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

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2015 by Lipomedix Pharmaceuticals Inc.
Sponsor:
Information provided by (Responsible Party):
Lipomedix Pharmaceuticals Inc.
ClinicalTrials.gov Identifier:
NCT01705002
First received: October 8, 2012
Last updated: November 15, 2015
Last verified: November 2015
  Purpose

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.


Condition Intervention Phase
Cancer
Solid Tumor
Metastatic Colorectal Cancer (mCRC)
Drug: Promitil
Drug: Capecitabine
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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.

Resource links provided by NLM:


Further study details as provided by Lipomedix Pharmaceuticals Inc.:

Primary Outcome Measures:
  • Maximal Tolerated Dose (MTD) of PROMITIL [ Time Frame: First cycle of treatment (4 weeks) ] [ Designated as safety issue: Yes ]
    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) ] [ Designated as safety issue: Yes ]
  • Pharmacokinetic (PK) profile of PROMITIL [ Time Frame: 3 cycles of treatment (12 weeks) ] [ Designated as safety issue: Yes ]
    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 Outcome Measures:
  • Anti-tumor responses to the delivered PROMITIL regimens [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • Toxicity profile of PROMITIL [ Time Frame: 3 cycles of treatment (12 weeks) ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 67
Study Start Date: October 2012
Estimated Study Completion Date: September 2016
Estimated Primary Completion Date: April 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort A: Promitil 0.5 mg/kg
Three treatment cycles, intravenous infusion of Promitil
Drug: Promitil
Experimental: Cohort B: Promitil 1.0 mg/kg
Three treatment cycles, intravenous infusion of Promitil
Drug: Promitil
Experimental: Cohort C: Promitil 1.5 mg/kg
Three treatment cycles, intravenous infusion of Promitil
Drug: Promitil
Experimental: Cohort D: Promitil 2.0 mg/kg
Three treatment cycles, intravenous infusion of Promitil
Drug: Promitil
Experimental: Cohort E: Promitil 2.5 mg/kg
Three treatment cycles, intravenous infusion of Promitil
Drug: Promitil
Experimental: Cohort F: Promitil 3.0 mg/kg
Three treatment cycles, intravenous infusion of Promitil
Drug: Promitil
Experimental: Cohort G: Promitil 3.5 mg/kg
Three treatment cycles, intravenous infusion of Promitil
Drug: Promitil
Experimental: Cohort H: Promitil 4.0 mg/kg
Three treatment cycles, intravenous infusion of Promitil
Drug: Promitil
Experimental: 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.

Drug: Promitil
Experimental: 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.

Drug: Promitil Drug: Capecitabine
Other Name: Xeloda

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.

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 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
  2. Histologically or cytologically confirmed diagnosis of solid tumor on file.
  3. Age 18-80 years
  4. BMI: 18-36
  5. ECOG Performance Status ≤ 2
  6. Estimated life expectancy of at least 3 months
  7. Adequate bone marrow function (an absolute neutrophil count ≥1500/mm3, hemoglobin ≥9.5 g/dl, HgbA1C≤7%, and a platelet count ≥100,000/mm3(
  8. Adequate liver function (serum bilirubin ≤2.0 mg/100 ml; alanine aminotransferase ≤2× ULN)
  9. Adequate renal function (serum creatinine ≤1.5 mg/100 ml or creatinine clearance ≥45 ml/min/1.73m2)
  10. No prior intravenous treatment with Mitomycin-C either alone or in combination
  11. No other myelosuppressive treatment within 4 weeks before start of the study drug.
  12. No other anti-cancer treatment within 2 weeks before start of the study drug
  13. 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.
  14. Women of child bearing potential practicing an acceptable method of birth control.
  15. Understanding of study procedures and willingness to comply for the entire length of the study and to give written informed consent.
  16. Additional criteria only for the Expanded Cohort: Patients with histologically or cytologically confirmed recurrent and/or metastatic measurable or nonmeasurable CRC, with tissue or cytological diagnosis of cancer on file.
  17. Patients who have received past treatment with oxaliplatin, irinotecan and fluopyrimidine-based chemotherapy, and, in the case of K-ras wild type tumors, received anti-EGFR antibodies (Cetuximab, Panitumumab). Patients who demonstrated either progression or intolerance when treated with the above. Prior treatment with Bevacizumab is allowed but not required.
  18. A ≥ 21 day treatment-free interval from chemotherapeutic treatment, 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).
  19. Additional criteria only for the Combination Cohort: Clinical decision made to initiate treatment with Capecitabine prior to enrollment in the study. Treatment with Capecitabine can be started either prior to or after signed ICF.

Exclusion Criteria:

  1. Known hypersensitivity to the study drug or to any of its components
  2. CHF (NYHA = Class IV) or LVEF≤40%
  3. COPD > Stage 3 (FEV1<50%, FEV1/FVC<70%);
  4. Cirrhosis (Child-Pugh Class C score);
  5. Serum Albumin level < 3 g/dl
  6. Any other severe concurrent disease which in the judgment of the investigator would make the subject inappropriate for entry into this study
  7. History of human immunodeficiency virus (HIV) infection
  8. History of chronic active hepatitis including subjects who are carriers of hepatitis B virus (HBV) or hepatitis C virus (HCV).
  9. Presence of uncontrolled infection.
  10. Evidence of active bleeding or bleeding diathesis
  11. 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.
  12. Pregnant or lactating
  13. 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.
  14. Additional criteria only for the Expanded Cohort: Patients with prior treatment with Regorafenib are excluded from entering the Expanded Cohort.
  15. Additional criteria only for the Combination cohort: Uncontrolled ascites (defined as 2 or more palliative taps in the last 30 days before screening).
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01705002

Contacts
Contact: Alberto Gabizon, Prof. +972 77 9055361 alberto.gabizon@lipomedix.com
Contact: Patricia Ohana, Dr. +972-2- 5866177 patricia.ohana@lipomedix.com

Locations
Israel
Rambam Health Care Campus Recruiting
Haifa, Israel
Contact: Ruth Perets, Dr.       ru_perets@rambam.health.gov.il   
Principal Investigator: Ruth Pererts, Dr.         
Shaare Zedek Medical Center Recruiting
Jerusalem, Israel
Contact: Esther Tahover, MD    +972-50-7163123    esthert@hadassah.org.il   
Contact: Novatrials CRO Noga Brunicki    +972 52-4532325    noga@novatrials.com   
Principal Investigator: Esther Tahover, MD         
Chaim Sheba Medical center Recruiting
Ramat Gan, Israel
Contact: Raanan Berger, MD    +972-3-5307038    Raanan.Berger@sheba.health.gov.il   
Contact: Novatrials CRO Noga Brunicki    +972 -52-4532325    noga@novatrials.com   
Principal Investigator: Raanan Berger, MD         
Tel-Aviv Sourasky Medical Center Recruiting
Tel-Aviv, Israel, 64239
Contact: Ravit Geva, Dr.    +972 3 6973494    ravitg@tlvmc.gov.il   
Principal Investigator: Ravit Geva, Dr.         
Sponsors and Collaborators
Lipomedix Pharmaceuticals Inc.
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Lipomedix Pharmaceuticals Inc.
ClinicalTrials.gov Identifier: NCT01705002     History of Changes
Other Study ID Numbers: PROMITIL-01 
Study First Received: October 8, 2012
Last Updated: November 15, 2015
Health Authority: Israel: Ministry of Health, Pharmaceutical department

Keywords provided by Lipomedix Pharmaceuticals Inc.:
phase 1
dose escalating
prodrug
mitomycin C
Capecitabine

Additional relevant MeSH terms:
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Capecitabine
Mitomycin
Mitomycins
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Alkylating Agents
Antibiotics, Antineoplastic
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on September 26, 2016