Non-Small Cell Lung Cancer
Conditions
Keywords
RRM1, ERCC1, Customized Chemotherapy
Brief summary
This is a clinical research study to evaluate if chemotherapy in the experimental arm (E) results in a better outcome compared to patients in the standard of care arm (C). 2:1 randomization to experimental arm (E) or standard arm (C). In arm E, treatment of dual-agent chemotherapy will be selected based on RRM1 and ERCC1 expression at the protein level. In arm C, treatment of dual-agent chemotherapy will be gemcitabine/carboplatin, i.e., standard of care.
Detailed description
Before each cycle, blood tests, vital signs, interim medical history, and a physical exam will be performed. Patients will be carefully checked so that immediate intervention can be initiated should an adverse event (i.e. hypersensitivity) occur. The last treatment cycle according to the study will be cycle #6, or any earlier cycle. Certain tests will be done within 28 days after the last drug infusion. These include physical exam, vital signs, temperature, weight, adverse event evaluation, imaging studies, and blood work. The study doctor will see the participants every 6 to 8 weeks for at least 12 months after they start treatment. After that, the participants will be followed every 3 months for an additional 24 months.
Interventions
DRUGDocetaxel
GD Group: 40 mg/m\^2 on days 1 and 8, every 21 days DCb Group: 75 mg/m\^2 on day 1 DV Group: 50 mg/m\^2 on days 1 and 15, every 28 days
DRUGVinorelbine
DV Group: 35 mg/m\^2 on days 1 and 15
DRUGCarboplatin
GCb Group: Area under the curve (AUC) 5 on day 1, every 21 days DCb Group: AUC 6 on day 1, every 21 days Control Arm: Patients received up to 6 cycles, and no maintenance therapy was allowed.
DRUGGemcitabine
GCb Group: 1,250 mg/m\^2 on days 1 and 8 GD Group: 1,250 mg/m\^2 on days 1 and 8 Control Arm: Patients received up to 6 cycles, and no maintenance therapy was allowed.
Sponsors
Sanofi
H. Lee Moffitt Cancer Center and Research Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed Non-Small Cell Lung Cancer (NSCLC) of adenocarcinoma, squamous cell carcinoma, large cell carcinoma, or NSCLC not otherwise specified. Patients with suspected NSCLC may enroll prior to the diagnostic biopsy in order to obtain both the diagnostic and molecular analysis-required specimen during the same procedure. Must have blood work within 30 days prior to biopsy to eliminate any unnecessary biopsies on patients that do not qualify (screen failures) due to laboratory values that do not meet the inclusion/
Exclusion criteria
. If a patient has blood work obtained at an outside facility, this can be utilized for the preliminary assessment prior to biopsy, but final inclusion/exclusion values must be obtained within 14 days of start of treatment. * Willing to undergo biopsy to enable customization of chemotherapy * Stage IV or IIIB (malignant pleural effusion) NSCLC * Measurable or evaluable disease by Response Evaluation Criteria In Solid Tumors (RECIST) * Performance status 0 or 1 by Eastern Cooperative Oncology Group (ECOG) criteria * Adequate bone marrow function as evidenced by the following (assessed within 14 days of starting treatment): Absolute neutrophil count \>= 1,500/mm³, Platelet count \>= 100,000/mm³, Hemoglobin \>= 8.0 gm/dL * Prothrombin time (PT) and activated prothrombin time with thromboplastin and kaolin (APTT) within normal laboratory ranges * Serum creatinine \<= 1.5 x upper limit of normal (ULN) assessed within 14 days of starting treatment * Adequate liver function as evidenced by the following (assessed within 14 days of starting treatment): Total bilirubin must be within normal limits; aspartic transaminase (AST) and alanine transaminase (ALT) \<= 2.5 x ULN with a normal alkaline phosphatases; alkaline phosphatases \<= 4 x upper limit of normal with normal AST and ALT; patients with elevations of alk phos and AST and/or ALT will be excluded * Serum calcium \<= 1.1 x ULN * Signed informed consent document * Women of childbearing potential must have a negative pregnancy test. Men with partners in the childbearing age group and women of childbearing potential must use effective contraception while on treatment and for 6 months thereafter. * Previous surgery for NSCLC (more that 30 days before study entry) * Previous radiotherapy (RT) is allowed if: the time between completion of RT and initiation of chemotherapy is at least 7 days; the patient has fully recovered from all toxic effects; at least one target lesion or evaluable disease is outside the radiation field * Previous chemotherapy allowed if the last dose was administered equal to or greater than 12 months ago. This chemotherapy must have been given in an adjuvant or neoadjuvant mode prior to or after a complete surgical resection (R0 resection) for a NSCLC. * Patients with stable brain metastases will be allowed to enroll. Stable brain metastases being defined as no progression of brain metastases 28 days after conclusion of definitive treatment as documented by a computed tomography (CT) scan or magnetic resonance imaging (MRI) of the brain. Patients with incidentally discovered asymptomatic brain metastases may be enrolled and treated with chemotherapy without prior brain irradiation if deemed feasible by the treating physician.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | 6 months | PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. The data of first documented disease progression or death, as defined by Response Evaluation Criteria In Solid Tumors (RECIST), was recorded, and the time interval from randomization to that date was calculated for each patient and used to generate Kaplan-Meier survival estimates and to calculate the PFS at 6 months. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | 12 months | OS at 12 months, determined from the date of randomization. The time interval from randomization to the date of death was calculated for each patient and used to generate Kaplan-Meier survival estimates and to calculate the overall survival. |
| Response Rate (RR) | 6 months | Number of participants per response category. Response to treatment was determined according to Response Evaluation Criteria in Solid Tumors (RECIST). Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. |
Countries
Germany, Puerto Rico, United States
Participant flow
Recruitment details
Participants were registered onto the trial between May 8, 2007 and December 23, 2010. Study sites included Moffitt Cancer Center and 8 other institutions with locations in the United States, Puerto Rico and Germany.
Participants by arm
| Arm | Count |
|---|---|
| E. Dual Agent Chemotherapy Experimental Arm E.
Patients received treatment according to gene expression strata with four doublet regimens.
Low ERCC1 and Low RRM1 Group - Gemcitabine (G) and Carboplatin (Cb): GCb Group.
Low RRM1 and High ERCC1 Group - Gemcitabine (G) and Docetaxel (D): GD Group.
High RRM1 and Low ERCC1 Group - Docetaxel (D) and Carboplatin (Cb): DCb Group.
High ERCC1 and High RRM1 Group - Vinorelbine (V) and Docetaxel (D): DV Group. | 183 |
| C. Standard of Care Control Arm Control Arm C: Gemcitabine and Carboplatin (GCb).
All patients in arm C were treated with GCb regardless of gene expression levels. Patients received up to 6 cycles, and no maintenance therapy was allowed. | 92 |
| Total | 275 |
Baseline characteristics
| Characteristic | E. Dual Agent Chemotherapy | C. Standard of Care Control Arm | Total |
|---|---|---|---|
| Age, Continuous | 64.1 years | 62.3 years | 63.5 years |
| Region of Enrollment Germany | 24 participants | 16 participants | 40 participants |
| Region of Enrollment Puerto Rico | 3 participants | 1 participants | 4 participants |
| Region of Enrollment United States | 156 participants | 75 participants | 231 participants |
| Sex: Female, Male Female | 93 Participants | 49 Participants | 142 Participants |
| Sex: Female, Male Male | 90 Participants | 43 Participants | 133 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 57 / 64 | 24 / 26 | 34 / 37 | 54 / 56 | 86 / 92 |
| serious Total, serious adverse events | 21 / 64 | 12 / 26 | 16 / 37 | 20 / 56 | 32 / 92 |
Outcome results
Primary
Progression Free Survival (PFS)
PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. The data of first documented disease progression or death, as defined by Response Evaluation Criteria In Solid Tumors (RECIST), was recorded, and the time interval from randomization to that date was calculated for each patient and used to generate Kaplan-Meier survival estimates and to calculate the PFS at 6 months.
Time frame: 6 months
Population: All participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| E. Dual Agent Chemotherapy | Progression Free Survival (PFS) | 52 estimated percentage of participants |
| C. Standard of Care Control Arm | Progression Free Survival (PFS) | 56.5 estimated percentage of participants |
Secondary
Overall Survival (OS)
OS at 12 months, determined from the date of randomization. The time interval from randomization to the date of death was calculated for each patient and used to generate Kaplan-Meier survival estimates and to calculate the overall survival.
Time frame: 12 months
Population: All participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| E. Dual Agent Chemotherapy | Overall Survival (OS) | 46.1 estimated percentage of participants |
| C. Standard of Care Control Arm | Overall Survival (OS) | 46.6 estimated percentage of participants |
Secondary
Response Rate (RR)
Number of participants per response category. Response to treatment was determined according to Response Evaluation Criteria in Solid Tumors (RECIST). Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: 6 months
Population: All evaluable participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| E. Dual Agent Chemotherapy | Response Rate (RR) | Complete Response (CR) | 0 participants |
| E. Dual Agent Chemotherapy | Response Rate (RR) | Partial Response (PR) | 64 participants |
| C. Standard of Care Control Arm | Response Rate (RR) | Complete Response (CR) | 0 participants |
| C. Standard of Care Control Arm | Response Rate (RR) | Partial Response (PR) | 31 participants |