Minnelide™ Capsules Alone and in Combination With Paclitaxel in Advanced Gastric Cancer

Study Overview
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Brief Summary
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A Phase 1, Open-label, Dose-Escalation, Safety, Pharmacokinetic and Pharmacodynamic Study of Minnelide™ Capsules given alone or in combination with paclitaxel in patients with Advanced Gastric Cancer.

Detailed Description
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Minnelide™ is a water soluble disodium salt variant of triptolide, a diterpenoid, an HSP70 inhibitor. Studies using orthotopic pancreatic cancer cell lines and human xenograft transplants demonstrate that Minnelide™ prevents tumor progression, increases survival, and causes tumor regression.

Official Title
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A Phase 1 Open-Label, Dose-Escalation, Safety, Pharmacokinetic, and Pharmacodynamic Study of Minnelide™ Capsules Given Alone or in Combination With Paclitaxel in Patients With Advanced Gastric Cancer

Conditions
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Gastric Cancer

Intervention / Treatment
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* Drug: Minnelide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with histologically confirmed advanced gastric cancer Tumor progression after receiving standard/approved chemotherapy or where there is no approved therapy One or more metastatic tumors measurable per RECIST v1.1 Criteria Karnofsky performance ≥ 70% Life expectancy of at least 3 months Age ³ 19 years Signed, written IRB-approved informed consent A negative pregnancy test (if female) Acceptable liver function: Bilirubin 1.5 times upper limit of normal AST (SGOT), ALT (SGPT) and Alkaline phosphatase 2.5 times upper limit of normal (if liver metastases are present, then 5 x ULN is allowed) Albumin ≥ 3.0 g/dL Acceptable renal function: o Serum creatinine within normal limits, OR calculated creatinine clearance ³ 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal. Acceptable hematologic status: Granulocyte Monotherapy: ³ 1,500 cells/mm3 Combination therapy with paclitaxel: ³ 2,000cells/mm3 Platelet count ³ 100,000 (plt/mm3) Hemoglobin ³ 9 g/dL Urinalysis: o No clinically significant abnormalities Acceptable coagulation status: PT ≤ 1.5 times institutional ULN PTT ≤ 1.5 times institutional ULN Women of child- bearing potential and men must agree to use adequate contraception For men and women of child-producing potential, the use of effective contraceptive methods during the study and until 90 days after the last dose of IP for men or until 6 months after the last dose of IP for women or 6 months after the last dose of IP with paclitaxel for both men and women. Exclusion Criteria: 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 470 msec (using the Bazett's formula) and/or patients receiving class 1A or class III antiarrhythmic agents. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy. Pregnant or nursing women. NOTE: For men and women of child-producing potential, the use of effective contraceptive methods during the study and until 90 days after the last dose of IP for men or until 6 months after the last dose of IP for women or 6 months after the last dose of IP with paclitaxel for both men and women. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Treatment with radiation therapy (local therapy, non-target lesion, 2 weeks), major surgery, chemotherapy, biological agents or investigational therapy within 3 weeks prior to study treatment. Unwillingness or inability to comply with procedures required in this protocol Known infection with HIV, hepatitis B, or hepatitis C 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 Patients who are currently receiving any other investigational agent Patients who are on a prohibited medication (section 4.3.2). Patients with biliary obstruction and/or biliary stent (Regimen B only) Patients with a history of severe hypersensitivity reactions to products containing Cremophor® EL (eg, cyclosporin for injection concentrate and teniposide for injection concentrate). • Patient with baseline ANC<1500/mm3

Ages Eligible for Study
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Minimum Age: 19 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
Interventional Model Description: Minnelide™ is a water soluble disodium salt variant of triptolide, a diterpenoid, an HSP70 inhibitor. Studies using orthotopic pancreatic cancer cell lines and human xenograft transplants demonstrate that Minnelide™ prevents tumor progression, increases survival, and causes tumor regression.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open-label, dose-escalation, safety, Pharmacodynamic, pharmacokinetic study.<br>One | Drug: Minnelide<br>* at the MTD dose level established for monotherapy or combination to confirm safety. With a sample of 12 patients, the probability is > 80% that a serious adverse event with at least a 16% incidence will be detected.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine any increase of treatment emergent adverse events when Minnelide capsules are given in combination with paclitaxel. | To observe any increase in the number of patients that experience 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 when Minnelide is given alone and in combination with paclitaxel compared to the incidence with gemcitabine and nab-paclitaxel. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of Minnelide when given with paclitaxel | Area under the concentration curve (AUC) will be determine the exposure of Minnelide | 24 months | 
| Plasma levels of Minnelide when given with paclitaxel | Maximum plasma concentration (Cmax) will be measured to determine the effect of Minnelide when given with paclitaxel | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gastric Cancer