A Phase I/Randomized Phase II Study of the Anti-IGF-1R Monoclonal Antibody IMC-A12 in Combination With Erlotinib Compared With Erlotinib Alone in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC)
I. To determine a tolerable dose of IMC-A12 (cixutumumab) in combination with erlotinib
(erlotinib hydrochloride) in the target NSCLC population to be administered in the
randomized phase II study section.
II. To determine the difference in PFS between the anti-IGF-1R monoclonal antibody IMC-A12
in combination with erlotinib compared to erlotinib alone in the target NSCLC population.
I. To evaluate the safety, tolerability, and adverse event profile of IMC-A12 in combination
with erlotinib in patients with advanced non-small cell lung cancer.
II. To describe preliminary evidence of clinical activity of the combination of IMC-A12 and
III. To determine the difference in overall response rate (ORR) between the two treatment
IV. To determine the response duration in patients who achieve an objective response in
either study arm.
V. To describe the response rate, time to disease progression, and response duration in the
population who cross over to the combination arm after disease progression with single agent
I. To explore the prognostic/predictive significance of the immunohistochemical, mutational,
and cytogenetic profiles from archived tumor tissue of key elements of the EGFR, IGF-1R and
other relevant signaling pathways in relationship to clinical benefit from treated
individuals in both Part A and Part B sections of the study.
II. To explore the prognostic/predictive significance of serum circulating markers (ligands
and binding proteins) and serum proteomic profiles pre-treatment and at progression in both
Part A and Part B sections of the study.
III. To explore the impact of SNPs in germline and tumor derived DNA on toxicity and
anti-cancer activity within both Part A and Part B sections of the study.
IV. To explore the impact of SNPs in germline DNA on erlotinib pharmacokinetics within both
Part A and Part B sections of the study.
OUTLINE: This is a multicenter study that includes a single-arm safety evaluation phase I
followed by a randomized phase II study.
Initially, patients are enrolled in the safety evaluation phase. If ≤ 2 of 10 patients
experience a dose-limiting toxicity, then the study may proceed to the randomized phase.
Safety evaluation phase I: Patients receive cixutumumab intravenously (IV) over 1 hour on
days 1, 8, 15, and 22 and erlotinib hydrochloride orally (PO) once daily on days 1-28.
Courses repeat every 28 days until disease progression or unacceptable toxicity.
Randomized phase II: Patients are stratified according to performance status, history of
smoking (never vs ex vs current), stage of disease (IIIA vs IIIB without malignant effusion
vs IIIB with malignant effusion vs IV), EGFR mutation (present vs absent vs not known), and
disease histology (squamous vs non-squamous). Patients are randomized to 1 of 2 treatment
ARM 1: Patients receive erlotinib hydrochloride PO once daily on days 1-21. Patients with
documented disease progression may cross over and receive treatment on arm II.
ARM II: Patients receive erlotinib hydrochloride PO as in arm I and cixutumumab IV over 1
hour on days 1, 8, and 15. Patients receive treatment in both arms as in the safety
evaluation portion. Courses repeat every 21 days in the absence of disease progression or
Archived tissue and blood samples are collected periodically for pharmacokinetic analysis of
erlotinib hydrochloride; pharmacogenomic analysis of EGRF, IGF1R, and CYP3A4/5 mutations;
IHC and FISH analysis of IGF1R, EGFR, cMET, ras, Akt1, and EMT; proteomic analysis of serum
ligand/binding proteins (i.e., IGF1, IGF2, IGFBPs, EGF, HRG, and TGF-α) using
matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF);
mutational status analysis of EGFR and related pathway proteins; and RT-PCR analysis.
After completion of study therapy, patients are followed for 4 weeks.
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Safety and Tolerability of IMC-A12 in Combination With Erlotinib Hydrochloride as Graded by Common Terminology Criteria for Adverse Event (CTCAE) Version 3.0 (DLTs During Cycle One)
Patients were evaluable for cohort dose escalation/de-escalation decision making either if they experienced DLTs in cycle 1 or if they had completed 24 of the planned 28 days (85%) dosing of erlotinib and three of the four planned days of weekly dosing of cixutumumab (75%) in cycle 1 in cohorts 1 and 2 in the absence of DLTs. In cohort 3, patients were evaluable for tolerability if they had completed 18 days (85%) dosing of erlotinib and had received the planned day 1 dose of cixutumumab.
From time of first dose up to 28 days
University of Colorado at Denver Health Sciences Center
United States: Food and Drug Administration
|Roswell Park Cancer Institute||Buffalo, New York 14263|
|University of Colorado||Denver, Colorado 80217|