The combination of insulin-like growth factor receptor 1 (IGF1R) antibody
cixutumumab and mitotane as a first-line therapy for patients with
recurrent/metastatic adrenocortical carcinoma: a multi-institutional
NCI-sponsored trial.
Author(s): Lerario AM(1), Worden FP, Ramm CA, Hesseltine EA, Stadler WM, Else T, Shah MH,
Agamah E, Rao K, Hammer GD.
Affiliation(s): Author information:
(1)Division of Metabolism, Endocrinology & Diabetes, Medical School, University
of Michigan, 109 Zina Pitcher Place, 1528 BSRB, Ann Arbor, MI, 48109, USA.
Publication date & source: 2014, Horm Cancer. , 5(4):232-9
Adrenocortical carcinoma (ACC) is an aggressive malignancy, which lacks an
effective systemic treatment. Abnormal activation of insulin-like growth factor
receptor 1 (IGF1R) has been frequently observed. Preclinical studies demonstrated
that pharmacological inhibition of IGF1R signaling in ACC has antiproliferative
effects. A previous phase I trial with an IGF1R inhibitor has demonstrated
biological activity against ACC. The objective of this study is to assess the
efficacy of the combination of the IGF1R inhibitor cixutumumab (IMC-A12) in
association with mitotane as a first-line treatment for advanced/metastatic ACC.
We conducted a multicenter, randomized double-arm phase II trial in patients with
irresectable recurrent/metastatic ACC. The original protocol included two
treatment groups: IMC-A12 + mitotane and mitotane as a single agent, after an
initial single-arm phase for safety evaluation with IMC-A12 + mitotane. IMC-A12
was dosed at 10 mg/kg intravenously every 2 weeks. The starting dose for mitotane
was 2 g daily, subsequently adjusted according to serum levels/symptoms. The
primary endpoint was progression-free survival (PFS) according to RECIST
(Response Evaluation Criteria in Solid Tumors). This study was terminated before
the randomization phase due to slow accrual and limited efficacy. Twenty patients
(13 males, 7 females) with a median age of 50.2 years (range 21.9-79.6) were
enrolled for the single-arm phase. Therapeutic effects were observed in 8/20
patients, including one partial response and seven stable diseases. The median
PFS was 6 weeks (range 2.66-48). Toxic events included two grade 4 (hyperglycemia
and hyponatremia) and one grade 5 (multiorgan failure). Although the regimen
demonstrated activity in some patients, the relatively low therapeutic efficacy
precluded further studies with this combination of drugs.
Erratum in
Horm Cancer. 2014 Dec;5(6):424. Hasseltine, Elizabeth A [corrected to Hesseltine,
Elizabeth A].
|