Search

Purpose: Guanylyl cyclase C (GCC) is highly expressed in several gastrointestinal malignancies and preclinical studies suggest that it is a promising target for antibody-based therapeutics. This phase I trial assessed the safety and tolerability of TAK-164, an investigational, anti-GCC antibody–drug conjugate (NCT03449030). Methods: Thirty-one patients with GCC-positive, advanced gastrointestinal cancers received intravenous TAK-164 on day 1 of 21-day cycles. Dose escalation proceeded based on cycle 1 safety data via a Bayesian model. Results: Median age was 58 years (range 32–72), 25 patients (80.6%) had colorectal carcinoma, and median number of prior therapies was four. No dose-limiting toxicities (DLTs) were reported during cycle 1 DLT evaluation period. After cycle 2 dosing, 3 patients reported dose-limiting treatment-emergent adverse events (TEAEs): grade 3 pyrexia and grade 5 hepatic failure (0.19 mg/kg), grade 4 hepatic failure and platelet count decreased (0.25 mg/kg), grade 3 nausea, grade 4 platelet and neutrophil count decreased (0.25 mg/kg). The recommended phase II dose (RP2D) was 0.064 mg/kg. Common TAK-164-related TEAEs included platelet count decreased (58.1%), fatigue (38.7%), and anemia (32.3%). There was a dose-dependent increase in TAK-164 exposure over the range, 0.032–0.25 mg/kg. TAK-164 half-life ranged from 63.5 to 159 h. One patient (0.008 mg/kg) with high baseline GCC expression had an unconfirmed partial response. Conclusions: TAK-164 appeared to have a manageable safety profile at 0.064 mg/kg. Hepatic toxicity was identified as a potential risk. The RP2D of 0.064 mg/kg was considered insufficient to derive clinical benefit; there are no plans for further clinical development. Clinical Trial Registration: NCT03449030. [ABSTRACT FROM AUTHOR]

Summary: We conducted a dose escalation Phase 1 study of autologous PBMCs loaded by microfluidic squeezing (Cell Squeeze® technology) with HPV16 E6 and E7 antigens (SQZ-PBMC-HPV), in HLA-A*02+ patients with advanced/metastatic HPV16+ cancers. Preclinical studies in murine models had shown such cells resulted in stimulation and proliferation of antigen specific CD8+ cells, and demonstrated antitumor activity. Administration of SQZ-PBMC-HPV was every 3 weeks. Enrollment followed a modified 3+3 design with primary objectives to define safety, tolerability, and the recommended Phase 2 dose. Secondary and exploratory objectives were antitumor activity, manufacturing feasibility, and pharmacodynamic evaluation of immune responses. Eighteen patients were enrolled at doses ranging from 0.5 × 106 to 5.0 × 106 live cells/kg. Manufacture proved feasible and required < 24 h within the overall vein-to-vein time of 1 – 2 weeks; at the highest dose, a median of 4 doses were administered. No DLTs were observed. Most related TEAEs were Grade 1 – 2, and one Grade 2 cytokine release syndrome SAE was reported. Tumor biopsies in three patients showed 2 to 8-fold increases in CD8+ tissue infiltrating lymphocytes, including a case that exhibited increased MHC-I+ and PD-L1+ cell densities and reduced numbers of HPV+ cells. Clinical benefit was documented for the latter case. SQZ-PBMC-HPV was well tolerated; 5.0 × 106 live cells/kg with double priming was chosen as the recommended Phase 2 dose. Multiple participants exhibited pharmacodynamic changes consistent with immune responses supporting the proposed mechanism of action for SQZ-PBMC-HPV, including patients previously refractory to checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

B Correction to: Cancer Chemotherapy and Pharmacology b https://doi.org/10.1007/s00280-023-04507-w The article "A phase I, first-in-human study of TAK-164, an antibody-drug conjugate, in patients with advanced gastrointestinal cancers expressing guanylyl cyclase C", written by Richard Kim - Alexis D. Leal - Aparna Parikh - David P. Ryan - Shining Wang - Brittany Bahamon -Neeraj Gupta - Aaron Moss - Joanna Pye - Harry Miao - Haig Inguilizian and James M. Cleary was originally published Online First without Open Access. Correction to: A phase I, first-in-human study of TAK-164, an antibody-drug conjugate, in patients with advanced gastrointestinal cancers expressing guanylyl cyclase C The original article can be found online at https://doi.org/10.1007/s00280-023-04507-w. [Extracted from the article]

Purpose: Adherence to guideline-consistent chemotherapy-induced nausea and vomiting (CINV) prophylaxis is suboptimal. The primary aim of this study was to evaluate the magnitude of compliance to institutional guideline-directed antiemetic prophylaxis using a computerized physician order entry system at a single tertiary care institution. A nurse survey was also performed to evaluate how oncology practices, within a cooperative group, managed clinician orders for the prevention of CINV. Methods: The electronic medical records of 100 consecutive patients were evaluated. The primary endpoint was the incidence of compliance to provide all aspects of scheduled institutional guideline-directed antiemetic prophylaxis for acute (day 1) and delayed (days 2–4) CINV. A descriptive analysis was performed on the convenience sample. Logistic regression was completed to determine the predictors of noncompliance. Results: The incidence of compliance on days 1–4 was 94 %. Half of the noncompliant events (three of six, 50 %) occurred on day 1 alone and involved patients receiving low-emetogenic chemotherapy. There was a high degree of compliance to institutional guidelines for the treatment of delayed CINV (97 %). Patients receiving minimally emetogenic and moderately emetogenic chemotherapy ( N = 70) were observed to be 100 % compliant. Patients receiving doxorubicin/cyclophosphamide were numerically less likely to receive institutional guidelines, compared to patients receiving other chemotherapy regimens (OR, 0.24 (0.04, 1.36), p value, 0.05). The nurse survey suggested significant variability amongst the involved institutions with regards to antiemetic prescribing practices. Conclusions: Computerized physician order entry is associated with impressive adherence to clinician-prescribing practices, according to institutional guidelines, for acute and delayed CINV. [ABSTRACT FROM AUTHOR]