A first-in-human phase 1 study of nofazinlimab, an anti-PD-1 antibody, in advanced solid tumors and in combination with regorafenib in metastatic colorectal cancer.

BACKGROUND: We assessed nofazinlimab, an anti-PD-1 antibody, in solid tumors and combined with regorafenib in metastatic colorectal cancer (mCRC). METHODS: This phase 1 study comprised nofazinlimab dose escalation (phase 1a) and expansion (phase 1b), and regorafenib dose escalation (80 or 120 mg QD, days 1-21 of 28-day cycles) combined with 300-mg nofazinlimab Q4W (part 2a) to determine safety, efficacy, and RP2D. RESULTS: In phase 1a (N = 21), no dose-limiting toxicity occurred from 1 to 10 mg/kg Q3W, with 200 mg Q3W determined as the monotherapy RP2D. In phase 1b (N = 87), 400-mg Q6W and 200-mg Q3W regimens were found comparable. In part 2a (N = 14), both regimens were deemed plausible RP2Ds. Fatigue was the most frequent treatment-emergent adverse event (AE) in this study. Any-grade and grade 3/4 nofazinlimab-related AEs were 71.4% and 14.3%, 56.3% and 5.7%, and 57.1% and 21.4% in phases 1a, 1b, and part 2a, respectively. ORRs were 14.3% and 25.3% in phases 1a and 1b, respectively. In part 2a, no patients had radiological responses. CONCLUSIONS: Nofazinlimab monotherapy was well tolerated and demonstrated preliminary anti-tumor activity in multiple tumor types. Regorafenib plus nofazinlimab had a manageable safety profile but was not associated with any response in mCRC. CLINICAL TRIAL REGISTR ATION: Clinicaltrials.gov (NCT03475251).

A phase 1 trial of 4-(N-(S-penicillaminylacetyl)amino)-phenylarsonous acid (PENAO) in patients with advanced solid tumours.

PURPOSE: This phase I study was conducted to evaluate the safety and Maximum Tolerated Dose of PENAO (4-(N-(S-penicillaminylacetyl)amino)-phenylarsonous acid), a second-generation organic arsenical with anti-mitochondrial activity, when given as a continuous intravenous infusion (CIVI), in patients with advanced solid tumours. METHODS: Eligibility criteria for this trial included age ≥ 18 years, advanced solid tumour, ECOG Performance Status ≤ 1 and adequate organ function. PENAO was administered by CIVI, with dose levels initially increased by infusion duration in a 21-day cycle at a fixed daily dose and then increased daily dose. Standard dose-limiting toxicity (DLT) definitions were used in a "3 + 3" design. Patients had regular monitoring of toxicity and efficacy. Pharmacokinetic assays of serum and urine As were performed. RESULTS: Twenty-six patients were treated across 8 dose levels. The only dose-limiting toxicity (DLT) observed was fatigue, that occurred in one patient treated at the highest dose level of 9 mg/m2/day. No significant organ toxicity or objective responses were observed, although there were two patients with stable disease lasting up to 7 months. Pharmacokinetic analysis unexpectedly indicated a half-life of 9-19 days, invalidating the CIVI dosing resulting in discontinuation of the study before the RP2D was defined. CONCLUSIONS: PENAO was administered by CIVI at dose levels up to 9 mg/m2/day with only one DLT noted. Pharmacokinetic studies invalidated the rationale for continuous dosing and led to discontinuation of the trial without defining a RP2D. Future clinical development of PENAO will use intermittent dosing schedule, alone and in combination with rapamycin.

KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors.

BACKGROUND: No therapies for targeting KRAS mutations in cancer have been approved. The KRAS p.G12C mutation occurs in 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRASG12C. METHODS: We conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. RESULTS: A total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma. CONCLUSIONS: Sotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).

Immune checkpoint inhibitor therapy in a liver transplant recipient with a rare subtype of melanoma: a case report and literature review.

Immunotherapy with immune checkpoint inhibitors (ICIs) may be considered as a treatment option for various types of tumors, but the transplant recipient population as well as patients requiring long-term systemic immunosuppression for other reasons have been systematically excluded from clinical trials involving ICIs. We report a case of successful treatment with ICI in a liver transplant recipient diagnosed with a rare subtype of melanoma. This patient had not required any modification to her antirejection immunosuppression before or during immunotherapy, had not experienced any serious immune-related adverse event, and had a durable objective response for nearly 1.5 year now. A summary of a literature review on other case reports is included to show that ICIs can be safe and provide clinically meaningful benefit in transplant patients, although acute rejection and graft loss remain a significant risk. Given the serious complication of graft failure, a detailed discussion of risks and benefits with immunotherapy needs to be made for an informed consent. Nevertheless, transplant recipients with cancer should not be deprived of this potentially life-saving or life-prolonging treatment, and inclusion of this population in future clinical trials should be considered.

Immune checkpoint inhibitors in the treatment of advanced mucosal melanoma.

Immunotherapy with immune checkpoint inhibitors is the standard of care in the treatment of advanced melanoma. Treatment outcome of these agents is less defined for the rare subtype of mucosal melanoma. In this single-institutional case series, the objective response rate was low at 11.8%, but durable response was seen, including a complete response to first-line ipilimumab and to second-line pembrolizumab. Survival remained poor; at the median follow-up of 10.1 months, the median progression-free survival and overall survival were 3.1 and 8.8 months respectively. Nevertheless, among the few responders, survival of up to 56+ months was observed. Other treatment strategies need to be explored to improve treatment outcome for this rare subtype.

A Rapid Access Clinic to improve delivery of ambulatory care to cancer patients.

BACKGROUND: Cancer patients may find it challenging to access timely advice and care. We evaluated the improvement in delivering ambulatory care in establishing a Rapid Assessment Clinic (RAC) in a cancer center. METHODS: Patients receiving chemotherapy who presented for assessment at the RAC from September 2013 to June 2014 were included for review. Patient demographics, tumor characteristics, presenting complaints, time to assessment, total time spent at the RAC and assessment outcome were extracted. Similar data for cancer patients presented to the emergency department (ED) but were appropriate for RAC assessment from February 2012 to August 2012 were reviewed for comparison. For patients with febrile neutropenia, time to empirical antibiotic therapy was also reviewed and analyzed. RESULTS: Comparing to ED presentation (n = 152), patients reviewed at the RAC (n = 217) had a shorter waiting time to medical review (28.5 vs 40 min, P = 0.12), shorter total time spent for review (3.1 vs 9.7 hrs, P < 0.001), lesser rate of hospital admission (14.3% vs 69.1%, P < 0.001) and shorter inpatient length of stay (4 vs 7 days, P = 0.013). Presentations of febrile neutropenia were reviewed more promptly in ED (6 vs 9.5 min, P = 0.37), but this did not result in earlier empirical antibiotic administration (79 vs 74 min, P = 0.84). CONCLUSION: Comparing to ED, RAC had improved timeliness of care, resulting in a lower rate of hospital admission and inpatient length of stay for cancer patients. There was, however, no difference in the management of febrile neutropenia.

Application of hypersensitivity skin testing in chemotherapy-induced pneumonitis.

Skin testing has been utilised to determine the culprit allergenic agent in drug reactions. Its application in the setting of hypersensitivity reaction relating to combination chemotherapeutic regimens may help identify the causative drug, allowing drug that is safe to be continued and avoiding limiting treatment options for patients. We report what we believe to be the first published case of hypersensitivity skin testing for gemcitabine-induced pneumonitis in a patient with metastatic leiomyosarcoma and another case of docetaxel-induced pneumonitis in a patient with metastatic HER2-positive breast cancer.

Administration of chemotherapy in patients on dialysis.

The prevalence of patients on dialysis has increased and these patients present a challenge for chemotherapy administration when diagnosed with cancer. A consensus on the dosage and timing of different chemotherapeutic agents in relation to dialysis has not been established. We describe the pattern of care and treatment outcome for cancer patients on dialysis in our institution. The dataset from the Australia and New Zealand Dialysis and Transplant Registry of patients on dialysis who had a diagnosis of cancer was obtained and matched to the pharmacy records in our institution to identify patients who had received chemotherapy while on dialysis. Relevant clinical information including details of the dialysis regimen, chemotherapy administration and adverse events was extracted for analysis. Between July 1999 and July 2014, 21 patients on dialysis were included for analysis. Five (23.8%) received chemotherapy, most of which was administered before dialysis sessions. As a result of adverse events, one patient discontinued treatment; two other patients required dose reduction or treatment delay. Chemotherapy administration was feasible in cancer patients on dialysis, but chemotherapy usage was low. Better understanding of the altered pharmacokinetics in patients on dialysis may improve chemotherapy access and practice.

Serious hepatic complications of selective internal radiation therapy with yttrium-90 microsphere radioembolization for unresectable liver tumors.

AIM: Selective internal radiation therapy with yttrium-90 microsphere radioembolization has been used to treat unresectable liver tumors and its acute toxicity has been well described. Subacute and long-term hepatic complications related to radioembolization however may be underreported in the literature. This retrospective study describes the incidence and sequelae of serious hepatic complications in patients who underwent radioembolization for unresectable liver tumors. METHODS: A retrospective review of clinical notes of patients who received radioembolization for unresectable liver tumors from 2001 to 2011 at two Australian institutions was performed to identify those who developed clinically significant hepatic complications. Relevant clinical data were obtained and analyzed to determine their incidence and sequelae. RESULTS: A total of 205 patients were identified, of whom 10 (4.9%) developed serious hepatic complications with 7 (3.4%) attributable to radioembolization-induced liver disease. None had preexisting underlying liver disease or progressive hepatic metastases at the time of developing hepatic complication. The median time to the onset of hepatic complications was 3.5 months (range 1-67 months); six patients had a complete resolution eventually, including one patient who subsequently underwent hepatic metastasectomy safely. Three patients died as a result of fulminant hepatic failure. CONCLUSION: Selective internal radiation therapy with radioembolization was associated with serious hepatic complications with an incidence of 4.9% and a mortality rate of 1.5% in 205 patients from two Australian institutions. The risk of serious hepatic toxicity therefore needs to be discussed when counseling patients regarding this potential treatment option.