Theodore F. Logan

Randomized Phase III Trial of High-Dose Interleukin-2 Versus Subcutaneous Interleukin-2 and Interferon in Patients With Metastatic Renal Cell Carcinoma

PURPOSEnThe Cytokine Working Group conducted a randomized phase III trial to determine the value of outpatient interleukin-2 (IL-2) and interferon alfa-2b (IFN) relative to high-dose (HD) IL-2 in patients with metastatic renal cell carcinoma.nnnPATIENTS AND METHODSnPatients were stratified for bone and liver metastases, primary tumor in place, and Eastern Cooperative Oncology Group performance status 0 or 1 and then randomly assigned to receive either IL-2 (5 MIU/m(2) subcutaneously every 8 hours for three doses on day 1, then daily 5 days/wk for 4 weeks) and IFN (5 MIU/m(2) subcutaneously three times per week for 4 weeks) every 6 weeks or HD IL-2 (600,000 U/kg/dose intravenously every 8 hours on days 1 through 5 and 15 to 19 [maximum 28 doses]) every 12 weeks.nnnRESULTSnOne hundred ninety-two patients were enrolled between April 1997 and July 2000. Toxicities were as anticipated for these regimens. The response rate was 23.2% (22 of 95 patients) for HD IL-2 versus 9.9% (nine of 91 patients) for IL-2/IFN (P = .018). Ten patients receiving HD IL-2 were progression-free at 3 years versus three patients receiving IL-2 and IFN (P = .082). The median response durations were 24 and 15 [corrected] months (P = .18) [corrected] and median survivals were 17.5 and 13 months (P = .24). For patients with bone or liver metastases (P = .001) or a primary tumor in place (P = .040), survival was superior with HD IL-2.nnnCONCLUSIONnThis randomized phase III trial provides additional evidence that HD IL-2 should remain the preferred therapy for selected patients with metastatic renal cell carcinoma.

Combination of vemurafenib and cobimetinib in patients with advanced BRAFV600-mutated melanoma: a phase 1b study

BACKGROUNDnAddition of a MEK inhibitor to a BRAF inhibitor enhances tumour growth inhibition, delays acquired resistance, and abrogates paradoxical activation of the MAPK pathway in preclinical models of BRAF-mutated melanoma. We assessed the safety and efficacy of combined BRAF inhibition with vemurafenib and MEK inhibition with cobimetinib in patients with advanced BRAF-mutated melanoma.nnnMETHODSnWe undertook a phase 1b study in patients with advanced BRAF(V600)-mutated melanoma. We included individuals who had either recently progressed on vemurafenib or never received a BRAF inhibitor. In the dose-escalation phase of our study, patients received vemurafenib 720 mg or 960 mg twice a day continuously and cobimetinib 60 mg, 80 mg, or 100 mg once a day for either 14 days on and 14 days off (14/14), 21 days on and 7 days off (21/7), or continuously (28/0). The primary endpoint was safety of the drug combination and to identify dose-limiting toxic effects and the maximum tolerated dose. Efficacy was a key secondary endpoint. All patients treated with vemurafenib and cobimetinib were included in safety and efficacy analyses (intention-to-treat). The study completed accrual and all analyses are final. This study is registered with ClinicalTrials.gov, number NCT01271803.nnnFINDINGSn129 patients were treated at ten dosing regimens combining vemurafenib and cobimetinib: 66 had recently progressed on vemurafenib and 63 had never received a BRAF inhibitor. Dose-limiting toxic effects arose in four patients. One patient on a schedule of vemurafenib 960 mg twice a day and cobimetinib 80 mg once a day 14/14 had grade 3 fatigue for more than 7 days; one patient on a schedule of vemurafenib 960 mg twice a day and cobimetinib 60 mg once a day 21/7 had a grade 3 prolongation of QTc; and two patients on a schedule of vemurafenib 960 mg twice a day and cobimetinib 60 mg 28/0 had dose-limiting toxic effects-one developed grade 3 stomatitis and fatigue and one developed arthralgia and myalgia. The maximum tolerated dose was established as vemurafenib 960 mg twice a day in combination with cobimetinib 60 mg 21/7. Across all dosing regimens, the most common adverse events were diarrhoea (83 patients, 64%), non-acneiform rash (77 patients, 60%), liver enzyme abnormalities (64 patients, 50%), fatigue (62 patients, 48%), nausea (58 patients, 45%), and photosensitivity (52 patients, 40%). Most adverse events were mild-to-moderate in severity. The most common grade 3 or 4 adverse events were cutaneous squamous-cell carcinoma (12 patients, 9%; all grade 3), raised amounts of alkaline phosphatase (11 patients, 9%]), and anaemia (nine patients, 7%). Confirmed objective responses were recorded in ten (15%) of 66 patients who had recently progressed on vemurafenib, with a median progression-free survival of 2·8 months (95% CI 2·6-3·4). Confirmed objective responses were noted in 55 (87%) of 63 patients who had never received a BRAF inhibitor, including six (10%) who had a complete response; median progression-free survival was 13·7 months (95% CI 10·1-17·5).nnnINTERPRETATIONnThe combination of vemurafenib and cobimetinib was safe and tolerable when administered at the respective maximum tolerated doses. The combination has promising antitumour activity and further clinical development is warranted in patients with advanced BRAF(V600)-mutated melanoma, particularly in those who have never received a BRAF inhibitor; confirmatory clinical testing is ongoing.nnnFUNDINGnF Hoffmann-La Roche/Genentech.

Transfusion-related acute lung injury following random donor platelet transfusion: a report of two cases.

Objectives: Transfusion‐related acute lung injury (TRALI) following random donor platelet (RDP) transfusion is a rare complication of transfusion without any well‐documented case reported in the English language literature. We describe 2 patients in whom TRALI occurred following RDP transfusion. Methods: Conventional clinical and laboratory methods. Results: Both patients developed acute shortness of breath 30–60 min after completion of RDP transfusion and required mechanical ventilatory support. Chest X‐ray (CXR) in both cases revealed bilateral pulmonary infiltrates. Patient 1 required vasopressors for hypotension. Right heart catheterization ruled out fluid overload. Patient 2 remained hemodynamically stable. Both patients improved rapidly with continued respiratory support and were extubated within 48 h. CXR at this time showed clearing of infiltrates. In both cases a granulocyte antibody was identified in the plasma of a platelet donor supporting the diagnosis of TRALI. Conclusions: In suspected cases of TRALI, HLA and granulocyte antibody testing is indicated for the recipients and for donors of implicated components. Implicated donors need not be excluded from the donor pool, but can be used for fractionated plasma and plasma‐free components.

Kidney cancer: the Cytokine Working Group experience (1986-2001): part II. Management of IL-2 toxicity and studies with other cytokines.

The Cytokine Working Group (CWG) was initially established in 1986 as the Extramural IL-2/LAK Working Group. With funding from the National Cancer Institute (NCI), the CWG was mandated to confirming data regarding the efficacy of the high-dose interleukin-2 (IL2)/lymphokine-activated killer cell (LAK cell) regimen piloted at the NCI in the treatment of renal cell cancer. Since those initial studies, the CWG has conducted a series of clinical trials, often with correlative immunologic investigations, to evaluate combination immunotherapy in attempts to enhance the efficacy of IL-2 or to reduce toxicity. Subsequently, the CWG conducted trials to demonstrate the activity of lower-dose outpatient combination cytokine regimens to help determine their role in the armamentarium of treatment for metastatic renal cell cancer. This has culminated in a phase III randomized trial comparing the activity of high-dose IL-2 with the activity of outpatient IL-2 plus interferon-α. The CWG also has honed the management of both high-dose IL-2 and outpatient IL-2 regimens to make these safer in the hands of experienced clinicians. In addition, the CWG has produced a series of carefully conducted clinical trials of new cytokines, again attempting to define their clinical efficacy as anticancer agents. These include studies of IL-4, IL-6, and IL-12. Currently, the CWG is conducting studies with new approaches to IL-2 therapy, as well as planning trials with new agents for treatment of renal cell cancer. This review describes these efforts conducted over the past 15 yr.

Safety profile and pharmacokinetic analyses of the anti-CTLA4 antibody tremelimumab administered as a one hour infusion

BackgroundCTLA4 blocking monoclonal antibodies provide a low frequency but durable tumor responses in patients with metastatic melanoma, which led to the regulatory approval of ipilimumab based on two randomized clinical trials with overall survival advantage. The similarly fully human anti-CTLA4 antibody tremelimumab had been developed in the clinic at a fixed rate infusion, resulting in very prolonged infusion times. A new formulation of tremelimumab allowed testing a shorter infusion time.MethodsA phase 1 multi-center study to establish the safety and tolerability of administering tremelimumab as a 1-hour infusion to patients with metastatic melanoma. Secondary endpoints included pharmacokinetic and clinical effects of tremelimumab.ResultsNo grade 3 or greater infusion-related adverse events or other adverse events preventing the administration of the full tremelimumab dose were noted in 44 treated patients. The overall side effect profile was consistent with prior experiences with anti-CTLA4 antibodies. Objective tumor responses were noted in 11% of evaluable patients with metastatic melanoma, which is also consistent with the prior experience with CTLA4 antagonistic antibodies.ConclusionsThis study did not identify any safety concerns when tremelimumab was administered as a 1-hour infusion. These data support further clinical testing of the 1-hour infusion of tremelimumab. (Clinical trial registration number NCT00585000).

Decreased tumor blood flow as measured by positron emission tomography in cancer patients treated with interleukin-1 and carboplatin on a phase I trial

AbstractnBackground. Positron emission tomography (PET) scanning can be used to measure blood flow. When interleukin-1α (IL-1) is given in a murine model, it induces acute hemorrhagic necrosis, tumor vascular injury and decreased tumor blood flow, and when given prior to carboplatin, there is enhanced antitumor activity compared to either agent alone.nMethods. In a phase I trial of IL-1 and carboplatin, eligible patients with metastatic disease to the lung had PET scanning performed with 15O water to assess tumor blood flow before and after IL-1 administration. Doses of IL-1 were 0.03, 0.06, 0.10, 0.15, 0.20 and 0.30xa0µg/kg given i.v. over 2xa0h. At 4xa0h after IL-1 initiation, carboplatin was administered as a 30-min i.v. infusion at a dose of 400xa0mg/m2. Treatment was repeated every 28xa0days. Other measured parameters included granulocyte kinetics, integrin expression on circulating WBC, and carboplatin pharmacokinetics. Of 16 patients, 11 (8 evaluable) underwent PET scanning before and at 2, 4 and 24xa0h after IL-1 initiation.nResults. Mean measured pretreatment tumor blood flow was 1.82xa0ml/min per g. At 2, 4 and 24xa0h it was 1.35, 1.67 and 1.62xa0ml/min per g respectively. Tumor blood flow was significantly decreased (P<0.008) at 2xa0h after IL-1 initiation. In four patients, liver blood flow was measured at the same time-points as tumor blood flow. Liver blood flow was discordant with the tumor blood flow measures, showing no statistically significant change. IL-1 also caused a decreased WBC at 2xa0h after initiation (n=14, P=0.025). In addition, polymorphonuclear leukocyte (PMN) and monocyte surface expression of CD11b at 2xa0h was increased when measured by mean fluorescence intensity flow cytometry (PMN P=0.0269, monocytes P=0.0420). No consistent effect of IL-1 on either carboplatin AUC or platelet nadir was demonstrated.nConclusions. We conclude that IL-1 has measurable effects on tumor blood flow and causes a significant decrease in blood flow as measured by PET scanning with 15O water at 2xa0h after initiation. This decrease is temporally associated with a significant leukopenia and an increased expression of the adhesion integrin CD11b on the circulating cell surface (PMN and monocytes). These results suggest that IL-1 causes decreased tumor blood flow in vivo in human cancer patients, an effect that was temporally related to cytokine-induced peripheral blood cellular changes. Furthermore, our findings suggest that PET scanning may be useful to assess the effect of a systemic antineoplastic agent on tumor blood flow in cancer patients.

A painful cutaneous nodule as the presentation of metastatic transitional cell carcinoma of the renal pelvis

We report a 43-year-old man with HIV who presented with a painful, vascular-appearing nodule as the initial manifestation of metastasis of a prior transitional cell carcinoma of the renal pelvis. The transitional cell carcinoma had been treated by nephroureterectomy 4 years before the appearance of the nodule. Histopathologic comparison of the nodule with the prior transitional cell carcinoma and immunoperoxidase staining with monoclonal antibodies confirmed that the nodule was a metastasis of the original transitional cell carcinoma. In general, metastasis of transitional cell carcinoma to the skin is quite uncommon. This case is the first reported episode of transitional cell carcinoma of the renal pelvis metastasizing to the skin in the form of a vascular-appearing nodule. The significance of this unusual metastasis occurring in a person with HIV is unknown.

Tolerability and anti-tumor activity of recombinant human IL-18 (rhIL-18) administered as five daily intravenous infusions in patients with solid tumors.

2553 Background: rhIL-18, a member of the Th-1 inducing family of cytokines, has demonstrated anti-tumor activity in a variety of preclinical tumor models.nnnMETHODSnIn an ongoing phase I dose-escalation study, rhIL-18 (SB485232) was administered as a 2 hour infusion daily for 5 consecutive days to patients (pts) with solid tumors. Doses ranging from 3-1000 μg/kg/day were planned. The objectives were to determine tolerability, define a biologically effective dose, and assess pharmacokinetics, immunogenicity, immunomodulatory and anti-tumor activity of rhIL-18. Pts with detectable anti-SB-485232 antibodies at screening were excluded.nnnRESULTSnTwenty-six pts {metastatic renal cell carcinoma (21), advanced melanoma (4), Hodgkins lymphoma (1)}were treated at dose levels up to1000 μg/kg/day . Two pts were withdrawn from the study: 1 pt at 10 μg/kg/day due to rapidly progressive disease and 1 pt at 100 μg/kg/day due to hypotension with bradycardia, a dose-limiting toxicity. This cohort was expanded to 6 pts with no further dose-limiting toxicities. Drug-related adverse event data are available for 25 pts: Grade (G) 1-2 fever (n=19), chills (n=14), rash (n=3) nausea/vomiting (n=8); G1 myalgia (n=3); G1-2 neutropenia (n=11), G1-3 lymphopenia (n=16), G1-2 thrombocytopenia (n=4), G1 elevated AST (n=4), G1-2 elevated ALT (n=5), G1 hypocalcemia (n=3), G1-2 hypoalbuminemia (n=12). Five pts developed antibodies to SB-485232. Increases in neopterin (24/25 pts), GM-CSF (25/25 pts), IL-18 BP (25/25 pts), sFas/L(22/25 pts), and INFγ (15/25 pts) were observed. Upregulation of FasL on NK, CD8+, and CD4+ cells as well as of CD69 on CD8+ cells was observed. Evidence of clinical activity was observed in two patients (metastatic melanoma and renal cell carcinoma) treated at 100 μg/kg/day.nnnCONCLUSIONSnrhIL-18 administered as a single cycle was well tolerated. Preliminary data demonstrate evidence of immunomodulatory and clinical activity. [Table: see text].

GRANULOCYTOPENIA IN CANCER PATIENTS TREATED IN A PHASE I TRIAL WITH RECOMBINANT HUMAN TUMOR NECROSIS FACTOR

We have examined the effect of recombinant human tumor necrosis factor (TNF) upon granulocyte kinetics in cancer patients in a phase I clinical trial. TNF was given to each patient intravenously over 2 h at varying doses. A marked drop in the total white blood cell count, absolute polymorphonuclear leukocyte (PMN) count, and absolute monocyte count occurred reproducibly at 30 min after TNF initiation. Also noted was a drop in the absolute lymphocyte and eosinophil counts, both of which reached their nadir at approximately 4 h. A marked increase in immature PMN leukocytes (bands) was noted be-ginning at 1 h. These changes were statistically significant. Statistically significant increases in hemoglobin and hematocrit occurred at the 30 min time point but subsequently decreased to approximately 90% of pretreatment baseline. Additionally, the platelet count decreased, reaching its nadir approximately 6 h after TNF initiation. In four serial studies in patients on the highest dose of TNF, the granulocyte adhesion protein CD11b was shown to increase on the surface of the PMN leukocytes by as early as 7–15 min after initiation of TNF infusion. In each of these, expression of CD11b antigen increased prior to the disappearance of PMN leukocytes from the peripheral circulation. A similar finding was obtained for monocytes. This work indicates that within 30 min of intravenous infusion of TNF, mature granulocytes and monocytes have left the peripheral circulation. This is followed by an apparent bone marrow response indicated by an outpouring of bands. The initial granulocyte and monocyte emigration from the peripheral circulation is preceded at highest-dose TNF by increased cell surface expression of CD11b for both cell types, suggesting a causal relationship between these temporally linked events.

Inflammatory cell infiltrate in a responding metastatic nodule after vaccine‐based immunotherapy

A patient with von Hippel Lindau disease, bilateral symmetric renal cell carcinoma and pulmonary metastases treated with immunotherapy is the subject of this study. A left kidney and tumour mass were removed and the tumour cells used to make an autologous tumour/bacille Calmette–Guérin (BCG) vaccine as part of the treatment protocol. The patients pulmonary nodules responded, but the remaining renal nodule subsequently grew. Samples of both tumours were obtained allowing for an internally controlled evaluation of the histological and immunohistologic differences between a responding and non‐responding tumour nodule after therapy. The immunotherapy protocol is designed to promote a T cell response to autologous tumour. Cellular infiltrates were demonstrated in both responding and non‐responding nodules compared with the pretreatment tumour specimen, but the responding nodule contained proportionately more T cells as well as markedly increased numbers of plasma cells and granulocytes. This suggested that several arms of the immune system may have been operative in the responding nodule.