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

NCT04729205 | Terminated Phase 1

• 1 other identifier: PROMIFOX
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Cancer; Gastro-Intestinal Intraepithelial Neoplasia

Keywords

Solid tumors; metastatic; locally advanced; inoperable

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (3)

• Measurement of Progression free survival (PFS)

  24 weeks

• Measure Overall survival

  52 weeks

• Plasma MLP level after Promitil infusion

  10 weeks

Study Arms (2)

Promitil 1.6 mg/kg

EXPERIMENTAL

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

Promitil 2.0 mg/kg

EXPERIMENTAL

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

Interventions

Promitil DRUG

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).

Also known as: Pegylated Liposomal Mitomycin-C Lipid-based Prodrug, Folfox

Promitil 1.6 mg/kg; Promitil 2.0 mg/kg

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• Esophagus (non-squamous) and GE junction
• Stomach
• Hepatocellular carcinoma
• Pancreas (exocrine) and ampulla
• Cholangiocarcinoma (intra-hepatic)
• Bile ducts and gall bladder
• Small bowel
• Large bowel
• Rectum
• Age 18-year or older
• ECOG Performance Status ≤ 2
• Estimated life expectancy of at least 3 months
• Adequate bone marrow function (absolute neutrophil count ≥1500/mm3, hemoglobin ≥9.5 g/dl, and a platelet count ≥100,000/mm3

You may not qualify if:

• Patients with squamous cell cancer, stromal tumor, sarcoma, neuroendocrine tumor
• Known hypersensitivity to the study drugs or to any of their components
• Cirrhosis (Child-Pugh Class C score)
• Serum albumin level \< 3.0 g/dl
• Any other severe concurrent disease, which in the judgment of the investigator, would make the subject inappropriate for entry into this study
• History of human immunodeficiency virus (HIV) infection
• History of chronic active hepatitis, including subjects who are carriers of hepatitis B virus (HBV) or hepatitis C virus (HCV).
• Uncontrolled diabetes: HgbA1C≥7.5%,
• Presence of uncontrolled infection
• Evidence of active bleeding or bleeding diathesis
• 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.
• Pregnant or lactating women
• 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.
• Uncontrolled ascites (defined as 2 or more palliative taps within 30 days of screening

Sponsors & Collaborators

• Lipomedix Pharmaceuticals Inc.: lead

Study Sites (1)

Shaare Zedek Medical Center

Jerusalem, 91031, Israel

Location

Related Publications (4)

• 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.

  PMID: 32777239 BACKGROUND

• 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.

  PMID: 26572644 BACKGROUND

• 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.

  PMID: 31955309 RESULT

• 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.

  PMID: 26172205 RESULT

MeSH Terms

Conditions

Neoplasms; Neoplasm Metastasis

Interventions

Folfox protocol

Condition Hierarchy (Ancestors)

Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Esther Tahover, MD

  Shaare Zedek Medica Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: There will be up to two cohorts, with six subjects per cohort. Eligible subjects will be consecutively assigned, in order of accrual, to receive three cycles of PROMITIL-FOLFOX treatment. Dosing regimens will begin with cohort 1 (PROMITIL dose of 1.6 mg/kg).Dose limiting toxicity (DLT) for the combination treatment will be considered cleared if fewer than two patients per cohort experience DLT events during the first two cycles of treatment. 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.

Study Record Dates

• First Submitted: January 24, 2021
• First Posted: January 28, 2021
• Study Start: January 13, 2021
• Primary Completion: September 10, 2023
• Study Completion: September 12, 2023
• Last Updated: September 14, 2023

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will not share

Locations

IL (1)