An Open-label, Phase 1b Study of Intravenously Administered Pegylated Liposomal Mitomycin C Lipid-based Prodrug (PROMITIL) in Combination With External Beam Radiotherapy in Patients With Advanced Cancer Requiring Palliative Radiotherapy
Overview
- Phase
- Phase 1
- Intervention
- Promitil
- Conditions
- Cancer
- Sponsor
- Lipomedix Pharmaceuticals Inc.
- Enrollment
- 18
- Locations
- 3
- Primary Endpoint
- To evaluate the response rate to PROMITIL in combination with external beam radiotherapy (EBR)
- Status
- Completed
- Last Updated
- 4 years ago
Overview
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schedule, all patients will be followed up by phone every 12 weeks, until either death, disease progression (PD), withdrawn consent or trial cut-off date, i.e., for up to 2 years after patient accrual to study, (whichever occurs first).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.
Detailed Description
As combination with radiotherapy is expected to provide an additive or synergistic effect, the current dose-escalation study will begin with a dose of 1.25 mg/kg, to be followed by an increase (1.5 mg/kg) in Cohort 2 and a further increase 1.8 mg/kg in Cohort 3 in the absence of DLTs after two treatment cycles, with an interluding 10-fraction course of radiotherapy. PROMITIL will be intravenously delivered on Day 1 of each of the two 21-day cycles. Cohort 1: The first 6 patients recruited to the study will receive 1.25 mg/kg PROMITIL. Cohort 2: 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. However, if 1 DLT is recorded, the second cohort of 6 patients will receive the same dose of 1.25 mg/kg PROMITIL. If 2 DLTs are recorded in Cohort 1, the second cohort of 6 patients will receive 1.0 mg/kg PROMITIL. Cohort 3: If no dose-limiting toxicities (DLTs) are recorded by day 43 of the study of the first 3 patients of Cohort 2, a third cohort will enroll 6 patients to receive treatment at a dose level of 1.8 mg/kg PROMITIL. If none or 1 DLT is recorded, the dose of 1.8 mg/kg will be cleared as recommended dose for phase 2. If 2 DLT are recorded, the study will be terminated as soon as the 2nd DLT is recorded, and the prior dose level of 1.5 mg/kg will be cleared as recommended dose for phase 2
Investigators
Eligibility Criteria
Inclusion Criteria
- •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
- •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)
Exclusion Criteria
- •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.
Arms & Interventions
Promitil 1.25 mg/kg
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.
Intervention: Promitil
Promitil 1.25 mg/kg
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.
Intervention: EBR
Promitil 1.5 mg/kg
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.
Intervention: Promitil
Promitil 1.5 mg/kg
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.
Intervention: EBR
Promitil 1.8 mg/kg
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.
Intervention: Promitil
Promitil 1.8 mg/kg
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.
Intervention: EBR
Outcomes
Primary Outcomes
To evaluate the response rate to PROMITIL in combination with external beam radiotherapy (EBR)
Time Frame: 7 weeks
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
Dose limiting toxicity (DLT) of Promitil in combination with external beam radiotherapy (EBR)
Time Frame: 6 weeks
Report of Dose limiting toxicity
Incidence of Treatment-Emergent Adverse Events
Time Frame: 6 weeks
Incidence all Adverse events of Promitil in combination with external beam radiotherapy (EBR)
Secondary Outcomes
- Duration of response of the irradiated tumor site(18 weeks)
- Overall survival(34 weeks)
- Plasma MLP level after Promitil infusion(6 weeks (2 cycles of treatment))
- Progression-free survival (PFS)(18 weeks)