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

Study Overview
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Brief Summary
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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schedule, all patients will be followed up by phone every 12 weeks, until either death, disease progression (PD), withdrawn consent or trial cut-off date, i.e., for up to 2 years after patient accrual to study, (whichever occurs first).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
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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

Official Title
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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

Conditions
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Cancer, Solid Tumor, Metastatic Disease

Intervention / Treatment
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* Drug: Promitil
* Radiation: EBR


Participation Criteria
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Eligibility Criteria
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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 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 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. 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). -

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Promitil 1.25 mg/kg<br>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<br>* 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.<br>* Other names: Pegylated Liposomal Mitomycin-C Lipid-based Prodrug;Radiation: EBR<br>* 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.<br>* Other names: external beam radiotherapy;|
| Experimental: Promitil 1.5 mg/kg<br>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<br>* 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.<br>* Other names: Pegylated Liposomal Mitomycin-C Lipid-based Prodrug;Radiation: EBR<br>* 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.<br>* Other names: external beam radiotherapy;|
| Experimental: Promitil 1.8 mg/kg<br>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<br>* 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.<br>* Other names: Pegylated Liposomal Mitomycin-C Lipid-based Prodrug;Radiation: EBR<br>* 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.<br>* Other names: external beam radiotherapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of response of the irradiated tumor site | Duration of response (in weeks) of the irradiated tumor site, from first evidence of response (Stable disease or better) to confirmed Progression disease (as per RECIST 1.1 criteria) | 18 weeks | 
| Progression-free survival (PFS) | Progression-free survival (PFS) (in weeks), from day of first dose of PROMITIL until confirmed Progression disease (as per RECIST 1.1 criteria) | 18 weeks | 
| Overall survival | Overall survival (in weeks), from day of first dose of PROMITIL to death of any cause | 34 weeks | 
| Plasma MLP level after Promitil infusion | Plasma MLP levels before and after (1 h and 24 h) each PROMITIL dose | 6 weeks (2 cycles of treatment) |