Study of Crenolanib With Ramucirumab and Paclitaxel for Advanced Esophagogastric Adenocarcinoma

Study Overview
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Brief Summary
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This is a single-arm phase I/Ib study of crenolanib combined with ramucirumab/paclitaxel as second line therapy for patients with advanced/metastatic adenocarcinoma of the esophagus, GEJ or stomach. Patients will be enrolled in two phases; dose escalation phase and dose expansion phase.

Official Title
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Phase I/Ib Study of Crenolanib With Ramucirumab and Paclitaxel as Second Line Therapy for Advanced Esophagogastric Adenocarcinoma

Conditions
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Esophagogastric Adenocarcinoma

Intervention / Treatment
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* Drug: Crenolanib
* Drug: Ramucirumab
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically confirmed adenocarcinoma of the esophagus, GEJ or stomach. Stage IV disease or locally advanced/unresectable tumors Prior progression on only 1 line of chemotherapy in the advanced/metastatic setting containing a fluoropyrimidine and/or platinum compound Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 Exclusion Criteria: Prior treatment with a taxane is not permitted in the dose-expansion phase. Patients in the dose escalation component may have received a taxane in the peri-operative setting, provided they developed disease recurrence >6 months after the completion of this therapy Known pre-existing liver disease (e.g. cirrhosis, chronic hepatitis B or C, nonalcoholic steatohepatitis, sclerosing cholangitis) Patients with any clinically apparent ascites or who have undergone a paracentesis within 7 days of enrollment Uncontrolled hypertension (systolic pressure >140 mm Hg or diastolic pressure > 90 mm Hg on repeated measurement) despite optimal medical management Active or clinically significant cardiac disease Patients with arterial thrombotic events, such as cerebrovascular accident or myocardial infarction, within 6 months of enrollment

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Crenolanib combined with ramucirumab/paclitaxel<br> | Drug: Crenolanib<br>* Crenolanib continuously on Days 1-28 at 1 of 3 BID doses - 60 mg, 80 mg or 100 mg<br>Drug: Ramucirumab<br>* Ramucirumab IV 8 mg/kg on Days 1 and 15 q28 days<br>Drug: Paclitaxel<br>* Paclitaxel IV 80 mg/m2 on Days 1, 8 and 15 q28 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD of oral continuous dosing of crenolanib (3 different doses) plus ramucirumab/paclitaxel in patients defined as the highest dose level in which <2 of 6 patients develop a DLT. The DLT is based on the 1st cycle adverse events. | The DLT is based on the first cycle (35 days) adverse events. If at least 2 of 3 or 2 of up to 6 patients experience a DLT at the starting dose level, then the study will be paused and the starting dose will be re-assessed. The MTD is defined as the highest dose level in which <2 of 6 patients develop a DLT. This will constitute the first part of the study which will enroll a maximum of 18 patients. | 5 weeks | 
| Response rate (RR) of the combination in patients will be radiographically evaluated until progressive disease (PD), intolerable toxicity, withdrawal of consent, physician's decision, death or the completion of 6 cycles. adenocarcinoma patients |  | Bi-monthly for up to 6 months. |