Intravenously Administered Liposomal PROMITIL in Combination With External Beam Radiotherapy in Cancer Patients

NCT03823989 | Completed Phase 1 DMC

• 1 other identifier: LIPORAD-2018
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 3

Brief Summary

This will be a multi-center, open-label, single-arm, prospective study, in which up to 18 adult patients requiring radiotherapy for metastatic disease or for an inoperable primary tumor with no definitive curative treatment option, will undergo a combination treatment of intravenously (IV) delivered PROMITIL and standard of care radiotherapy. The treatment regimen will involve administration of two PROMITIL doses, delivered at a 21-day interval, and a course of EBR (type of RT according to investigator's preference), initiated 1-3 days after the first PROMITIL dose and completed within a 2-week period. EBR will consist of no more than 10 fractions delivered within 2 weeks as conventionally fractionated RT, or SBRT. Treatment safety will be assessed on a weekly basis throughout the two 21-day treatment courses (42 days) and throughout the follow-up period (up to Day 127). AEs will only be logged until 6 weeks after the last PROMITIL dose (up until Day 64). Disease status will be reevaluated between days 43-50 of the study, and every 6 weeks thereafter (Days 85 and 127±7 days). In addition, following completion of the treatment schedule, all patients will be followed up by phone every 12 weeks, until either death, disease progression (PD), withdrawn consent or trial cut-off date, i.e., for up to 2 years after patient accrual to study, (whichever occurs first). The following anticancer agents will NOT be allowed during the screening period, 6-week treatment period and until first disease reevaluation: cytotoxic agents, non-cytotoxic myelosuppressive agents (CDK 4/6 inibitiors, PARP inhibitors, m-TORS inhibitors and tyrosine kinase-inhibitors). Treatment with hormonal agents, monoclonal antibodies (anti-EGFr, anti-Her2, anti-VEGF and VEGFr, anti-PD1, anti-PDL1) and bisphosphonates can be continued during the study.

Conditions

Cancer; Solid Tumor; Metastatic Disease

Outcome Measures

Primary Outcomes (3)

• Dose limiting toxicity (DLT) of Promitil in combination with external beam radiotherapy (EBR)

  Report of Dose limiting toxicity

  6 weeks

• Incidence of Treatment-Emergent Adverse Events

  Incidence all Adverse events of Promitil in combination with external beam radiotherapy (EBR)

  6 weeks

• To evaluate the response rate to PROMITIL in combination with external beam radiotherapy (EBR)

  Local disease control in irradiated tumor areas at first reevaluation (Day 43-50), defined as rate of complete response \[CR\], partial response \[PR\] and stable disease \[SD\], as per RECIST 1.1 criteria

  7 weeks

Secondary Outcomes (4)

• Duration of response of the irradiated tumor site

  18 weeks

• Progression-free survival (PFS)

  18 weeks

• Overall survival

  34 weeks

• Plasma MLP level after Promitil infusion

  6 weeks (2 cycles of treatment)

Study Arms (3)

Promitil 1.25 mg/kg

EXPERIMENTAL

Two treatment cycles, intravenous infusion of Promitil at a dosage of 1.25 mg/kg delivered at 21 days interval and a 10-fraction course of EBR (3 Gy/fraction), initiated 1-3 days after the first PROMITIL dose and completed within a 2-week period.

Drug: Promitil; Radiation: EBR

Promitil 1.5 mg/kg

EXPERIMENTAL

Two treatment cycles, intravenous infusion of Promitil at a dosage of 1.5 mg/kg delivered at 21 days interval and a 10-fraction course of EBR (3 Gy/fraction), initiated 1-3 days after the first PROMITIL dose and completed within a 2-week period.

Drug: Promitil; Radiation: EBR

Promitil 1.8 mg/kg

EXPERIMENTAL

two treatment cycles, intravenous infusion of Promitil at a dosage of 1.8 mg/kg delivered at 21 days interval (confirmatory cohort) and a 10-fraction course of EBR (3 Gy/fraction), initiated 1-3 days after the first PROMITIL dose and completed within a 2-week period.

Drug: Promitil; Radiation: EBR

Interventions

Promitil DRUG

The first 6 patients recruited to the study will receive 1.25 mg/kg PROMITIL. If no dose-limiting toxicities (DLTs) are recorded by day 43 of the study, the second cohort of 6 patients will begin treatment at a dose level of 1.5 mg/kg PROMITIL. Upon completion of two treatment cycles, with ≤1 incident of DLTs in Cohort 2, a third cohort (n=6) will be recruited and will be treated with a dose level of 1.8 mg/kg.

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

Promitil 1.25 mg/kg; Promitil 1.5 mg/kg; Promitil 1.8 mg/kg

EBR RADIATION

A 10-fraction course of EBR (3 Gy/fraction), initiated 1-3 days after the first PROMITIL dose and completed within a 2-week period.

Also known as: external beam radiotherapy

Promitil 1.25 mg/kg; Promitil 1.5 mg/kg; Promitil 1.8 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 recurrent and/or metastatic, cancer, with at least one measurable lesion (≤10 cm diameter) on file, and with no definitive curative treatment option.
• A ≥21-day treatment-free interval from last chemotherapeutic treatment (including cytotoxic or non-cytotoxic myelosuppressive agents), and ≥14-day treatment-free interval from biological therapies consisting of CDK 4/6 inibitiors, PARP inhibitors, m-TOR inhibitors Hormonal therapies including LH-RH analogs or anagonists, tamoxifen, aromatase inhibitors, bicalutamide, aboraterone, corticosteroids, or enzalutamide may be continued uninterruptedly.
• No prior intravenous treatment with mitomycin-C either alone or in combination
• No prior extensive radiotherapy (e.g., whole pelvis, or greater than 50% of neuroaxis, whole abdomen, whole body or half-body) or bone marrow transplantation with high dose chemotherapy.
• No prior radiotherapy to the same anatomic site aimed for radiotherapy.
• Age ≥18years
• BMI: 18-36
• ECOG Performance Status ≤ 2
• Estimated life expectancy of at least 3 months
• Adequate bone marrow function (an absolute neutrophil count ≥1500/mm3, hemoglobin ≥9.5 g/dl, and a platelet count ≥100,000/mm3);
• Adequate liver function (serum bilirubin ≤2.0 mg/100 ml; alanine aminotransferase ≤3× ULN, albumin ≥34g/L)
• Adequate renal function (serum creatinine ≤1.5 mg/100 ml or creatinine clearance ≥40 ml/min/1.73m2)
• Women of child-bearing potential practicing an acceptable method of birth control.
• Understanding of study procedures and willingness to comply for the entire length of the study and to provide written informed consent

You may not qualify if:

• Known hypersensitivity to the study drug or to any of its components
• Prior intravenous treatment with mitomycin C
• Patients requiring whole-brain irradiation
• Patients requiring re-irradiation of the same tumor/anatomical site.
• CHF (NYHA = Class IV)
• Severe COPD or Stage ≥3 severe emphysema with FEV1 between 30 and 50 percent of normal
• Chronic liver disease or cirrhosis with Child-Pugh Class C score
• Any other severe concurrent disease which in the judgment of the investigator would make the subject unsuitable 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), unless adequately treated and shown to be serum virus-free.
• Presence of uncontrolled infection.
• Evidence of active bleeding or bleeding diathesis
• Pregnant or lactating
• Treatment with other investigational drugs within \<21 days of start of day 1 of study drug.
• Uncontrolled ascites (defined as 2 or more palliative taps in the last 21 days before screening).

Sponsors & Collaborators

• Lipomedix Pharmaceuticals Inc.: lead

Study Sites (3)

Assuta Ashdod

Ashdod, 7747629, Israel

Location

Hadassah Medical Center

Jerusalem, 9112001, Israel

Location

Assuta Medical Center

Tel Aviv, 6971028, Israel

Location

Related Publications (2)

• Tian X, Warner SB, Wagner KT, Caster JM, Zhang T, Ohana P, Gabizon AA, Wang AZ. Preclinical Evaluation of Promitil, a Radiation-Responsive Liposomal Formulation of Mitomycin C Prodrug, in Chemoradiotherapy. Int J Radiat Oncol Biol Phys. 2016 Nov 1;96(3):547-55. doi: 10.1016/j.ijrobp.2016.06.2457. Epub 2016 Jul 1.

  PMID: 27681751 BACKGROUND

• Tahover E, Bar-Shalom R, Sapir E, Pfeffer R, Nemirovsky I, Turner Y, Gips M, Ohana P, Corn BW, Wang AZ, Gabizon AA. Chemo-Radiotherapy of Oligometastases of Colorectal Cancer With Pegylated Liposomal Mitomycin-C Prodrug (Promitil): Mechanistic Basis and Preliminary Clinical Experience. Front Oncol. 2018 Nov 26;8:544. doi: 10.3389/fonc.2018.00544. eCollection 2018.

  PMID: 30534533 BACKGROUND

MeSH Terms

Conditions

Neoplasms; Neoplasm Metastasis

Condition Hierarchy (Ancestors)

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

Study Officials

• Adi Levy, MD

  Hadassah Medical Organization

  PRINCIPAL INVESTIGATOR

• Eli Sapir, MD

  Assuta Medical Center

  STUDY DIRECTOR

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: dose-escalation study will begin with a dose of 1.25 mg/kg, to be followed by an increase to 1.5 mg/kg PROMITIL and a further increase 1.8 mg/kg in the absence of DLTs after two treatment cycles, with an interluding 10-fraction course of radiotherapy. Upon completion of two treatment cycles, with ≤1 incident of DLTs in Cohort 2, a third confirmatory cohort (n=6) will be recruited and will be treated with the same dose as that administered to Cohort 2

Study Record Dates

• First Submitted: January 22, 2019
• First Posted: January 31, 2019
• Study Start: January 3, 2019
• Primary Completion: October 31, 2021
• Study Completion: December 30, 2021
• Last Updated: January 6, 2022

Record last verified: 2022-01

Data Sharing

• IPD Sharing: Will not share

Locations

IL (3)