Non Small Cell Lung Cancer, BRCA1 Mutation
Conditions
Keywords
Lung Cancer, Chemotherapy, Personalized medicine
Brief summary
Primary objective: · Progression free survival. Secondary objectives: * Assess Overall survival of both treatment groups. * Assess Tumor response rate using RECIST criteria * Assess Toxicity profile of patients enrolled in the study. * Exploratory evaluation of potential genetic markers of response or resistance to chemotherapy.
Detailed description
Study population: Patients with advanced non-small-cell lung cancer who have not received treatment for the disease at this stage and who have a good performance status (ECOG 0-1) and measurable disease (at least one target lesion according to RECIST criteria). Duration of treatment: Six chemotherapy cycles will be given. The duration of every cycle will be 21 days. If the treatment is beneficial, it may be prolonged to a total of 8 cycles at the discretion of the investigator. Calendar and planned finalization date: The approximate duration of the study is 3 years of recruitment followed by 1 year of follow-up.
Interventions
Docetaxel 75 mg/m2 and cisplatin 75 mg/m2, both on day 1, every 21 days. Total number of cycles: 6
Gemcitabine 1250 mg/m2, days 1 and 8, and Cisplatin 75 mg/m2, day 1. 21-day cycles. Total number of cycles: 6
Docetaxel 75 mg/m2 and Cisplatin 75 mg/m2, both administered on day 1, every 21 days. Total number of cycles: 6
DRUGDocetaxel
Docetaxel 75 mg/m2, day 1. 21-day cycles. Total number of cycles: 6
Sponsors
Spanish Lung Cancer Group
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
1. Patients age 18 years or more. 2. Histologically confirmed diagnosis of non-small-cell lung carcinoma. 3. Only patients with advanced disease defined as stage IV or IIIB with or without pleural effusion will be included. In the event of IIIB disease without pleural effusion those patients, who for some reason (respiratory disease, large radiation volume...) may not be candidates to have chemotherapy and radiotherapy treatment and may only be treated with chemotherapy, will be considered. 4. Tumor specimen available (according to the criterion of the specimen-processing laboratory) for the analysis of RAP80 and BRCA1 expression in mRNA. 5. A measurable lesion, as defined by RECIST criteria. 6. Karnofsky score 80% or more (ECOG \< 2). 7. No previous treatment with chemotherapy or other agents for disseminated disease. Chemotherapy is allowed if the patient's initial diagnosis is limited disease and the patient has received adjuvant or neoadjuvant treatment, as long as a minimum of 6 months has passed since the end of the adjuvant and/or neo-adjuvant chemotherapy. 8. Patients with cerebral disease may be included without any time limitations after holocranial irradiation or complementary antiedema treatment, as long as there is correct control of the clinical symptoms arising from the brain disease or is symptomatic. 9. Patients with the following hematologic values: ANC ≥ 1.5 x 109/L Hb ≥ 10 g/dl Platelets ≥ 100 x 109/L 10. Patients with the following biochemical values: Bilirubin ≤ 1.5 mg/dL AST and ALT \< 1.5 upper limit of normality Creatinine clearance ≥ 60 ml/min. 11. Patients of childbearing age of either sex must use effective contraceptive methods (barrier methods or other birth control methods) before entering the study and while participating in the study. 12. Patients should sign an informed consent form before inclusion in the study that specifies that the clinical trial treatment entails consent for the analysis of biological specimens of tumor and blood. 13. Patients must be available for clinical follow-up.
Exclusion criteria
1. Previous chemotherapy treatment, except the supposition reflected in inclusion criterion 7. 2. Patients diagnosed of another neoplasm, with the exception of cervical carcinoma in situ, treated squamous cell carcinomas or superficial bladder tumors (Ta and TIS), or other malignant tumors that have received curative treatment within the last 5 years before inclusion in the study. 3. Patients with serious active bacterial or fungal infective processes from a clinical vantage point (= grade 2 of NCI-CTC, Version 3). 4. Patients who have received an investigational medicinal product in the 21 days before inclusion in the study. 5. Patients with HIV infection, HCV infection, coronary artery disease or uncontrolled arrhythmia, uncontrolled cerebrovascular disease, or other clinical conditions that, in the judgment of the investigator, contraindicate the patient's participation in the study. 6. Patients who are pregnant or breastfeeding. Women of childbearing age must have a negative pregnancy test performed within 7 days before the onset of treatment. 7. Substance abuse and clinical, psychological or social conditions that can undermine the validity of the informed consent or protocol compliance. 8. Patients who present any contraindication or suspected allergy to the products under investigation in the study 9. Impossibility to comply with chemotherapy treatment due to cultural or geographic circumstances. 10. Significant weight loss (= 10% of body weight) in the 6 weeks before inclusion in the study. 11. Any condition that is unstable or could endanger the patient's safety and/or the patient's compliance with the study. 12. Contraindication for steroid use.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | From the day of start of treatment until first documented progression or death due to any cause,up to 18 months. | Defined as the length of time from the start of treatment to the date of the first documented progression of disease. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From the date of start of the treatment until death or end of follow up, up to 18 months. | Defined as the length of time from the start of the treatment that patients diagnosed with the disease are still alive. |
Countries
Spain
Participant flow
Recruitment details
There has been a total screening of 1161 patients from which a total of 382 patients could finally be included and randomized.
Participants by arm
| Arm | Count |
|---|---|
| A Control Group Docetaxel 75 mg/m2 and cisplatin 75 mg/m2, both on day 1, every 21 days. Total number of cycles: 6
Cisplatin, Docetaxel: Docetaxel 75 mg/m2 and cisplatin 75 mg/m2, both on day 1, every 21 days. Total number of cycles: 6 | 142 |
| Experimental Group Include experimental groups Arm B1+ Arm B2+ Arm B3 | 137 |
| Total | 279 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Inclusion error | 4 | 4 | 0 | 0 |
| Overall Study | Missing data | 44 | 30 | 13 | 6 |
| Overall Study | Withdrawal by Subject | 0 | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Experimental Group | A Control Group |
|---|---|---|---|
| Age, Continuous | 62.5 years | 63 years | 62 years |
| BRCA1 mRNA level Hight BRCA mRNA level | 93 participants | 47 participants | 46 participants |
| BRCA1 mRNA level Intermediate BRCA mRNA level | 88 participants | 42 participants | 46 participants |
| BRCA1 mRNA level Low BRCA mRNA level | 98 participants | 48 participants | 50 participants |
| ECOG ECOG 0 | 93 participants | 49 participants | 44 participants |
| ECOG ECOG 1-2 | 186 participants | 88 participants | 98 participants |
| Histology NonSquamous | 180 participants | 88 participants | 92 participants |
| Histology Squamous | 99 participants | 49 participants | 50 participants |
| Median number of cycles | 4.5 cycles | 4 cycles | 5 cycles |
| mRNA BRCA1 expression values | 12 fg/μg | 12.28 fg/μg | 11.86 fg/μg |
| mRNA RAP80 expression values | 1.7 fg/μg | 1.74 fg/μg | 1.65 fg/μg |
| RAP 80 mRNA level Hight RAP80 mRNA level | 70 participants | 34 participants | 36 participants |
| RAP 80 mRNA level Intermediate RAP80 mRNA level | 105 participants | 55 participants | 50 participants |
| RAP 80 mRNA level Low RAP80 mRNA level | 100 participants | 48 participants | 52 participants |
| RAP 80 mRNA level Undetermined level RAP80 mRNA | 4 participants | 0 participants | 4 participants |
| Region of Enrollment Spain | 279 participants | 137 participants | 142 participants |
| Sex: Female, Male Female | 52 Participants | 19 Participants | 33 Participants |
| Sex: Female, Male Male | 227 Participants | 118 Participants | 109 Participants |
| Smoking status No data | 13 participants | 6 participants | 7 participants |
| Smoking status Non-smoker | 192 participants | 95 participants | 97 participants |
| Smoking status Smoker | 74 participants | 36 participants | 38 participants |
| Stage IV disease extension at study entrance Extra-thoracic | 247 participants | 123 participants | 124 participants |
| Stage IV disease extension at study entrance No data | 4 participants | 2 participants | 2 participants |
| Stage IV disease extension at study entrance Thoracic | 28 participants | 12 participants | 16 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 142 | 7 / 45 | 19 / 49 | 3 / 43 |
| other Total, other adverse events | 0 / 142 | 0 / 45 | 0 / 49 | 0 / 43 |
| serious Total, serious adverse events | 9 / 142 | 29 / 45 | 49 / 49 | 6 / 43 |
Outcome results
Primary
Progression Free Survival
Defined as the length of time from the start of treatment to the date of the first documented progression of disease. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
Time frame: From the day of start of treatment until first documented progression or death due to any cause,up to 18 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Control Group | Progression Free Survival | 5.49 Month |
| B1: Experimental Group 1 | Progression Free Survival | 5.43 Month |
| B2 Experimental Group 2 | Progression Free Survival | 5.49 Month |
| B3 Experimental Group 3 | Progression Free Survival | 2.50 Month |
Comparison: This is a futility analysis. The initial hypothesis of the clinical trial was that the experimental group as a whole was superior to the control group.p-value: 0.5695% CI: [0.76, 1.67]Log Rank
p-value: 0.7995% CI: [0.73, 1.51]Log Rank
p-value: 0.000195% CI: [1.38, 2.95]Log Rank
Secondary
Overall Survival
Defined as the length of time from the start of the treatment that patients diagnosed with the disease are still alive.
Time frame: From the date of start of the treatment until death or end of follow up, up to 18 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Control Group | Overall Survival | 12.66 Month |
| B1: Experimental Group 1 | Overall Survival | 8.52 Month |
p-value: 0.00695% CI: [1.13, 2.12]Log Rank