Advanced Gastric Cancer
Conditions
Keywords
lenvatinib, pembrolizumab, phase II, gastric cancer
Brief summary
The efficacy and safety of the use of pembrolizumab in combination with lenvatinib.
Detailed description
In this study, if combination therapy with lenvatinib and pembrolizumab in patients with gastric cancer is judged to be effective, a prospective treatment regimen can be expected for a larger number of participating subjects. The anticipated disadvantages include any adverse events associated with lenvatinib and pembrolizumab. To minimize the risk and disadvantages of adverse events, the data center together with the Data and Safety Monitoring Committee will monitor any adverse events in the present trial to determine whether or not they are within the expected range. These bodies will also conduct a thorough examination in the event that serious or unexpected adverse events occur, and adopt an appropriate system to take any necessary actions.
Interventions
DRUGLenvatinib
Lenvatinib will be administered with water orally once a day (with or without food) in 21-day cycles at approximately the same time each day. On Day 1 of each cycle, in case concomitantly administered, it will be administered approximately within 1 hour after completion of pembrolizumab administration.
DRUGPembrolizumab
Pembrolizumab will be administered as a dose of 200 mg as a 30-minute IV infusion, every 3 weeks (25 minutes to 40 minutes are acceptable).
Sponsors
Merck Sharp & Dohme LLC
Eisai Co., Ltd.
National Cancer Center Hospital East
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients have histologically or cytologically confirmed advanced or recurrent gastric cancer. 2. Patients at least 20 years of age on the day of providing consent. 3. Patients have measurable disease as defined by RECIST 1.1 as determined by investigator. 4. Patients with a performance status of 0 or 1 on the Eastern Cooperative Oncology Group. 5. Patients with adequate organ function at the time of enrollment as defined below: * Neutrophil count ≥1200mm3 * Platelet count ≥7.5 × 104/mm3 * Hemoglobin (Hb) ≥ 8.0 g/dL, * Total bilirubin ≤1.5 mg/dL * Asparate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 100 IU/L for subjects with liver metastases ≤ 200 IU/L * Creatinine ≤1.5-times the upper limit of normal * International normalized ratio (INR) ≤ 1.5 * Urinary protein : It satisfies one of the following (if any of the inspection criteria are satisfied, other examination may not be carried out) (i) Urinary protein (test paper method) is 2+ or less (ii) Urine Protein Creatinine (UPC) ratio \<3.5 (iii) 24-hour urine protein was measured, urinary protein ≦ 3500 mg 6. Patients who not received a blood transfusion within 7 days of registration. 7. Patients have recovered adverse events associated with chemotherapy, radiation and surgical operation as pretreatment to Grade 1 or lower with CTCAE v4.0 excluding stable symptoms (eg alopecia, peripheral sensory neuropathy, skin hyperpigmentation, dysgeusia etc.). 8. Female of childbearing potential who are negative in a pregnancy test within 14 days before enrollment. Both male and female patients should agree to use an adequate method of contraception (total abstinence, an intrauterine device or hormone releasing system, an contraceptive implant and an oral contraceptive) starting with the first dose of study therapy through 120 days after the last dose of study therapy. Duration will be determined when the subject is assigned to treatment. 9. Patients capable of taking oral medication 10. Patients who provided written informed consent to be subjects in this trial
Exclusion criteria
1. Patients who received prior anticancer treatment within 14 days (or 5 times the half-life time, whichever is shorter) or any investigational agent within 28 days prior to the first dose of study drugs. 2. Patients who have undergone surgical treatment and radiotherapy with in 2 weeks before enrollment. 3. Patients with a history of prior treatment with Lenvatinib or any anti-programmed death 1, anti-programmed ligand death 1, or anti-programmed ligand death 2. 4. Patients with hypertension that is difficult to control (systolic blood pressure ≥160 mmHg and diastolic blood pressure ≥90 mmHg) despite treatment with several hypotensive agents. 5. Patients with acute coronary syndrome (including myocardial infarction and unstable angina), and with a history of coronary angioplasty or stent placement performed within 6 months before enrollment. 6. Patients with symptomatic brain metastasis. 7. Patients with a history of New York Heart Association congestive heart failure of grade II or above, unstable angina, myocardial infarction within the past 6 months, or serious cardiac arrhythmia associated with significant cardiovascular impairment within the past 6 months 8. Patients have an active malignancy (except for definitively treated melanoma in-situ, basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix) within the past 24 months 9. Patients have severe (hospitalization required) complications (intestinal palsy, intestinal obstruction, pulmonary fibrosis, diabetes difficult to control, heart failure, myocardial infarction, unstable angina, renal failure, liver failure, mental disease, cerebrovascular disease etc). 10. Patients with a history of a gastrointestinal perforation and /or gastrointestinal fistula within 6 months before enrollment. 11. Patients with active hepatitis. 12. Patients with a history of human immunodeficiency virus (HIV). 13. Patients with active symptoms or signs of interstitial lung disease. 14. Patients with concurrent autoimmune disease, or a history of chronic or recurrent autoimmune disease 15. Patients who require systemic corticosteroids (excluding temporary usage for tests, prophylactic administration for allergic reactions, or to alleviate swelling associated with radiotherapy) or immunosuppressants, or who have received such a therapy \<14 days before enrollment. 16. Patients have a history of (non-infectious) pneumonitis that required steroids or have current pneumonitis 17. Patients who are administered live vaccines \<30 days before the initiation of treatment with the investigational drug. 18. Patients have serious non-healing wound, ulcer, or bone fracture. 19. Females who are pregnant or breastfeeding 20. Patients have no intention to comply with the protocol or cannot comply. 21. Patients were judged unsuitable as subject of this trial by investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | 12 months | ORR will be defined as the proportion of patients who achieved Complete Response (CR) or Partial Response (PR) for best overall response (confirmation required) according to immune-related RECIST (irRECIST) and RECIST v1.1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs) | Basically 2 years, maximum 28 months | * Number of each AE of the worst grade occurring in this study was evaluated based on Common Terminology Criteria for Adverse Events (CTCAE) v4.03 and tabulated throughout all cycles. This study also includes a special note regarding abnormal laboratory values. When clinical signs and symptoms observed in this study were elicited, diagnosis and related data were collected based on whether they were due to abnormal laboratory values. Therefore, for example, grading results for liver dysfunction may differ between non-hematologic toxicities and laboratory values. * Adverse-Events occurrences means prevalence proportion of any undesirable occurrence based on investigator's medical decision in this study. |
| Objective Response Rate (irORR) | 12 months | Objective response rate (irORR) according to immune-related (ir) RECIST |
| Progression-free Survival (PFS) | 12 months | * 1 Progression will be PD based on diagnostic imaging according to overall response by RECIST v1.1. The day of the imaging test will be defined as the day of progression. When the treatment are discontinued due to clinical PD and diagnostic imaging can't be performed, the day of clinical PD will be defined as the day of progression. * 2 Surviving patients, who are not assessed as progression will be censored on the last day when no progression is confirmed on imaging (last day of PFS confirmed) * 3 For patients who died without being assessed as progression, whether to consider to be an event on the day of death or censoring on the last day of PFS confirmed should be decided at the time of data review performed prior to data fixation. In principle, they should be an event on the day of death unless the period from the last day of PFS confirmed to the day of death is long. |
| Overall Survival (OS) | 28 months | * The period will be from the day of enrollment, as the starting date of the computation, to the day of death of any cause. Surviving patients should be censored on the last day of PFS confirmed. Patients who are lost to follow up should be censored on the last day when their survival is confirmed before being lost to follow up. * The protocol for this clinical trial stipulated that the observation period was 2 years from the date of registration of the last case. Meanwhile, OS was stipulated as the period from the date of registration to the date of death from any cause. For surviving cases, the period was censored at the date of last confirmed survival. The observation period varied by case, with follow-up surveys lasting up to 28 months. |
| Disease Control Rate (DCR) | 2 years | The DCR will be defined as the percentage of patients who achieved CR or PR, or Stable Disease (SD) for best overall response according to RECIST v1.1. |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Lenvatinib + Pembrolizumab Lenvatinib and Pembrolizumab will be administrated simultaneously for advanced gastric cancer patients.
Lenvatinib: Lenvatinib will be administered with water orally once a day (with or without food) in 21-day cycles at approximately the same time each day. On Day 1 of each cycle, in case concomitantly administered, it will be administered approximately within 1 hour after completion of pembrolizumab administration.
Pembrolizumab: Pembrolizumab will be administered as a dose of 200 mg as a 30-minute IV infusion, every 3 weeks (25 minutes to 40 minutes are acceptable). | 29 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Patient's refusal | 1 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Progression of primary disease (PD) | 25 |
| Overall Study | The protocol treatment was discontinued for undergoing primary tumor resection. | 1 |
Baseline characteristics
| Characteristic | Lenvatinib + Pembrolizumab | — |
|---|---|---|
| Age, Categorical <=18 years | 0 Participants | — |
| Age, Categorical >=65 years | 21 Participants | — |
| Age, Categorical Between 18 and 65 years | 8 Participants | — |
| Age, Continuous | 70 years | — |
| Epstein Barr Virus (EBV) Negative | 28 participants | — |
| Epstein Barr Virus (EBV) Positive | 1 participants | — |
| Lauren classification Diffuse type | 14 participants | — |
| Lauren classification Intestinal type | 15 participants | — |
| Mismatch Repair (MMR) Deficient | 2 participants | — |
| Mismatch Repair (MMR) Proficient | 27 participants | — |
| Number of metastatic organs 0 | 0 participants | — |
| Number of metastatic organs 1 piece | 11 participants | — |
| Number of metastatic organs 2 pieces | 14 participants | — |
| Number of metastatic organs 3 pieces | 3 participants | — |
| Number of metastatic organs 4 pieces | 1 participants | — |
| Number of prior treatment regimens 0 | 14 participants | — |
| Number of prior treatment regimens 1 | 15 participants | — |
| Number of prior treatment regimens 2 | 0 participants | — |
| Number of prior treatment regimens 3 | 0 participants | — |
| Number of prior treatment regimens 4 | 0 participants | — |
| Peritoneal metastasis Absent | 20 participants | — |
| Peritoneal metastasis Present | 9 participants | — |
| Primary site Gastric adenocarcinoma | 25 participants | — |
| Primary site Gastroesophageal junction adenocarcinoma | 4 participants | — |
| Programmed death-Ligand 1 (PD-L1) Negative | 3 participants | — |
| Programmed death-Ligand 1 (PD-L1) Positive | 26 participants | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment Japan | 29 participants | — |
| Sex: Female, Male Female | 3 Participants | — |
| Sex: Female, Male Male | 26 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 15 / 29 |
| other Total, other adverse events | 29 / 29 |
| serious Total, serious adverse events | 4 / 29 |
Outcome results
Primary
Objective Response Rate (ORR)
ORR will be defined as the proportion of patients who achieved Complete Response (CR) or Partial Response (PR) for best overall response (confirmation required) according to immune-related RECIST (irRECIST) and RECIST v1.1.
Time frame: 12 months
Population: ORR will be defined as the proportion of patients who achieved CR or PR for best overall response (confirmation required) according to immune-related RECIST (irRECIST) and RECIST v1.1.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lenvatinib + Pembrolizumab | Objective Response Rate (ORR) | Complete Response (CR) | 1 Participants |
| Lenvatinib + Pembrolizumab | Objective Response Rate (ORR) | Partial Response (PR) | 19 Participants |
| Lenvatinib + Pembrolizumab | Objective Response Rate (ORR) | Stable disease (SD) | 9 Participants |
| Lenvatinib + Pembrolizumab | Objective Response Rate (ORR) | Progressive disease (PD) | 0 Participants |
| Lenvatinib + Pembrolizumab | Objective Response Rate (ORR) | Not Evaluable (NE) | 0 Participants |
Secondary
Disease Control Rate (DCR)
The DCR will be defined as the percentage of patients who achieved CR or PR, or Stable Disease (SD) for best overall response according to RECIST v1.1.
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenvatinib + Pembrolizumab | Disease Control Rate (DCR) | 100 percentage of participants |
Secondary
Number of Participants With Adverse Events (AEs)
* Number of each AE of the worst grade occurring in this study was evaluated based on Common Terminology Criteria for Adverse Events (CTCAE) v4.03 and tabulated throughout all cycles. This study also includes a special note regarding abnormal laboratory values. When clinical signs and symptoms observed in this study were elicited, diagnosis and related data were collected based on whether they were due to abnormal laboratory values. Therefore, for example, grading results for liver dysfunction may differ between non-hematologic toxicities and laboratory values. * Adverse-Events occurrences means prevalence proportion of any undesirable occurrence based on investigator's medical decision in this study.
Time frame: Basically 2 years, maximum 28 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lenvatinib + Pembrolizumab | Number of Participants With Adverse Events (AEs) | 29 Participants |
Secondary
Objective Response Rate (irORR)
Objective response rate (irORR) according to immune-related (ir) RECIST
Time frame: 12 months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lenvatinib + Pembrolizumab | Objective Response Rate (irORR) | irCR | 1 Participants |
| Lenvatinib + Pembrolizumab | Objective Response Rate (irORR) | irPR | 19 Participants |
| Lenvatinib + Pembrolizumab | Objective Response Rate (irORR) | irSD | 9 Participants |
| Lenvatinib + Pembrolizumab | Objective Response Rate (irORR) | irPD | 0 Participants |
| Lenvatinib + Pembrolizumab | Objective Response Rate (irORR) | irNE | 0 Participants |
Secondary
Overall Survival (OS)
* The period will be from the day of enrollment, as the starting date of the computation, to the day of death of any cause. Surviving patients should be censored on the last day of PFS confirmed. Patients who are lost to follow up should be censored on the last day when their survival is confirmed before being lost to follow up. * The protocol for this clinical trial stipulated that the observation period was 2 years from the date of registration of the last case. Meanwhile, OS was stipulated as the period from the date of registration to the date of death from any cause. For surviving cases, the period was censored at the date of last confirmed survival. The observation period varied by case, with follow-up surveys lasting up to 28 months.
Time frame: 28 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenvatinib + Pembrolizumab | Overall Survival (OS) | 24.5 months |
Secondary
Progression-free Survival (PFS)
* 1 Progression will be PD based on diagnostic imaging according to overall response by RECIST v1.1. The day of the imaging test will be defined as the day of progression. When the treatment are discontinued due to clinical PD and diagnostic imaging can't be performed, the day of clinical PD will be defined as the day of progression. * 2 Surviving patients, who are not assessed as progression will be censored on the last day when no progression is confirmed on imaging (last day of PFS confirmed) * 3 For patients who died without being assessed as progression, whether to consider to be an event on the day of death or censoring on the last day of PFS confirmed should be decided at the time of data review performed prior to data fixation. In principle, they should be an event on the day of death unless the period from the last day of PFS confirmed to the day of death is long.
Time frame: 12 months
Population: Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of at least 5 mm.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenvatinib + Pembrolizumab | Progression-free Survival (PFS) | 7.1 months |