Clinical Trials /

T-DM1 and Non-pegylated Liposomal Doxorubicin in HER2-positive Metastatic Breast Cancer

NCT02562378

Description:

The primary goal is to determine the maximum tolerated dose (MTD) of the combination of T-DM1 and non-pegylated liposomal doxorubicin in metastatic breast cancer (mBC) patients previously treated with taxanes and trastuzumab-based therapy. In addition, pharmacokinetic data on the combination of T-DM1 and lyposomal doxorubicin will be obtained.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: T-DM1 and Non-pegylated Liposomal Doxorubicin in HER2-positive Metastatic Breast Cancer
  • Official Title: Phase I Multicenter Clinical Trial Evaluating the Combination of Trastuzumab Emtansine (T-DM1) and Non-pegylated Liposomal Doxorubicin in HER2-positive Metastatic Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: Medopp038
  • NCT ID: NCT02562378

Conditions

  • Breast Cancer

Interventions

DrugSynonymsArms
Trastuzumab and non-pegylated liposomal doxorubicinT-DM1 and non-pegylated liposomal doxorubicinTrastuzumab + doxorubicin

Purpose

The primary goal is to determine the maximum tolerated dose (MTD) of the combination of T-DM1 and non-pegylated liposomal doxorubicin in metastatic breast cancer (mBC) patients previously treated with taxanes and trastuzumab-based therapy. In addition, pharmacokinetic data on the combination of T-DM1 and lyposomal doxorubicin will be obtained.

Detailed Description

      Subjects: Age ≥ 18 years with HER2-positive metastatic breast cancer that have relapsed or
      progressed on or after taxanes and trastuzumab-based therapy. Subjects must have histologic
      or cytologic confirmation of the HER2-positive metastatic breast cancer. Evidence of
      measurable or evaluable metastatic disease is required.

      Primary objective:

        -  To determine the maximum tolerated dose (MTD) of the combination of T-DM1 and
           non-pegylated liposomal doxorubicin in metastatic breast cancer (mBC) patients
           previously treated with taxanes and trastuzumab-based therapy.

      Secondary objectives:

        -  To determine the efficacy of the combination of T-DM1 and non-pegylated liposomal
           doxorubicin, defined by the overall response rate (ORR), clinical benefit rate (CBR),
           number of progressions and number and reasons for deaths.

        -  To assess the safety profile of the combination of T-DM1 and non-pegylated liposomal
           doxorubicin, defined by all toxicities reported during the study.

        -  To evaluate the cardiac safety of the combination of T-DM1 and non-pegylated liposomal
           doxorubicin measured by LVEF as assessed by echocardiography, cardiac troponin I and
           B-type natriuretic peptide (BNP) levels.

        -  To evaluate the potential role of single nucleotide polymorphisms (SNP) in the
           predisposition for developing cardiotoxicity.

        -  To analyze the pharmacokinetics (PK) profile of T-DM1 and its metabolites and
           non-pegylated liposomal doxorubicin.

      Type of study: This is a prospective dose-finding, multicenter and open-label phase I
      clinical trial.

      Treatment: Trastuzumab emtansine (T-DM1) will be administered at a fixed dose of 3.6 mg/kg IV
      on Day 1 every 3 weeks and three cohorts of patients with three different dose levels of
      conventional non-pegylated liposomal doxorubicin (45 mg/m2, 50 mg/m2 and 60 mg/m2) IV on Day
      1 in cycles of 21 days each are planned.
    

Trial Arms

NameTypeDescriptionInterventions
Trastuzumab + doxorubicinExperimentalTrastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (45 mg/m2, 50 mg/m2 and 60 mg/m2) IV
  • Trastuzumab and non-pegylated liposomal doxorubicin

Eligibility Criteria

        Inclusion Criteria:

          -  Signed informed consent

          -  Patient able and willing to comply with protocol

          -  Cytologically or histologically confirmed carcinoma of the breast.

          -  Incurable locally advanced or metastatic disease who have previously received up to
             two previous chemotherapy regimens in this setting. Patient must have progressed or
             relapsed on or after taxane and trastuzumab-based therapy.

          -  HER2-positive disease

          -  At least one measurable lesion according to RECIST version 1.1; or patients with non
             measurable lesions could be included with these exceptions:

             o patients with only blastic bone lesions / with only pleural, peritoneal or cardiac
             effusion, or meningeal carcinomatosis

          -  ≥ 18 years of age

          -  ECOG 0 or 1

          -  Life expectancy ≥ 3 months

          -  Adequate bone marrow function:

               -  Hemoglobin ≥ 10 g/dl.

               -  Absolute neutrophil count ≥ 1.5 x 109/L.

               -  Platelets ≥ 100 x 109/L without transfusions within 21 days

               -  International normalized ratio (INR) < 1.5 × the upper limit of normal (ULN).

          -  Adequate hepatic and renal function

          -  Adequate cardiovascular function with LVEF ≥ 55%

          -  Recovery from all reported toxicities of previous anti-cancer therapies to baseline or
             grade ≤ 1 (CTCAE version 4.0), except for alopecia

          -  For women of childbearing potential and not postmenopausal, and who have not undergone
             surgical sterilization with a hysterectomy and/or bilateral oophorectomy, and men with
             partners of childbearing potential, use of forms of contraception

        Exclusion Criteria:

          -  Previous treatment with T-DM1 or anthracyclines

          -  More than two chemotherapeutic regimens for locally advanced incurable disease or
             metastatic disease

          -  Prior anti-cancer treatment with chemotherapy, immunotherapy or radiotherapy within 3
             weeks (6 weeks for nitrosoureas or mitomycin-C), hormonal therapy or lapatinib within
             7 days, prior trastuzumab within 21 days (7 days if weekly trastuzumab) or any other
             targeted therapy within the last 21 days prior to starting study treatment

          -  Previous radiotherapy for the treatment of unresectable, locally advanced/recurrent or
             mBC is not allowed if:

               -  The last fraction of radiotherapy has been administered within 21 days prior to
                  first study drug administration (except for brain irradiation; at least 28 days
                  will be required)

               -  More than 25% of marrow-bearing bone has been irradiated

          -  History of intolerance (including Grade 3 or 4 infusion reaction) or hypersensitivity
             to the active substance or to any of the excipients of T-DM1 or non-pegylated
             liposomal doxorubicin

          -  Patients with CNS involvement. However, patients with metastatic CNS tumors may
             participate in this trial if the patient is > 4 weeks from radiotherapy completion, is
             clinically stable with respect to CNS tumor at the time of study entry and is not
             receiving steroid therapy for brain metastases

          -  Severe/uncontrolled intercurrent illness including, but not limited to, ongoing or
             active infection, or psychiatric illness/social situations that would limit compliance
             with study requirements.

          -  Cardiopulmonary dysfunction

          -  Current peripheral neuropathy of Grade ≥ 3 per the NCI CTCAE, v4.0

          -  History of a decrease in LVEF to < 40% or symptomatic CHF with previous trastuzumab
             treatment

          -  Prior malignancy, other than carcinoma in situ of the cervix, or non-melanoma skin
             cancer, unless the prior malignancy was cured ≥ 5 years before first dose of study
             drug with no subsequent evidence of recurrence

          -  Current known active infection with HIV, hepatitis B, and/or hepatitis C virus

          -  Women who are pregnant or breast-feeding
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose Limiting Toxicities
Time Frame:Baseline up to 6 weeks after patient entry
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Overall response rate
Time Frame:Baseline up to 18 weeks after patient entry
Safety Issue:
Description:Patients with best overall response of confirmed complete response (CR) or partial response (PR) based on local investigator's assessment according to RECIST criteria guidelines (version 1.1)
Measure:Clinical Benefit Rate
Time Frame:Baseline up to 18 weeks after patient entry
Safety Issue:
Description:Patients with a best overall response of complete response (CR) or partial response (PR) or stable disease (SD) based on local investigator's assessment according to RECIST criteria guidelines (version 1.1)
Measure:Progressions
Time Frame:Baseline up to 18 weeks after patient entry
Safety Issue:
Description:Patients with progression. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or measurable increase in a non-target lesion, or the appearance of new lesions
Measure:Grade 3/4 adverse events, SAEs, deaths and discontinuations
Time Frame:Baseline up to 18 weeks after patient entry
Safety Issue:
Description:Patients with grade 3/4 adverse events, SAEs, deaths and discontinuations
Measure:Level I cardiotoxicities
Time Frame:Baseline up to 18 weeks after patient entry
Safety Issue:
Description:Sudden death (defined as within 24 hours; unexplained); Heart failure NYHA criteria class III-IV and LVEF decline defined as an absolute drop ≥10% resulting in a final LVEF <50%
Measure:Level II cardiotoxicities
Time Frame:Baseline up to 18 weeks after patient entry
Safety Issue:
Description:Absolute drop ≥10% resulting in a final LVEF <50% and asymptomatic or heart failure NYHA criteria class II
Measure:Polymorphism of HER2 gene (SNP)
Time Frame:Baseline
Safety Issue:
Description:
Measure:Plasma concentration (Cmax)
Time Frame:Baseline up to 12 weeks after patient entry
Safety Issue:
Description:
Measure:Volum of distribution (Vd)
Time Frame:Baseline up to 12 weeks after patient entry
Safety Issue:
Description:
Measure:Area under the plasma concentration versus time curve (AUC)
Time Frame:Baseline up to 12 weeks after patient entry
Safety Issue:
Description:
Measure:Clearance (CL)
Time Frame:Baseline up to 12 weeks after patient entry
Safety Issue:
Description:
Measure:Apparent half-life (t1/2)
Time Frame:Baseline up to 12 weeks after patient entry
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:MedSIR

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