Study of Minnelide™ in Patients With Advanced GI Tumors

Study Overview
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Brief Summary
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The primary objective of this study is to determine the maximum tolerated dose (MTD) and the dose limiting toxicities (DLT) of Minnelide™ and to establish the dose of Minnelide™ recommended for future phase 2 protocol

Detailed Description
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This is a Phase 1, open label, multicenter, dose-escalation study of safety, pharmacokinetics, and pharmacodynamics of Minnelide™ Minnelide™ will be given as a single agent intravenously as a 30-minute infusion daily x 21 days followed by a 7-day rest period. One cycle will equal 28 days. Dose escalation will follow a modified Fibonacci design.

Official Title
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A Phase 1, Multi-Center, Open-Label, Dose-Escalation, Safety, Pharmacokinetic, and Pharmacodynamic Study of Minnelide™ Given Daily for 21 Days Followed by 7 Days Off Schedule in Patients With Advanced GI Tumors.

Conditions
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Advanced Gastrointestinal Tumors

Intervention / Treatment
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* Drug: Minnelide™ 001


Participation Criteria
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Eligibility Criteria
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ELIGIBILITY CRITERIA: Inclusion Criteria: Histologically or cytologically confirmed gastrointestinal (GI) carcinoma, which has progressed on standard therapies (surgery, radiotherapy, endocrine therapy, chemotherapy), for which effective therapy is not available or for which patients are not a candidate for or intolerant of such therapies. Have one or more metastatic tumors measurable on CT scan or locally advanced measurable disease that has clearly progressed after prior treatment per RECIST criteria. Male and female patients at least 18 years of age Laboratory data as specified: Hematology: ANC >1500 cells/mm3, platelet count > 150,000 cells/mm3 and Hemoglobin > 9 g/dL Hepatic: Direct bilirubin ≤1.5 X ULN; alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 2.5 X ULN. For patients with known liver metastases or liver neoplasms, then ALT or AST ≤ 5.0 X ULN is allowed Renal: serum creatinine WNL or calculated creatinine clearance ≥ 50 mL/min/1.73m2 for patients with creatinine levels above institutional normal Urinalysis: No clinically significant abnormalities Coagulation: INR within normal limits, PTT within normal limits Estimated life expectancy of at least 3 months Karnofsky Performance ≥ 70% A negative serum pregnancy test (if female) For men and women of child-producing potential - willingness to employ appropriate contraceptive methods (including abstinence) during the study. Ability to understand the requirements of the study, provide written informed consent and authorization of use and disclosure of protected health information, and agree to abide by the study restrictions and to return for the required assessments. Exclusion Criteria: Women who are pregnant or nursing. NOTE: 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 the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. New York Heart Association Class III or IV, cardiac disease, myocardial infarction within the past 6 months, unstable arrhythmia, or evidence of ischemia on ECG. Baseline QTc exceeding 450 msec (470 msec for females) using the Bazetts formula and/or patients receiving class 1A or class III antiarrythmic agents. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy. Treatment with radiotherapy, chemotherapy or investigational therapy within 1 month (or 5 half lifes for cytotoxics) prior to study entry (6 weeks for nitrosoureas or Mitomycin C). Known HIV, Hepatitis A, B or Hepatitis C infection Serious nonmalignant disease (e.g., hydronephrosis, liver failure, or other conditions) that could compromise protocol objectives in the opinion of the investigator and/or the sponsor. Participation in concurrent study of an investigational agent or device. Unwillingness or inability to comply with procedures required in this protocol. Any other condition including but not limited to major co-morbidities, which in the opinion of the investigator would render the patient ineligible.

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: Minnelide™ 001<br>A Phase 1, Multi-Center, Open-label, Dose-Escalation, Safety, Pharmacokinetic and Pharmacodynamic Study of Minnelide™ given daily for 21 days followed by 7 days off schedule in patients with Advanced GI Tumors | Drug: Minnelide™ 001<br>* Minnelide™ will be given as a single agent intravenously as a 30-minute infusion daily x 21 days followed by a 7-day rest period. One cycle will equal 28 days.<br>* Other names: Minnelide;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the maximum tolerated dose (MTD) and the dose limiting toxicities (DLT) of Minnelide™ | The MTD will be determined using a 3 + 3 design and will continue until 2 patients at any dose level experience a DLT. A DLT will be defined as Grade 4 neutropenia lasting ≥ 5 days or Grade 3 or 4 neutropenia with fever and/or infection;Grade 4 thrombocytopenia (or Grade 3 with bleeding);Grade 3 or 4 treatment-related non-hematological toxicity (Grade 3 nausea, vomiting or diarrhea that last > 72 hours despite maximal treatment constitutes a DLT, insufficient treatment will not constitute an exception to the DLT criteria, as this would constitute inadequate conduct of the study); Dosing delay greater than 2 weeks due to treatment-emergent AEs or related severe laboratory abnormalities. | 24 months | 
| To establish the dose of Minnelide™ recommended for future phase 2 protocol | Once the MTD has been determined this will be the dose going forward in phase 2 studies | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the pharmacokinetics of Minnelide™ | Plasma concentration data will be used to determine the following PK parameters: AUC Area under the concentration curve Cmax Maximum plasma concentration Tmax Time to maximum plasma concentration t1/2 Terminal phase half life CL/F Total body clearance Vd/F Apparent volume of distribution | 24 months | 
| To observe patients for any evidence of antitumor activity of Minnelide™ per RECIST criteria | Objective measurements of tumor size will be recorded from PET, CT scan and other measures. | 24 months | 
| To determine pharmacodynamic effect of Minnelide™ on HSP70 levels. And to explore pharmacodynamics effect of Minnelide™ on PET Scans and using Choi criteria on the CT scans. | As part of exploratory PD, the following assessments will be performed: Biomarkers including CA19-9 (or CA125, CEA if non-secretors for pancreas cancer), CEA and CA125 as applicable, any tumor marker appropriate to the given cancer or that is known to be elevated in a given patient will be evaluated according the Investigator's discretion, prior to every Cycle. Serum HSP70 levels PET Scans Evaluation of CT scans using Choi criteria | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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gastrointestinal tract, GI tract, advanced gastrointestinal tumors, gastrointestinal tumors, GI tumors, biliary, gallbladder,, colorectal,, gastric,, hepatocellular, esophageal, pancreatic