S0720: Adjuvant Therapy Based on Gene Expression in Stage IA and IB Non-Small Cell Lung Cancer

Phase II ERCC1 and RRM1-Based Adjuvant Therapy Trial in Patients With Stage I Non-Small Cell Lung Cancer (NSCLC)

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00792701

Enrollment

Registered

2008-11-18

Start date

2008-11-30

Completion date

2016-04-30

Last updated

2020-03-06

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Lung Cancer

Keywords

stage I non-small cell lung cancer

Brief summary

RATIONALE: Drugs used in chemotherapy, such as gemcitabine and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving chemotherapy drugs after surgery may kill any tumor cells that remain after surgery. Sometimes, after surgery, the tumor may not need more treatment until it progresses. In this case, observation may be sufficient. PURPOSE: This phase II trial is studying how well giving gemcitabine together with cisplatin works in treating patients with stage I non-small cell lung cancer that was removed by surgery.

Detailed description

OBJECTIVES: Primary * To assess the feasibility of assigning adjuvant treatment based on tumoral RRM1 and ERCC1 gene expression in patients with complete surgical resection of stage IA (≥ 2 cm) or IB non-small cell lung cancer. Secondary * To estimate the collective 2-year disease-free survival of these patients. * To assess the frequency and severity of toxicities resulting from the administration of cisplatin and gemcitabine hydrochloride. * To explore, preliminarily, the relationship between RNA and protein expression of RRM1 and ERCC1, and the relationship between RRM1 and ERCC1 expression in the formalin-fixed and paraffin-embedded tumor specimens, and to generate results on in situ protein expression and other assays for genes involved in drug efficacy. * To assess the analytical performance of the biomarker assay. OUTLINE: This is a multicenter study. Patients are assigned to 1 of 2 treatment arms based on RRM1 and ERCC1 gene expression. * Arm I (RRM1 ≥ 40 and ERCC1 ≥ 65): Patients undergo active monitoring after surgery with disease assessments at 8, 16, and 24 weeks. * Arm II (RRM1 \< 40 and/or ERCC1 \< 65): Beginning within 84 days after surgery, patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and cisplatin IV over 30-90 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Tumor samples acquired at the time of surgery are analyzed by immunofluorescence-based automated quantitative analysis for in situ expression of RRM1 and ERCC1. If available, additional samples are assessed using RT-PCR and real-time quantitative PCR for RRM1 and ERCC1 expression levels; polymorphism analysis for RRM1 and ERCC1 expression at the protein level; and tissue microarray analysis of genes associated with DNA synthesis, damage repair, and drug efficacy. After completion of study therapy, patients are followed every 6 months for up to 2 years.

Interventions

DRUGcisplatin

Given IV

DRUGgemcitabine hydrochloride

Given IV

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 120 Years

Healthy volunteers

Inclusion criteria

DISEASE CHARACTERISTICS: * Histologically confirmed non-small cell lung cancer * Stage IA (longest tumor diameter 2-3 cm) or stage IB disease * Must have undergone preoperative CT scan of the chest (including the entire liver and adrenals) with IV contrast AND a whole body PET scan or a combined PET/CT scan with no evidence of N1, N2, N3, or M1 disease within 42 days prior to surgery * A whole body PET scan or a combined PET/CT must be performed within 84 days * Any finding on PET scan that clinically suggests N1, N2, N3, or M1 disease must have been cleared by further evaluation, including, but not limited to, any of the following: * Ultrasonography, X-ray radiology, magnetic resonance imaging, or nuclear medicine imaging * Completely resected (R0) disease by lobectomy, bilobectomy, or pneumonectomy performed by open thoracotomy or video-assisted thoracoscopic surgery within the past 35 days * Completely excised primary lesion with negative gross and microscopic margins * At least two mediastinal lymph node stations sampled * Must have tumor tissue available from the surgical resection specimen AND agree to have treatment assignment determined by a gene expression analysis performed on that tissue PATIENT CHARACTERISTICS: * Zubrod performance status 0-1 * ANC ≥ 1,500/mm³ * Platelet count ≥ 100,000/mm³ * Hemoglobin ≥ 10 mg/dL * Serum bilirubin ≤ 1.5 times upper limit of normal (ULN) * AST and ALT ≤ 1.5 times ULN * Serum creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 60 mL/min * Not pregnant or nursing * Fertile patients must use effective contraception * No other prior malignancy except for the following: * Adequately treated basal cell or squamous cell skin cancer * In situ cervical cancer * Adequately treated stage I-II cancer from which the patient is currently in complete remission * Any other cancer from which the patient has been disease-free for 5 years * Willing to provide prior smoking history PRIOR CONCURRENT THERAPY: * See Disease Characteristics * No prior systemic chemotherapy or biologic therapy for lung cancer * No prior thoracic radiation therapy (RT) (including RT to the chest wall) * No other concurrent investigational agents, chemotherapeutic agents, RT, or hormonal therapy * Steroids administered for antiemesis, adrenal failure, or septic shock OR hormones administered for non-disease-related conditions (e.g., insulin for diabetes) allowed

Design outcomes

Primary

Measure	Time frame	Description
Feasibility of Pharmacogenomics-based Treatment Assignment in the Cooperative Group Setting	From time of registration to 84 days after surgical resection.	Feasibility will be assessed both by accrual rate and the percentage of patients successfully assigned to adjuvant chemotherapy or active monitoring.

Secondary

Measure	Time frame	Description
Two-year Disease-free Survival	From time of registration to maximum of 2 years	—
Frequency and Severity of Toxicities as Assessed by NCI CTCAE v3.0	From time of registration to maximum of 2 years	Patients in the active monitoring arm were not followed for adverse events.
Relationship Between RRM1 and ERCC1 Expression in the Formalin-fixed and Paraffin-embedded Tumor Specimens.	From time of registration to maximum of 2 years	RRM1 and ERCC1 protein levels are expressed as a simple score with no units.

Other

Measure	Time frame
Generation of Results on in Situ Protein Expression and Other Assays for Genes Involved in Drug Efficacy	From time of registration to maximum of 2 years
Relationship Between RNA and Protein Expression of RRM1 and ERCC1	From time of registration to maximum of 2 years
Analytical Performance of the Biomarker Assay	From time of registration to maximum of 2 years

Countries

United States

Participant flow

Participants by arm

Arm	Count
Active Monitoring Patients undergo active monitoring after surgery with disease assessments at 8, 16, and 24 weeks. Active surveillance: Patients undergo active monitoring	18
Gemcitabine Hydrochloride and Cisplatin Beginning within 84 days after surgery, patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and cisplatin IV over 30-90 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Cisplatin: Given IV Gemcitabine Hydrochloride: Given IV	63
Total	81

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	0	22
Overall Study	Ineligible	1	3
Overall Study	Not protocol specified	17	0
Overall Study	Withdrawal by Subject	1	19

Baseline characteristics

Characteristic	Gemcitabine Hydrochloride and Cisplatin	Total	Active Monitoring
Age, Continuous	63.3 years	64 years	68.8 years
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	0 Participants	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	58 Participants	74 Participants	16 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	5 Participants	7 Participants	2 Participants
Histology Adenocarcinoma	44 Participants	52 Participants	8 Participants
Histology Bronchioloalveolar	0 Participants	1 Participants	1 Participants
Histology Large Cell	1 Participants	1 Participants	0 Participants
Histology Other	1 Participants	2 Participants	1 Participants
Histology Squamous	17 Participants	25 Participants	8 Participants
Performance Status 0	31 Participants	44 Participants	13 Participants
Performance Status 1	32 Participants	37 Participants	5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	2 Participants	3 Participants	1 Participants
Race (NIH/OMB) Black or African American	8 Participants	8 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants	2 Participants	1 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	2 Participants	2 Participants
Race (NIH/OMB) White	52 Participants	66 Participants	14 Participants
Sex: Female, Male Female	37 Participants	44 Participants	7 Participants
Sex: Female, Male Male	26 Participants	37 Participants	11 Participants
Smoking History Current	26 Participants	33 Participants	7 Participants
Smoking History Former	30 Participants	39 Participants	9 Participants
Smoking History Never	7 Participants	9 Participants	2 Participants
Stage IA	22 Participants	25 Participants	3 Participants
Stage IB	41 Participants	56 Participants	15 Participants
Weight Loss Last 6 Months 10-20%	3 Participants	4 Participants	1 Participants
Weight Loss Last 6 Months >20%	1 Participants	1 Participants	0 Participants
Weight Loss Last 6 Months <5%	49 Participants	64 Participants	15 Participants
Weight Loss Last 6 Months 5-<10%	7 Participants	9 Participants	2 Participants
Weight Loss Last 6 Months Unknown	3 Participants	3 Participants	0 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	41 / 43
serious Total, serious adverse events	2 / 43

Outcome results

Primary

Feasibility of Pharmacogenomics-based Treatment Assignment in the Cooperative Group Setting

Feasibility will be assessed both by accrual rate and the percentage of patients successfully assigned to adjuvant chemotherapy or active monitoring.

Time frame: From time of registration to 84 days after surgical resection.

Population: Percentage of patients successfully assigned to adjuvant chemotherapy or active monitoring.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
All Eligible Patients	Feasibility of Pharmacogenomics-based Treatment Assignment in the Cooperative Group Setting	71 Participants

Secondary