Pilot Trial of CRLX101 in Treatment of Patients With Advanced or Metastatic Stomach, Gastroesophageal, or Esophageal Cancer That Cannot be Removed by Surgery

Study Overview
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Brief Summary
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This pilot clinical trial studies cyclodextrin-based nanopharmaceutical CRLX101 in treating patients with advanced or metastatic stomach, gastroesophageal, or esophageal cancer that has progressed through at least one prior regimen of chemotherapy and cannot be removed by surgery. CRLX101 delivers the cytotoxic topoisomerase-1 inhibitor camptothecin into tumor cells and is hypothesized to interrupt the growth of tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate pre- and post-treatment biopsies to assess CRLX101 (cyclodextrin-based polymer-camptothecin CRLX101) nanoparticle and 20(S)-Camptothecin (CPT) uptake in tumor and normal tissue. SECONDARY OBJECTIVES: I. To evaluate the safety and toxicity of CRLX101 in this patient population. II. To examine the antitumor efficacy of CRLX101 in advanced gastric/gastroesophageal junction (GEJ)/esophageal squamous or adenocarcinoma including clinical benefit rate (complete response [CR] + partial response [PR] + stable disease [SD]) at 4 months and overall survival. OUTLINE: Patients receive cyclodextrin-based polymer-camptothecin CRLX101 intravenously (IV) over 60 minutes on days 1 and 15. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients achieving stable disease or better, may receive treatment for an additional 6 months. After completion of study treatment, patients are followed up monthly.

Official Title
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Pilot Trial of CRLX101 in the Treatment of Patients With Advanced Gastric, Gastroesophageal, or Esophageal Squamous or Adenocarcinoma

Conditions
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Adenocarcinoma of the Esophagus, Adenocarcinoma of the Gastroesophageal Junction, Diffuse Adenocarcinoma of the Stomach, Intestinal Adenocarcinoma of the Stomach, Mixed Adenocarcinoma of the Stomach, Recurrent Esophageal Cancer, Recurrent Gastric Cancer, Squamous Cell Carcinoma of the Esophagus, Stage IIIB Esophageal Cancer, Stage IIIB Gastric Cancer, Stage IIIC Esophageal Cancer, Stage IIIC Gastric Cancer, Stage IV Esophageal Cancer, Stage IV Gastric Cancer

Intervention / Treatment
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* Drug: cyclodextrin-based polymer-camptothecin CRLX101
* Other: Laboratory biomarker analysis
* Other: Pharmacological studies


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically confirmed advanced or metastatic squamous adenocarcinoma of the esophagus, GEJ, or stomach Patients must have primary tumor and adjacent normal tissue accessible via endoscopic biopsy Patients must have received at least one prior chemotherapy regimen for their unresectable or metastatic disease, not including treatment administered in the adjuvant and/or neoadjuvant setting for curative intent Patients must have measurable or evaluable disease Absolute neutrophil count >= 1500 cells/uL Platelets >= 100,000 cells/uL Total bilirubin =< 1.5 times the upper limit of normal (ULN) Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN AST/ALT =< 5 x ULN if liver metastasis is present Serum creatinine =< 1.5 mg/dL or a measured creatinine clearance >= 50 mL/min Prothrombin time (PT)/partial thromboplastin time (PTT) =< 1.5 x ULN Subjects with an Eastern Cooperative Oncology Group (ECOG) performance status of =< 2 Subjects with a life expectancy >= 12 weeks Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for six months following duration of study participation; should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately and be discontinued on study; subjects should be instructed to notify the investigator if it is determined after completion of the study that they became pregnant during the treatment phase of the study; the anticipated date or birth or termination of the pregnancy should be provided at the time of the initial report; whenever possible, a pregnancy should be followed to term, any premature terminations reported, and the status of the mother and the child should be reported to the study monitor after delivery; if the outcome of the pregnancy meets any severe adverse events (SAE) classification criterion, the investigator must follow the procedures for reporting SAEs; any neonatal death occurring =< 30 days after birth must also be reported as a SAE Subjects must have an electrocardiogram without evidence of clinically significant conduction abnormalities or active ischemia as determined by the investigator and an acceptable QTc interval All subjects must have the ability to understand and the willingness to sign a written informed consent Subjects must not have received prior chemotherapy or radiation within < 4 weeks prior to first dose of study drug Subjects may be entered if they have received prior radiation therapy involving =< 30% of the bone marrow; any prior radiation therapy must have been administered >= 4 weeks prior to first dose of study drug and the subject must be recovered from the acute toxic effects of the treatment prior to first dose of study drug (defined as a return to baseline or a severity of =< grade 1) Subjects may be enrolled with a history of treated brain metastases that are clinically stable for >= 4 weeks prior to the first dose of study drug; subjects may not be currently receiving dexamethasone Exclusion Criteria: Female subjects who are pregnant or nursing Subjects who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to first dose of study drug or those who have not had adverse events return to baseline severity level or a severity of grade 1 due to agents administered more than 4 weeks prior to first dose of study drug Subjects with a history of congestive heart failure (CHF) requiring medical therapy Subjects with serum amylase or lipase > 1.5 ULN Subjects with previous high dose chemotherapy with autologous stem cell rescue bone marrow transplantation History of organ or allogeneic bone marrow transplant Use of any investigational agent or device within 4 weeks prior to first dose of study drug Metastatic disease to the central nervous system (CNS) requiring treatment or radiation therapy Subjects with known untreated brain metastases or treated brain metastases that have not been stable >= 4 weeks prior to first dose of study drug Uncontrolled intercurrent illness including, but not limited to ongoing or active infection (including human immunodeficiency virus [HIV] not stable on antiretroviral therapy), symptomatic congestive heart failure, hypertension, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements, as determined by the investigator History of prior malignancy not cured by excision; patients with non-melanoma skin cancer or carcinoma in situ of the cervix are not excluded, but patients with other prior malignancies must have had at least 2-year disease free interval Concurrent therapeutic anticoagulation: PTT less than or equal to 1.5 x ULN or low dose aspirin and low-molecular weight heparin only are allowed; Coumadin will be allowed on a case by case basis if use is chronic and approved by the study medical monitors Any major surgery =< 4 week prior to first dose of study drug Concurrent use of filgrastim (G-CSF) or growth factors at the time of initiation of study drug History of allergic reactions attributed to compounds of similar chemical or biologic composition to CRLX101 and camptothecins Subjects with marked baseline prolongation of QT/QTc interval (for females QTc interval >= 470 msec and for males QTc interval >= 450 msec) Subjects, who in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (cyclodextrin-based polymer-camptothecin CRLX101)<br>Patients receive cyclodextrin-based polymer-camptothecin CRLX101 IV over 60 minutes on days 1 and 15. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. After the completion of 6 courses, patients achieving stable disease or better may receive treatment for an additional 6 months. | Drug: cyclodextrin-based polymer-camptothecin CRLX101<br>* Given IV<br>* Other names: IT-101;Other: Laboratory biomarker analysis<br>* Correlative studies<br>Other: Pharmacological studies<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CRLX101 (CPT) Uptake in Tumor and Nearby Normal Tissue | Using Fisher's Exact to determine statistical significance in detection of a CPT fluorescence signal posttreatment between tumor and adjacent normal tissue biopsy specimens. | Baseline and day 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Objective Response Rate | Patients with best response of Complete Response or Partial Response assessed using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR | Up to 4 years | 
| Clinical Benefit Rate | Patients with a best response of Complete Response, Partial Response or Stable Disease after at least 4 months of treatment assessed using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), not a CR, PR, Progression or Symptomatic Deterioration; Progression (PD), a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Symptomatic Deterioration, global deterioration of health status requiring discontinuation of treatment without objective evidence of progression. Clinical Benefit (CR + PR +SD≥4months). | At least 4 months post treatment, assessed up to 4 years | 
| Overall Survival | Estimated using the product-limit method of Kaplan and Meier. | From date of start of therapy to date of death due to any cause, assessed up to 4 years | 
| Incidence of Adverse Events | Incidence of treatment related adverse events graded per NCI CTCAE version 4.03 | Up to 4 years |