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

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

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).

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