Safety, tolerability, and pharmacokinetics of the anti-IGF-1R monoclonal antibody figitumumab in patients with refractory adrenocortical carcinoma

Abstract

Purpose: Insulin-like growth factor 1 receptor signaling through upregulation of the stimulatory ligand IGF-II has been implicated in the pathogenesis of adrenocortical carcinoma. As there is a paucity of effective therapies, this dose expansion cohort of a phase 1 study was undertaken to determine the safety, tolerability, pharmacokinetics, and effects on endocrine markers of figitumumab in patients with adrenocortical carcinoma.

Methods: Figitumumab was administered on day 1 of each 21-day cycle at the maximal feasible dose (20 mg/kg) to a cohort of patients with metastatic, refractory adrenocortical carcinoma. Serum glucose, insulin, and growth hormone were measured pre-study, at cycle 4 and study end. Pharmacokinetic evaluation was performed during cycles 1 and 4.

Results: Fourteen patients with adrenocortical carcinoma received 50 cycles of figitumumab at the 20 mg/kg. Treatment-related toxicities were generally mild and included hyperglycemia, nausea, fatigue, and anorexia. Single episodes of grade 4 hyperuricemia, proteinuria, and elevated gamma-glutamyltransferase were observed. Pharmacokinetics of figitumumab was comparable to patients with solid tumors other than adrenocortical carcinoma. Treatment with figitumumab increased serum insulin and growth hormone levels. Eight of 14 patients (57%) had stable disease.

Conclusions: The side effect profile and pharmacokinetics of figitumumab were similar in patients with adrenocortical carcinoma in comparison to patients with other solid tumors. While hyperglycemia was the most common adverse event, no clear patterns predicting severity were observed. The majority of patients receiving protocol therapy with single agent figitumumab experienced stability of disease, warranting further evaluation.

Fig. 1

Treatment-related toxicities. Adverse events were graded as per National Cancer Institute Common Toxicity Criteria (version 3.0). Abbreviations: ALT alanine aminotransferase, AST aspartate aminotransferase, GGT gamma-glutamyltransferase IV intravenous catheter

Fig. 2

Pharmacokinetic prolife of figitumumab in patients with adrenocortical carcinoma versus other solid tumors. a Mean (± standard deviation) plasma concentration–time profiles of figitumumab in patients with adrenocortical carcinoma (ACC) and non-ACC solid tumors during treatment cycle 1 (C1) and cycle 4 (C4). b, c Comparison of cycle 1 exposure parameters (C1hr and AUC_0-Day22) of figitumumab at 20 mg/kg between patients with ACC and patients with other solid tumors. The lower and upper boundaries of the box represent the 25th and 75th percentiles; whiskers above and below the box represent the 90th and 10th percentiles. The solid and dotted lines within the box indicate the median and mean values. Solid dots indicate outlying measurements

Fig. 3

Endocrine laboratory findings. Fasting serum determinations for patients prior to cycles 1 (C1D1) and 4 (C4D1), and at the end of study (EOS) for glucose (a), insulin (b), and human growth hormone (hGH) (c). The lower and upper boundaries of the box represent the 25th and 75th percentiles; whiskers above and below the box represent the 90th and 10th percentiles. The solid lines within the box indicate the median values. Solid dots indicate outlying measurements. d A comprehensive distribution of the glucose values collected for all patients while on study with Common Terminology Criteria for Adverse Events grading ranges indicated. Individual patients are noted by various symbols and 4-digit values. The x-axis denotes the cycle (c) and day number within each cycle (d) from which values are reported. EOS end of study

Fig. 4

a Best response on study. The graph represents the % of tumor increase between consecutive scans taken every 2 cycles or highest percentage of tumor decrease on study when compared to baseline. The total number of cycles of figitumumab by individual patients is noted. ^† Patients with evaluable disease only on treatment for six cycles. b Chest radiograph for patient # 1020 before and after therapy with figitumumab. The timing of the figures are indicated by the annotated dates, which represent prior to (left) and after (right) four cycles of therapy with figitumumab. The arrows indicate a right upper lobe lung lesion (open single arrow), multiple right lower lobe lesions (three arrows) and a lingular lesion (closed single arrow) that were initially identified by computed tomography scanning and followed during the course of treatment by chest radiograph. After four cycles of therapy, these lesions were notably smaller including a nearly unidentifiable lingular lesion