Search

Background: Procaspase-3 (PC-3) is overexpressed in multiple tumour types and procaspase-activating compound 1 (PAC-1) directly activates PC-3 and induces apoptosis in cancer cells. This report describes the first-in-human, phase I study of PAC-1 assessing maximum tolerated dose, safety, and pharmacokinetics., Methods: Modified-Fibonacci dose-escalation 3 + 3 design was used. PAC-1 was administered orally at 7 dose levels (DL) on days 1-21 of a 28-day cycle. Dose-limiting toxicity (DLT) was assessed during the first two cycles of therapy, and pharmacokinetics analysis was conducted on days 1 and 21 of the first cycle. Neurologic and neurocognitive function (NNCF) tests were performed throughout the study., Results: Forty-eight patients were enrolled with 33 completing ≥2 cycles of therapy and evaluable for DLT. DL 7 (750 mg/day) was established as the recommended phase 2 dose, with grade 1 and 2 neurological adverse events noted, while NNCF testing showed stable neurologic and cognitive evaluations. PAC-1's t 1/2 was 28.5 h after multi-dosing, and systemic drug exposures achieved predicted therapeutic concentrations. PAC-1 clinical activity was observed in patients with neuroendocrine tumour (NET) with 2/5 patients achieving durable partial response., Conclusions: PAC-1 dose at 750 mg/day was recommended for phase 2 studies. Activity of PAC-1 in treatment-refractory NET warrants further investigation., Clinical Trial Registration: Clinical Trials.gov: NCT02355535., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

The purpose of this study was to first characterize the prevalence of recall, recognition, and knowledge of colon cancer screening tests and guidelines (collectively, "awareness") among non-Hispanic black (NHB) and NH white (NHW) urban colon cancer patients. Second, we sought to examine whether awareness was associated with mode of cancer detection. Low awareness regarding colon cancer screening tests and guidelines may explain low screening rates and high prevalence of symptomatic detection. We examined recall, recognition, and knowledge of colorectal cancer (CRC) screening tests and guidelines and their associations with mode of cancer detection (symptomatic versus screen-detected) in 374 newly diagnosed NHB and NHW patients aged 45-79. Patients were asked to name or describe any test to screen for colon cancer (recall); next, they were given descriptions of stool testing and colonoscopy and asked if they recognized each test (recognition). Lastly, patients were asked if they knew the screening guidelines (knowledge). Overall, awareness of CRC screening guidelines was low; just 20% and 13% of patients knew colonoscopy and fecal test guidelines, respectively. Awareness of CRC screening tests and guidelines was especially low among NHB males, socioeconomically disadvantaged individuals, and those diagnosed at public healthcare facilities. Inability to name or recall a single test was associated with reduced screen-detected cancer compared with recall of at least one test (36% vs. 22%, p = 0.01). Low awareness of CRC screening tests is a risk factor for symptomatic detection of colon cancer.

Objectives: Insulin-like growth factor-methotrexate (IGF-MTX) is a conjugate of methotrexate and 765IGF, a variant of IGF-1 with high affinity for insulin-like growth factor type 1 receptor. The study aim was to determine the maximum tolerated dose of IGF-MTX in refractory solid organ and hematologic malignancies expressing insulin-like growth factor type 1 receptor., Materials and Methods: This phase I trial used a modified toxicity probability interval design with 5 cohort dose levels, and expansion cohort at maximum tolerated dose. IGF-MTX was given intravenously over 90 minutes on days 1, 8, and 15 of a 28-day cycle., Results: A total of 17 patients were enrolled. The highest tolerated dose tested was 0.80 µEq/kg with dose-limiting toxicity of grade 3 hypoglycemia. Drug-related grade 3 and 4 toxicities included abdominal pain (26%), hypoglycemia (10%), and hypotension (10%). Of the 15 evaluable for response, 3 patients (20%) had stable disease, including the patient with Hodgkin lymphoma with stable disease for 12 cycles of therapy. IGF-MTX concentrations declined rapidly, with half-lives of 5.2 to 14 minutes for the initial distribution phase and 6.5 to 7.5 hours for the terminal elimination phase. Higher IGF-R1 expression did not correlate with better outcome., Conclusions: IGF-MTX is well tolerated. IGF-MTX pharmacokinetics suggest rapid cellular uptake. The activity of IGF-MTX in Hodgkin lymphoma should be explored.

In the USA, the incidence of cutaneous melanoma is increasing rapidly. It has been shown to be responsive to immune-stimulating drugs. Allovectin-7 allows the immune system to recognize metastatic melanoma lesions as foreign by incorporating a MHC class I complex into the tumor through direct injection. Once transfected, tumor biopsies have shown an increased presence of cytotoxic T lymphocytes in the tumor beds themselves. Phase I and II trials have shown local and systemic response to these tumors, with an excellent safety profile. Currently, a Phase III trial has completed enrollment and is set to determine the safety and efficacy of treatment in comparison with standard chemotherapy.