A Phase I, Dose-Escalating, Safety Study of an Intravenously Administered Pegylated Liposomal Mitomycin-C Lipid-based Prodrug (PL-MLP, PROMITIL) in Cancer Patients With Solid Tumors.
Overview
- Phase
- Phase 1
- Intervention
- Promitil
- Conditions
- Cancer
- Sponsor
- Lipomedix Pharmaceuticals Inc.
- Enrollment
- 88
- Locations
- 4
- Primary Endpoint
- Maximal Tolerated Dose (MTD) of PROMITIL
- Status
- Completed
- Last Updated
- 7 years ago
Overview
Brief Summary
This is a Phase I, multi-center, Dose-Escalating, Safety Study of an Intravenously Administered Pegylated Liposomal Mitomycin-C Lipid-based Prodrug (PL-MLP, PROMITIL) in Cancer Patients with Solid Tumors. The study comprised of:
Escalated cohorts A-H: 27 male or female participants, ages 18-80, BMI 18-36 diagnosed with inoperable, recurrent or metastatic malignant solid tumors, deemed incurable, and who have failed to respond to standard therapy or for whom no standard therapy is available. Eligible subjects will be assigned, successively in order of accrual, to one of eight cohorts, to receive escalating doses of intravenously infused PROMITIL. PROMITIL will be administered as an intravenous infusion. Dose escalation will only proceed in the absence of dose-limiting toxicity (DLT). For this purpose, each cohort will only begin its first cycle of PROMITIL when the cohort preceding it has successfully completed its first 4-week cycle without any signs of DLT.
Expanded cohort: 17 adult patients with metastatic CRC. The purpose of this expanded cohort is to further evaluate the safety of Promitil and to search for signs of antitumor activity of Promitil in this specific patient population.
Combination Cohort (Promitil concomitantly with Capecitabine): 23 adult patients with metastatic CRC.
Triple combination Cohort: 13 additional subjects with metastatic CRC, received combination of Promitil concomitantly with Bevacizumab (5 mg/kg) on day 1 of a 28 day cycle and Capecitabine on days 1-14 of a 28 day cycle.
3 weekly cohort- 9 subjects with metastatic CRC will receive Promitil and Bevacizumab (7.5 mg/kg) on day 1 of a 21 day cycle.
Detailed Description
For all cohorts, PROMITIL will be administered as an intravenous infusion at an initial rate of 0.25mg/min followed by gradual increase to a maximal rate of 2mg/min until completion of dosing, if absence of infusion reactions is established and in line with most updated version of IFU available for this study. For each subject, subsequent dosing will take place 28 days after the previous treatment, provided they are deemed fit to be dosed again. Patients will return to the study center on days 8, 15, 22 of cycle 1, and on day 15 of cycles 2 and 3, for monitoring assessments. All patients will be followed-up for survival and post-Promitil treatment. Patients who did not received 3 cycles of PROMITIL will be followed up only until PD. For the 3 weekly cohort Promitil will be administered at 3 week interval together with Bevacizumab (7.5 mg/kg). Patients will return to the study center on days 8 and 15 of cycle 1, and on day 15 of cycles 2 and 3, for monitoring assessments.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients diagnosed with inoperable, recurrent or metastatic malignant solid tumors, deemed incurable, and who have either:
- •Failed to respond to standard therapy or
- •For whom no standard therapy is available or
- •Refuse to receive standard therapies
- •Histologically or cytologically confirmed diagnosis of solid tumor on file.
- •Age 18-80 years
- •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, HgbA1C≤7%, and a platelet count ≥100,000/mm3(
- •Adequate liver function (serum bilirubin ≤2.0 mg/100 ml; alanine aminotransferase ≤2× ULN)
Exclusion Criteria
- •Known hypersensitivity to the study drug or to any of its components
- •CHF (NYHA = Class IV) or LVEF≤40%
- •COPD \> Stage 3 (FEV1\<50%, FEV1/FVC\<70%);
- •Cirrhosis (Child-Pugh Class C score);
- •Serum Albumin level \< 3 g/dl
- •Any other severe concurrent disease which in the judgment of the investigator would make the subject inappropriate 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).
- •Presence of uncontrolled infection.
- •Evidence of active bleeding or bleeding diathesis
Arms & Interventions
Cohort B: Promitil 1.0 mg/kg
Three treatment cycles, intravenous infusion of Promitil
Intervention: Promitil
Cohort A: Promitil 0.5 mg/kg
Three treatment cycles, intravenous infusion of Promitil
Intervention: Promitil
Cohort C: Promitil 1.5 mg/kg
Three treatment cycles, intravenous infusion of Promitil
Intervention: Promitil
Cohort D: Promitil 2.0 mg/kg
Three treatment cycles, intravenous infusion of Promitil
Intervention: Promitil
Cohort E: Promitil 2.5 mg/kg
Three treatment cycles, intravenous infusion of Promitil
Intervention: Promitil
Cohort F: Promitil 3.0 mg/kg
Three treatment cycles, intravenous infusion of Promitil
Intervention: Promitil
Cohort G: Promitil 3.5 mg/kg
Three treatment cycles, intravenous infusion of Promitil
Intervention: Promitil
Cohort H: Promitil 4.0 mg/kg
Three treatment cycles, intravenous infusion of Promitil
Intervention: Promitil
Expanded Cohort
Patients treated with the selected RP2D of PROMITIL (3 mg/kg) intravenously administered on their first cycle and reduced dose of 2 mg/kg from cycle 2 and onwards. Only for mCRC patients.
Intervention: Promitil
Combination Cohort
Patients treated with one cycle of 2.5mg/kg Promitil day 1 together with Capecitabine 1,000 mg bid po days 1-21 followed by two cycles of 2.0 mg/kg Promitil day 1 together with Capecitabine 1,000 mg bid po days 1-21, at four-week intervals. Only for mCRC patients.
Intervention: Promitil
Combination Cohort
Patients treated with one cycle of 2.5mg/kg Promitil day 1 together with Capecitabine 1,000 mg bid po days 1-21 followed by two cycles of 2.0 mg/kg Promitil day 1 together with Capecitabine 1,000 mg bid po days 1-21, at four-week intervals. Only for mCRC patients.
Intervention: Capecitabine
Triple combination Cohort
Patients treated with one cycle of 2mg/kg Promitil I.v and 5 mg/kg Bevacizumab i.v on day 1 together with Capecitabine 1,000 mg bid p.o days 1-14 at four-week intervals. Only for mCRC patients.
Intervention: Promitil
Triple combination Cohort
Patients treated with one cycle of 2mg/kg Promitil I.v and 5 mg/kg Bevacizumab i.v on day 1 together with Capecitabine 1,000 mg bid p.o days 1-14 at four-week intervals. Only for mCRC patients.
Intervention: Capecitabine
Triple combination Cohort
Patients treated with one cycle of 2mg/kg Promitil I.v and 5 mg/kg Bevacizumab i.v on day 1 together with Capecitabine 1,000 mg bid p.o days 1-14 at four-week intervals. Only for mCRC patients.
Intervention: Bevacizumab
3 Weekly Cohort
Patients treated with one cycle of 2mg/kg Promitil I.v and 7.5 mg/kg Bevacizumab i.v on day 1 together at three-week intervals. Only for mCRC patients.
Intervention: Promitil
3 Weekly Cohort
Patients treated with one cycle of 2mg/kg Promitil I.v and 7.5 mg/kg Bevacizumab i.v on day 1 together at three-week intervals. Only for mCRC patients.
Intervention: Bevacizumab
Outcomes
Primary Outcomes
Maximal Tolerated Dose (MTD) of PROMITIL
Time Frame: First cycle of treatment (4 weeks)
Only DLTs occurring during the first cycle of treatment for each participant will determine MTD endpoint
Dose Limiting Toxicity (DLT) of PROMITIL
Time Frame: First cycle of treatment (4 weeks)
Pharmacokinetic (PK) profile of PROMITIL
Time Frame: 3 cycles of treatment (12 weeks)
PK assessments will monitor plasma levels of MLP and metabolite (MMC), as well as PK parameters (Cmax, AUC0-t, AUC 0-∞, MRT, t½ , Kel, Cl, VD).
Secondary Outcomes
- Anti-tumor responses to the delivered PROMITIL regimens(12 months)
- Toxicity profile of PROMITIL(3 cycles of treatment (12 weeks))