The primary objective of this study is to estimate the best objective response rates (ORR; complete response [CR] + partial response [PR]) associated with gemcitabine-cisplatin plus necitumumab in chemotherapy-naïve patients with Stage IV squamous…
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Brief title
Condition
- Respiratory and mediastinal neoplasms malignant and unspecified
- Respiratory tract neoplasms
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective of this study is to estimate ORR. The denominator of ORR
should count each patient enrolled who receives any amount of study drug
(necitumumab, gemcitabine, and/or cisplatin), who has a complete radiographic
assessment at baseline, and who has at least 1 complete radiographic assessment
postbaseline. Among patients counted in the denominator, the numerator counts
those with a best tumor response of PR or CR.
Efficacy: For these definitions, the date of study enrollment is the date of
first dose of study drug (necitumumab, gemcitabine, and/or cisplatin).
* Tumor response will be assessed according to RECIST 1.1 every 6 weeks (±3
days) by the investigator with confirmatory assessment for patients with an
objective assessment of PR or CR obtained at the next routine scheduled imaging
time point (that is, after 6 weeks ±3 days).
Secondary outcome
* OS is defined as the time from the date of study enrollment until the date of
death.
* PFS is defined as the time from the date of study enrollment until the date
of radiographically documented PD or death due to any cause, whichever comes
first.
* DCR is defined as best tumor response of PR, CR, or SD.
* CTS is defined as the maximum percent improvement in the sum of target
lesions.
Safety: The safety of necitumumab in combination with gemcitabine-cisplatin
chemotherapy will be assessed by reported SAEs, AEs, vital sign measurements,
electrocardiogram results, and laboratory analyses. The National Cancer
Institute * Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version
4.0, will serve as the reference document for choosing appropriate terminology
for, and grading the severity of, all AEs and other symptoms. This collection
is in addition to the verbatim text used to describe the AE. In addition to
collecting the AE verbatim, the CTCAE term, and the CTCAE severity grade, AE
verbatim text will also be mapped by the Sponsor or designee to corresponding
terminology within the Medical Dictionary for Regulatory Activities (MedDRA*)
dictionary.
Pharmacokinetics: Blood for determination of serum concentrations of
necitumumab will be drawn from patients at the following time points: prior to
the first infusion on Day 1 of Cycles 1, 2, 3, 4, 5, and 6 and Day 8 of Cycle
1; at the end of infusion on Day 1 of Cycles 1, 3, and 5; at the 30-day safety
follow-up visit; and in the setting of any hypersensitivity/infusion-related
reaction.
Immunogenicity: Analysis of antibodies against necitumumab (immunogenicity)
will be performed based on blood drawn from patients at the following time
points: prior to the initial necitumumab infusion on Day 1 of Cycles 1, 2, 4,
and 6; at the 30-day safety follow-up visit; and in the setting of any
hypersensitivity/infusion-related reaction.
Background summary
Necitumumab (LY3012211; IMC-11F8) is a recombinant human monoclonal antibody
(Mab) of the immunoglobin G, subclass 1, that blocks the ligand binding site of
the epidermal growth factor receptor (EGFR). The EGFR is a member of the human
EGFR family of tyrosine kinases. EGFR activation leads to stimulation of
tyrosine kinase-dependent signal transduction pathways that can contribute to
neoplastic transformation and tumor growth. Inhibition of the EGFR pathway in
cells can result in disruption of cell cycle progression and mitosis, and
blocks the inhibitory effect on apoptosis. Decreased angiogenesis may also
occur as a result of EGFR inhibition through effects on angiogenic factor
production.
Necitumumab has shown in vivo antitumor activity against a variety of human
xenograft tumors, including non-small cell lung cancer (NSCLC). Phase 1 and
Phase 2 studies investigating necitumumab drug product have provided
information regarding safety and tolerability at clinically relevant doses,
with preliminary evidence of clinical efficacy in a variety of human cancers.
In clinical settings, the feasibility of administering EGFR-directed Mabs in
combination with a standard platinum-based doublet in the first-line treatment
of advanced NSCLC has been demonstrated in several randomized trials. Two
randomized Phase 3 trials were conducted with cetuximab in combination with
either vinorelbine-cisplatin (FLEX; Pirker et al. 2009) or carboplatin-taxane
(BMS-099; Lynch et al. 2010) as the chemotherapy backbone. The addition of
cetuximab to both regimens resulted in a statistically significant improvement
in the best overall response rate (complete response [CR] + partial response
[PR]), but not in progression-free survival (PFS) in both studies. In FLEX, a
significant prolongation of overall survival (OS) with statistical significance
was observed. The analyses of both studies by histologic subtypes showed, that
for cetuximab-containing regimens, a more pronounced trend in improvement of OS
in squamous cell carcinoma (hazard ratio [HR] 0.80 [FLEX], HR 0.87 [BMS-099])
than in adenocarcinoma (HR 0.94 [FLEX], HR 0.89 [BMS-099]) when compared to
chemotherapy alone only.
According to current National Comprehensive Cancer Network guidelines, the
combination chemotherapy of gemcitabine-cisplatin is a preferred regimen for
patients with squamous cell NSCLC.
This single-arm, Phase 2 study is being conducted to evaluate objective
response rate, OS, PFS, disease control rate (DCR), and change in tumor size
(CTS) associated with the study treatment of gemcitabine-cisplatin plus
necitumumab in chemotherapy-naïve patients with Stage IV squamous cell NSCLC.
Study objective
The primary objective of this study is to estimate the best objective response
rates (ORR; complete response [CR] + partial response [PR]) associated with
gemcitabine-cisplatin plus necitumumab in chemotherapy-naïve patients with
Stage IV squamous cell NSCLC.
The secondary objectives of this study are:
* to evaluate OS, PFS, DCR, and CTS;
* to evaluate the safety profile of necitumumab in combination with
gemcitabine-cisplatin chemotherapy;
* to characterize pharmacokinetics of necitumumab; and
* to determine the immunogenicity of necitumumab.
Study design
Study Design: This is a single-arm, multicenter, open-label Phase 2 study of
60 patients with Stage IV squamous NSCLC (American Joint Committee on Cancer
[AJCC] Staging Manual, 7th edition) who have received no prior chemotherapy for
NSCLC. All patients enrolled will receive first-line therapy with necitumumab
plus chemotherapy consisting of gemcitabine and cisplatin.
A treatment cycle will be defined as 3 weeks.
Study therapy, consisting of necitumumab plus gemcitabine-cisplatin, will
continue for a maximum of 6 cycles (or until there is radiographic
documentation of progressive disease [PD], toxicity requiring cessation,
protocol noncompliance or withdrawal of consent).
Patients with a response of stable disease (SD) or better after completion of 6
cycles of study therapy will continue to receive necitumumab until radiographic
documentation of PD, toxicity requiring cessation, protocol noncompliance, or
withdrawal of consent. No additional anticancer treatment is allowed until
radiographic documentation of PD.
If toxicity leads to an interruption of some or all components of study
therapy, those components may be held for a maximum of 6 weeks following Day 1
of the most recent treatment cycle. If a patient cannot be treated with a
given study agent for more than 6 weeks following Day 1 of the most recent
cycle, that agent will be permanently discontinued. Patients who discontinue
study treatment for any reason other than PD will continue to undergo
radiographic tumor assessments every 6 weeks (± 3 days) until PD.
All patients will be followed up for survival and any subsequent anticancer
treatment approximately every 3 months until death or until study completion,
defined as when the clinical trial database has been locked and the Sponsor has
determined that the available data are sufficient for key analyses.
Baseline radiographic assessment of disease will be performed within 21 days
prior to first dose of study therapy. Patients will undergo radiographic
assessment (computed tomography or magnetic resonance imaging) of disease
status every 6 weeks (±3 days) after the first dose of study therapy,
regardless of treatment delays, until there is radiographic documentation of PD
as defined by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1).
Adverse event (AE) information will be collected until at least 30 days after
the decision is made to discontinue study treatment and until the event has
resolved or is explained. A 30-day safety follow-up visit will be held at
least 30 days (+0-7 days) after the decision to discontinue. After the 30-day
safety follow-up visit, only new and ongoing serious adverse events (SAEs)
deemed related to study treatment will be collected.
Intervention
Necitumumab DP is a sterile, preservative-free, intravenous (I.V.) infusion
supplied in 50-mL single-use vials containing 16 mg/mL (800 mg/50 mL) of
product, and administered at a dose of 800 mg on Days 1 and 8 of each 3-week
cycle.
Study burden and risks
There are risks associated with the use of the study drug Necitumumab, and with
Gemzar and Cisplatin. Appendix 3 of the patient information leaflet provides an
overview. Risks associated with the study procedures are as follows: X-rays, CT
scans (reaction to contrast), MRI (metal objects in the body; claustrophobia),
complications associated with punctions for blood tests. These risks are
explained in appendix 3 of the patient information leaflet.
Necitumumab (IMC-11F8), Gemzar and Cisplatin and the combination of the study
drugs and the study procedures may have other unknown risks.
Lilly Corporate Center N/A
Indianapolis IN46285
NL
Lilly Corporate Center N/A
Indianapolis IN46285
NL
Listed location countries
Age
Inclusion criteria
Histologically or cytologically confirmed squamous NSCLC;
Stage IV disease at time of study entry based on AJCC 7th edition;
Measurable disease at time of study entry as defined by RECIST 1.1;
The patient has an Eastern Cooperative Oncology Group performance status score of 0-1, the patient has an estimated life expectancy of at least 12 weeks and in the judgment of the investigator, will be able to complete at least 2 cycles of treatment.
Exclusion criteria
Nonsquamous NSCLC;
Prior anticancer therapy with monoclonal antibodies, signal transduction inhibitors, or any therapies targeting the EGFR, vascular endothelial growth factor (VEGF), or VEGF receptor;
Previous chemotherapy for NSCLC;
Major surgery or received any investigational therapy in the 4 weeks prior to study enrollment;
Chest irradiation within 12 weeks prior to study enrollment (except palliative irradiation of bone lesions,
which is allowed);
Brain metastases that are symptomatic or require ongoing treatment with steroids or anticonvulsants (Patients who have completed radiotherapy for brain metastases at least 4 weeks prior to receiving treatment, who are now nonsymptomatic and have not required treatment with steroids or anticonvulsants during the 2 weeks prior to receiving treatment, are eligible.)
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 | EUCTR2012-003201-96-NL |
| CCMO | NL42363.060.12 |