Non Small Cell Lung Cancer
Conditions
Keywords
GOAL, Lung, Non small cell lung cancer, EGFR mutations
Brief summary
This is a study of gefitinib plus olaparib gefitinib in combination with olaparib (AZD2281) versus gefitinib alone, in patients with Epidermal Growth Factor Receptor (EGFR) mutation positive advanced non-small-cell lung cancer.
Detailed description
GOAL is a multicenter, randomized phase IB/II study performed in two countries, Spain and Mexico. Eligible patients were 18 years or older, treatment-naïve, pathologically confirmed stage IV NSCLC, with centrally confirmed EGFR mutations and measurable disease. Patients were randomly allocated (1:1) to receive gefitinib 250 mg daily or gefitinib 250 mg daily plus olaparib 200 mg three times daily in 28-day cycles. The primary endpoint was PFS. Secondary endpoints included overall survival (OS), response rate, safety and tolerability.
Interventions
DRUGGefitinib
Gefitinib 250 mg once a day, continuously, in 28-day cycles, until progression
DRUGOlaparib
Gefitinib 250 mg once a day, in combination with olaparib (at the recommended dose in the previous Phase Ib study) twice a day, continuously, in 28-day cycles.
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. Stage IV disease, following the Seventh Edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual (27). 4. Tumor tissue available (according to the criterion of the specimen-processing laboratory) for EGFR mutation assessment: to be included in the study patients should present at least one EGFR mutation (exon 19 deletion or L858R with or without T790M). 5. Evidence of measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1. 6. ECOG score ≤ 2. 7. Life expectancy of ≥ 3 months. 8. For the Phase II part of the study, patients should not have received previous treatment with chemotherapy or other agents for advanced disease: chemotherapy is allowed if the initial diagnosis of the patient 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. This criterion is not mandatory to patients to be included in the Phase I part of the study (these patients are allowed to have received a prior line of treatment for advanced disease). 9. Patients with the following hematologic values: * Absolute Neutrophil Count (ANC) ≥1.5 x 109/L * Hemoglobin (Hb) ≥ 10 g/dl * Platelets ≥ 100 x 109/L 10. Patients with the following biochemical values: * Bilirubin ≤ 1.5 mg/dL * Aspartate aminotransferase (AST) and Alanine transaminase (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 plus 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 samples of tumor and blood. 13. Patients must be available for clinical follow-up.
Exclusion criteria
1. Patients diagnosed of another neoplasm, with the exception of cervical carcinoma insitu, treated squamous cell carcinoma or superficial bladder tumor (Ta and TIS), or other malignant tumors that have received curative treatment within the last 5 years before inclusion in the study. 2. Simultaneous participation in any other study involving an investigational medicinal product, or having participated in a study less than 28 days prior to the start of study treatment. 3. Patients with HIV infection, HCV infection, coronary disease or uncontrolled arrhythmia, uncontrolled cerebrovascular disease and other clinical conditions that, in the judgment of the investigator, contraindicate the patient's participation in the study. 4. Past medical history of interstitial lung disease (ILD), drug-induced interstitial disease, radiation pneumonitis which required steroid treatment or any evidence of clinically active interstitial lung disease. 5. Pre-existing idiopathic pulmonary fibrosis evidenced by CT scan at baseline. 6. Uncontrolled seizures. 7. Patients considered requiring radiotherapy to the lung at the time of study entry or in the near future. 8. Known or suspected brain metastases or spinal cord compression, unless treated with surgery and/or radiation and stable without steroid treatment for at least 4 weeks prior to the first dose of study medication. 9. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication. 10. Patients who are pregnant or breastfeeding. Women of childbearing potential must have a negative pregnancy test performed within 7 days before the onset of treatment(Appendix 8). 11. Patients receiving the following classes of inhibitors of CYP3A4 (see Appendix 5 for guidelines and wash out periods): * Azole antifungals * Macrolide antibiotics * Protease inhibitors 12. Concomitant use of known CYP3A4 inducers such as phenytoin, carbamazepine, rifampicin, barbiturates, or St John's Wort. 13. Major surgery within 2 weeks of starting study treatment; patients must have recovered from any effects of any major surgery. 14. Significant weight loss (= 10% of body weight) in the 6 weeks before inclusion in the study. 15. Any condition that is unstable or could endanger the patient's safety and/or the patient's compliance with the study. 16. Substance abuse or clinical, psychological or social conditions that can undermine the validity of the informed consent or protocol compliance. 17. Patients who present any contraindication or suspected allergy to the products under investigation in the study. Tablets of gefitinib contain lactose: patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose and galactose malabsorption, will not be included in this trial. 18. Contraindication for steroid use. 19. Impossibility to comply with treatment due to cultural or geographic circumstances.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | From the date of randomization until end of follow up, up to 30 months. | Defined as the length of time from the date of randomization 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 randomization until end of follow up, up to 30 months | Defined as the length of time from either the date of diagnosis or the start of the treatment that patients diagnosed with the disease are still alive. |
| Best Global Response During Treatment Period | From the date of randomization until end of follow up, up to 30 months | To evaluate the best global response of the treatment as measured by investigator-assessed overall response rate (ORR) according to RECIST v1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR |
Countries
Spain
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Control Gefitinib Gefitinib will be administered once daily, continuously, in 28-day cycles, as a fixed dose of 250 mg/day.
Gefitinib: Gefitinib 250 mg once a day, continuously, in 28-day cycles, until progression | 91 |
| Experimental: Gefitinib in Combination With Olaparib Gefitinib 250 mg once a day, in combination with olaparib (at the recommended dose in the previous Phase I study) twice a day, continuously, in 28-day cycles.
Gefitinib: Gefitinib 250 mg once a day, continuously, in 28-day cycles, until progression
Olaparib: Gefitinib 250 mg once a day, in combination with olaparib (at the recommended dose in the previous Phase Ib study) twice a day, continuously, in 28-day cycles. | 91 |
| Total | 182 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Inclusion Error | 1 | 7 |
| Overall Study | Not receive study treatment | 3 | 1 |
Baseline characteristics
| Characteristic | Experimental: Gefitinib in Combination With Olaparib | Total | Control Gefitinib |
|---|---|---|---|
| Age, Continuous | 63.40 years STANDARD_DEVIATION 11.39 | 65.95 years STANDARD_DEVIATION 11.29 | 65.97 years STANDARD_DEVIATION 11.29 |
| Bone metastasis No | 61 participants | 127 participants | 66 participants |
| Bone metastasis Yes | 30 participants | 55 participants | 25 participants |
| CNS metastasis No | 81 participants | 161 participants | 80 participants |
| CNS metastasis Yes | 10 participants | 21 participants | 11 participants |
| ECOG Performance Status Scale ECOG 0 | 24 participants | 49 participants | 25 participants |
| ECOG Performance Status Scale ECOG 1 | 59 participants | 118 participants | 59 participants |
| ECOG Performance Status Scale ECOG 2 | 8 participants | 15 participants | 7 participants |
| EGFR mutation del 19 | 57 participants | 109 participants | 52 participants |
| EGFR mutation EGFR exon 18 | 3 participants | 6 participants | 3 participants |
| EGFR mutation EGFR exon 20 | 2 participants | 3 participants | 1 participants |
| EGFR mutation Exon 21 L858R | 25 participants | 60 participants | 35 participants |
| EGFR mutation UK | 4 participants | 4 participants | 0 participants |
| Region of Enrollment Mexico | 13 participants | 23 participants | 10 participants |
| Region of Enrollment Spain | 78 participants | 159 participants | 81 participants |
| Sex: Female, Male Female | 66 Participants | 123 Participants | 57 Participants |
| Sex: Female, Male Male | 25 Participants | 59 Participants | 34 Participants |
| Smoking status Former smoker | 26 participants | 53 participants | 27 participants |
| Smoking status Never smoker | 55 participants | 115 participants | 60 participants |
| Smoking status Smoker | 10 participants | 14 participants | 4 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 10 / 91 | 9 / 91 |
| other Total, other adverse events | 88 / 91 | 90 / 91 |
| serious Total, serious adverse events | 39 / 91 | 22 / 91 |
Outcome results
Primary
Progression-free Survival (PFS)
Defined as the length of time from the date of randomization 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 date of randomization until end of follow up, up to 30 months.
Population: The PFS analysis is performed on the PP population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Control Gefitinib | Progression-free Survival (PFS) | 10.9 Month |
| Experimental: Gefitinib in Combination With Olaparib | Progression-free Survival (PFS) | 10.9 Month |
p-value: 0.12495% CI: [1, 1.92]Log Rank
Secondary
Best Global Response During Treatment Period
To evaluate the best global response of the treatment as measured by investigator-assessed overall response rate (ORR) according to RECIST v1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
Time frame: From the date of randomization until end of follow up, up to 30 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Control Gefitinib | Best Global Response During Treatment Period | Partial Response | 59 participants |
| Control Gefitinib | Best Global Response During Treatment Period | Progressive Disease | 6 participants |
| Control Gefitinib | Best Global Response During Treatment Period | Stable disease | 21 participants |
| Control Gefitinib | Best Global Response During Treatment Period | Not evaluable | 3 participants |
| Control Gefitinib | Best Global Response During Treatment Period | Complete Response | 2 participants |
| Experimental: Gefitinib in Combination With Olaparib | Best Global Response During Treatment Period | Not evaluable | 11 participants |
| Experimental: Gefitinib in Combination With Olaparib | Best Global Response During Treatment Period | Complete Response | 1 participants |
| Experimental: Gefitinib in Combination With Olaparib | Best Global Response During Treatment Period | Partial Response | 59 participants |
| Experimental: Gefitinib in Combination With Olaparib | Best Global Response During Treatment Period | Stable disease | 12 participants |
| Experimental: Gefitinib in Combination With Olaparib | Best Global Response During Treatment Period | Progressive Disease | 8 participants |
Secondary
Overall Survival
Defined as the length of time from either the date of diagnosis or the start of the treatment that patients diagnosed with the disease are still alive.
Time frame: From the date of randomization until end of follow up, up to 30 months
Population: The OS analysis is performed on the mITT population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Control Gefitinib | Overall Survival | 23.1 Month |
| Experimental: Gefitinib in Combination With Olaparib | Overall Survival | 23.3 Month |
p-value: 0.345595% CI: [0.806, 1.845]Log Rank