Selinexor in Combination With Irinotecan in Adenocarcinoma of Stomach and Distal Esophagus

Study Overview
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Brief Summary
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The main purpose of this study is to see whether the combination of selinexor (KPT-330) and irinotecan can help people with esophageal or stomach cancer. Researchers also want to find out if the combination of selinexor (KPT-330) and irinotecan is safe and tolerable.

Detailed Description
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This is an open label, single group, non-randomized, phase I study with cohort expansion that utilizes the standard 3+3 design for dose. The dose of selinexor will be escalated in combination with the standard doses of irinotecan. The maximum tolerated dose (MTD) for study is defined as the highest dose level at which 1 or less of 6 patients experience a dose limiting toxicity DLT. Once the MTD is reached and/or the recommended dose for expansion is determined, an additional cohort of 15 patients with advanced gastric or esophageal cancer will be accrued to better define the safety and tolerability of the combination regimen.

Official Title
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An Investigator Sponsored Phase 1a/1b Trial of Selinexor in Combination With Irinotecan in Patients With Adenocarcinoma of Stomach and Distal Esophagus

Conditions
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Esophageal Cancer, Gastric Cancer

Intervention / Treatment
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* Drug: Selinexor
* Drug: Irinotecan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have histologically confirmed gastric, gastro-esophageal junction or distal esophageal adenocarcinoma (predominant histology) that is recurrent, metastatic or unresectable Must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1 Must have received at least one line but less than three lines of prior systemic therapies and have either progressed or intolerant to prior therapies. Patients who have received adjuvant/neoadjuvant therapy within last one year will be eligible as well. Eastern Cooperative Oncology Group (ECOG) performance status ≤1 Life expectancy of greater than 3 months Must have normal organ and marrow function Women of child-bearing potential (WOCBP) must agree to use dual methods of contraception and have a negative serum pregnancy test at screening. Male participants must use an effective barrier method of contraception if sexually active with a WOCBP. For both male and female participants, effective methods of contraception must be used throughout the study and for three months following the last dose. Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Have had chemotherapy, biologic therapy or radiotherapy within 3 weeks prior to entering the study Are receiving any other investigational agents for anti-cancer treatment within 3 weeks of starting study medication Symptomatic central nervous system (CNS) metastases Progression on irinotecan containing regimen History of allergic reactions attributed to compounds of similar chemical or biologic composition to irinotecan Major surgery within 2 weeks before cycle 1 Day 1 (C1D1) Unstable cardiovascular function Patients who are pregnant or lactating Uncontrolled infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose; patients with controlled infection or on prophylactic antibiotics are permitted in the study. Known active hepatitis A, B, or C infection; or known to be positive for HCV RNA or HBsAg (HBV surface antigen) Any underlying condition that would significantly interfere with the absorption of an oral medication > Grade 2 peripheral neuropathy at baseline Serious psychiatric or medical conditions that could interfere with treatment Concurrent therapy with approved or investigational anticancer therapeutic other than steroids History of gastrointestinal perforation and/or fistulae within 6 months prior to C1D1 Use of strong CYP3A4 inducers or inhibitors within 2 weeks of starting study medication

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: Selinexor in Combination with Irinotecan<br>The first study drug is called selinexor (KPT-330). This drug is taken by mouth on days 1, 3, 8 and 10 of each cycle. The starting dose of selinexor will be dependent on the cohort in which the patient is enrolled into. Level -1: 25 mg/m^2; Level 1: 40 mg/m^2; Level 2: 50 mg/m^2; Level 3: 65 mg/m^2. The second drug is called irinotecan. This drug is given as intravenous (IV) infusion on days 1 and 8 of each cycle. Participants will receive the standard recommended dose: 125 mg/m^2. | Drug: Selinexor<br>* Selinexor is a potent slowly reversible covalent Selective Inhibitor of Nuclear Export (SINE) that specifically blocks the karyopherin protein Exportin 1 or XPO1.<br>* Other names: KPT-330;Drug: Irinotecan<br>* Irinotecan is a topoisomerase inhibitor and is approved by FDA to treat colorectal cancer. It is administered intravenously.<br>* Other names: Camptosar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) | The MTD for study is defined as the highest dose level at which 1 or less of 6 patients experience a dose limiting toxicity (DLT). | Up to 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Progression will be evaluated using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). | Up to 18 months | 
| Objective Response Rate (ORR) | Only those participants who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response. Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. | Up to 18 months | 
| Best Overall Response | The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). Response will be evaluated using RECIST guideline V 1.1. Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. | Up to 18 months | 
| Overall Survival (OS) | Overall Survival is defined as the time period from start of treatment to death. | Up to 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Distal Esophagus, Esophageal, Gastric, Carcinoma, Adenocarcinoma, Stomach, Gastro-esophageal junction, Recurrent, Metastatic, Unresectable