A Study of TRK-950 When Used in Combination With Ramucirumab and Paclitaxel in Patients With Gastric Cancer

Study Overview
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Brief Summary
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This study will assess the efficacy, safety, optimal dose and ADA and NAbs development of TRK-950 at two separate dose levels in combination with ramucirumab and paclitaxel (RAM+PTX) as compared with RAM + PTX treatment alone in participants with gastric or gastro-esophageal junction (GEJ) adenocarcinoma.

Detailed Description
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This study will assess and compare the efficacy, safety, pharmacokinetics (PK), optimal dose and anti-drug antibodies (ADA) and neutralizing antibodies (NAbs) development of TRK-950 at two separate dose levels in combination with RAM + PTX as compared with RAM + PTX treatment alone in participants with gastric or gastro-esophageal junction (GEJ) adenocarcinoma. The primary objective is progression free survival (PFS). Secondary objectives are overall survival, objective response rate, best overall response, duration of response, disease control rate, safety, pharmacokinetics, and immunogenicity of TRK-950 when used in combination with RAM+PTX.

Official Title
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A Randomized, Multicenter, Open-Label, Phase 2 Study of TRK-950 When Used in Combination With Ramucirumab and Paclitaxel in Patients With Gastric Cancer

Conditions
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Gastric Cancer, Gastric Adenocarcinoma, Gastroesophageal Junction Adenocarcinoma

Intervention / Treatment
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* Biological: TRK-950
* Drug: Ramucirumab
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed metastatic, or locally advanced and unresectable gastric or GEJ adenocarcinoma. The patient is eligible to receive Ramucirumab + Paclitaxel as second-line therapy. Documented objective radiographic or clinical disease progression (e.g., any new or worsening malignant effusion documented by ultrasound examination) which may be confirmed by pathologic criteria (histology and/or cytology) if appropriate, during any first line therapy or within 4 months after the last dose of first-line therapy for metastatic or locally advanced disease. Presence of primary or metastatic disease, measurable per RECIST v1.1 on CT scan. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. Life expectancy of at least 3 months. Age ≥ 18 years in the US and Japan, and ≥ 19 years of age in Korea. Signed, written IRB-approved informed consent. Adequate organ function from specimens collected within 14 days prior to Day 1. For men and women of child-producing potential, the use of effective contraceptive methods during the study and for 6 months after the last dose of TRK-950. All patients must sign a pre-screening consent to assess tumor tissue to determine eligibility. Tumor tissue must be evaluable for CAPRIN-1 staining at a CLIA certified laboratory and meet or exceed the cutoff value (30% at ≥ 2+ staining) as defined in the expression level requirements. Exclusion Criteria: Prior history of treatment with ramucirumab or paclitaxel. HER2 positive gastric or GEJ adenocarcinoma. Major surgery within 28 days prior to randomization. Baseline corrected QT (QTc) interval of > 470 msec for females and > 450 msec for males calculated using Fridericia's formula. New York Heart Association Class II - IV symptomatic congestive heart failure, or symptomatic or poorly controlled cardiac arrhythmia. The patient has experienced any arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, within 3 months prior to randomization. The patient has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis. Clinically symptomatic venous thromboembolism or treatment with anti-coagulants. Uncontrolled arterial hypertension ≥ 150 mmHg (systolic) or ≥ 90 mmHg (diastolic) despite standard medical management. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy. Pregnant or nursing women. Treatment with radiation therapy within 2 weeks, or treatment with chemotherapy, immunotherapy, targeted therapy, or investigational therapy within 4 weeks prior to randomization (within 2 weeks for Oral FU (S1 and capecitabine)). The patient has significant bleeding disorders, vasculitis, or had a significant bleeding episode from the gastrointestinal tract within 3 months prior to randomization. Clinically significant ascites, paracentesis in the last 3 months, or undergoes regular paracentesis procedures. History of gastrointestinal perforation and/or fistulae within 6 months prior to randomization. The patient has a serious or non-healing wound, peptic ulcer, or bone fracture within 28 days prior to randomization. The patient has a bowel obstruction, history or presence of inflammatory enteropathy or extensive intestinal resection (e.g., hemicolectomy or extensive small intestine resection with chronic diarrhea), Crohn's disease, ulcerative colitis, or chronic diarrhea. Known active infection with HIV, hepatitis B or hepatitis C. Patients with a history of hepatitis B or C are allowed if HBV DNA or Hep C RNA are undetectable. The patient is currently enrolled in or discontinued within the last 28 days from a clinical trial involving an investigational product or non-approved use of a drug, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study. Patients participating in surveys or observational studies are eligible to participate in this study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: TRK-950(5 mg/kg)+Ramucirumab+Paclitaxel<br>Participants who will be randomized to receive a 5 mg/kg intravenous(IV) dose of TRK-950 on days 1, 8, 15 and 22 in combination with 8 mg/kg IV dose of ramucirumab on days 1 and 15 and 80 mg/m^2 IV dose of paclitaxel on Days 1, 8, and 15 of a 28-day cycle. | Biological: TRK-950<br>* 5 mg/kg or 10 mg/kg IV infusion over 60 minutes on Day 1, 8, 15 and 21 of each 28 day cycle<br>Drug: Ramucirumab<br>* 8 mg/kg IV infusion on Days 1 and 15 of a 28-day cycle<br>* Other names: CYRAMZA®;Drug: Paclitaxel<br>* 80 mg/m^2 IV infusion on Days 1, 8, and 15 of a 28-day cycle<br>|
| Experimental: Arm B: TRK-950(10 mg/kg)+Ramucirumab+Paclitaxel<br>Participants who will be randomized to receive a 10 mg/kg intravenous(IV) dose of TRK-950 on days 1, 8, 15 and 22 in combination with 8 mg/kg IV dose of ramucirumab on days 1 and 15 and 80 mg/m^2 IV dose of paclitaxel on Days 1, 8, and 15 of a 28-day cycle. | Biological: TRK-950<br>* 5 mg/kg or 10 mg/kg IV infusion over 60 minutes on Day 1, 8, 15 and 21 of each 28 day cycle<br>Drug: Ramucirumab<br>* 8 mg/kg IV infusion on Days 1 and 15 of a 28-day cycle<br>* Other names: CYRAMZA®;Drug: Paclitaxel<br>* 80 mg/m^2 IV infusion on Days 1, 8, and 15 of a 28-day cycle<br>|
| Active Comparator: Arm C: Ramucirumab+Paclitaxel<br>Participants who will be randomized to receive a 8 mg/kg IV dose of ramucirumab on Days 1 and 15 in combination with 80 mg/m^2 IV dose of paclitaxel on Days 1, 8, and 15 of a 28-day cycle. | Drug: Ramucirumab<br>* 8 mg/kg IV infusion on Days 1 and 15 of a 28-day cycle<br>* Other names: CYRAMZA®;Drug: Paclitaxel<br>* 80 mg/m^2 IV infusion on Days 1, 8, and 15 of a 28-day cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free Survival (PFS) | Progression free Survival (PFS) is defined as time from the date of randomization to the date of progressive disease or death due to any cause based on Independent Central Review. | Time from date of randomization to the date of progressive disease or death due to any cause, whichever occurs first, up to approximately 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | Overall survival is defined as the time from the date of randomization to the date of death due to any cause. | Time from the date of randomization to the date of death due to any cause, up to approximately 24 months | 
| Objective response rate (ORR) | Objective response rate (ORR) is defined as the proportion of participants who achieve a best overall response of complete response (CR) or partial response (PR) using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) criteria as assessed by Independent Central Review. | From start of treatment to date of documented disease progression, up to approximately 24 months | 
| Progression free Survival (PFS) | Progression free Survival (PFS) is defined as time from the date of randomization to the date of progressive disease or death due to any cause based on investigator assessment. | Time from date of randomization to the date of progressive disease or death due to any cause, whichever occurs first, up to approximately 24 months | 
| Objective response rate (ORR) | Objective response rate (ORR) is defined as the proportion of participants who achieve a best overall response of complete response (CR) or partial response (PR) using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) criteria as assessed by investigator. | From start of treatment to date of documented disease progression, up to approximately 24 months | 
| Best overall response (BOR) | The best overall response is defined as the best overall response (BOR) recorded from the start of treatment until the end of treatment and includes CR, PR, stable disease (SD), progressive disease (PD) and not evaluable (NE) using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) criteria as assessed by Independent Central Review based. | From start of treatment to date of documented disease progression, up to approximately 24 months | 
| Best overall response (BOR) | The best overall response is defined as the best overall response (BOR) recorded from the start of treatment until the end of treatment and includes CR, PR, stable disease (SD), progressive disease (PD) and not evaluable (NE) using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) criteria as assessed by investigator. | From start of treatment to date of documented disease progression, up to approximately 24 months | 
| Disease control rate (DCR) | Disease control rate (DCR) is defined as the proportion of participants who achieve a best overall response of complete response (CR), partial response (PR) or stable disease (SD) for a minimum of 6 weeks using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) criteria as assessed by Independent Central Review based. | From start of treatment to date of documented disease progression, up to approximately 24 months | 
| Disease control rate (DCR) | Disease control rate (DCR) is defined as the proportion of participants who achieve a best overall response of complete response (CR), partial response (PR) or stable disease (SD) for a minimum of 6 weeks using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) criteria as assessed by investigator. | From start of treatment to date of documented disease progression, up to approximately 24 months | 
| Duration of response (DoR) | Duration of response (DoR) is defined as the time from the initial response (CR or PR) until documented tumor progression or death from any cause based on Independent Central Review based. | Time from initial response (CR or PR) to date of documented disease progression or death due to any cause, whichever occurs first, up to approximately 24 months | 
| Duration of response (DoR) | Duration of response (DoR) is defined as the time from the initial response (CR or PR) until documented tumor progression or death from any cause based on investigator assessment. | Time from initial response (CR or PR) to date of documented disease progression or death due to any cause, whichever occurs first, up to approximately 24 months | 
| Incidence of Treatment-emergent Adverse Events (TEAE) | Adverse events will be graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events Version 5.0. | From time subjects are enrolled up to 45 days after last study dose | 
| Serious Adverse Events (SAEs) | Adverse events will be graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events Version 5.0. | From time subjects are enrolled up to 45 days after last study dose | 
| Adverse Events of Special Interest (AESI) | Adverse events will be graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events Version 5.0. | From time subjects are enrolled up to 45 days after last study dose | 
| Incidence of Discontinuation due to AE | Adverse events will be graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events Version 5.0. | From time subjects are enrolled up to 45 days after last study dose | 
| Incidence of Physical Examination Findings, Vital sign measurements, Standard clinical laboratory parameters, ECG parameters |  | From time subjects signs informed consent form up to 45 days after last study dose | 
| Pharmacokinetic Parameter of Concentration of drug at the end of infusion (CEOI) of TRK-950 |  | Cycle 1 on day 1 and 15, subsequent cycles on day 1 (each cycle is 28 days) | 
| Pharmacokinetic Parameter of Trough Serum Concentration (Ctrough) of TRK-950 |  | Cycle 1 on day 1 and 15, subsequent cycles on day 1 (each cycle is 28 days) | 
| Pharmacokinetic Parameter of Area Under the Curve (AUC) of TRK-950 |  | Cycle 1 on day 1 and 15, subsequent cycles on day 1 (each cycle is 28 days) | 
| Pharmacokinetic Parameter of Concentration of drug at the end of infusion (CEOI) of Ramucirumab |  | Cycle 1 and 4 on day 1 and 15, Cycles 2, 3 and subsequent cycles on day 1 (each cycle is 28 days) | 
| Pharmacokinetic Parameter of Trough Serum Concentration (Ctrough) of Ramucirumab |  | Cycle 1 and 4 on day 1 and 15, Cycles 2, 3 and subsequent cycles on day 1 (each cycle is 28 days) | 
| Pharmacokinetic Parameter of Area Under the Curve (AUC) of Ramucirumab |  | Cycle 1 and 4 on day 1 and 15, Cycles 2, 3 and subsequent cycles on day 1 (each cycle is 28 days) | 
| Pharmacokinetic Parameter of Concentration of drug at the end of infusion (CEOI) of Paclitaxel |  | Cycle 1 and 4 on day 1 and 15 (each cycle is 28 days) | 
| Pharmacokinetic Parameter of Trough Serum Concentration (Ctrough) of Paclitaxel |  | Cycle 1 and 4 on day 1 and 15 (each cycle is 28 days) | 
| Pharmacokinetic Parameter of Area Under the Curve (AUC) of Paclitaxel |  | Cycle 1 and 4 on day 1 and 15 (each cycle is 28 days) | 
| Percentage of participants who are Anti-drug antibody (ADA)-Positive and Neutralizing antibodies (NAbs) |  | Cycle 1 on day 1 and 15, subsequent cycles on day 1 (each cycle is 28 days) | 
| Change from Baseline in Patient Reported Quality of Life assessed by the Questionnaire - Core questionnaire EORTC QLQ-C30 scores | The EORTC QLQ-C30 consists of 30 questions assessing global health-related quality of life for cancer patients. It incorporates five functional scale (physical, emotional, role, cognitive, and social), three symptom scales (fatigue, nausea and vomiting, and pain), and six single-items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. | From Cycle 1 on day 1 through study completion, up to approximately 24 months (each cycle is 28days) | 
| Change from Baseline in Patient Reported Quality of Life assessed by Questionnaire - EuroQOL Five Dimensions questionnaire 3L (EQ-5D-3L) scores | The EQ-5D questionnaire consists of the following five dimensions, each describing a different aspect of health: Mobility, Self-Care, Usual Activities, Pain/Discomfort and Anxiety/ Depression. The participants self-assess each dimension has three response levels of severity: no problems, some problems, extreme problems. | From Cycle 1 on day 1 through study completion, up to approximately 24 months (each cycle is 28days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CAPRIN-1, Gastric Cancer, Adenocarcinoma, Gastroesophageal Junction Adenocarcinoma, TRK-950