Assessment of Safety and Therapeutic Efficacy of Promitil in Combination With Folfox in Patients With GI Malignancies

This single center, Phase 1b, prospective, dose limiting toxicity (DLT)-clearing study, will assess the safety and efficacy of intravenously administered PROMITIL in combination with FOLFOX in cancer patients with inoperable, locally advanced or metastatic GI solid tumors.

Based on previous clinical results, we hypothesized that the addition of PROMITIL to FOLFOX, a treatment protocol consisting of oxaliplatin and fluoropyrimidine and commonly used to treat gastrointestinal (GI) malignancies, may enhance the overall efficacy of this combination regimen while maintain a reasonable safety profile.

Each patient will undergo screening, conducted up to 21 days before start of treatment, and receive 3 cycles of PROMITIL treatment, administered at four-week intervals, in combination with FOLFOX, administered at two-week intervals. Thereafter, patients may continue treatment with FOLFOX only, or with another regime at the investigator's discretion and will be followed up until death. Patients will be successively assigned, in order of accrual, to be concomitantly treated with PROMITIL and FOLFOX, at doses of PROMITIL meant to clear a dose of this combination treatment from DLT. Six patients will be treated with an initial DLT-clearing dose (Cohort 1). PROMITIL dose escalation from Cohort 1 to Cohort 2 will be authorized after 5 or 6 Cohort 1 patients complete their first two cycles of combination treatment with up to 1 DLT event reported for all 6 treated patients. If 2 or more Cohort 1 patients suffer from a DLT event in the first two cycles of treatment, 6 patients will be enrolled to Cohort -1 and treated with one dose level lower of PROMITIL. If 2 or more DLT events occur in Cohorts 2 or -1, the study will be discontinued for these patients and only patients in Cohort 1 will complete the study as planned. In any case, the total number of evaluable patients in the DLT-clearing phase will be no more than 12.

Eligibility Criteria:
Inclusion Criteria:

1. Patients with histologically or cytologically confirmed diagnoses of GI malignancies, deemed incurable (inoperable and locally advanced or metastatic), and X-ray computed tomography (CT)-evaluable (measurable or non-measurable) disease, with or without contrast enhancement

   Patients must have one the following carcinomas (including adenocarcinomas, signet ring cell, and mucinous carcinomas) to be eligible to be included in the study:
   1. Esophagus (non-squamous) and GE junction
   2. Stomach
   3. Hepatocellular carcinoma
   4. Pancreas (exocrine) and ampulla
   5. Cholangiocarcinoma (intra-hepatic)
   6. Bile ducts and gall bladder
   7. Small bowel
   8. Large bowel
   9. Rectum
2. Age 18-year or older
3. ECOG Performance Status ≤ 2
4. Estimated life expectancy of at least 3 months
5. Adequate bone marrow function (absolute neutrophil count ≥1500/mm3, hemoglobin ≥9.5 g/dl, and a platelet count ≥100,000/mm3
6. Adequate liver function (serum bilirubin ≤2.0 mg/100 ml; alanine aminotransferase ≤3× upper limit of normal \[ULN\], albumin ≥30 g/L, normal INR of prothrombin time (unless on coumadin treatment)
7. Adequate renal function (serum creatinine ≤1.5 mg/100 ml or creatinine clearance ≥45 ml/min/1.73m2).
8. A ≥21-day treatment-free interval from chemotherapeutic treatment, with the exception of 5-FU, capecitabine and biological therapies, where ≥14-day treatment-free intervals suffice.
9. No other myelosuppressive treatment within 4 weeks of initiation of the study drug.
10. No prior intravenous treatment with mitomycin-C, either alone or in combination
11. No prior oxaliplatin treatment for inoperable locally advanced or metastatic disease
12. A ≥6-month treatment-free interval from oxaliplatin, if given as adjuvant therapy or as neoadjuvant therapy for potentially operable disease
13. No prior extensive radiotherapy (e.g., whole pelvis, total neuroaxis or greater than 50% of neuroaxis, whole abdomen, whole body or half body) or bone marrow transplantation with high-dose chemotherapy and/or total body irradiation.
14. Women of child-bearing potential must be practicing an acceptable method of birth control.
15. Understanding of study procedures and willingness to comply throughout the entire course of the study and to provide written informed consent

Exclusion Criteria:

1. Patients with squamous cell cancer, stromal tumor, sarcoma, neuroendocrine tumor
2. Known hypersensitivity to the study drugs or to any of their components
3. Cirrhosis (Child-Pugh Class C score)
4. Serum albumin level \< 3.0 g/dl
5. Any other severe concurrent disease, which in the judgment of the investigator, would make the subject inappropriate for entry into this study
6. History of human immunodeficiency virus (HIV) infection
7. History of chronic active hepatitis, including subjects who are carriers of hepatitis B virus (HBV) or hepatitis C virus (HCV).
8. Uncontrolled diabetes: HgbA1C≥7.5%,
9. Presence of uncontrolled infection
10. Evidence of active bleeding or bleeding diathesis
11. Untreated (no surgery, no radiation) brain metastases, whether patient is symptomatic or asymptomatic. Patients with brain metastases treated by surgery or radiation who are stable and symptom-free requiring ≤4 mg dexamethasone/day, are eligible.
12. Pregnant or lactating women
13. Treatment with other investigational non-myelosuppressive drugs within 14 days of start of the study drug, and/or with myelosuppressive agents within 28 days of start of the study drug.
14. Uncontrolled ascites (defined as 2 or more palliative taps within 30 days of screening