PDM08 Clinical Trial in Advanced Solid Tumors

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Prodimed S.A.
ClinicalTrials.gov Identifier:
NCT01380249
First received: May 31, 2011
Last updated: January 4, 2013
Last verified: January 2013
  Purpose

This phase I study in adult patients with advanced solid tumours is designed to evaluate toxicity, drug exposure (pharmacokinetics) and drug action (pharmacodynamics) of a new molecule, PDM08, administered twice a week cycles of 4 weeks. This drug has shown antitumoral activity in several murine cancer models.


Condition Intervention Phase
Malignant Solid Tumours
Drug: PDM08
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Study, Open, Dose Escalation, in Adult Patients With Advanced Solid Tumours, to Evaluate Tolerability, Pharmacokinetics and Pharmacodynamics of PDM08 Administered Twice a Week Cycles of 4 Weeks.

Resource links provided by NLM:


Further study details as provided by Prodimed S.A.:

Primary Outcome Measures:
  • Number and grade of adverse events by participant related to PDM08. [ Time Frame: 6 weeks for each cohort. ] [ Designated as safety issue: Yes ]

    Drug safety will be measured by the number and grade of adverse events, by participant, related to the drug in study (PDM08) in the cohorts studied: 560 μg, 1.12 mg, 2.24 mg, 3.5 mg and 14 mg, 28 mg and 56 mg administered twice a week for four weeks.

    The drug will be administered twice a week for four weeks.

    Safety and tolerability will be measured considering the adverse events occurred, by participant, related with the drug in study, PDM08, at each cohort.


  • Dose limiting toxicity (DLT) [ Time Frame: 6 weeks. ] [ Designated as safety issue: Yes ]
    Drug tolerability will be assessed by determining the DLT. It will be determined for each cohort (increasing multiple doses of PDM08): 560 μg, 1.12 mg, 2.24 mg, 3.5 mg and 14 mg, 28 mg and 56 mg administered twice a week for four weeks). Dose Limiting Toxicity will be considered the dose that produces adverse events of a severity grade 3 or greater, related to the drug in study (PDM08) in the classification specified in the list of Toxicity Criteria of the National Cancer Institute (CTCAE v04.03).


Secondary Outcome Measures:
  • AUC [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]

    Blood sampling collected on Day 1 and 25 of each cohort cycle.Cohorts (doses): 560 μg, 1.12 mg, 2.24 mg, 3.5 mg and 14 mg, 28 mg and 56 mg administered twice a week for four weeks.

    Blood collection scheme: - Dose of 560 μg and 1.12 mg: 0,0.25, 1, 2, 4, 8, 12 hours post-dose, on day 1 and day 25 of each cycle. - Doses of 2.24 mg, 3.5 mg, 14 mg, 28 mg, and 56 mg: 0,0.25, 1, 2, 4, 8, 12, 16 and 24 hours post-dose, on day 1 and day 25 of each cycle.

    Pharmacokinetic parameters will be expressed as mean ± standard deviation and confidence interval 95%. Linearity will be analyzed.


  • Cmax [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]

    Blood sampling will be collected on Day 1 and Day 25 of each cohort cycle.Cohorts(doses): 560 μg, 1.12 mg, 2.24 mg, 3.5 mg and 14 mg, 28 mg and 56 mg administered twice a week for four weeks.

    Blood collection scheme:

    • Dose of 560 μg and 1.12 mg: 0,0.25, 1, 2, 4, 8, 12 hours post-dose, on day 1 and day 25 of each cycle.
    • Dose of 3.5 mg and 14 mg, 28 mg and 56 mg: 0,0.25, 1, 2, 4, 8, 12, 16 and 24 hours post-dose, on day 1 and day 25 of each cycle.

    Pharmacokinetic parameters will be expressed as mean ± standard deviation and confidence interval 95%. Linearity will be analyzed.


  • Volume of distribution (Vd) [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]

    Blood sampling will be collected on Day 1 and Day 25 of each cohort cycle.Cohorts(dose): 560 μg, 1.12 mg, 2.24 mg, 3.5 mg and 14 mg, 28 mg and 56 mg administered twice a week for four weeks.

    Blood collection scheme:

    • Dose of 1.12 mg and 2.24 mg: 0,0.25, 1, 2, 4, 8, 12 hours post-dose, on day 1 and day 25 of each cycle.
    • Dose of 2.24 mg; 3.5 mg and 14 mg, 28 mg and 56 mg: 0,0.25, 1, 2, 4, 8, 12, 16 and 24 hours post-dose, on day 1 and day 25 of each cycle.

    Pharmacokinetic parameters will be expressed as mean ± standard deviation and confidence interval 95%. Linearity will be analyzed.


  • Plasma half-life of PDM08 (T ½) [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]

    Blood sampling will be collected on Day 1 and Day 25 of each cohort cycle.Cohorts(dose): 560 μg, 1.12 mg, 2.24 mg, 3.5 mg and 14 mg, 28 mg and 56 mg administered twice a week for four weeks.

    Blood collection scheme:

    • Dose of 560 μg and 1.12 mg: 0,0.25, 1, 2, 4, 8, 12 hours post-dose, on day 1 and day 25 of each cycle.
    • Dose of 2.24 mg, 3.5 mg and 14 mg, 28 mg and 56 mg: 0,0.25, 1, 2, 4, 8, 12, 16 and 24 hours post-dose, on day 1 and day 25 of each cycle.

    Pharmacokinetic parameters will be expressed as mean ± standard deviation and confidence interval 95%. Linearity will be analyzed.


  • Changes in tumour size by Computed Tomography (CT) [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]

    Changes in tumour size will be measured by CT (RECIST criteria v.1.1) at each cohort on days 1, 4, 11, 25, 29 and 43 of the study.

    Pharmacodynamic parameters will be tabulated as raw values and sorted by dose. Statistical analysis will be performed using ANOVA with repeated measures, including baseline values as cofactor.


  • Tumour activity: Positron emission tomography (PET) [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]

    Changes in tumour activity will be measured by PET in each cohort on days 1, 4 11, 25, 29 and 43 of the study.

    Pharmacodynamic parameters will be tabulated as raw values and sorted by dose. Statistical analysis will be performed using ANOVA with repeated measures, including baseline values as cofactor.


  • Myeloid cells in peripheral blood. [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]
    Myeloid cells in peripheral blood (total myeloid cells, monocyte-macrophage series, granulocytes and myeloid suppressor in peripheral blood) will be measured in each cohort on days 1, 4, 11, 25, 29 and 43 of the study.

  • B and T lymphocytes and NK cells Populations [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]
    In order to determine the function of these populations the exresion of membrane markers will be analyze; and membrane markers displayed in relation to the degree of activation of lymphocytes. These parameters will be measured at each cohort on days 1, 4, 11, 25, 29 and 43 of the study.

  • Serum Immunoglobulins [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]
    Serum Immunoglobulins and subtypes (IgG1, IgG2, IgG3, IgG4, IgM, IgA) will be measured at each cohort on days 1, 4, 11, 25, 29 and 43 of the study.

  • Complement components: C3 and C4; and C-Reactive Protein (CRP) [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]
    C3 and C4 components of the complement system, CRP, and the total activity of the classical complement pathway. measured as haemolytic capacity CH50,will be measured in serum of all the participants at each cohort on days 1, 4, 11, 25, 29 and 43 of the study.

  • Serum cytokines [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]
    Serum cytokines that will be measured will be:IL1α, IL1β, IL2, IL4, IL5, IL6, IL7, IL10, IL12, IL17, TNFα, IFNγ, G-CSF, GM-CSF, VEGF. Serum cytokines will be measured in serum at each cohort on days 1, 4, 11, 25, 29 and 43 of the study.


Enrollment: 22
Study Start Date: June 2011
Study Completion Date: January 2013
Primary Completion Date: June 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: PDM08
To assess the tolerability and safety of increasing multiple doses administration of PDM08: 560 μg, 1.12 mg, 2.24 mg, 3.5 mg and 14 mg, 28 mg and 56 mg administered twice a week for four weeks in patients with advanced solid tumours for which there is no standard therapy or the patient is refractory to it.
Drug: PDM08
To assess the tolerability and safety of increasing multiple doses administration of PDM08: 560 μg, 1.12, 2.24, 3.5, 14, 28 and 56 mg administered twice a week for four weeks in patients with advanced solid tumours for which there is no standard therapy or they are refractory to it.
Other Names:
  • 4-amino-5-oxo-4(pyridinium-1-ylmethyl)proline D-cis
  • 3S,5R-1-(3-Amino-5-carboxy-2-oxopyrrolidin-3-ylmethyl)pyridinium bromide hidrobromide

Detailed Description:

Phase I study, open, dose escalation, in adult patients with advanced solid tumours, to evaluate tolerability, pharmacokinetics and pharmacodynamics of ascending PDM08 doses administered twice a week cycles of 4 weeks.

After checking the safety of the first drug doses, a new dose escalation was proposed and approved by the Ethic Committee and the Medicines Agency.

This clinical trial is carried out in adult patients with advanced solid tumours whose disease has progressed despite standard therapy, or for which there is no standard antineoplastic therapy, or are refractory to it.

In pharmacodynamic non clinical studies, PDM08 presented antitumour activity against different tumour models including, renal, colon, lung, prostate and breast cancer models.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Population: Adult patients with advanced solid tumours whose disease has progressed despite standard therapy, or for which there is no standard antineoplastic therapy, or are refractory to it.
  • Informed consent must be obtained for each patient, in accordance with the guideline for Good Clinical Practice (GCP) of the International Conference of Harmonization (ICH) and with the local requirements.
  • Malignant tumour, histologically or cytologically demonstrated.
  • Patients age equal or greater than 18 years.
  • Patients must not have an ECOG>2 (ECOG 2: Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours)
  • The life expectancy of the patient should be superior to 3 months.
  • Bilirubin<1,5 times the laboratory upper limit.
  • AST and ALT less than 2,5 times the laboratory upper limit, In case of liver metastases to a value less than 5 times the laboratory upper limit.
  • Women in fertile age: a pregnant test must be carried out.
  • Men and women in fertile age must commit to to practice one method of birth control during their participation in the trial, and 30 days after the administration of the last dose of the experimental drug.
  • The patient should have renal function parameters (creatinine) not exceeding 1.5 times the normal upper limit.
  • The patient must present a hemoglobin > 9 mg/dL.
  • The patient must show basal platelet count > 100.000 /mm3.
  • Specific criteria:
  • Patients included in the expansion cohort must present a measurable disease by RECIST criteria 1.1, and disease progression in the last 6 months.
  • Patients who agree to enter into the pharmacodynamic tumour tissue substudy should present accessible tissue to carry out the biopsy safely.

Exclusion Criteria:

  • Patients who have received chemotherapy, radiotherapy, immunotherapy or investigational drugs for their disease within 4 weeks prior to PDM08 first dose.
  • Patients who have had surgery within 4 weeks before treatment.
  • Patients with untreated brain metastases.
  • Patients who are pregnant or breast-feeding.
  • Those patients who present an intercurrent non-controlled disease including, but not limited to, active infections, cicatrization problems, congestive heart failure, unstable angina, cardiac arrhythmia, pulmonary disease with non controlled symptoms, non controlled psychiatric disorders or social situations that may affect the compliance with the requirements of the study.
  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: NCT01380249

Locations
Spain
Hospital Universitario La Paz
Madrid, Spain, 28046
Sponsors and Collaborators
Prodimed S.A.
Investigators
Principal Investigator: Jorge Barriuso, MD, PhD Hospital Universitario La Paz, Madrid (Spain)
  More Information

No publications provided

Responsible Party: Prodimed S.A.
ClinicalTrials.gov Identifier: NCT01380249     History of Changes
Other Study ID Numbers: 2009-017133-21
Study First Received: May 31, 2011
Last Updated: January 4, 2013
Health Authority: Spain: Spanish Agency of Medicines

Keywords provided by Prodimed S.A.:
Phase I
Phase I multiple doses
PDM08
Cancer Treatment
Pharmacokinetics and Pharmacodynamics
Advanced Solid Tumors
Prodimed

Additional relevant MeSH terms:
Neoplasms

ClinicalTrials.gov processed this record on October 23, 2014