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

Primary Purpose

Cancer, Solid Tumor, Metastatic Disease

Status

Completed

Phase

Phase 1

Locations

Israel

Study Type

Interventional

Intervention

Promitil

EBR

About this trial

This is an interventional treatment trial for Cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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).
-

Sites / Locations

Assuta Ashdod
Hadassah Medical Center
Assuta Medical Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

Promitil 1.25 mg/kg

Promitil 1.5 mg/kg

Promitil 1.8 mg/kg

Arm Description

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.

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.

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.

Outcomes

Primary Outcome Measures

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

Report of Dose limiting toxicity

Incidence of Treatment-Emergent Adverse Events

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

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

Secondary Outcome Measures

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)

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)

Overall survival

Overall survival (in weeks), from day of first dose of PROMITIL to death of any cause

Plasma MLP level after Promitil infusion

Plasma MLP levels before and after (1 h and 24 h) each PROMITIL dose

Full Information

NCT ID

NCT03823989

First Posted

January 22, 2019

Last Updated

January 5, 2022

Sponsor

Lipomedix Pharmaceuticals Inc.

1. Study Identification

Unique Protocol Identification Number

NCT03823989

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

January 2022

Overall Recruitment Status

Completed

Study Start Date

January 3, 2019 (Actual)

Primary Completion Date

October 31, 2021 (Actual)

Study Completion Date

December 30, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Lipomedix Pharmaceuticals Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Cancer, Solid Tumor, Metastatic Disease

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Sequential Assignment

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)

Allocation

Non-Randomized

Enrollment

18 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Promitil 1.25 mg/kg

Arm Type

Experimental

Arm Description

Arm Title

Promitil 1.5 mg/kg

Arm Type

Experimental

Arm Description

Arm Title

Promitil 1.8 mg/kg

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Promitil

Other Intervention Name(s)

Pegylated Liposomal Mitomycin-C Lipid-based Prodrug

Intervention Description

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.

Intervention Type

Radiation

Intervention Name(s)

EBR

Other Intervention Name(s)

external beam radiotherapy

Intervention Description

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 Measure Information:

Title

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

Description

Report of Dose limiting toxicity

Time Frame

6 weeks

Title

Incidence of Treatment-Emergent Adverse Events

Description

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

Time Frame

6 weeks

Title

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

Description

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

Time Frame

7 weeks

Secondary Outcome Measure Information:

Title

Duration of response of the irradiated tumor site

Description

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)

Time Frame

18 weeks

Title

Progression-free survival (PFS)

Description

Progression-free survival (PFS) (in weeks), from day of first dose of PROMITIL until confirmed Progression disease (as per RECIST 1.1 criteria)

Time Frame

18 weeks

Title

Overall survival

Description

Overall survival (in weeks), from day of first dose of PROMITIL to death of any cause

Time Frame

34 weeks

Title

Plasma MLP level after Promitil infusion

Description

Plasma MLP levels before and after (1 h and 24 h) each PROMITIL dose

Time Frame

6 weeks (2 cycles of treatment)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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 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). -

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Adi Levy, MD

Organizational Affiliation

Hadassah Medical Organization

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Eli Sapir, MD

Organizational Affiliation

Assuta Medical Center

Official's Role

Study Director

Facility Information:

Facility Name

Assuta Ashdod

City

Ashdod

ZIP/Postal Code

7747629

Country

Israel

Facility Name

Hadassah Medical Center

City

Jerusalem

ZIP/Postal Code

9112001

Country

Israel

Facility Name

Assuta Medical Center

City

Tel Aviv

ZIP/Postal Code

6971028

Country

Israel

12. IPD Sharing Statement

Plan to Share IPD

IPD Sharing Plan Description

The PI and the sponsor have still to discuss what will be the plan to share IPD

Citations:

PubMed Identifier

27681751

Citation

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.

Results Reference

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PubMed Identifier

30534533

Citation

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.

Results Reference

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

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