Tucatinib, Trastuzumab, Ramucirumab, and Paclitaxel Versus Paclitaxel and Ramucirumab in Previously Treated HER2+ Gastroesophageal Cancer

Study Overview
=================
Brief Summary
-----------------
This study is being done to see if tucatinib with trastuzumab, ramucirumab and paclitaxel works better than ramucirumab and paclitaxel to treat HER2-positive (HER2+) cancer of the gut (stomach or gastroesophageal cancer). This study will also look at what side effects happen when participants take this combination of drugs. A side effect is anything the drug does other than treating cancer. Study treatment will be given in 28-day cycles. In the Phase 2 part of the trial, participants and their doctors will know what drugs are being given (open-label). In the Phase 3 part, the study is blinded. This means that participants, their doctor, and the study sponsor will not know which drugs are being given.

Official Title
-----------------
A Randomized, Double-blind, Placebo-controlled, Active Comparator Phase 2/3 Study of Tucatinib in Combination With Trastuzumab, Ramucirumab, and Paclitaxel in Subjects With Previously Treated, Locally-advanced Unresectable or Metastatic HER2+ Gastric or Gastroesophageal Junction Adenocarcinoma (GEC)

Conditions
-----------------
Gastric Adenocarcinoma, Gastroesophageal Junction Adenocarcinoma, Esophageal Adenocarcinoma

Intervention / Treatment
-----------------
* Drug: tucatinib
* Drug: trastuzumab
* Drug: ramucirumab
* Drug: paclitaxel
* Other: tucatinib placebo
* Other: trastuzumab placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically or cytologically confirmed diagnosis of locally-advanced unresectable or metastatic HER2+ gastric or gastroesophageal junction adenocarcinoma (GEC) HER2+ disease documented since progression of the most recent line of systemic therapy, as follows: Phase 2 paclitaxel dose optimization stage: HER2 amplification in a blood-based NGS assay performed at a central laboratory, or HER2 overexpression/amplification immunohistochemistry (IHC) and in situ hybridization (ISH) (IHC3+ or IHC2+/ISH+) assay of a tumor tissue sample Phase 2 dose expansion stage: Cohort 2A: HER2 amplification in a blood-based NGS assay performed at a central laboratory Cohort 2B: No HER2 amplification by blood-based NGS assay, but HER2 overexpression/amplification by IHC and ISH (IHC3+ or IHC2+/ISH+) assay of a tumor tissue sample Phase 3: HER2 amplification in a blood-based NGS assay performed at a central laboratory History of prior treatment with a HER2-directed antibody Progressive disease during or after first-line therapy for locally-advanced unresectable or metastatic GEC Phase 2: Measurable disease according to RECIST version 1.1 Phase 3: Measurable or non-measurable disease according to RECIST version 1.1 Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 Life expectancy of at least 3 months, in the opinion of the investigator Exclusion Criteria: Subjects with squamous cell or undifferentiated GEC Having received more than 1 line of prior systemic therapy for locally-advanced unresectable or metastatic disease Having received taxanes ≤12 months prior to enrollment, prior treatment with ramucirumab, or prior treatment with tucatinib, lapatinib, neratinib, afatinib, or any other investigational anti-HER2 and/or anti-EGFR tyrosine kinase inhibitor, or with T-DM1, T-Dxd, or any other HER2-directed antibody-drug conjugate Phase 2 paclitaxel dose optimization stage only: history of prior partial or total gastrectomy Unable to swallow pills

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 2 Arm<br>Tucatinib + trastuzumab + ramucirumab + paclitaxel | Drug: tucatinib<br>* 300 mg given twice daily orally<br>* Other names: TUKYSA, ONT-380, ARRY-380;Drug: trastuzumab<br>* 6 mg/kg loading dose will be administered intravenously (IV; into the vein) on Cycle 1 Day 1, followed by 4 mg/kg IV on Cycle 1 Day 15 and then Days 1 and 15 of each cycle thereafter<br>Drug: ramucirumab<br>* 8 mg/kg will be administered IV on Days 1 and 15 of each cycle<br>* Other names: CYRAMZA;Drug: paclitaxel<br>* 60 or 80 mg/m^2 IV on Days 1, 8, and 15 of each cycle<br>|
| Experimental: Arm 3A<br>Tucatinib + trastuzumab + ramucirumab + paclitaxel | Drug: tucatinib<br>* 300 mg given twice daily orally<br>* Other names: TUKYSA, ONT-380, ARRY-380;Drug: trastuzumab<br>* 6 mg/kg loading dose will be administered intravenously (IV; into the vein) on Cycle 1 Day 1, followed by 4 mg/kg IV on Cycle 1 Day 15 and then Days 1 and 15 of each cycle thereafter<br>Drug: ramucirumab<br>* 8 mg/kg will be administered IV on Days 1 and 15 of each cycle<br>* Other names: CYRAMZA;Drug: paclitaxel<br>* 60 or 80 mg/m^2 IV on Days 1, 8, and 15 of each cycle<br>|
| Active Comparator: Arm 3B<br>Ramucirumab + paclitaxel + tucatinib placebo + trastuzumab placebo | Drug: ramucirumab<br>* 8 mg/kg will be administered IV on Days 1 and 15 of each cycle<br>* Other names: CYRAMZA;Drug: paclitaxel<br>* 60 or 80 mg/m^2 IV on Days 1, 8, and 15 of each cycle<br>Other: tucatinib placebo<br>* Given twice daily orally<br>Other: trastuzumab placebo<br>* IV on Days 1 and 15 of each cycle<br>|
| Experimental: Arm 3C<br>Tucatinib + ramucirumab + paclitaxel + trastuzumab placebo | Drug: tucatinib<br>* 300 mg given twice daily orally<br>* Other names: TUKYSA, ONT-380, ARRY-380;Drug: ramucirumab<br>* 8 mg/kg will be administered IV on Days 1 and 15 of each cycle<br>* Other names: CYRAMZA;Drug: paclitaxel<br>* 60 or 80 mg/m^2 IV on Days 1, 8, and 15 of each cycle<br>Other: trastuzumab placebo<br>* IV on Days 1 and 15 of each cycle<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) (Phase 3 only) | OS is defined as the time from randomization to death due to any cause | 60 months | 
| Progression-free survival (PFS) per Response evaluation criteria in solid tumors (RECIST) version 1.1 according to investigator assessment (Phase 3 only) | PFS is defined as the time from randomization to the date of disease progression or death from any cause | 36 months | 
| Incidence of dose-limiting toxicities (DLTs) (Phase 2 only) |  | During first cycle of treatment; up to one month | 
| Incidence of adverse events (AEs) (Phase 2 only) | An adverse event is any untoward medical occurrence in a subject or clinical investigational subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment. | 18 months | 
| Incidence of laboratory abnormalities (Phase 2 only) | To be summarized using descriptive statistics. | 18 months | 
| Incidence of dose modifications (Phase 2 only) |  | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed objective response rate (ORR) per RECIST version 1.1 according to investigator assessment (Phases 2 and 3) | ORR is defined as the proportion of subjects with best overall response of CR or PR | 36 months | 
| ORR per RECIST version 1.1 according to investigator assessment (Phases 2 and 3) | ORR is defined as the proportion of subjects with best overall response of CR or PR | 36 months | 
| Duration of response (DOR) per RECIST version 1.1 according to investigator assessment (Phases 2 and 3) | DOR is defined as the time from first documentation of objective response of CR or PR to the first documentation of disease progression or death from any cause | 36 months | 
| Disease control rate (DCR) per RECIST version 1.1 according to investigator assessment (Phases 2 and 3) | DCR is defined as subjects with CR, PR, or stable disease (SD or non-CR/non-progressive disease) | 36 months | 
| PFS per RECIST v1.1 according to blinded independent central review (BICR) assessment (Phase 3 only) | PFS is defined as the time from randomization to the date of disease progression or death from any cause | 36 months | 
| Confirmed ORR per RECIST version 1.1 according to BICR assessment (Phase 3 only) | ORR is defined as the proportion of subjects with best overall response of CR or PR | 36 months | 
| ORR per RECIST version 1.1 according to BICR assessment (Phase 3 only) | ORR is defined as the proportion of subjects with best overall response of CR or PR | 36 months | 
| DOR per RECIST version 1.1 according to BICR assessment (Phase 3 only) | DOR is defined as the time from first documentation of objective response of CR or PR to the first documentation of disease progression or death from any cause | 36 months | 
| DCR per RECIST version 1.1 according to BICR assessment (Phase 3 only) | DCR is defined as subjects with CR, PR, or stable disease (SD or non-CR/non-progressive disease) | 36 months | 
| Incidence of AEs (Phase 3 only) | An adverse event is any untoward medical occurrence in a subject or clinical investigational subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment. | 36 months | 
| Incidence of laboratory abnormalities (Phase 3 only) | To be summarized using descriptive statistics. | 36 months | 
| Incidence of dose modifications (Phase 3 only) |  | 36 months | 
| PFS per RECIST version 1.1 according to investigator assessment (Phase 2 only) | PFS is defined as the time from the date of treatment initiation to the date of disease progression or death from any cause | 18 months | 
| Area under the plasma concentration-time curve (AUC) to the time of the last quantifiable concentration (AUClast) of tucatinib (Phase 2 only) | Pharmacokinetic (PK) parameter | 1 month | 
| AUC to AUClast of paclitaxel (Phase 2 only) | PK parameter | 1 month | 
| Maximum observed concentration (Cmax) of tucatinib (Phase 2 only) | PK parameter | 1 month | 
| Cmax of paclitaxel (Phase 2 only) | PK parameter | 1 month | 
| Time of Cmax (Tmax) of tucatinib (Phase 2 only) | PK parameter | 1 month | 
| Tmax of paclitaxel (Phase 2 only) | PK parameter | 1 month | 
| Trough concentration (Ctrough) of tucatinib (Phase 2 only) | PK parameter | 18 months | 
| Ctrough of paclitaxel (Phase 2 only) | PK parameter | 18 months | 
| Metabolic ratio of tucatinib based on AUC (MRAUC) (Phase 2 only) | PK parameter | 1 month | 
| MRAUC of paclitaxel (Phase 2 only) | PK parameter | 1 month | 
| Time to deterioration of GEC symptoms as assessed by the European Organisation for Research and Treatment or Cancer (EORTC) quality of life questionnaire (QLQ)-C30 and EORTC QLQ-OG25 questionnaires. | The EORTC questionnaires measure aspects of health-related quality of life (HRQoL). Time to deterioration will be assessed in specific pre-specified single items from either the EORTC QLQ-C30 or EORTC QLQ OG25 and deterioration is defined as a 10-point increase from baseline in the symptom scales and a 10-point decrease from baseline for overall HRQoL. | 36 months | 
| Change from baseline in health-related quality of life (HRQoL) |  | 36 months | 
| Utility index values as assessed by the EQ-5D-5L | The EQ-5D-5L questionnaire is used as a preference based measurement of HRQoL outcomes. Data will be summarized using descriptive statistics. | 36 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
HER2+, HER2-positive, GEA, GEC, GEJ, Seattle Genetics