In advanced cancers, transforming growth factor-beta (TGFβ) promotes tumor growth and metastases and suppresses host antitumor immunity. GC1008 is a human anti-TGFβ monoclonal antibody that ...neutralizes all isoforms of TGFβ. Here, the safety and activity of GC1008 was evaluated in patients with advanced malignant melanoma and renal cell carcinoma.
In this multi-center phase I trial, cohorts of patients with previously treated malignant melanoma or renal cell carcinoma received intravenous GC1008 at 0.1, 0.3, 1, 3, 10, or 15 mg/kg on days 0, 28, 42, and 56. Patients achieving at least stable disease were eligible to receive Extended Treatment consisting of 4 doses of GC1008 every 2 weeks for up to 2 additional courses. Pharmacokinetic and exploratory biomarker assessments were performed.
Twenty-nine patients, 28 with malignant melanoma and 1 with renal cell carcinoma, were enrolled and treated, 22 in the dose-escalation part and 7 in a safety cohort expansion. No dose-limiting toxicity was observed, and the maximum dose, 15 mg/kg, was determined to be safe. The development of reversible cutaneous keratoacanthomas/squamous-cell carcinomas (4 patients) and hyperkeratosis was the major adverse event observed. One malignant melanoma patient achieved a partial response, and six had stable disease with a median progression-free survival of 24 weeks for these 7 patients (range, 16.4-44.4 weeks).
GC1008 had no dose-limiting toxicity up to 15 mg/kg. In patients with advanced malignant melanoma and renal cell carcinoma, multiple doses of GC1008 demonstrated acceptable safety and preliminary evidence of antitumor activity, warranting further studies of single agent and combination treatments.
Clinicaltrials.gov NCT00356460.
Kaposi sarcoma (KS) is a multifocal, vascular lesion of low-grade malignant potential that presents most frequently in mucocutaneous sites. KS also commonly involves lymph nodes and visceral organs. ...This article deals with the manifestation of KS in unusual anatomic regions. Unusual locations of KS involvement include the musculoskeletal system, central and peripheral nervous system, larynx, eye, major salivary glands, endocrine organs, heart, thoracic duct, urinary system and breast. The development of KS within wounds and blood clots is also presented. KS in these atypical sites may prove difficult to diagnose, resulting in patient mismanagement. Theories to explain the rarity and development of KS in these unusual sites are discussed.
Since the advent of HAART, patients with HIV infection have seen a significant improvement in their morbidity, mortality, and life expectancy. The incidence of AIDS-defining illnesses, including ...AIDS-defining malignancies, has been on the decline. However, deaths due to non-AIDS-defining illnesses have been on the rise. These so-called non-AIDS-defining cancers (NADCs) include cancers of the lung, liver, kidney, anus, head and neck, and skin, as well as Hodgkin's lymphoma. It is poorly understood why this higher rate of NADCs is occurring. The key challenge facing oncologists is how to administer chemotherapy effectively and safely to patients on antiretroviral therapy. The challenge to clinicians caring for HIV-infected patients is to develop and implement effective means to screen, treat, and prevent NADCs in the future. This review presents data on the epidemiology and etiology of NADCs, as well as ongoing research into this evolving aspect of the HIV epidemic.
Summary
This trial was conducted to determine the dose‐limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the first in class NEDD8‐activating enzyme (NAE) inhibitor, pevonedistat, and to ...investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Pevonedistat was administered via a 60‐min intravenous infusion on days 1, 3 and 5 (schedule A, n = 27), or days 1, 4, 8 and 11 (schedule B, n = 26) every 21‐days. Dose escalation proceeded using a standard ‘3 + 3’ design. Responses were assessed according to published guidelines. The MTD for schedules A and B were 59 and 83 mg/m2, respectively. On schedule A, hepatotoxicity was dose limiting. Multi‐organ failure (MOF) was dose limiting on schedule B. The overall complete (CR) and partial (PR) response rate in patients treated at or below the MTD was 17% (4/23, 2 CRs, 2 PRs) for schedule A and 10% (2/19, 2 PRs) for schedule B. Pevonedistat plasma concentrations peaked after infusion followed by elimination in a biphasic pattern. Pharmacodynamic studies of biological correlates of NAE inhibition demonstrated target‐specific activity of pevonedistat. In conclusion, administration of the first‐in‐class agent, pevonedistat, was feasible in patients with MDS and AML and modest clinical activity was observed.
Combined PARP and immune checkpoint inhibition has yielded encouraging results in ovarian cancer, but predictive biomarkers are lacking. We performed immunogenomic profiling and highly multiplexed ...single-cell imaging on tumor samples from patients enrolled in a Phase I/II trial of niraparib and pembrolizumab in ovarian cancer (NCT02657889). We identify two determinants of response; mutational signature 3 reflecting defective homologous recombination DNA repair, and positive immune score as a surrogate of interferon-primed exhausted CD8 + T-cells in the tumor microenvironment. Presence of one or both features associates with an improved outcome while concurrent absence yields no responses. Single-cell spatial analysis reveals prominent interactions of exhausted CD8 + T-cells and PD-L1 + macrophages and PD-L1 + tumor cells as mechanistic determinants of response. Furthermore, spatial analysis of two extreme responders shows differential clustering of exhausted CD8 + T-cells with PD-L1 + macrophages in the first, and exhausted CD8 + T-cells with cancer cells harboring genomic PD-L1 and PD-L2 amplification in the second.
BackgroundWe sought to determine the prevalence of JC virus (JCV) in bone marrow samples from human immunodeficiency virus (HIV)–positive and HIV-negative patients and to determine whether bone ...marrow is a site of latency and neurotropic transformation of JCV, the agent of progressive multifocal leukoencephalopathy (PML) MethodsWe collected bone marrow aspirates, archival bone marrow samples, and blood and urine samples from 75 HIV-negative and 47 HIV-positive patients without PML as well as bone marrow and urine or kidney samples from 8 HIV-negative and 15 HIV-positive patients with PML. Samples were tested for JCV DNA by quantitative polymerase chain reaction and for JCV protein expression by immunohistochemical analysis. JCV regulatory regions (RRs) were characterized by sequencing ResultsJCV DNA was detected in bone marrow samples from 10 (13%) of 75 and 22 (47%) of 47 of the HIV-negative and HIV-positive patients without PML, respectively, compared with 3 (38%) of 8 and 4 (27%) of 15 of the HIV-negative and HIV-positive patients with PML. JCV DNA (range, 2–1081 copies/μg of cellular DNA) was detected in multiple leukocyte subpopulations of blood and bone marrow samples. JCV large T antigen, but not VP1 capsid protein, was expressed in bone marrow plasma cells. Bone marrow JCV RR sequences were similar to those usually found in the brains of patients with PML ConclusionsBone marrow is an important reservoir and a possible site of neurotropic transformation for JCV
Evaluate the safety, pharmacokinetic profile, pharmacodynamic effects, and antitumor activity of the first-in-class investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat ...(TAK-924/MLN4924) in patients with relapsed/refractory lymphoma or multiple myeloma.
Patients with relapsed/refractory myeloma (n = 17) or lymphoma (n = 27) received intravenous pevonedistat 25 to 147 mg/m(2) on days 1, 2, 8, 9 (schedule A; n = 27) or 100 to 261 mg/m(2) on days 1, 4, 8, 11 (schedule B; n = 17) of 21-day cycles.
Maximum tolerated doses were 110 mg/m(2) (schedule A) and 196 mg/m(2) (schedule B). Dose-limiting toxicities included febrile neutropenia, transaminase elevations, muscle cramps (schedule A), and thrombocytopenia (schedule B). Common adverse events included fatigue and nausea. Common grade ≥3 events were anemia (19%; schedule A), and neutropenia and pneumonia (12%; schedule B). Clinically significant myelosuppression was uncommon. There were no treatment-related deaths. Pevonedistat pharmacokinetics exhibited a biphasic disposition phase and approximate dose-proportional increases in systemic exposure. Consistent with the short mean elimination half-life of approximately 8.5 hours, little-to-no drug accumulation in plasma was seen after multiple dosing. Pharmacodynamic evidence of NAE inhibition included increased skin levels of CDT-1 and NRF-2 (substrates of NAE-dependent ubiquitin ligases), and increased NRF-2-regulated gene transcript levels in whole blood. Pevonedistat-NEDD8 adduct was detected in bone marrow aspirates, indicating pevonedistat target engagement in the bone marrow compartment. Three lymphoma patients had partial responses; 30 patients achieved stable disease.
Pevonedistat demonstrated anticipated pharmacodynamic effects in the clinical setting, a tolerable safety profile, and some preliminary evidence that may be suggestive of the potential for activity in relapsed/refractory lymphoma.
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