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

NCT01705002 | Completed Phase 1 DMC

• 1 other identifier: PROMITIL-01
• Study Type: interventional
• Target: 88
• Locations: 1 country
• Sites: 4

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.

Conditions

Cancer; Solid Tumor; Metastatic Colorectal Cancer (mCRC)

Keywords

phase 1; dose escalating; prodrug; mitomycin C; Capecitabine

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (2)

• Anti-tumor responses to the delivered PROMITIL regimens

  12 months

• Toxicity profile of PROMITIL

  3 cycles of treatment (12 weeks)

Study Arms (12)

Cohort A: Promitil 0.5 mg/kg

EXPERIMENTAL

Three treatment cycles, intravenous infusion of Promitil

Drug: Promitil

Cohort B: Promitil 1.0 mg/kg

EXPERIMENTAL

Three treatment cycles, intravenous infusion of Promitil

Drug: Promitil

Cohort C: Promitil 1.5 mg/kg

EXPERIMENTAL

Three treatment cycles, intravenous infusion of Promitil

Drug: Promitil

Cohort D: Promitil 2.0 mg/kg

EXPERIMENTAL

Three treatment cycles, intravenous infusion of Promitil

Drug: Promitil

Cohort E: Promitil 2.5 mg/kg

EXPERIMENTAL

Three treatment cycles, intravenous infusion of Promitil

Drug: Promitil

Cohort F: Promitil 3.0 mg/kg

EXPERIMENTAL

Three treatment cycles, intravenous infusion of Promitil

Drug: Promitil

Cohort G: Promitil 3.5 mg/kg

EXPERIMENTAL

Three treatment cycles, intravenous infusion of Promitil

Drug: Promitil

Cohort H: Promitil 4.0 mg/kg

EXPERIMENTAL

Three treatment cycles, intravenous infusion of Promitil

Drug: Promitil

Expanded Cohort

EXPERIMENTAL

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

Combination Cohort

EXPERIMENTAL

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; Drug: Capecitabine

Triple combination Cohort

EXPERIMENTAL

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; Drug: Capecitabine; Drug: Bevacizumab

3 Weekly Cohort

EXPERIMENTAL

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; Drug: Bevacizumab

Interventions

Promitil DRUG

2 mg/kg dose IV

3 Weekly Cohort; Cohort A: Promitil 0.5 mg/kg; Cohort B: Promitil 1.0 mg/kg; Cohort C: Promitil 1.5 mg/kg; Cohort D: Promitil 2.0 mg/kg; Cohort E: Promitil 2.5 mg/kg; Cohort F: Promitil 3.0 mg/kg; Cohort G: Promitil 3.5 mg/kg; Cohort H: Promitil 4.0 mg/kg; Combination Cohort; Expanded Cohort; Triple combination Cohort

Capecitabine DRUG

1000 mg dose BID PO for days 1-21 for Combination Cohort and on day 1-14 on Triple combination Cohort

Also known as: Xeloda

Combination Cohort; Triple combination Cohort

Bevacizumab DRUG

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.

Also known as: Avastin

3 Weekly Cohort; Triple combination Cohort

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Lipomedix Pharmaceuticals Inc.: lead

Study Sites (4)

Rambam Health Care Campus

Haifa, Israel

Location

Shaare Zedek Medical Center

Jerusalem, Israel

Location

Chaim Sheba Medical center

Ramat Gan, Israel

Location

Tel-Aviv Sourasky Medical Center

Tel Aviv, 64239, Israel

Location

Related Publications (1)

• Golan T, Grenader T, Ohana P, Amitay Y, Shmeeda H, La-Beck NM, Tahover E, Berger R, Gabizon AA. Pegylated liposomal mitomycin C prodrug enhances tolerance of mitomycin C: a phase 1 study in advanced solid tumor patients. Cancer Med. 2015 Oct;4(10):1472-83. doi: 10.1002/cam4.491. Epub 2015 Jul 14.

  PMID: 26172205 DERIVED

MeSH Terms

Conditions

Neoplasms; Colorectal Neoplasms

Interventions

Capecitabine; Bevacizumab

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 8, 2012
• First Posted: October 12, 2012
• Study Start: October 1, 2012
• Primary Completion: November 1, 2017
• Study Completion: June 1, 2018
• Last Updated: July 10, 2018

Record last verified: 2018-07

Locations

IL (4)