Intravenously Administered Pegylated Liposomal Mitomycin-C Lipid-based Prodrug (PROMITIL) in Cancer Patients With Solid Tumors.

Study Overview
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Brief Summary
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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
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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.

Official Title
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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.

Conditions
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Cancer, Solid Tumor, Metastatic Colorectal Cancer (mCRC)

Intervention / Treatment
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* Drug: Promitil
* Drug: Capecitabine
* Drug: Bevacizumab


Participation Criteria
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Eligibility Criteria
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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 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, HgbA1C≤7%, and a platelet count ≥100,000/mm3( Adequate liver function (serum bilirubin ≤2.0 mg/100 ml; alanine aminotransferase ≤2× ULN) Adequate renal function (serum creatinine ≤1.5 mg/100 ml or creatinine clearance ≥45 ml/min/1.73m2) No prior intravenous treatment with Mitomycin-C either alone or in combination No other myelosuppressive treatment within 4 weeks before start of the study drug. No other anti-cancer treatment within 2 weeks before start of the study drug No prior extensive radiotherapy (e.g., whole pelvis total neuroaxis or greater than 50% of neuroaxis, whole abdomen, whole body or half-body) or bone marrow transplantation with high dose chemotherapy and/or total body irradiation. Re-irradiation of a field in abdomen/pelvis will be considered as extensive radiotherapy, excluding such patients from the study. 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 give written informed consent. Additional criteria only for the Expanded Cohort and both Combination cohorts: Patients with histologically or cytologically confirmed recurrent and/or metastatic measurable or nonmeasurable CRC, with tissue or cytological diagnosis of cancer on file. Additional criteria only for the Expanded Cohort and both Combination cohort: Patients who demonstrated either progression or intolerance when treated with irinotecan and fluopyrimidine-based chemotherapy, and, in the case of K-ras wild type tumors, anti-EGFR antibodies (Cetuximab, Panitumumab). Prior treatment with oxaliplatin or bevacizumab is allowed but not required. Additional criteria only for the Expanded Cohort and both Combination cohorts: A ≥28 day treatment-free interval between last chemotherapeutic treatment and first treatment with Promitil, with the exception of Capecitabine and biological therapies, where 14-day treatment-free intervals suffice. this is also relevant for patients in the Combination Cohort that are currently taking Capecitabine prior to enter the study). Additional criteria for the Triple Combination Cohort with bevacizumab only: Prior exposure to oxaliplatin should have terminated at least 6 months before start of PROMITIL, whether given as adjuvant therapy or as therapy for metastatic disease. Additional criteria for the triple Combination Cohort with bevacizumab only: A ≥ 28 day treatment-free interval from last bevacizumab treatment 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 Brain metastases in symptomatic patients requiring ≥4 mg dexamethasone/day. However, patients with treated brain metastases by surgery or radiation who are stable and symptom-free (<4 mg dexamethasone/day) for a minimum period of 4 weeks post-treatment are eligible. Pregnant or lactating Treatment with other investigational drugs within 14 days of start of the study drug for non-myelosuppressive agents, and within 28 days of start of the study drug for myelosuppressive agents. Additional criteria for the Combination cohorts: Uncontrolled ascites (defined as 2 or more palliative taps in the last 30 days before screening). Additional criteria for the Combination cohorts with bevacizumab only: uncontrolled clinically significant cardiac disease, hypertension, arrhythmias, or angina pectoris; acute myocardial infarction or cerebrovascular accident within 12 months of initiation of PROMITIL treatment. Additional criteria for the Combination cohorts with bevacizumab only: Any contraindication for treatment with Bevacizumab (e.g active bleeding, recent extensive surgery).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A: Promitil 0.5 mg/kg<br>Three treatment cycles, intravenous infusion of Promitil | Drug: Promitil<br>* 2 mg/kg dose IV<br>|
| Experimental: Cohort B: Promitil 1.0 mg/kg<br>Three treatment cycles, intravenous infusion of Promitil | Drug: Promitil<br>* 2 mg/kg dose IV<br>|
| Experimental: Cohort C: Promitil 1.5 mg/kg<br>Three treatment cycles, intravenous infusion of Promitil | Drug: Promitil<br>* 2 mg/kg dose IV<br>|
| Experimental: Cohort D: Promitil 2.0 mg/kg<br>Three treatment cycles, intravenous infusion of Promitil | Drug: Promitil<br>* 2 mg/kg dose IV<br>|
| Experimental: Cohort E: Promitil 2.5 mg/kg<br>Three treatment cycles, intravenous infusion of Promitil | Drug: Promitil<br>* 2 mg/kg dose IV<br>|
| Experimental: Cohort F: Promitil 3.0 mg/kg<br>Three treatment cycles, intravenous infusion of Promitil | Drug: Promitil<br>* 2 mg/kg dose IV<br>|
| Experimental: Cohort G: Promitil 3.5 mg/kg<br>Three treatment cycles, intravenous infusion of Promitil | Drug: Promitil<br>* 2 mg/kg dose IV<br>|
| Experimental: Cohort H: Promitil 4.0 mg/kg<br>Three treatment cycles, intravenous infusion of Promitil | Drug: Promitil<br>* 2 mg/kg dose IV<br>|
| Experimental: Expanded Cohort<br>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. | Drug: Promitil<br>* 2 mg/kg dose IV<br>|
| Experimental: Combination Cohort<br>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. | Drug: Promitil<br>* 2 mg/kg dose IV<br>Drug: Capecitabine<br>* 1000 mg dose BID PO for days 1-21 for Combination Cohort and on day 1-14 on Triple combination Cohort<br>* Other names: Xeloda;|
| Experimental: Triple combination Cohort<br>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. | Drug: Promitil<br>* 2 mg/kg dose IV<br>Drug: Capecitabine<br>* 1000 mg dose BID PO for days 1-21 for Combination Cohort and on day 1-14 on Triple combination Cohort<br>* Other names: Xeloda;Drug: Bevacizumab<br>* for Triple combination cohort an IV dose of 5 mg/kg on day 1 at 4 week interval. For the 3 weekly cohort an IV dose of 7.5 mg/kg at 3 week interval.<br>* Other names: Avastin;|
| Experimental: 3 Weekly Cohort<br>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. | Drug: Promitil<br>* 2 mg/kg dose IV<br>Drug: Bevacizumab<br>* for Triple combination cohort an IV dose of 5 mg/kg on day 1 at 4 week interval. For the 3 weekly cohort an IV dose of 7.5 mg/kg at 3 week interval.<br>* Other names: Avastin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal Tolerated Dose (MTD) of PROMITIL | Only DLTs occurring during the first cycle of treatment for each participant will determine MTD endpoint | First cycle of treatment (4 weeks) | 
| Dose Limiting Toxicity (DLT) of PROMITIL |  | First cycle of treatment (4 weeks) | 
| Pharmacokinetic (PK) profile of PROMITIL | 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). | 3 cycles of treatment (12 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-tumor responses to the delivered PROMITIL regimens |  | 12 months | 
| Toxicity profile of PROMITIL |  | 3 cycles of treatment (12 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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phase 1, dose escalating, prodrug, mitomycin C, Capecitabine