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

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ClinicalTrials.gov Identifier: NCT03823989
Recruitment Status : Recruiting
First Posted : January 31, 2019
Last Update Posted : August 27, 2019
Sponsor:
Information provided by (Responsible Party):
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 30 Gy course of EBR delivered in 10 fractions (3 Gy/fraction), initiated 1-3 days after the first PROMITIL dose and completed within a 2-week period. 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schedule, all patients will be followed up by phone every 12 weeks, until either death, disease progression (PD), withdrawn consent or trial cut-off date, i.e., for up to 2 years after patient accrual to study, (whichever occurs first). No other anticancer treatments will be allowed during the 6-week treatment period and until disease reevaluation.

Condition or disease Intervention/treatment Phase
Cancer Solid Tumor Metastatic Disease Drug: Promitil Radiation: EBR Phase 1

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, which will be escalated to 1.5 mg/kg PROMITIL 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: 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. If 2 DLTs are recorded in Cohort 2 or 3, the study will be terminated


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: dose-escalation study will begin with a dose of 1.25 mg/kg, which will be escalated to 1.5 mg/kg PROMITIL 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)
Primary Purpose: Treatment
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
Actual Study Start Date : January 3, 2019
Estimated Primary Completion Date : October 2019
Estimated Study Completion Date : February 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 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.
Drug: Promitil
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 confirmatory cohort (n=6) will be recruited and will be treated with the same dose as that administered to Cohort 2.
Other Name: Pegylated Liposomal Mitomycin-C Lipid-based Prodrug

Radiation: EBR
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.
Other Name: external beam radiotherapy

Experimental: 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.
Drug: Promitil
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 confirmatory cohort (n=6) will be recruited and will be treated with the same dose as that administered to Cohort 2.
Other Name: Pegylated Liposomal Mitomycin-C Lipid-based Prodrug

Radiation: EBR
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.
Other Name: external beam radiotherapy

Experimental: Promitil 1.5 mg/kg confirmatory
two treatment cycles, intravenous infusion of Promitil at a dosage of 1.5 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
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 confirmatory cohort (n=6) will be recruited and will be treated with the same dose as that administered to Cohort 2.
Other Name: Pegylated Liposomal Mitomycin-C Lipid-based Prodrug

Radiation: EBR
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.
Other Name: external beam radiotherapy




Primary Outcome Measures :
  1. Dose limiting toxicity (DLT) of Promitil in combination with external beam radiotherapy (EBR) [ Time Frame: 6 weeks ]
    Report of Dose limiting toxicity

  2. Incidence of Treatment-Emergent Adverse Events [ Time Frame: 6 weeks ]
    Incidence all Adverse events of Promitil in combination with external beam radiotherapy (EBR)

  3. 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


Secondary Outcome Measures :
  1. Duration of response of the irradiated tumor site [ Time Frame: 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)

  2. Progression-free survival (PFS) [ Time Frame: 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)

  3. Overall survival [ Time Frame: 34 weeks ]
    Overall survival (in weeks), from day of first dose of PROMITIL to death of any cause

  4. Plasma MLP level after Promitil infusion [ Time Frame: 6 weeks (2 cycles of treatment) ]
    Plasma MLP levels before and after (1 h and 24 h) each PROMITIL dose



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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. Patients with treatment history of one or more regimens (or lines) of standard systemic therapy for metastatic disease.
  3. A ≥21-day treatment-free interval from last chemotherapeutic treatment, and ≥14-day treatment-free interval from any biological therapies (for ex., bevacizumab, cetuximab, check-point inhibitor antibodies, kinase inhibitors)
  4. No prior intravenous treatment with mitomycin-C either alone or in combination
  5. No other myelosuppressive treatment within 3 weeks preceding start of the study drug.
  6. No other anti-cancer treatment within 3 weeks preceding start of the study drug.
  7. 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.
  8. No prior radiotherapy to the same anatomic site aimed for radiotherapy.
  9. Age ≥18years
  10. BMI: 18-36
  11. ECOG Performance Status ≤ 2
  12. Estimated life expectancy of at least 3 months
  13. Adequate bone marrow function (an absolute neutrophil count ≥1500/mm3, hemoglobin ≥9.5 g/dl, and a platelet count ≥100,000/mm3);
  14. Adequate liver function (serum bilirubin ≤2.0 mg/100 ml; alanine aminotransferase ≤3× ULN, albumin ≥34g/L)
  15. Adequate renal function (serum creatinine ≤1.5 mg/100 ml or creatinine clearance ≥40 ml/min/1.73m2)
  16. Women of child-bearing potential practicing an acceptable method of birth control.
  17. 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).

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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03823989


Contacts
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Contact: Patricia Ohana, PhD +972-2- 5866177 patricia.ohana@lipomedix.com
Contact: Eli Sapir, MD +972508946318 delsap18@gmail.com

Locations
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Israel
Assuta Ashdod Recruiting
Ashdod, Israel, 7747629
Contact: Vered Nussboim    +972-72-3398279    verednu@assuta.co.il   
Contact: Aviva Fridman    +972 3 5364041    aviva@avivaclinical.com   
Principal Investigator: Eli Sapir, MD         
Hadassah Medical Center Recruiting
Jerusalem, Israel, 9112001
Contact: Adi Raz    972-54-7584565    adira@hadassah.org.il   
Contact: Aviva Fridman    +972 52 4798127    aviva@avivaclinical.com   
Principal Investigator: Adi Levy, MD         
Assuta Medical Center Recruiting
Tel Aviv, Israel, 6971028
Contact: Osnat Albak    972-3-7644016    Osnatalb@assuta.co.il   
Contact: Aviva Fridman    +972 52 4798127    aviva@avivaclinical.com   
Sponsors and Collaborators
Lipomedix Pharmaceuticals Inc.
Investigators
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Principal Investigator: Adi Levy, MD Hadassah Medical Center
Study Director: Eli Sapir, MD Assuta Medical Center

Publications:
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Responsible Party: Lipomedix Pharmaceuticals Inc.
ClinicalTrials.gov Identifier: NCT03823989     History of Changes
Other Study ID Numbers: LIPORAD-2018
First Posted: January 31, 2019    Key Record Dates
Last Update Posted: August 27, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: The PI and the sponsor have still to discuss what will be the plan to share IPD

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Neoplasm Metastasis
Neoplastic Processes
Neoplasms
Pathologic Processes
Mitomycins
Mitomycin
Antibiotics, Antineoplastic
Antineoplastic Agents
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors