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

NCT ID: NCT04729205

Last Updated: 2023-09-14

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 9 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-01-13
• Study Completion Date: 2023-09-12

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.

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.

Conditions

Cancer; Gastro-Intestinal Intraepithelial Neoplasia

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: EXPERIMENTAL

Promitil

Intervention Type: 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).

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

Group Type: EXPERIMENTAL

Promitil

Intervention Type: 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).

Interventions

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).

Intervention Type: DRUG

Other Intervention Names

Pegylated Liposomal Mitomycin-C Lipid-based Prodrug; Folfox

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Lipomedix Pharmaceuticals Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Esther Tahover, MD

Role: PRINCIPAL_INVESTIGATOR

Shaare Zedek Medica Center

Locations

Shaare Zedek Medical Center

Jerusalem, , Israel

Countries

Israel

References

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.

Reference Type: BACKGROUND

PMID: 32777239 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 26572644 (View on PubMed)

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.

Reference Type: RESULT

PMID: 31955309 (View on PubMed)

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.

Reference Type: RESULT

PMID: 26172205 (View on PubMed)

Other Identifiers

PROMIFOX

Identifier Type: -

Identifier Source: org_study_id