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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)


Phase 1/Phase 2
18 Years
N/A
Not Enrolling
Both
Recurrent Non-small Cell Lung Cancer, Stage IIIA Non-small Cell Lung Cancer, Stage IIIB Non-small Cell Lung Cancer, Stage IV Non-small Cell Lung Cancer

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Trial Information

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)


PRIMARY OBJECTIVES:

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.

SECONDARY OBJECTIVES:

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
erlotinib.

III. To determine the difference in overall response rate (ORR) between the two treatment
arms.

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
erlotinib therapy.

TERTIARY OBJECTIVES:

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
arms.

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
unacceptable toxicity.

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.


Inclusion Criteria:



- Histologically or cytologically confirmed non-small cell lung cancer (NSCLC)

- Stage IIIA, IIIB, or IV disease

- Mixed histology permitted provided small-cell elements are not present

- Measurable disease, defined as ≥ 1unidimensionally measurable lesion ≥ 20 mm by
conventional techniques or ≥ 10 mm by spiral CT scan

- Must have failed ≥ 1 platinum-containing chemotherapy regimen

- CNS metastases are eligible if received prior radiotherapy to site(s) of CNS
metastatic disease, or have had definitive resection of CNS metastatic disease and
have no overt evidence of neurological deficits, are not requiring anti-epileptics,
remain asymptomatic, and have been off steroids for ≥ 8 weeks

- ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%

- Life expectancy > 3 months

- Leukocytes ≥ 3,000/mm³

- Absolute neutrophil count ≥ 1,500/mm³

- Hemoglobin ≥ 9 g/dL

- Platelets ≥ 100,000/mm³

- Total bilirubin normal

- AST and ALT ≤ 2.5 times upper limit of normal (ULN)

- Creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 60 mL/min

- Fasting serum glucose < 120 mg/dL OR normal

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to anti-IGF-1R recombinant monoclonal antibody IMC-A122 or
erlotinib hydrochloride

- No poorly controlled diabetes mellitus

- Patients with a history of diabetes mellitus are eligible, provided their blood
glucose is within normal range at screening and they are on a stable dietary or
therapeutic regimen for this condition

- No uncontrolled intercurrent illness including, but not limited to, any of the
following:

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia

- Psychiatric illness or social situation that would limit compliance with study
requirements

- No inability to take oral medications or, in the investigator's opinion,
gastrointestinal conditions or abnormalities likely to influence the absorption of
oral medications

- No prior or concurrent exposure to other EGFR or IGFR inhibitors

- Recovered from all prior therapy with acute effects resolved to ≤ grade 1

- At least 28 days since prior anticancer or investigational agent (within predicted 5
half-lives of agent)

- More than 4 weeks since prior radiotherapy to target lesions and documented disease
progression at these sites

- More than 2 weeks since prior radiotherapy to non-target lesions

- More than 4 months since prior major surgery or hormonal therapy (other than
replacement)

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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)

Outcome Description:

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.

Outcome Time Frame:

From time of first dose up to 28 days

Safety Issue:

Yes

Principal Investigator

David Camidge

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Colorado at Denver Health Sciences Center

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2009-00286

NCT ID:

NCT00778167

Start Date:

October 2008

Completion Date:

Related Keywords:

  • Recurrent Non-Small Cell Lung Cancer
  • Stage IIIA Non-Small Cell Lung Cancer
  • Stage IIIB Non-Small Cell Lung Cancer
  • Stage IV Non-Small Cell Lung Cancer
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms

Name

Location

Roswell Park Cancer InstituteBuffalo, New York  14263
University of ColoradoDenver, Colorado  80217