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

An Open Phase 1B Study for Assessment of Safety and Therapeutic Efficacy of Promitil in Combination With Oxaliplatin-based Chemotherapy in Patients With Gastro-intestinal 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.

Study Overview

• Status: Terminated
• Conditions: Cancer; Gastro-Intestinal Intraepithelial Neoplasia
• Intervention / Treatment: Drug: Promitil

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 1

Contacts and Locations

Study Locations

• Israel
  • Jerusalem, Israel, 91031
    • Shaare Zedek Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Promitil 1.6 mg/kg; PROMITIL (1.6 mg/kg body weight) will be intravenously (IV) administered on the first day of three 28-day cycles. On days 1 and 15 of each PROMITIL cycle, patients will be treated with the mFOLFOX6 regimen, which includes concurrent treatment with oxaliplatin 85 mg/m2 IV and leucovorin 200 mg/m2 IV, immediately followed by 5-FU 400 mg/m2 IV bolus, and then continuous infusion of 5-FU 1200 mg/m2/day, for 2 days (46-48 h	Drug: Promitil; The first 6 patients recruited to the study will receive 1.6 mg/kg Promitil. Dose escalation to cohort 2 (PROMITIL dose of 2mg/kg) will be authorized after 5 or 6 patients of cohort 1 have completed the second cycle with DLT detected in fewer than two patients. If ≥2 patients of Cohort 1 develop DLT, dose escalation will be halted and Cohort -1 (PROMITIL dose of 1.2 mg/kg) will be opened. Should ≥2 patients in Cohort -1 or Cohort 2 experience DLT events, the study will be discontinued. In parallel, on days 1 and 15 of each cycle, patients will be treated with the mFOLFOX6 regime, which involves concurrent treatment with oxaliplatin 85 mg/m2 IV and leucovorin 200 mg/m2 IV, immediately followed by 5-FU 400 mg/m2 IV bolus, and then continuous infusion of 5-FU 1200 mg/m2/day, for 2 days (46-48 h).; Other Names: Folfox; Pegylated Liposomal Mitomycin-C Lipid-based Prodrug
Experimental: Promitil 2.0 mg/kg; PROMITIL (2.0 mg/kg body weight) will be intravenously (IV) administered on the first day of three 28-day cycles. On days 1 and 15 of each PROMITIL cycle, patients will be treated with the mFOLFOX6 regimen, which includes concurrent treatment with oxaliplatin 85 mg/m2 IV and leucovorin 200 mg/m2 IV, immediately followed by 5-FU 400 mg/m2 IV bolus, and then continuous infusion of 5-FU 1200 mg/m2/day, for 2 days (46-48 h	Drug: Promitil; The first 6 patients recruited to the study will receive 1.6 mg/kg Promitil. Dose escalation to cohort 2 (PROMITIL dose of 2mg/kg) will be authorized after 5 or 6 patients of cohort 1 have completed the second cycle with DLT detected in fewer than two patients. If ≥2 patients of Cohort 1 develop DLT, dose escalation will be halted and Cohort -1 (PROMITIL dose of 1.2 mg/kg) will be opened. Should ≥2 patients in Cohort -1 or Cohort 2 experience DLT events, the study will be discontinued. In parallel, on days 1 and 15 of each cycle, patients will be treated with the mFOLFOX6 regime, which involves concurrent treatment with oxaliplatin 85 mg/m2 IV and leucovorin 200 mg/m2 IV, immediately followed by 5-FU 400 mg/m2 IV bolus, and then continuous infusion of 5-FU 1200 mg/m2/day, for 2 days (46-48 h).; Other Names: Folfox; Pegylated Liposomal Mitomycin-C Lipid-based Prodrug

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment-Emergent Adverse Events	The incidence FOLFOX and characteristics of adverse events associated with the PROMITIL-combination treatment	12 weeks
Report Dose limiting toxicity (DLT)	Dose clearance of PROMITIL in combination therapy with FOLFOX at week 8	8 weeks
Evaluate Disease Control Rate	Disease control rate (complete response [CR] + partial response [PR]+ stable disease [SD]), according to RECIST 1.1 criteria, at 11-12 weeks	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measurement of Progression free survival (PFS)	Progression free survival (PFS), measured in weeks from time of first dose of PROMITIL until PD	24 weeks
Measure Overall survival	Overall survival, measured in weeks from start of study treatment until death due to any cause	52 weeks
Plasma MLP level after Promitil infusion	Pharmacokinetic of PROMITIL when administered along with FOLFOX, as measured in cycles 1 and 3	10 weeks

Collaborators and Investigators

• Sponsor: Lipomedix Pharmaceuticals Inc.
• Investigators: Principal Investigator: Esther Tahover, MD, Shaare Zedek Medica Center

Publications and helpful links

General Publications

• Gabizon A, Shmeeda H, Tahover E, Kornev G, Patil Y, Amitay Y, Ohana P, Sapir E, Zalipsky S. Development of Promitil(R), a lipidic prodrug of mitomycin c in PEGylated liposomes: From bench to bedside. Adv Drug Deliv Rev. 2020;154-155:13-26. doi: 10.1016/j.addr.2020.07.027. Epub 2020 Aug 7.
• Amitay Y, Shmeeda H, Patil Y, Gorin J, Tzemach D, Mak L, Ohana P, Gabizon A. Pharmacologic Studies of a Prodrug of Mitomycin C in Pegylated Liposomes (Promitil((R))): High Stability in Plasma and Rapid Thiolytic Prodrug Activation in Tissues. Pharm Res. 2016 Mar;33(3):686-700. doi: 10.1007/s11095-015-1819-7. Epub 2015 Nov 16.
• Gabizon AA, Tahover E, Golan T, Geva R, Perets R, Amitay Y, Shmeeda H, Ohana P. Pharmacokinetics of mitomycin-c lipidic prodrug entrapped in liposomes and clinical correlations in metastatic colorectal cancer patients. Invest New Drugs. 2020 Oct;38(5):1411-1420. doi: 10.1007/s10637-020-00897-3. Epub 2020 Jan 18.
• Golan T, Grenader T, Ohana P, Amitay Y, Shmeeda H, La-Beck NM, Tahover E, Berger R, Gabizon AA. Pegylated liposomal mitomycin C prodrug enhances tolerance of mitomycin C: a phase 1 study in advanced solid tumor patients. Cancer Med. 2015 Oct;4(10):1472-83. doi: 10.1002/cam4.491. Epub 2015 Jul 14.

Study record dates

Study Major Dates

• Study Start (Actual): January 13, 2021
• Primary Completion (Actual): September 10, 2023
• Study Completion (Actual): September 12, 2023

Study Registration Dates

• First Submitted: January 24, 2021
• First Submitted That Met QC Criteria: January 24, 2021
• First Posted (Actual): January 28, 2021

Study Record Updates

• Last Update Posted (Actual): September 14, 2023
• Last Update Submitted That Met QC Criteria: September 12, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Solid tumors; inoperable; metastatic; locally advanced
• Additional Relevant MeSH Terms: Neoplasms; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Alkylating Agents; Antibiotics, Antineoplastic; Mitomycins; Mitomycin
• Other Study ID Numbers: PROMIFOX

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No