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

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

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.

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.

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