Clinical Trials /

SAFIR02_Breast - Efficacy of Genome Analysis as a Therapeutic Decision Tool for Patients With Metastatic Breast Cancer

NCT02299999

Description:

Open label multicentric phase II randomized trial, using high throughput genome analysis as a therapeutic decision tool, which aims at comparing a targeted treatment administered according to the identified molecular anomalies of the tumor with maintenance chemotherapy (targeted substudy 1) as well as immunotherapy with maintenance chemotherapy in patients without actionable genomic alterations or non eligible to substudy 1 (immune substudy 2).

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: SAFIR02_Breast - Efficacy of Genome Analysis as a Therapeutic Decision Tool for Patients With Metastatic Breast Cancer
  • Official Title: PERSONALIZED MEDICINE GROUP / UCBG UC-0105/1304: SAFIR02_Breast - Evaluation of the Efficacy of High Throughput Genome Analysis as a Therapeutic Decision Tool for Patients With Metastatic Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: UC-0105/1304
  • SECONDARY ID: 2013-001652-36
  • NCT ID: NCT02299999

Conditions

  • Metastatic Breast Cancer

Interventions

DrugSynonymsArms
AZD2014Substudy 1: targeted agent
AZD4547Substudy 1: targeted agent
AZD5363Substudy 1: targeted agent
AZD8931Substudy 1: targeted agent
SelumetinibARRY-142866Substudy 1: targeted agent
VandetanibCAPRELSASubstudy 1: targeted agent
BicalutamideCasodexSubstudy 1: targeted agent
OlaparibLynparzaSubstudy 1: targeted agent
AnthracyclinesDoxorubicin, Epirubicin, liposomal doxorubicinSubstudy 1: standard maintenance therapy
Taxanespaclitaxel, docetaxelSubstudy 1: standard maintenance therapy
cyclophosphamideNovatrex, ImethSubstudy 1: standard maintenance therapy
DNA intercalatorscapecitabine, 5-FU, gemcitabineSubstudy 1: standard maintenance therapy
MethotrexateSubstudy 1: standard maintenance therapy
vinca alkaloidsvinorelbine, vinblastine, vincristineSubstudy 1: standard maintenance therapy
Platinum based chemotherapiesPlatinum, carboplatin, cisplatinSubstudy 1: standard maintenance therapy
BevacizumabAvastinSubstudy 1: standard maintenance therapy
Mitomycine CAmetycineSubstudy 1: standard maintenance therapy
EribulineHalavenSubstudy 1: standard maintenance therapy
MEDI4736Substudy 2: Immunotherapy

Purpose

Open label multicentric phase II randomized trial, using high throughput genome analysis as a therapeutic decision tool, which aims at comparing a targeted treatment administered according to the identified molecular anomalies of the tumor with maintenance chemotherapy (targeted substudy 1) as well as immunotherapy with maintenance chemotherapy in patients without actionable genomic alterations or non eligible to substudy 1 (immune substudy 2).

Detailed Description

      Screening phase:

      New frozen biopsy or an archived frozen sample or ctDNA sample will be sent to the genomic
      plateforms for DNA extraction and genomic analysis (DNA microarrays and Next generation
      sequencing).

      Patients can be considered as pre-eligible for the targeted substudy 1 randomisation phase
      when both following mandatory conditions have been met: stable or responding disease has been
      observed (investigator judgment) after 6 to 8 cycles of chemotherapy (or at least after 4
      cycles of chemotherapy if stopped for toxicity) and targetable alteration has been identified
      by the Molecular Tumor Board (MTB).

      If not eligible for the substudy 1 randomisation phase, patients can be considered as
      pre-eligible for the immune substudy 2 randomization phase when both following mandatory
      conditions are met: stable or responding disease (investigator judgment) is observed after 6
      to 8 cycles of chemotherapy (or at least after 4 cycles if treatment was stopped due to
      toxicity) AND not eligible to randomization in the substudy 1 (because patient had no
      targetable alteration identified by the Molecular Tumor Board, or failed to have a genomic
      profile for the tumor [low tumor cells percentage, technical issue during genomic analysis,
      etc.], or a non inclusion criteria that precluded entry into the substudy 1)

      Randomization phase:

      The mandatory post-chemotherapy wash-out period, of 28 days for 21 or 28 day-cycle
      chemotherapies or of 15 days for weekly (except monoclonal antibodies) or daily
      chemotherapies,will provide time to achieve all the required tests and examinations.

      The randomization program will allocate the following treatments with a 2:1 ratio in favor of
      Arm A of the considered substudy:

      Substudy 1 : targeted therapies versus standard maintenance chemotherapy

        -  Arm A1 / targeted arm: targeted maintenance from a list of 8 targeted drugs (see
           Appendix 5 - List of medications and targets) guided by the genomic analysis, or

        -  Arm B1 / chemotherapy arm : maintenance chemotherapy (or no antineoplastic treatment in
           case of toxicity at the time of randomization)

      Substudy 2 : immunotherapy versus standard maintenance chemotherapy

        -  Arm A2 / immunotherapy maintenance arm: MEDI4736 or

        -  Arm B2 / chemotherapy arm: chemotherapy continued as a maintenance chemotherapy (or no
           antineoplastic treatment in case of toxicity)
    

Trial Arms

NameTypeDescriptionInterventions
Substudy 1: targeted agentExperimentalArm A1 / Targeted Arm : targeted maintenance from a list of 8 targeted drugs guided by the genomic analysis, AZD2014 tablet per os 50 mg bd, continuous dosing, AZD4547 tablet per os 80 mg bd, 2 weeks on/1 week off, AZD5363 capsule per os 480 mg bd, 4 days on/3 days off, AZD8931 tablet per os 40 mg bd, continuous dosing, selumetinib capsule per os 75 mg bd, continuous dosing, vandetanib tablet per os 300 mg od, continuous dosing, bicalutamide tablet per os 150 od, continuous dosing, olaparib tablet per os 300 mg bd, continuous dosing
  • AZD2014
  • AZD4547
  • AZD5363
  • AZD8931
  • Selumetinib
  • Vandetanib
  • Bicalutamide
  • Olaparib
Substudy 1: standard maintenance therapyActive ComparatorArm B1/ maintenance Standard Chemotherapy Arm : such as Anthracyclines (Doxorubicine or Epirubicine or Liposomal Doxorubicine), Taxanes (Paclitaxel, Docetaxel), Cyclophosphamide, DNA Intercalators (Capecitabine, 5-FU, gemcitabine), Methotrexate, Vinca alkaloids (Vinorelbine, Vinblastine, Vincristine), Platinum based chemotherapies (Carboplatin, Cisplatin), Bevacizumab, Mitomycine C, Eribuline
  • Anthracyclines
  • Taxanes
  • cyclophosphamide
  • DNA intercalators
  • Methotrexate
  • vinca alkaloids
  • Platinum based chemotherapies
  • Bevacizumab
  • Mitomycine C
  • Eribuline
Substudy 2: ImmunotherapyExperimentalArm A2/ Immunotherapy arm: maintenance with MEDI4736 for patient without actionable genomic alterations or non eligible to Targeted substudy 1, MEDI4736 Intra-venous 10 mg/kg, Q2W
  • MEDI4736
Substudy 2: standard maintenance therapyActive ComparatorArm B2/ maintenance Standard Chemotherapy Arm : such as Anthracyclines (Doxorubicine or Epirubicine or Liposomal Doxorubicine), Taxanes (Paclitaxel, Docetaxel), Cyclophosphamide, DNA Intercalators (Capecitabine, 5-FU, gemcitabine), Methotrexate, Vinca alkaloids (Vinorelbine, Vinblastine, Vincristine), Platinum based chemotherapies (Carboplatin, Cisplatin), Bevacizumab, Mitomycine C, Eribuline
  • Anthracyclines
  • Taxanes
  • cyclophosphamide
  • DNA intercalators
  • Methotrexate
  • vinca alkaloids
  • Platinum based chemotherapies
  • Bevacizumab
  • Mitomycine C
  • Eribuline

Eligibility Criteria

        Screening phase:

        Inclusion Criteria:

          -  Women (or men) with histologically proven breast cancer

          -  Metastatic relapse or progression or stage IV at diagnosis

          -  No Her2 over-expression

          -  Patients with metastases that can be biopsied, except bone metastases

          -  Patients who are eligible for a first or a second line of chemotherapy in metastatic
             setting (left to the discretion of investigators), or who are currently treated with a
             first or second line of chemotherapy with a maximum of 2 cycles at the time of biopsy.
             Screening of patients currently treated with a second line chemotherapy should have a
             stable disease

          -  For patients with ER+ disease, relapse or progression occurred during endocrine
             therapy, whatever the line, or less than 12 months after the end of endocrine therapy
             in adjuvant context

          -  Age ≥ 18 years

          -  WHO Performance Status 0/1

          -  Presence of measurable target lesion according to RECIST criteria v1.1

        Exclusion criteria:

          -  Spinal cord compression and/or symptomatic or progressive brain metastases

          -  Bone metastases when this is the only site of biopsiable disease

          -  Patients with all target lesions in a previously irradiated region, except if clear
             progression has been observed prior to study in at least one of them

          -  Patient who received more than 2 lines of chemotherapy at the time of the biopsy

          -  Tumor progression observed with the current line of treatment when under 2nd line

          -  Patients who already had a genomic profile (both CGH and NGS analysis) in which no
             SAFIR02 targetable alterations have been identified

          -  Abnormal coagulation contraindicating biopsy

          -  Inability to swallow

          -  Major problem with intestinal absorption Any clinically important abnormalities in
             rhythm, conduction or morphology of resting ECG Any factors increasing the risk of QTc
             prolongation or arrhythmic events Experience of any of the following in the preceding
             12 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial
             infarction, past or current uncontrolled angina pectoris, congestive heart failure
             NYHA Grade ≥2, torsades de pointes, current uncontrolled hypertension, cardiomyopathy
             Past medical history of interstitial lung disease, drug-induced interstitial disease,
             radiation pneumonitis which requires steroid treatment or any evidence of clinically
             interstitial lung disease Previous or current malignancies of other histologies within
             the last 5 years, Evidence of severe or uncontrolled systemic disease (active bleeding
             diatheses, or active Hepatitis B, C and HIV)

          -  diagnosis of acne rosacea, severe psoriasis and severe atopic eczema

          -  Prior exposure to anthracyclines or mitoxantrone with cumulative exposure in excess of
             360 mg/m² for doxorubicin, 720 mg/m² for epirubicin, or 72 mg/m² for mitoxantrone

          -  Previous treatment with the same agent or in the same class as one of those used in
             the SAFIR02 trial (patients who received this previous targeted agent without the
             target prescreening are eligible but may not be eligible for randomisation in substudy
             1 if the treatment allocated by the MTB is in the same class) History of retinal
             degenerative disease, eye injury or corneal surgery in the previous 3 months, past
             history of central serous retinopathy or retinal vein occlusion, intraocular pressure
             >21 mmHg, or uncontrolled glaucoma.

          -  History of heamorrhagic or thrombotic stroke, TIA or other CNS bleeds

          -  Renal disease including glomerulonephritis, nephritic syndrome, Fanconi syndrome,
             renal tubular acidosis

          -  Patients using drugs that are known potent inhibitors or potent inducers or substrates
             of cytochrome P450

        Randomized phase:

        Substudy 1:

        Inclusion Criteria:

          -  Patients who received 6 to 8 cycles of chemotherapy, or having received at least 4
             cycles of chemotherapy definitively stopped for toxicity reasons, and who are
             presenting a SD or PR at randomization

          -  presenting at least one genomic alteration from the predefined list

          -  Age ≥ 25 years for patients planned to receive AZD4547

          -  28-day wash-out period from chemo prior to randomization and grade ≤1 residual
             toxicities

        Exclusion Criteria:

          -  More than 2 previous lines of chemotherapy for metastatic disease before randomization

          -  Life expectancy < 3 months

          -  Disease progression occuring at any time during chemotherapy and before randomization
             or toxicity that led to the discontinuation of the last chemotherapy before 4 full
             cycles have been delivered

          -  Less than 28 days from radiotherapy, less than 2 weeks from palliative radiation

          -  Patients previously treated with a targeted agent in the same class as the agent to be
             given to the patient in substudy 1

          -  Toxicities of grade ≥2 from any previous anti-cancer therapy

          -  Altered haematopoietic or organ function

          -  Mean resting corrected QT interval (QTc)>480msec (or QTcF >450 msec) obtained from 3
             consecutive ECGs

          -  LVEF <55% (MUGA scan or Echocardiogram)

          -  Altered ophthalmic conditions confirmed by an ophthalmology specialist for patients
             likely to be treated with AZD4547 orAZD8931 or Selumetinib

          -  Patients using non-substitutable drugs, that are known to prolong QT interval or
             induce Torsades de Pointes, when they are supposed to be treated with vandetanib,
             AZD5363 or AZD8931

        Substudy 2:

        Inclusion Criteria:

          -  Patients who received 6 to 8 cycles of chemotherapy, or having received at least 4
             cycles of chemotherapy definitively stopped for toxicity reasons, and who are
             presenting a SD or a RP at randomization

          -  Patients not eligible to substudy 1

          -  wash-out period of at least 15 days for weekly (except monoclonal antibodies) or daily
             chemotherapies or 28 days for other chemotherapies from last chemotherapy
             administration prior to randomization and grade ≤1 residual toxicities

        Exclusion Criteria:

          -  More than 2 previous lines of chemotherapy for metastatic disease before randomization

          -  Life expectancy < 3 months

          -  Disease progression occuring at any time during chemotherapy and before randomization
             or toxicity that led to the discontinuation of the last chemotherapy before 4 full
             cycles have been delivered

          -  Any previous treatment with a PD1 or PD-L1 inhibitor, including MEDI4736

          -  Toxicities of grade ≥2 from any previous anti-cancer therapy

          -  Altered haematopoietic or organ function

          -  Mean resting QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3
             consecutive ECGs using Bazett's Correction

          -  Current or prior use of immunosuppressive medication within 28 days before the first
             dose of MEDI4736, with the exceptions of intranasal and inhaled corticosteroids or
             systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of
             prednisone, or an equivalent corticosteroid

          -  Active or prior documented autoimmune disease within the past 2 years NOTE: Subjects
             with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within
             the past 2 years) are not excluded

          -  History of primary immunodeficiency
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival in the targeted drug arm compared to standard maintenance therapy arm
Time Frame:from randomization to disease progression or death from any cause, whichever comes first, up to 16 months (estimated treatment duration average: 4 months)
Safety Issue:
Description:To evaluate whether treatment with targeted agents guided by high throughput molecular analysis (CGH array, next generation sequencing) improves progression-free survival as compared to standard maintenance therapy in patients with metastatic Breast Cancer

Secondary Outcome Measures

Measure:progression-free survival in patients treated with anti-PDL1 antibody (MEDI4736) compared to standard maintenance therapy arm
Time Frame:from randomization to disease progression or death from any cause, whichever comes first, up to 16 months (estimated treatment duration average: 4 months)
Safety Issue:
Description:To evaluate whether treatment with MEDI4736 improves progression-free survival as compared to standard maintenance therapy in patients with metastatic Breast Cancer
Measure:overall survival in each substudy
Time Frame:from randomization to death (any cause), up to 16 months
Safety Issue:
Description:To evaluate whether treatment with targeted agents guided by high throughput molecular analysis (CGH array, next generation sequencing) or MEDI4736 improves overall survival as compared to standard maintenance therapy in patients with metastatic Breast Cancer
Measure:overall response rates and changes in tumor size in each substudy
Time Frame:tumor response is assessed every 21 days from treatment initiation until first progression or death from any cause, whichever comes first, up to 16 months (estimated treatment duration average: 4 months)
Safety Issue:
Description:tumor response is defined as a complete or partial response, upon RECIST v1.1 criteria
Measure:evaluate safety, in each substudy
Time Frame:toxicities will be assessed during the whole treatment period (4 months expected in average) followed by a 1-year post-treatment follow-up period, and reported during the visits scheduled by the study flow chart
Safety Issue:
Description:Toxicities are graded according to the CTCAE V4
Measure:efficacy (response rate, change in tumor size, progression-free survival, overall survival) and safety of each individual targeted agent (substudy 1)
Time Frame:tumor response is assessed every 21 days from treatment initiation until first progression or death from any cause, whichever comes first, up to 16 months (estimated treatment duration average: 4 months)
Safety Issue:
Description:tumor response is defined as a complete or partial response, upon RECIST v1.1 criteria
Measure:correlate molecular characteristics in patients with the efficacy endpoints (response rate, progression-free and overall survival) in each substudy
Time Frame:from randomization or treatment initiation to disease progression or death from any cause, whichever comes first, up to 16 months (estimated treatment duration average: 4 months)
Safety Issue:
Description:tumor response is defined as a complete or partial response, upon RECIST v1.1 criteria

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:UNICANCER

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