Advanced or Metastatic Solid Tumors, Previously Untreated Gastric Cancer
Conditions
Keywords
Cancer, Solid Tumors, Gastric, Phase I, Phase II
Brief summary
The purpose of this study is to determine the following: 1. Find the maximum tolerated dose of E7050 when given in combination with cisplatin and capecitabine in patients with advance or metastatic solid tumors, and 2) Whether E7050 in combination with cisplatin and capecitabine is more effective in patients with previously untreated gastric cancer versus cisplatin and capecitabine alone.
Detailed description
This open-label, multicenter, randomized study will consist of 2 phases: Phase Ib: a safety run-in period with 3 ascending doses of E7050 in combination with fixed doses of Cisplatin and Capecitabine. This phase will enroll approximately 10 to 15 patients. * Phase II: a randomized 2-arm design which will enroll 80 patients. In the phase II portion, Patients will receive study treatment , E7050 in combination with Cisplatin and Capecitabine versus Cisplatin and Capecitabine Alone) for approximately six 21-day cycles (18 weeks). Beyond 18 weeks, patients who are experiencing clinical benefit may continue E7050, with or without Capecitabine (Arm 1), or may continue Capecitabine alone (Arm 2), depending on the original randomization treatment arm. Patients will continue treatment for as long as clinical benefit is sustained and the treatment is well tolerated, until the occurrence of progressive disease (PD), unacceptable toxicity, withdrawal of consent, or withdrawal by investigator, whichever occurs first. Patients will participate in either phase Ib or phase II.
Interventions
DRUGE7050
E7050 given orally at either 200, 300, or 400 mg once daily.
DRUGcisplatin
Cisplatin will be administered at 80 mg/m2 by intravenous infusion over 60 minutes on Day 1 of each 21-day treatment cycle.
DRUGcapecitabine
Capecitabine will be administered at 1000 mg/m2 orally, twice daily (2000 mg/m2 total daily dose) on Days 1 through 14 of each 21-day treatment cycle.
Sponsors
Quintiles, Inc.
Eisai Inc.
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
* Histologically confirmed, unresectable, locally advanced or metastatic gastric cancer, including adenocarcinoma of the gastroesophageal junction (Phase II). For the Phase Ib portion, any unresectable, locally advanced or metastatic solid tumor; * ECOG PS of 0-1; * Blood pressure must be well-controlled. Patients must have no history of hypertensive crisis or hypertensive encephalopathy; Adequate end organ function
Exclusion criteria
* Gastric cancer patients who have had a complete gastrectomy; * Patients with known HER2 over-expressing advanced or metastatic gastric cancer; * Previously received E7050, its chemical derivatives, anti-cMet, anti-angiogenic therapy, (prior anti-angiogenic therapy is permitted in Phase Ib only). * For Phase Ib prior systemic therapy is allowed as long as PS and end organ function meet entry criteria; * For Phase II no prior palliative chemotherapy is permitted. Adjuvant/neoadjuvant chemotherapy is permitted if less than 12 months have elapsed between the end of adjuvant/neoadjuvant therapy and first recurrence; * Known central nervous system lesions, except for asymptomatic non-progressing, treated brain metastases. Treatment for brain mets, but have been completed at least 4 weeks prior to Day 1 * Palliative radiotherapy is not permitted throughout the study period. Prior palliative radiotherapy within 30 days prior to commencing study treatment; * Clinically significant hemoptysis; * Patients with known dihydropyrimidine dehydrogenase deficiency; * Patients with clinically significant hearing loss that may be further diminished by treatment with cisplatin plus capecitabine (significance of hearing loss to be determined by the Investigator; * Serious non-healing wound, ulcer, or active bone fracture; * Major surgical procedure, open biopsy, or significant traumatic injury within the 21 days prior to commencing study treatment; * Clinically significant gastrointestinal bleeding within 6 months prior to first dose.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under The Concentration-Time Curve (AUC) From 0 to 24 Hours of Golvatinib | Cycle 1 (Day -2); predose, 30 minutes, 1, 2, 3, 4, 8, 12 (if feasible), 24, and 48 hours after study treatment. Cycle 2 (Day 1); predose, 30 minutes, 1, 2, 3, 4, 8, 12 (if feasible), and 24 hours after study treatment. | On days when pharmacokinetic (PK) samples were to be drawn, a predose blood sample was obtained prior to administration of golvatinib and capecitabine. After administration of study drugs, a second postdose blood sample was taken. The amount of golvatinib in the participant's blood was analyzed and the AUC was calculated. The AUC reflects the actual body exposure to drug after administration of a dose of the drug and is dependent on the rate of elimination of the drug from the body and the dose administered. Predose samples that were below the limit of quantitation (BLQ) or missing were assigned a numerical value of zero for the calculation of AUC. Any other BLQ concentrations were assigned a value of zero. Results were expressed in nanograms·hour/milliter (ng·h/mL). |
| Maximum Concentration (Cmax) of Golvatinib | Cycle 1 (Day -2); predose, 30 minutes, 1, 2, 3, 4, 8, 12 (if feasible), 24, and 48 hours after study treatment. Cycle 2 (Day 1); predose, 30 minutes, 1, 2, 3, 4, 8, 12 (if feasible), and 24 hours after study treatment. | Blood samples were drawn to analyze the amount of golvatinib in the participant's serum. Maximum concentration refers to the maximum (or peak) serum concentration of study drug in the participant's system after administration of the study drug and prior to the administration of a second dose of the study drug. Results were expressed in nanograms/milliliter (ng/mL). |
| Number of Participants With a Treatment-Emergent Adverse Event (TEAE) | From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. | Safety assessments consisted of monitoring and recording all adverse events (AEs) and serious AEs; regular monitoring of hematology, blood chemistry, and urine values; periodic measurement of vital signs and electrocardiograms (ECGs); and performance of physical examinations. A TEAE was defined as an adverse event (AE) that had an onset date, or a worsening in severity from Baseline (pretreatment), on or after the first dose of study drug up to 30 days after the date of last study treatment. |
| Time to Maximum Concentration (Tmax) of Golvatinib | Cycle 1 (Day -2); predose, 30 minutes, 1, 2, 3, 4, 8, 12 (if feasible), 24, and 48 hours after study treatment. Cycle 2 (Day 1); predose, 30 minutes, 1, 2, 3, 4, 8, 12 (if feasible), and 24 hours after study treatment. | Tmax was defined as the time at which Cmax was observed for golvatinib in combination with cisplatin and capecitabine. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | Until disease progression or death for 3 years | The study was terminated prior to enrollment in Phase 2 so this outcome measure was not conducted. |
| Time to Progression (TTP) | Until disease progression or death for 3 years | The study was terminated prior to enrollment in Phase 2 so this outcome measure was not conducted. |
Countries
Russia, Ukraine, United Kingdom, United States
Participant flow
Pre-assignment details
Subjects were to only participate in either the Phase 1b or Phase 2 portion of the study.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1b: Golvatinib+Capecitabine+Cisplatin Oral golvatinib (200 mg) was taken at about the same time each day of every 21-day treatment cycle, with or without food. Oral capecitabine (1000 mg/m\^2 tablet) was taken twice a day (2000 mg/m\^2 total daily) with food at about the same time (after golvatinib), on Days 1 through 14 of each 21-day cycle. At least 2 hours after capecitabine was taken, cisplatin (80 mg/m\^2) was administered by intravenous (IV) infusion over 60 minutes (after appropriate hydration or according to the institutional guidelines), on Day 1 of each 21-day cycle. Pretreatment hydration included 1 liter of normal saline by IV infusion over 120 minutes. Posttreatment hydration included 500 mL normal saline over 60 minutes. The dose level of golvatinib was to be escalated (to 300 and 400 mg) for additional cohorts after 3 participants enrolled into a given cohort unless there was a dose-limiting toxicity (DLT) in the first 3 participants. | 7 |
| Total | 7 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Phase 1b | Death | 4 | 0 | 0 |
| Phase 1b | Study terminated by sponsor | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Phase 1b: Golvatinib+Capecitabine+Cisplatin |
|---|---|
| Age, Customized Age range 47 to 80 years | 7 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 7 / 7 |
| serious Total, serious adverse events | 5 / 7 |
Outcome results
Primary
Area Under The Concentration-Time Curve (AUC) From 0 to 24 Hours of Golvatinib
On days when pharmacokinetic (PK) samples were to be drawn, a predose blood sample was obtained prior to administration of golvatinib and capecitabine. After administration of study drugs, a second postdose blood sample was taken. The amount of golvatinib in the participant's blood was analyzed and the AUC was calculated. The AUC reflects the actual body exposure to drug after administration of a dose of the drug and is dependent on the rate of elimination of the drug from the body and the dose administered. Predose samples that were below the limit of quantitation (BLQ) or missing were assigned a numerical value of zero for the calculation of AUC. Any other BLQ concentrations were assigned a value of zero. Results were expressed in nanograms·hour/milliter (ng·h/mL).
Time frame: Cycle 1 (Day -2); predose, 30 minutes, 1, 2, 3, 4, 8, 12 (if feasible), 24, and 48 hours after study treatment. Cycle 2 (Day 1); predose, 30 minutes, 1, 2, 3, 4, 8, 12 (if feasible), and 24 hours after study treatment.
Population: Pharmacokinetic (PK) population: All participants in the Safety Population who had sufficient concentration data to derive one or more of the PK parameters. Participants with partial data were evaluated on a case-by-case basis to determine if sufficient data were available for meaningful PK analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1b: Golvatinib+Capecitabine+Cisplatin | Area Under The Concentration-Time Curve (AUC) From 0 to 24 Hours of Golvatinib | Cycle 1, Day -2 | 23400 ng·h/mL |
| Phase 1b: Golvatinib+Capecitabine+Cisplatin | Area Under The Concentration-Time Curve (AUC) From 0 to 24 Hours of Golvatinib | Cycle 2, Day 1 | 26300 ng·h/mL |
Primary
Maximum Concentration (Cmax) of Golvatinib
Blood samples were drawn to analyze the amount of golvatinib in the participant's serum. Maximum concentration refers to the maximum (or peak) serum concentration of study drug in the participant's system after administration of the study drug and prior to the administration of a second dose of the study drug. Results were expressed in nanograms/milliliter (ng/mL).
Time frame: Cycle 1 (Day -2); predose, 30 minutes, 1, 2, 3, 4, 8, 12 (if feasible), 24, and 48 hours after study treatment. Cycle 2 (Day 1); predose, 30 minutes, 1, 2, 3, 4, 8, 12 (if feasible), and 24 hours after study treatment.
Population: Pharmacokinetic (PK) population: All participants in the Safety Population who had sufficient concentration data to derive one or more of the PK parameters. Participants with partial data were evaluated on a case-by-case basis to determine if sufficient data were available for meaningful PK analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1b: Golvatinib+Capecitabine+Cisplatin | Maximum Concentration (Cmax) of Golvatinib | Cycle 1, Day -2 | 1680 ng/mL |
| Phase 1b: Golvatinib+Capecitabine+Cisplatin | Maximum Concentration (Cmax) of Golvatinib | Cycle 2, Day 1 | 1620 ng/mL |
Primary
Number of Participants With a Treatment-Emergent Adverse Event (TEAE)
Safety assessments consisted of monitoring and recording all adverse events (AEs) and serious AEs; regular monitoring of hematology, blood chemistry, and urine values; periodic measurement of vital signs and electrocardiograms (ECGs); and performance of physical examinations. A TEAE was defined as an adverse event (AE) that had an onset date, or a worsening in severity from Baseline (pretreatment), on or after the first dose of study drug up to 30 days after the date of last study treatment.
Time frame: From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month.
Population: Safety Population included all participants who received at least one dose of study drug and who had at least one safety assessment after the first dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b: Golvatinib+Capecitabine+Cisplatin | Number of Participants With a Treatment-Emergent Adverse Event (TEAE) | 7 Participants |
Primary
Time to Maximum Concentration (Tmax) of Golvatinib
Tmax was defined as the time at which Cmax was observed for golvatinib in combination with cisplatin and capecitabine.
Time frame: Cycle 1 (Day -2); predose, 30 minutes, 1, 2, 3, 4, 8, 12 (if feasible), 24, and 48 hours after study treatment. Cycle 2 (Day 1); predose, 30 minutes, 1, 2, 3, 4, 8, 12 (if feasible), and 24 hours after study treatment.
Population: Pharmacokinetic (PK) population: All participants in the Safety Population who had sufficient concentration data to derive one or more of the PK parameters. Participants with partial data were evaluated on a case-by-case basis to determine if sufficient data were available for meaningful PK analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1b: Golvatinib+Capecitabine+Cisplatin | Time to Maximum Concentration (Tmax) of Golvatinib | Cycle 1, Day -2 | 3.00 Hours |
| Phase 1b: Golvatinib+Capecitabine+Cisplatin | Time to Maximum Concentration (Tmax) of Golvatinib | Cycle 2, Day 1 | 6.07 Hours |
Secondary
Overall Response Rate (ORR)
The study was terminated prior to enrollment in Phase 2 so this outcome measure was not conducted.
Time frame: Until disease progression or death for 3 years
Population: The study was terminated prior to enrollment in Phase 2 so this outcome measure was not conducted.
Secondary
Time to Progression (TTP)
The study was terminated prior to enrollment in Phase 2 so this outcome measure was not conducted.
Time frame: Until disease progression or death for 3 years
Population: The study was terminated prior to enrollment in Phase 2 so this outcome measure was not conducted.