The primary objective of this study is to evaluate the hypothesis that cixutumumab given in combination with cisplatin and pemetrexed is superior to cisplatin and pemetrexed as first-line therapy for patients with advanced nonsquamous non-small cell…
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Brief title
Condition
- Miscellaneous and site unspecified neoplasms benign
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Criteria for Evaluation:
Efficacy:
• Progression-free survival is defined as the time from the date of
randomization until the date of objectively determined date of progression as
defined by RECIST v. 1.1, or death from any cause, whichever is first.
• Overall response rate is defined as the proportion of all randomized patients
with measurable disease with the best response of partial response (PR) or
complete response (CR) according to RECIST v. 1.1 in a given arm.
• Time to progressive disease is defined as the elapsed time in days from the
date of randomization to the first date of objective progression of disease.
• Change in tumor size is defined as the change from baseline measurement to
the measurement at the end of cycle 2, as assessed using radiographic imaging.
If CTS is observed after 2 cycles, the log ratio of tumor size at Visit 2 to
tumor size at baseline will be calculated for each patient.
• Overall survival is defined as the time from the date of randomization to the
date of death from any cause.
• Duration of response is defined as the time measurement criteria are first
met for confirmed PR/CR (whichever is first recorded) until the first date that
the criteria for progressive disease is met or death.
Safety:
• Adverse event (AE) grading (Common Terminology Criteria for Adverse Events
[CTCAE] v. 4.0)
• Laboratory investigations (hematology/clinical chemistry)
• Concomitant medications assessments
• Physical examinations/vital signs
Health Outcomes:
• For each of the LCSS items: Time to worsening symptoms is defined as the
time from the date of randomization to the first date of worsening.
Pharmacokinetic/Pharmacodynamic:
• Standard pharmacokinetic analysis (Arm B only)
• Pharmacodynamic markers: including, but not limited to, free IGF-I, total
IGF-I, IGFBP-3
Translational research:
• Immunohistochemical analysis: including, but not limited to, IGF-IR
mutational analysis: including, but not limited to, p53, KRAS, and EGFR Gene
copy number: IGF-IR Gene promoter methylation (IGFBP 3)
• Single nucleotide polymorphisms (SNPs) in IGF system-related genes
• Gene expression analysis: including, but not limited to, IGFBP-3, IGF-IR,
insulin receptor, IGF-I, and IGF-II.
Secondary outcome
Not applicable
Background summary
Study Rationale
Over half of all patients with non-small cell lung cancer (NSCLC) present with
advanced stage disease. Chemotherapy, usually employing platinum-based agents
(cisplatin, carboplatin) in combination with other agents (including but not
limited to paclitaxel, docetaxel, vinorelbine, and gemcitabine), is the initial
choice for patients with advanced NSCLC; combination chemotherapy of this type
may extend expected median overall survival (OS) to 10.3 months. Though
improvements in survival have been observed in recent years as a result of the
availability of newer agents, these improvements have been modest and the
mainstay of treatment in most countries continues to be platinum-based
chemotherapy doublets. Further exploration of the efficacy of both current and
new treatments is needed in patients with advanced NSCLC.
The combination of pemetrexed with cisplatin has shown promising activity as a
first-line treatment for advanced NSCLC. In a Phase 3 study,
pemetrexed/cisplatin showed similar efficacy to gemcitabine/cisplatin as
first-line treatment of advanced NSCLC, with an overall survival (OS) of 10.3
months in both arms. In a preplanned subset analysis, pemetrexed/cisplatin
showed statistically superior OS over gemcitabine/cisplatin in patients with
NSCLC other than predominantly squamous cell histology (11.0 months versus 10.1
months). Based on the results of this study, pemetrexed in combination with
cisplatin is now a standard of care for the first-line treatment of patients
with locally advanced or metastatic NSCLC with nonsquamous histology.
The upregulation or overexpression of the insulin-like growth factor-I receptor
(IGF-IR), often in concert with overexpression of IGF ligands, can lead to the
potentiation of receptor signaling and the enhancement of cell proliferation
and survival. As a result, targeting and inhibiting the IGF-IR pathway is an
attractive anticancer therapeutic strategy. Cixutumumab possesses high
affinity for IGF-IR and acts as an antagonist of IGF-I and IGF-II ligand
binding and signaling. In NSCLC xenograft models, cixutumumab in combination
with pemetrexed plus cisplatin demonstrated a statistically significant
increase in antitumor activity compared to pemetrexed plus cisplatin alone.
Thus, the addition of cixutumumab to the combination therapy of cisplatin and
pemetrexed for the treatment of patients with advanced NSCLC may result in
improved patient outcomes.
Study objective
The primary objective of this study is to evaluate the hypothesis that
cixutumumab given in combination with cisplatin and pemetrexed is superior to
cisplatin and pemetrexed as first-line therapy for patients with advanced
nonsquamous non-small cell lung carcinoma (NSCLC) as measured by
progression-free survival (PFS).
The secondary objectives of the study are:
• to evaluate the hypothesis that cixutumumab given in combination with
cisplatin and pemetrexed is superior to cisplatin and pemetrexed, as measured
by the following:
o Objective response rate (ORR)
o Time to progressive disease (TTPD)
o Change in tumor size (CTS)
o Overall survival (OS)
o Duration of response
• to evaluate the safety profile of cixutumumab given in combination with
cisplatin and pemetrexed
• to assess the pharmacokinetic profile of cixutumumab (Arm B only)
• to assess the immunogenicity of cixutumumab (Arm B only)
• to assess the pharmacodynamic profile of cixutumumab, including:
o potential surrogates of cixutumumab pharmacodynamic activity including, but
not limited to, free IGF-I, total IGF-I, IGFBP-3
• to evaluate the time to worsening symptoms (TWS) as measured by Lung Cancer
Symptom Scale (LCSS) scores (patient scale only)
Additional exploratory biomarker objectives of the study are as follows:
• Characterize single-nucleotide polymorphisms, DNA mutations, RNA analysis,
and copy number variation in IGF-IR and other pathway-related genes, relevant
to the safety, efficacy, and mechanism of action of cixutumumab in germ-line
DNA and tissue; and,
• Investigate the association between biomarkers and clinical outcome
Study design
Study Design: This is an open-label, multicenter, randomized, Phase 2 trial in
which patients with advanced
nonsquamous NSCLC receive cisplatin and pemetrexed with or without cixutumumab
as first-line
therapy. Approximately 220 patients will be randomized in a 1:1 ratio to 1 of 2
treatment arms as follows:
* Arm A - cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 every 21 days
* Arm B - cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 plus cixutumumab 20 mg/kg
every 21 days.
Randomization will be stratified by gender, smoking status, and Eastern
Cooperative Oncology Group (ECOG)
performance status. After discontinuation of cisplatin treatment (maximum of 4
to 6 cycles), maintenance therapy
may continue as follows:
* Arm A - pemetrexed 500 mg/m2 every 21 days
* Arm B - pemetrexed 500 mg/m2 plus cixutumumab 20 mg/kg every 21 days.
Intervention
Approximately 220 patients will be randomized in a 1:1 ratio to 1 of 2
treatment arms as follows:
• Arm A - cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 every 21 days
• Arm B - cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 plus cixutumumab 20 mg/kg
every 21 days.
Randomization will be stratified by gender, smoking status, and Eastern
Cooperative Oncology Group (ECOG) performance status. After discontinuation of
cisplatin treatment (maximum of 4 cycles), maintenance therapy may continue as
follows:
• Arm A - pemetrexed 500 mg/m2 every 21 days
Arm B - pemetrexed 500 mg/m2 plus cixutumumab 20 mg/kg every 21 days.
Study burden and risks
A detailed overview of side effects of cixutumumab is included in appendix 2 of
the patient infiormation sheet. Very common side effects are:
a lack of energy and high blood glucose levels. Common side effects are amongst
others: diabetes, blurrred vision, nausea, fever, weight decrease, liver
function abnormalities, loss of apetite, shortness of breat, dizzyness and
headache.
Furthermore patients could find discomfort during the study procedures:
bloodtests, MRI-scan and CT-scan. We refer to appendix 2 of the patient
information sheet for a more detailed overview of the possible discomforts of
these procedures.
Lilly Corporate Center 1
Indianapolis Indiana 46285
US
Lilly Corporate Center 1
Indianapolis Indiana 46285
US
Listed location countries
Age
Inclusion criteria
Patients will be at least 18 years old with histologically or cytologically confirmed Stage IV (AJCC edition 7) nonsquamous NSCLC. Patients may have either measurable or nonmeasurable disease based on the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v. 1.1), and must have ECOG status of 0 or 1 as well as adequate hematologic, coagulation, and organ function. Patients must have fasting serum glucose < 125 mg/dL (6.9 mmol/L), and hemoglobin A1C <= 6%.
Exclusion criteria
Patients must not have an uncontrolled intercurrent illness, leptomeningeal disease, or active infection requiring parenteral therapy.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-024014-60-NL |
| ClinicalTrials.gov | NCT01232452 |
| CCMO | NL34880.028.11 |