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

Phase 1

Completed

• Conditions: Metastatic Disease; Cancer; Solid Tumor
• Interventions: Drug: Promitil; Radiation: EBR

• Registration Number: NCT03823989
• Lead Sponsor: Lipomedix Pharmaceuticals Inc.

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schedule, all patients will be followed up by phone every 12 weeks, until either death, disease progression (PD), withdrawn consent or trial cut-off date, i.e., for up to 2 years after patient accrual to study, (whichever occurs first).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

Study Timeline

• Study Start: 2019-01-03
• Study First Submitted: 2019-01-22
• Study First Submitted QC: 2019-01-29
• Study First Posted: 2019-01-31
• Primary Completion: 2021-10-31
• Study Completion: 2021-12-30
• Status Verified: 2022-01
• Last Update Submitted: 2022-01-05
• Last Update Posted: 2022-01-06

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 18

Inclusion Criteria

1. 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.
2. 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.
3. No prior intravenous treatment with mitomycin-C either alone or in combination
4. 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.
5. No prior radiotherapy to the same anatomic site aimed for radiotherapy.
6. Age ≥18years
7. BMI: 18-36
8. ECOG Performance Status ≤ 2
9. Estimated life expectancy of at least 3 months
10. Adequate bone marrow function (an absolute neutrophil count ≥1500/mm3, hemoglobin ≥9.5 g/dl, and a platelet count ≥100,000/mm3);
11. Adequate liver function (serum bilirubin ≤2.0 mg/100 ml; alanine aminotransferase ≤3× ULN, albumin ≥34g/L)
12. Adequate renal function (serum creatinine ≤1.5 mg/100 ml or creatinine clearance ≥40 ml/min/1.73m2)
13. Women of child-bearing potential practicing an acceptable method of birth control.
14. Understanding of study procedures and willingness to comply for the entire length of the study and to provide written informed consent

Exclusion Criteria

1. Known hypersensitivity to the study drug or to any of its components

2. Prior intravenous treatment with mitomycin C

3. Patients requiring whole-brain irradiation

4. Patients requiring re-irradiation of the same tumor/anatomical site.

5. CHF (NYHA = Class IV)

6. Severe COPD or Stage ≥3 severe emphysema with FEV1 between 30 and 50 percent of normal

7. Chronic liver disease or cirrhosis with Child-Pugh Class C score

8. Any other severe concurrent disease which in the judgment of the investigator would make the subject unsuitable for entry into this study

9. History of human immunodeficiency virus (HIV) infection

10. 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.

11. Presence of uncontrolled infection.

12. Evidence of active bleeding or bleeding diathesis

13. Pregnant or lactating

14. Treatment with other investigational drugs within <21 days of start of day 1 of study drug.

15. Uncontrolled ascites (defined as 2 or more palliative taps in the last 21 days before screening).

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Promitil 1.25 mg/kg	EBR	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.
Promitil 1.5 mg/kg	EBR	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.
Promitil 1.8 mg/kg	EBR	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.
Promitil 1.25 mg/kg	Promitil	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.
Promitil 1.5 mg/kg	Promitil	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.
Promitil 1.8 mg/kg	Promitil	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.

Primary Outcome Measures

Name	Time	Method
To evaluate the response rate to PROMITIL in combination with external beam radiotherapy (EBR)	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)	6 weeks	Report of Dose limiting toxicity
Incidence of Treatment-Emergent Adverse Events	6 weeks	Incidence all Adverse events of Promitil in combination with external beam radiotherapy (EBR)

Secondary Outcome Measures

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

Trial Locations

Locations (3)

Hadassah Medical Center; 🇮🇱 Jerusalem, Israel

Assuta Ashdod; 🇮🇱 Ashdod, Israel

Assuta Medical Center; 🇮🇱 Tel Aviv, Israel