Non-small Cell Lung Cancer, Non-small Cell Lung Cancer Metastatic, Non-small Cell Lung Cancer Recurrent
Conditions
Keywords
RET-rearrangement, advanced NSCLC
Brief summary
A research study to evaluate the activity of alectinib for the Treatment of pretreated patients with advanced NSCLC that have confirmed RETrearrangement.
Detailed description
The trial is investigating the efficacy of alectinib in patients with advanced stage RET-rearranged NSCLC, treated with at least one platinum based systemic chemotherapy regimen. Preclinical studies have shown that alectinib, a highly selective next generation ALK inhibitor, has potent anti-tumour activity in RET-rearranged NSCLC. Therapeutically, several multiple kinases inhibitors, are potentially able to inhibit RET kinase function, which has been tested in several unselected NCSLC trials. However, those result were negative and none of the tested drugs was approved for lung cancer treatment. The ALERT-lung trial is a single arm, phase II trial with the primary objective to assess the efficacy of alectinib in terms of best overall response (OR) assessed by RECIST v1.1 in selected NSCLC patients with RET rearrangement. The secondary objectives are to evaluate secondary measures of clinical efficacy including disease control, progression-free survival (PFS), and overall survival (OS) as well as to assess safety and tolerability of the treatment and to describe the association of primary and secondary outcomes with tumour characteristics. Alectinib is administered orally, 600 mg, twice per day, until progression, refusal or unacceptable toxicity. Trial treatment may also continue beyond progression, with physician and patient agreement, for as long as the patient may still derive clinical benefit. A total sample size of 44 patients is required.
Interventions
DRUGAlectinib
Alectinib is administered orally 600mg (4x150mg capsules), twice per day (8 capsules, total 1200mg daily). The appropriate number of alectinib capsules will be provided to patients to be self-administered at home. Alectinib capsules must be taken at the same time each day with food. If a planned dose of alectinib is missed, patients can take the missed dose up until 6 hours before the next dose.
Sponsors
ETOP IBCSG Partners Foundation
Hoffmann-La Roche
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histologically or cytologically documented non-small cell lung carcinoma 2. Advanced disease defined as recurrent stage IV (according to 8th TNM classification) or recurrent or progressive disease following multimodal therapy (radiation therapy, surgical resection, or definitive chemo-radiation therapy for locally advanced disease) 3. At least one prior platinum-based systemic regimen: Adjuvant or neoadjuvant or definitive platinum-based chemo-radiotherapy treatments are considered as a line of treatment only if completed less than 6 months before enrolment. Maintenance therapy following platinum doublet-based chemotherapy is not considered a separate regimen of therapy. 4. RET rearrangement detected by FISH, Nanostring or by parallel-sequencing on FFPE tumour tissue assessed locally. 5. Availability of FFPE tumour material for central confirmation of RETrearrangement 6. Measurable or non-measurable, but radiologically evaluable (except for skin lesions) disease according to RECIST v1.1 criteria 7. Age ≥18 years 8. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 9. Life expectancy \>3 months 10. Adequate haematological function: * Haemoglobin ≥9 g/dL * Neutrophil count ≥1.5 ×109/L * Platelet count ≥100 × 109/L * WBC ≥2 ×109/L 11. Adequate renal function: Calculated creatinine clearance ≥45 mL/min (according to Cockcroft-Gault formula) 12. Adequate liver function: * Total bilirubin ≤2x ULN (except patients with Gilbert Syndrome, who can have total bilirubin ≤3.0 mg/dL) * ALT and AST ≤3x ULN (≤5x ULN for patients with concurrent liver ¨ metastasis) 13. Patient capable of proper therapeutic compliance, and accessible to correct followup. 14. Women of childbearing potential, including women who had their last menstrual period in the last 2 years, must have a negative serum or urine beta HCG pregnancy test within 7 days before enrolment into the trial and within 3 days before alectinib treatment start. 15. Sexually active men and women of childbearing potential must use an effective contraceptive method (intrauterine devices without hormones, bilateral tubal occlusion, vasectomized partner or total abstinence) during the trial treatment and for a period of at least 3 months following the last dose of alectinib. 16. Recovered from any previous therapy related toxicity to Grade ≤1 at date of enrolment (except for recovery to Grade ≤2 of alopecia, fatigue, creatinine increased, lack of appetite or peripheral neuropathy) 17. Written Informed Consent (IC) for trial treatment must be signed and dated by the patient and the investigator prior to any trial-related intervention.
Exclusion criteria
1. Untreated, active CNS metastases 2. Carcinomatous meningitis 3. Any previous (in the past 3 years) or concomitant malignancy EXCEPT adequately treated basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix or bladder, in situ ductal carcinoma of the breast 4. Any serious diseases or clinical conditions, including but not limited to uncontrolled active infection and any other serious underlying medical processes, that could affect the patient's capacity to participate in the trial 5. Liver disease characterized by: * ALT or AST \>3 × ULN (\>5 × ULN for patients with concurrent liver metastasis) confirmed on two consecutive measurements or * Impaired excretory function (e.g., hyperbilirubinaemia) or synthetic function or other conditions of decompensated liver disease such as coagulopathy, hepatic encephalopathy, hypoalbuminaemia, ascites, and bleeding from oesophageal varices or * Acute viral or active autoimmune, alcoholic, or other types of acute hepatitis 6. Patients with baseline symptomatic bradycardia 7. Previous treatment with any RET TKI or RET targeted therapy. 8. Known EGFR, ALK, ROS, and BRAF mutation (in addition to RET rearrangement) 9. Any concurrent systemic anticancer therapy. 10. Any GI disorder that may affect absorption of oral medications, such as malabsorption syndrome or status post major bowel resection. 11. History of hypersensitivity to any of the additives in the alectinib drug formulation. 12. Known HIV positivity or AIDS-related illness. 13. Women who are pregnant or in the period of lactation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response (BOR) | Evaluated from enrollment through study completion, up to a maximum of 28 months. | Best overall response (OR = CR or PR), per investigator assessment. OR was determined using the Response Evaluation Criteria in Solid Tumors (RECIST v1.1). OR is defined as the best overall response \[Complete Response (disappearance of all target and non-target lesions, no new lesions) or Partial Response (at least a 30% decrease in the sum of the longest diameter of target lesions taking as reference the baseline sum of diameters, no measurable increase in a non-target lesion, no new lesions)\] across all assessment points. Radiological tumour assessments were performed using CT scans. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control at 24-weeks | From first documented response (CR, PR, SD, non-CR/non-PD) to 24 weeks or first documented progression or death from any cause, whichever came first, assessed every 8 weeks (±4 days). | Best overall response of CR or PR, or SD (or non-CR/non-PD in the case of non-measurable disease only) by RECIST v1.1 criteria. Complete Response (CR): disappearance of all target and non-target lesions and no new lesions detected; Partial Response (PR): at least 30% decrease in the sum of the longest diameter of target lesions taking as reference the baseline sum of diameters (no measurable increase in a non-target lesion and no new lesion detected); Stable disease (SD): at most 20% increase or at most 30% decrease in the sum of the longest diameter of target lesions taking as reference the baseline sum of diameters (no measurable increase in a non-target lesion and no new lesion detected). Radiological tumour assessments were performed using CT scans. |
| Progression-free Survival (PFS) | Evaluated from enrollment through study completion, up to a maximum of 28 months. | Progression-free survival time was measured from the date of enrolment until documented progression or death from any cause, whichever came first. PFS is assessed according to RECIST 1.1 criteria. Progressive disease: at least a 20% increase in the sum of the longest diameter of target lesions taking as reference the baseline sum of diameters, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
| Overall Survival (OS) | Evaluated from enrollment through study completion, up to a maximum of 28 months. | Overall survival time is measured from the date of enrolment until death from any cause. |
| Number of Patients Experienced Adverse Events | Evaluated from enrollment through study completion, up to a maximum of 28 months. | The safety and tolerability of alectinib treatment is assessed through analysis of the worst grade of toxicity/adverse events according to CTCAE v4.0 criteria observed over the whole treatment period. |
Countries
Belgium, Ireland, Italy, Netherlands, Spain, Switzerland
Contacts
STUDY_CHAIREnriqueta Felip, MD-PhD
Vall d'Hebron University Hospital
STUDY_CHAIRJürgen Wolf, MD-PhD
University Hospital Cologne
STUDY_CHAIREgbert F. Smith, MD-PhD
The Netherlands Cancer Institute Amsterdam
Participant flow
Recruitment details
Recruitment period ranged from November 2018 to April 2020.
Pre-assignment details
Overall, 15 patients were screened with 14 of them successfully enrolled in the trial (one patient was ineligible due to active CNS metastases).
Participants by arm
| Arm | Count |
|---|---|
| Trial Treatment Alectinib is administered orally, 600 mg, twice per day (1200 mg per day) until progression, refusal or unacceptable toxicity.
Trial treatment may also continue beyond progression, with physician and patient agreement, for as long as the patient may still derive clinical benefit as per investigator decision.
Alectinib: Alectinib is administered orally 600mg (4x150mg capsules), twice per day (8 capsules, total 1200mg daily). The appropriate number of alectinib capsules will be provided to patients to be self-administered at home.
Alectinib capsules must be taken at the same time each day with food. If a planned dose of alectinib is missed, patients can take the missed dose up until 6 hours before the next dose. | 14 |
| Total | 14 |
Baseline characteristics
| Characteristic | Trial Treatment |
|---|---|
| Age, Continuous | 60.6 years |
| Age, Customized ≤ 60 years | 6 Participants |
| Age, Customized >60 years | 8 Participants |
| ECOG Performance Status 0 | 4 Participants |
| ECOG Performance Status 1 | 10 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 14 Participants |
| Region of Enrollment Belgium | 1 participants |
| Region of Enrollment Italy | 2 participants |
| Region of Enrollment Netherlands | 6 participants |
| Region of Enrollment Spain | 5 participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 4 Participants |
| Smoking status Current | 1 Participants |
| Smoking status Former (≥ 100 cigarettes in the past during the whole life) | 3 Participants |
| Smoking status Never (0-99 cigarettes during the whole life) | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 3 / 14 |
| other Total, other adverse events | 14 / 14 |
| serious Total, serious adverse events | 4 / 14 |
Outcome results
Primary
Best Overall Response (BOR)
Best overall response (OR = CR or PR), per investigator assessment. OR was determined using the Response Evaluation Criteria in Solid Tumors (RECIST v1.1). OR is defined as the best overall response \[Complete Response (disappearance of all target and non-target lesions, no new lesions) or Partial Response (at least a 30% decrease in the sum of the longest diameter of target lesions taking as reference the baseline sum of diameters, no measurable increase in a non-target lesion, no new lesions)\] across all assessment points. Radiological tumour assessments were performed using CT scans.
Time frame: Evaluated from enrollment through study completion, up to a maximum of 28 months.
Population: The efficacy cohort encompasses all evaluable patients, e.g. all enrolled patients excluding patients that were found to be ineligible (in retrospective review), patients that never started treatment and patients that were lost to follow-up before their first response evaluation (by RECIST 1.1). The efficacy cohort consists of 13 patients (there is one patient who was lost to follow-up before the first tumour assessment).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Trial Treatment | Best Overall Response (BOR) | Complete response | 0 Participants |
| Trial Treatment | Best Overall Response (BOR) | Partial response | 0 Participants |
| Trial Treatment | Best Overall Response (BOR) | Stable disease | 9 Participants |
| Trial Treatment | Best Overall Response (BOR) | Non-Complete response/ Non-Progressive disease (in case of non-measurable disease only) | 1 Participants |
| Trial Treatment | Best Overall Response (BOR) | Progressive disease | 2 Participants |
| Trial Treatment | Best Overall Response (BOR) | Not evaluable | 1 Participants |
Secondary
Disease Control at 24-weeks
Best overall response of CR or PR, or SD (or non-CR/non-PD in the case of non-measurable disease only) by RECIST v1.1 criteria. Complete Response (CR): disappearance of all target and non-target lesions and no new lesions detected; Partial Response (PR): at least 30% decrease in the sum of the longest diameter of target lesions taking as reference the baseline sum of diameters (no measurable increase in a non-target lesion and no new lesion detected); Stable disease (SD): at most 20% increase or at most 30% decrease in the sum of the longest diameter of target lesions taking as reference the baseline sum of diameters (no measurable increase in a non-target lesion and no new lesion detected). Radiological tumour assessments were performed using CT scans.
Time frame: From first documented response (CR, PR, SD, non-CR/non-PD) to 24 weeks or first documented progression or death from any cause, whichever came first, assessed every 8 weeks (±4 days).
Population: The efficacy cohort encompasses all evaluable patients, e.g. all enrolled patients excluding patients that were found to be ineligible (in retrospective review), patients that never started treatment and patients that were lost to follow-up before their first response evaluation (by RECIST 1.1). The efficacy cohort consists of 13 patients (there is one patient who was lost to follow-up before the first tumour assessment).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trial Treatment | Disease Control at 24-weeks | 23.1 percentage of patients |
Secondary
Number of Patients Experienced Adverse Events
The safety and tolerability of alectinib treatment is assessed through analysis of the worst grade of toxicity/adverse events according to CTCAE v4.0 criteria observed over the whole treatment period.
Time frame: Evaluated from enrollment through study completion, up to a maximum of 28 months.
Population: The safety cohort includes all patients who received at least one dose of trial treatment (i.e. all 14 patients).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Trial Treatment | Number of Patients Experienced Adverse Events | Experienced adverse event(s) | 14 Participants |
| Trial Treatment | Number of Patients Experienced Adverse Events | Experienced serious adverse event(s) | 4 Participants |
Secondary
Overall Survival (OS)
Overall survival time is measured from the date of enrolment until death from any cause.
Time frame: Evaluated from enrollment through study completion, up to a maximum of 28 months.
Population: The efficacy cohort encompasses all evaluable patients, e.g. all enrolled patients excluding patients that were found to be ineligible (in retrospective review), patients that never started treatment and patients that were lost to follow-up before their first response evaluation (by RECIST 1.1). The efficacy cohort consists of 13 patients (there is one patient who was lost to follow-up before the first tumour assessment).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trial Treatment | Overall Survival (OS) | NA months |
Secondary
Progression-free Survival (PFS)
Progression-free survival time was measured from the date of enrolment until documented progression or death from any cause, whichever came first. PFS is assessed according to RECIST 1.1 criteria. Progressive disease: at least a 20% increase in the sum of the longest diameter of target lesions taking as reference the baseline sum of diameters, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: Evaluated from enrollment through study completion, up to a maximum of 28 months.
Population: The efficacy cohort encompasses all evaluable patients, e.g. all enrolled patients excluding patients that were found to be ineligible (in retrospective review), patients that never started treatment and patients that were lost to follow-up before their first response evaluation (by RECIST 1.1). The efficacy cohort consists of 13 patients (there is one patient who was lost to follow-up before the first tumour assessment).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trial Treatment | Progression-free Survival (PFS) | 3.7 months |