients. The median survival time was 10.5 months (95% confidence interval, 7.6-12.2 months) for the combined standard care and placebo groups. The median survival time for the combined LMWH arms was 7.3 months (95% confidence interval, 4.8-12.2 months). These median survival times were not significantly different (log-rank
P=.46). The median survival times for the blinded and unblinded LMWH groups were 6.2 months and 9.0 months, respectively. The median survival times were 10.3 months for the blinded placebo arm and 10.5 months for the standard care arm. The rate of severe or life-threatening venous thromboembolism was 6% in the LMWH arms and 7% in the control arms. The rate of severe or life-threatening bleeding was 3% in the LMWH arms and 7% in the control arms.
This trial was unable to demonstrate any survival benefit for LMWH in patients with advanced cancer.
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