Assessment of nivolumab benefit-risk profile of a 240-mg flat dose relative to a 3-mg/kg dosing regimen in patients with advanced tumors.

BACKGROUND: Nivolumab 3 mg/kg every 2 weeks (Q2W) has shown benefit versus the standard of care in melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). However, flat dosing is expected to shorten preparation time and improve ease of administration. With knowledge of nivolumab safety, efficacy, and pharmacokinetics across a wide dose range in body weight (BW) dosing, assessment of the benefit-risk profile of a 240-mg flat dose relative to the approved 3-mg/kg dose was approached by quantitative clinical pharmacology. PATIENTS AND METHODS: A flat dose of 240 mg was selected based on its equivalence to the 3-mg/kg dose at the median BW of ∼80 kg in patients in the nivolumab program. The benefit-risk profile of nivolumab 240 mg was evaluated by comparing exposures at 3 mg/kg Q2W and 240 mg Q2W across BW and tumor types; clinical safety at 3 mg/kg Q2W by BW and exposure quartiles in melanoma, NSCLC, and RCC; and safety and efficacy at 240 mg Q2W relative to 3 mg/kg Q2W in melanoma, NSCLC, and RCC. RESULTS: The median nivolumab exposure and its distribution at 240 mg Q2W were similar to 3 mg/kg Q2W in the simulated population. Safety analyses did not demonstrate a clinically meaningful relationship between BW or nivolumab exposure quartiles and frequency or severity of adverse events. The predicted safety and efficacy were similar across nivolumab exposure ranges achieved with 3 mg/kg Q2W or 240 mg Q2W flat dose. CONCLUSION: Based on population pharmacokinetic modeling, established flat exposure-response relationships for efficacy and safety, and clinical safety, the benefit-risk profile of nivolumab 240 mg Q2W was comparable to 3 mg/kg Q2W. The quantitative clinical pharmacology approach provided evidence for regulatory decision-making on dose modification, obviating the need for an independent clinical study.

Survival follow-up and ipilimumab retreatment of patients with advanced melanoma who received ipilimumab in prior phase II studies.

BACKGROUND: This report provides a survival update at a follow-up of >5 years (5.5-6 years) for patients with advanced melanoma who previously received ipilimumab in phase II clinical trials. Safety and efficacy data following ipilimumab retreatment are also reported. PATIENTS AND METHODS: Patients who previously received ipilimumab 0.3, 3, or 10 mg/kg in one of six phase II trials (CA184-004, CA184-007, CA184-008, CA184-022, MDX010-08, and MDX010-15) were eligible to enroll in the companion study, CA184-025. Upon enrollment, patients initially received ipilimumab retreatment, extended maintenance therapy, or were followed for survival only. Overall survival (OS) rates were evaluated in patients from studies CA184-004, CA184-007, CA184-008, and CA184-022. Safety and best overall response during ipilimumab retreatment at 10 mg/kg were assessed in study CA184-025. RESULTS: Five-year OS rates for previously treated patients who received ipilimumab induction at 0.3, 3, or 10 mg/kg were 12.3%, 12.3%-16.5%, and 15.5%-28.4%, respectively. Five-year OS rates for treatment-naive patients who received ipilimumab induction at 3 or 10 mg/kg were 26.8% and 21.4%-49.5%, respectively. Little to no change in OS was observed from year 5 up to year 6. The objective response rate among retreated patients was 23%. Grade 3/4 immune-related adverse events occurred in 25%, 5.9%, and 13.2% of retreated patients who initially received ipilimumab 0.3, 3, and 10 mg/kg, with the most common being observed in the skin (4.2%, 2.9%, 3.8%) and gastrointestinal tract (12.5%, 2.9%, 3.8%), respectively. CONCLUSIONS: At a follow-up of 5-6 years, ipilimumab continues to demonstrate durable, long-term survival in a proportion of patients with advanced melanoma. In some patients, ipilimumab retreatment can re-establish disease control with a safety profile that is comparable with that observed during ipilimumab induction. Further studies are needed to determine the contribution of ipilimumab retreatment to OS. CLINICALTRIALSGOV: NCT00162123.

Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: results from an open-label, multicenter phase I/II study.

BACKGROUND: This phase I/II study in patients with metastatic castration-resistant prostate cancer (mCRPC) explored ipilimumab as monotherapy and in combination with radiotherapy, based on the preclinical evidence of synergistic antitumor activity between anti-CTLA-4 antibody and radiotherapy. PATIENTS AND METHODS: In dose escalation, 33 patients (≥6/cohort) received ipilimumab every 3 weeks × 4 doses at 3, 5, or 10 mg/kg or at 3 or 10 mg/kg + radiotherapy (8 Gy/lesion). The 10-mg/kg cohorts were expanded to 50 patients (ipilimumab monotherapy, 16; ipilimumab + radiotherapy, 34). Evaluations included adverse events (AEs), prostate-specific antigen (PSA) decline, and tumor response. RESULTS: Common immune-related AEs (irAEs) among the 50 patients receiving 10 mg/kg ± radiotherapy were diarrhea (54%), colitis (22%), rash (32%), and pruritus (20%); grade 3/4 irAEs included colitis (16%) and hepatitis (10%). One treatment-related death (5 mg/kg group) occurred. Among patients receiving 10 mg/kg ± radiotherapy, eight had PSA declines of ≥50% (duration: 3-13+ months), one had complete response (duration: 11.3+ months), and six had stable disease (duration: 2.8-6.1 months). CONCLUSIONS: In mCRPC patients, ipilimumab 10 mg/kg ± radiotherapy suggested clinical antitumor activity with disease control and manageable AEs. Two phase III trials in mCRPC patients evaluating ipilimumab 10 mg/kg ± radiotherapy are ongoing. ClinicalTrials.gov identifier: NCT00323882.

Nuclear magnetic resonance-determined lipoprotein subclass profile in the DCCT/EDIC cohort: associations with carotid intima-media thickness.

AIMS: To relate nuclear magnetic resonance lipoprotein subclass profiles (NMR-LSP) and other lipoprotein-related factors with carotid intima-media thickness (IMT) in Type 1 diabetes. METHODS: Lipoprotein-related factors were determined in sera (obtained in 1997-1999) from 428 female [age 39 +/- 7 years (mean +/- SD)] and 540 male (age 40 +/- 7 years) Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) participants. NMR quantifies chylomicrons, three very low-density lipoprotein (VLDL) subclasses, intermediate density lipoprotein (IDL), three low-density lipoprotein (LDL) subclasses, two high-density lipoprotein (HDL) subclasses, mean VLDL, LDL and HDL size, and LDL particle concentration. Conventional lipids, ApoA1, ApoB and Lp(a) and in vitro LDL oxidizibility were also measured. IMT was determined (in 1994-1995) using high-resolution B-mode ultrasound. Relationships between IMT and lipoproteins were analysed by multiple linear regression, controlling for age, diabetes-related factors, and cardiovascular disease (CVD) risk factors. RESULTS: IMT associations with lipoproteins were stronger for the internal than the common carotid artery, predominantly involving LDL. Internal carotid IMT was positively (P < 0.05) associated with NMR-based LDL subclasses and particle concentration, and with conventional LDL-cholesterol and ApoB in both genders. Common carotid IMT was associated, in men only, with large VLDL, IDL, conventional LDL cholesterol and ApoB. CONCLUSIONS: NMR-LSP reveals significant associations with carotid IMT in Type 1 diabetic patients, even 4 years after IMT measurement. NMR-LSP may aid early identification of high-risk diabetic patients and facilitate monitoring of interventions. Longer DCCT/EDIC cohort follow-up will yield CVD events and IMT progression, permitting more accurate assessment of pre-morbid lipoprotein profiles as determinants of cardiovascular risk in Type 1 diabetes.

Historical cohort study of US man-made vitreous fiber production workers: IV. Quantitative exposure-response analysis of the nested case-control study of respiratory system cancer.

As part of the 1992 update of an historical cohort study of 32,110 workers employed for at least 1 year in any of 10 US fiberglass manufacturing plants, a nested case-control study was done in which data on tobacco smoking were obtained for 631 male case subjects with respiratory system cancer (RSC) and 570 control subjects matched on age and year of birth. In this more extensive analysis of the nested case-control data, we provide a detailed assessment of the most prominent findings from the initial report. We expand the scope of the analysis to consider quantitative measures of exposure to respirable fibers (RFib), formaldehyde (FOR), and silica (Sil) and consider these and other exposures together in the same model. We investigate the functional form of possible exposure-response relationships between RSC risk, RFib, and FOR. In addition, we address the statistical issues of collinearity, effect modification, and potential confounding by coexposures. All analyses are adjusted for smoking. Neither measure of exposure to RFib (average intensity of exposure or cumulative exposure) was statistically significantly associated with RSC risk in any of the hundreds of fractional polynomial models considered. This more extensive analysis has substantiated our initial finding of no apparent exposure-response relationship between RSC risk and either cumulative or average intensity of exposure to RFib at the levels experienced by these workers. This study provides some evidence of increased RSC risk among workers at the higher observed levels of average intensity of exposure to FOR and/or Sil. No positive associations were identified between RSC risk and any of the other exposures considered in this case-control study.