KIF5B-RET-Positive Adenocarcinoma of the Lung
Conditions
Keywords
KIF5B-RET-Positive Adenocarcinoma, Lung Cancer, NSCLC, Non-Small Cell Lung Cancer
Brief summary
This is a Phase 2, open-label, safety and activity study of lenvatinib in subjects with KIF5B-RET-positive adenocarcinoma of the lung and other confirmed RET translocations. At least 20 subjects with KIF5B-RET and other RET translocations will be treated and will receive lenvatinib at a starting dose of 24 mg orally, once per day. The study will consist of 3 phases: The Pretreatment Phase, The Treatment Phase and the Extension Phase. The Pretreatment Phase will include screening procedures and eligibility assessments. The Pretreatment Phase consists of a Screen 1, Screen 2 and Baseline Period. The Treatment Phase will begin when the subject has met all eligibility criteria on Day 1 of the first Treatment Cycle. The Treatment Phase contains the Treatment and Follow-up Periods. The Extension Phase will begin for subjects who received treatment in the study (either in the Treatment Period or Follow-up Period) at the time of database cutoff.
Interventions
DRUGLenvatinib
Starting dose of 24 mg orally, once per day
Sponsors
Eisai Inc.
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. Subjects must have a cytological or histological confirmed diagnosis of adenocarcinoma of the lung. 2. Subject must be known to be RET positive (known KIF5B-RET translocation, or other confirmed RET translocations (e.g., CCDC6-RET)) or have an available tumor sample for local or central testing obtained prior to consent (Screen 1). Subjects whose samples need to be submitted for central laboratory testing must be current non-smokers and not known to have mutation in EGFR, KRAS, or ALK. 3. Subjects may have received up to three prior systemic anticancer treatment regimens for adenocarcinoma of the lung (including adjuvant therapies and tyrosine-kinase inhibitors \[TKI\]), unless discussed with the sponsor. 4. Subjects must have a clinically indicated need for systemic chemotherapy for adenocarcinoma of the lung based on the investigator's assessment 5. Presence of measurable disease meeting the following criteria: 1. At least one lesion of at least 1.0 cm in the long-axis diameter for a non-lymph node or at least 1.5 cm in the short-axis diameter for a lymph node which is serially measurable according to Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) using either computerized tomography (CT) or magnetic resonance imaging (MRI). If there is only one target lesion and it is a non-lymph node, it should have a longest diameter of at least 1.5 cm. 2. Lesions previously treated with radiotherapy or locoregional therapy must show radiographic evidence of disease progression to be deemed a target lesion. 6. Subjects with known brain metastases who have completed whole brain radiotherapy, stereotactic radiosurgery, or complete surgical resection will be eligible if they have remained clinically stable, asymptomatic and off of steroids for 28 days. 7. Adequate bone marrow function, defined as: 1. Absolute neutrophil count (ANC) greater than or equal to 1.5 x 10\^9/L (greater than or equal to 1500/mm\^3) 2. Hemoglobin (Hb) greater than or equal 8.5 g/dL 3. Platelet count greater than or equal 75 x 10\^9/L (greater than or equal 75,000/mm\^3) 8. Adequate liver function, defined as: 1. Bilirubin less than or equal 1.5 x upper limit of normal (ULN) except for unconjugated hyperbilirubinemia or Gilbert's syndrome 2. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) less than or equal 3 x ULN (less than or equal 5 x ULN if subject has liver metastases). If alkaline phosphatase is greater than 3 x ULN (in absence of liver metastases) or greater than 5 x ULN (in presence of liver metastases) AND the subject also is known to have bone metastases, the liver-specific alkaline phosphatase must be separated from the total and used to assess the liver function instead of total alkaline phosphatase. 9. Adequate renal function, defined as calculated creatinine clearance greater than 40 mL/min per the Cockcroft and Gault formula. 10. Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP less than 150/90 mmHg at screening and no change in antihypertensive medications within 1 week before Cycle 1/Day 1 (C1D1). 11. Eastern Cooperative Oncology Group (ECOG)-Performance Status (PS) of 0 or 1. 12. Survival expectation of 12 weeks or longer after starting study drug. 13. Males or females aged at least 18 years (or any age greater than 18 years as determined by country legislation) at the time of informed consent (Screen 1). 14. Females must not be breast-feeding or pregnant at Screening or Baseline (as documented by a negative beta-human chorionic gonadotropin \[B-hCG\] test with a minimum sensitivity of 25 IU/L or equivalent units of B-hCG). A separate baseline assessment is required if a negative Screening pregnancy test was obtained more than 72 hours before the first dose of study drug. 15. All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group and without other known or suspected cause) or have been sterilized surgically (i.e., bilateral tubal ligation, total hysterectomy or bilateral oophorectomy, all with surgery at least one month before dosing). 16. Females of childbearing potential must not have had unprotected sexual intercourse within 30 days before study entry and must agree to use a highly effective method of contraception (e.g., total abstinence, an intrauterine device, a double-barrier method \[such as condom plus diaphragm with spermicide\], a contraceptive implant, an oral contraceptive, or have a vasectomized partner with confirmed azoospermia) throughout the entire study period and for 30 days after study drug discontinuation. If currently abstinent, the subject must agree to use a double barrier method as described above if she becomes sexually active during the study period or for 30 days after study drug discontinuation. Females who are using hormonal contraceptives must have been on a stable dose of the same hormonal contraceptive product for at least 4 weeks before dosing and must continue to use the same contraceptive during the study and for 30 days after study drug discontinuation. 17. Male subjects must have had a successful vasectomy (confirmed azoospermia) or they and their female partners must meet the criteria above (i.e., not of childbearing potential or practicing highly effective contraception throughout the study period and for 30 days after study drug discontinuation). No sperm donation is allowed during the study period and for 30 days after study drug discontinuation. 18. Provide written informed consent (Screen 1 and Screen 2) 19. Willing and able to comply with all aspects of the protocol
Exclusion criteria
1. Subjects who have received any anticancer therapy (including surgery, locoregional, biological, immunotherapy, hormonal, or radiotherapy) within 21 days before the first dose of study drug (28 days for investigational therapies). 2. Leptomeningeal metastases or brain metastases except as for Inclusion Criterion #6. 3. Subjects who have not recovered from toxicities as a result of prior anticancer therapy to less than Grade 2 severity per the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v4.0, except alopecia and infertility. 4. Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction, or stroke within 6 months of the first dose of study drug, or cardiac arrhythmia requiring medical treatment at Screening. 5. Gastrointestinal malabsorption or any other condition in the opinion of the investigator that might affect the absorption of lenvatinib. 6. Active malignancy (except for adenocarcinoma of the lung or definitively treated melanoma in-situ, basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix) within the past 24months. 7. Major surgery within 3 weeks before the first dose of study drug. 8. Bleeding or thrombotic disorders or use of anticoagulants such as warfarin or similar agents requiring therapeutic international normalized ratio (INR) monitoring. (Treatment with low molecular weight heparin is allowed.) 9. Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks before the first dose of study drug. 10. Active infection (any infection requiring treatment). 11. Symptomatic central nervous system (CNS) disease. 12. Subjects having greater than 1+ proteinuria on urine dipstick testing will undergo 24-hour urine collection for quantitative assessment of proteinuria. Subjects with urine protein greater than or equal to 1 g/24-hour will be ineligible. 13. Any medical or other condition that in the opinion of the investigator(s) would preclude the subject's participation in a clinical study or would preclude them from completing the study. 14. Scheduled for surgery during the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | From first dose date until PD, development of unacceptable toxicity, withdrawal of consent, participant's choice to stop study treatment (up to approximately 2 years 10 months) | ORR was defined as the percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR), based on the investigator assessment of radiologic response according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. No independent review of tumor assessments was performed. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to less than (\<) 10 millimeter (mm). PR was defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum of diameters. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | From first dose date until PD or death (up to approximately 2 years 10 months) | PFS was defined as the time from the first dose to the date of first documentation of PD, or date of death, whichever occurred first. Tumor response data used to analyze PFS was obtained from the investigator's assessment of the imaging scans using RECIST 1.1. No independent review of tumor assessments were performed. PFS was calculated using Kaplan-Meier estimate and presented with 2-sided 95% Cl based on the Greenwood formula. PD was defined as at least 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions. |
| Overall Survival (OS) | From first dose date until date of death from any cause (approximately up to 2 years 10 months) | OS was defined as the time from the date of first dose to the date of death from any cause. OS was calculated using Kaplan-Meier estimate and presented with 2-sided 95% Cl based on the Greenwood formula. |
| Plasma Concentrations of Lenvatinib | Cycle 1 Day 1: 0.5-4 hours, 6-10 hours postdose; Cycle 1 Day 15: predose, 0.5-4 hours, 6-10 hours postdose; Cycle 2 Day 1: predose, 2-12 hours postdose; Cycle 3 Day 1: predose; (Cycle length is equal to [=] 28 days) | — |
Countries
Hong Kong, Japan, Singapore, Taiwan, United States
Participant flow
Recruitment details
Participants took part in the study at 14 investigative sites in the United States, Japan, Singapore, and Taiwan from 05 April 2013 to 2 November 2017.
Pre-assignment details
A total of 25 participants with kinesin family 5B oncogene rearranged during transfection (KIF5B-RET)-positive adenocarcinoma of the lung or other RET translocations were enrolled and treated, 5 participants were ongoing in the Extension Phase at the time of data cut-off.
Participants by arm
| Arm | Count |
|---|---|
| Lenvatinib 24 mg Participants with KIF5B-RET-positive adenocarcinoma and other RET translocations received lenvatinib 24 mg, capsule, orally, once daily in 28-day continuous cycles until PD, development of unacceptable toxicity, withdrawal of consent, or termination of lenvatinib development by the sponsor. | 25 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Extension Phase | Adverse Event | 2 |
| Extension Phase | Disease Progression | 3 |
| Treatment Phase | Adverse Event | 6 |
| Treatment Phase | Clinical Progression | 1 |
| Treatment Phase | Disease Progression | 10 |
| Treatment Phase | Lost to Follow-up | 1 |
| Treatment Phase | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Lenvatinib 24 mg |
|---|---|
| Age, Continuous | 60.0 Years STANDARD_DEVIATION 13.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 17 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 | 8 Participants |
| Sex: Female, Male Female | 18 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 13 / 25 |
| other Total, other adverse events | 25 / 25 |
| serious Total, serious adverse events | 16 / 25 |
Outcome results
Primary
Objective Response Rate (ORR)
ORR was defined as the percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR), based on the investigator assessment of radiologic response according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. No independent review of tumor assessments was performed. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to less than (\<) 10 millimeter (mm). PR was defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum of diameters.
Time frame: From first dose date until PD, development of unacceptable toxicity, withdrawal of consent, participant's choice to stop study treatment (up to approximately 2 years 10 months)
Population: FAS included all participants who received at least 1 dose of lenvatinib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenvatinib 24 mg | Objective Response Rate (ORR) | 16.0 percentage of participants |
Secondary
Overall Survival (OS)
OS was defined as the time from the date of first dose to the date of death from any cause. OS was calculated using Kaplan-Meier estimate and presented with 2-sided 95% Cl based on the Greenwood formula.
Time frame: From first dose date until date of death from any cause (approximately up to 2 years 10 months)
Population: FAS included all participants who received at least 1 dose of lenvatinib.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenvatinib 24 mg | Overall Survival (OS) | NA months |
Secondary
Plasma Concentrations of Lenvatinib
Time frame: Cycle 1 Day 1: 0.5-4 hours, 6-10 hours postdose; Cycle 1 Day 15: predose, 0.5-4 hours, 6-10 hours postdose; Cycle 2 Day 1: predose, 2-12 hours postdose; Cycle 3 Day 1: predose; (Cycle length is equal to [=] 28 days)
Population: The pharmacokinetic (PK) Analysis Set included all participants who received at least one dose of lenvatinib and had at least one quantifiable lenvatinib concentration. Participants who were evaluable at a particular time point for this outcome measure were included in the assessment.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Lenvatinib 24 mg | Plasma Concentrations of Lenvatinib | Cycle 1 Day 1: 0.5 to 4 hours postdose | 37.0 microgram per milliliter (mcg/mL) |
| Lenvatinib 24 mg | Plasma Concentrations of Lenvatinib | Cycle 1 Day 1: 6 to 10 hours postdose | 278.5 microgram per milliliter (mcg/mL) |
| Lenvatinib 24 mg | Plasma Concentrations of Lenvatinib | Cycle 1 Day 15: predose | 83.6 microgram per milliliter (mcg/mL) |
| Lenvatinib 24 mg | Plasma Concentrations of Lenvatinib | Cycle 1 Day 15: 0.5 to 4 hours postdose | 89.2 microgram per milliliter (mcg/mL) |
| Lenvatinib 24 mg | Plasma Concentrations of Lenvatinib | Cycle 1 Day 15: 6 to 10 hours postdose | 277.5 microgram per milliliter (mcg/mL) |
| Lenvatinib 24 mg | Plasma Concentrations of Lenvatinib | Cycle 2 Day 1: predose | 66.4 microgram per milliliter (mcg/mL) |
| Lenvatinib 24 mg | Plasma Concentrations of Lenvatinib | Cycle 2 Day 1: 2 to 12 hours postdose | 345.0 microgram per milliliter (mcg/mL) |
| Lenvatinib 24 mg | Plasma Concentrations of Lenvatinib | Cycle 3 Day 1: predose | 59.8 microgram per milliliter (mcg/mL) |
Secondary
Progression-free Survival (PFS)
PFS was defined as the time from the first dose to the date of first documentation of PD, or date of death, whichever occurred first. Tumor response data used to analyze PFS was obtained from the investigator's assessment of the imaging scans using RECIST 1.1. No independent review of tumor assessments were performed. PFS was calculated using Kaplan-Meier estimate and presented with 2-sided 95% Cl based on the Greenwood formula. PD was defined as at least 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions.
Time frame: From first dose date until PD or death (up to approximately 2 years 10 months)
Population: FAS included all participants who received at least 1 dose of lenvatinib.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenvatinib 24 mg | Progression-free Survival (PFS) | 7.3 months |