Trial record 2 of 24 for:    methotrexate and uc

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

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2016 by UNICANCER
Sponsor:
Collaborators:
Fondation ARC
AstraZeneca
Information provided by (Responsible Party):
UNICANCER
ClinicalTrials.gov Identifier:
NCT02299999
First received: October 1, 2014
Last updated: February 19, 2016
Last verified: February 2016
  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).

Condition Intervention Phase
Metastatic Breast Cancer
Drug: AZD2014
Drug: AZD4547
Drug: AZD5363
Drug: AZD8931
Drug: Selumetinib
Drug: Vandetanib
Drug: Bicalutamide
Drug: Olaparib
Drug: Anthracyclines
Drug: Taxanes
Drug: cyclophosphamide
Drug: DNA intercalators
Drug: Methotrexate
Drug: vinca alkaloids
Drug: Platinum based chemotherapies
Drug: Bevacizumab
Drug: Mitomycine C
Drug: Eribuline
Drug: MEDI4736
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by UNICANCER:

Primary Outcome Measures:
  • 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) ] [ Designated as safety issue: No ]
    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:
  • 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) ] [ Designated as safety issue: No ]
    To evaluate whether treatment with MEDI4736 improves progression-free survival as compared to standard maintenance therapy in patients with metastatic Breast Cancer

  • overall survival in each substudy [ Time Frame: from randomization to death (any cause), up to 16 months ] [ Designated as safety issue: No ]
    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

  • 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) ] [ Designated as safety issue: No ]
    tumor response is defined as a complete or partial response, upon RECIST v1.1 criteria

  • 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 ] [ Designated as safety issue: Yes ]
    Toxicities are graded according to the CTCAE V4

  • 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) ] [ Designated as safety issue: No ]
    tumor response is defined as a complete or partial response, upon RECIST v1.1 criteria

  • 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) ] [ Designated as safety issue: No ]
    tumor response is defined as a complete or partial response, upon RECIST v1.1 criteria


Estimated Enrollment: 460
Study Start Date: April 2014
Estimated Study Completion Date: October 2018
Estimated Primary Completion Date: October 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Substudy 1: targeted agent
Arm 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
Drug: AZD2014
Target: m-TOR
Drug: AZD4547
Target: EGFR
Drug: AZD5363
Target: AKT
Drug: AZD8931
Target: HER2, EGFR
Drug: Selumetinib
Target: MEK
Other Name: ARRY-142866
Drug: Vandetanib
Target: VEGF, EGFR
Other Name: CAPRELSA
Drug: Bicalutamide
target: Androgen receptor
Other Name: Casodex
Drug: Olaparib
Target: PARP
Other Name: Lynparza
Active Comparator: Substudy 1: standard maintenance therapy
Arm 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
Drug: Anthracyclines
DNA intercalation
Other Name: Doxorubicin, Epirubicin, liposomal doxorubicin
Drug: Taxanes
Target: mitotic tubulin and microtubules
Other Names:
  • paclitaxel
  • docetaxel
Drug: cyclophosphamide
Alkylating agents
Other Names:
  • Novatrex
  • Imeth
Drug: DNA intercalators
DNA intercalators
Other Names:
  • capecitabine
  • 5-FU
  • gemcitabine
Drug: Methotrexate
DNA intercalators
Drug: vinca alkaloids
Target: mitotic tubulin and microtubules
Other Names:
  • vinorelbine
  • vinblastine
  • vincristine
Drug: Platinum based chemotherapies
Platinum based chemotherapies
Other Names:
  • Platinum
  • carboplatin
  • cisplatin
Drug: Bevacizumab
Target: VEGF
Other Name: Avastin
Drug: Mitomycine C
Alkylating agents
Other Name: Ametycine
Drug: Eribuline
Microtubule modulator
Other Name: Halaven
Experimental: Substudy 2: Immunotherapy
Arm 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
Drug: MEDI4736
Target: PD-L1
Active Comparator: Substudy 2: standard maintenance therapy
Arm 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
Drug: Anthracyclines
DNA intercalation
Other Name: Doxorubicin, Epirubicin, liposomal doxorubicin
Drug: Taxanes
Target: mitotic tubulin and microtubules
Other Names:
  • paclitaxel
  • docetaxel
Drug: cyclophosphamide
Alkylating agents
Other Names:
  • Novatrex
  • Imeth
Drug: DNA intercalators
DNA intercalators
Other Names:
  • capecitabine
  • 5-FU
  • gemcitabine
Drug: Methotrexate
DNA intercalators
Drug: vinca alkaloids
Target: mitotic tubulin and microtubules
Other Names:
  • vinorelbine
  • vinblastine
  • vincristine
Drug: Platinum based chemotherapies
Platinum based chemotherapies
Other Names:
  • Platinum
  • carboplatin
  • cisplatin
Drug: Bevacizumab
Target: VEGF
Other Name: Avastin
Drug: Mitomycine C
Alkylating agents
Other Name: Ametycine
Drug: Eribuline
Microtubule modulator
Other Name: Halaven

Detailed Description:

Screening phase:

New frozen biopsy or an archived frozen 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)
  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  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: NCT02299999

Contacts
Contact: Stéphanie HERVE, Ms 01 71 93 63 64 s-herve@unicancer.fr

Locations
France
Institut de Cancérologie de l'Ouest/Paul Papin Recruiting
Angers, France
Contact: Mario CAMPONE, MD       mario.campone@ico.unicancer.fr   
Principal Investigator: Mario CAMPONE, MD         
Institut Sainte-Catherine Recruiting
Avignon, France
Contact: Alice Mege, MD       a.mege@isc84.org   
Principal Investigator: Alice Mege, MD         
Institut Bergonié Recruiting
Bordeaux, France
Contact: Hervé Bonnefoi, MD       h.bonnefoi@bordeaux.unicancer.fr   
Principal Investigator: Hervé Bonnefoi, MD         
Centre François Baclesse Recruiting
Caen, France
Contact: Christelle Lévy, MD       c.levy@baclesse.unicancer.fr   
Principal Investigator: Christelle Lévy, MD         
Centre Jean Perrin Recruiting
Clermont-Ferrand, France
Contact: Marie-Ange Mouret Reynier, MD       marie-ange.mouret-reynier@cjp.fr   
Principal Investigator: Marie-Ange Mouret Reynier, MD         
Centre Georges François Leclerc Recruiting
Dijon, France, 21079
Contact: Nicolas Isambert, MD       nisambert@cgfl.fr   
Principal Investigator: Nicolas Isambert, MD         
Centre Oscar Lambret Recruiting
Lille, France
Contact: Géraldine Lauridant, MD       g-lauridant@o-lambret.fr   
Principal Investigator: Géraldine Lauridant, MD         
Centre Léon Bérard Recruiting
Lyon, France
Contact: Thomas Bachelot, MD       thomas.bachelot@lyon.unicancer.fr   
Principal Investigator: Thomas Bachelot, MD         
Centre Hospitalier Lyon Sud Active, not recruiting
Lyon, France
Institut Paoli Calmettes Recruiting
Marseille, France
Contact: Anthony Gonçalves, MD       goncalvesa@ipc.unicancer.fr   
Principal Investigator: Anthony Gonçalves, MD         
Institut Régional du Cancer Montpellier Val d'Aurelle Recruiting
Montpellier, France
Contact: William Jacot, MD       william.jacot@icm.unicancer.fr   
Principal Investigator: William Jacot, MD         
Centre Alexis Vautrin Recruiting
Nancy, France
Contact: Elisabeth Luporsi, MD       e.luporsi@nancy.unicancer.fr   
Principal Investigator: Elisabeth Luporsi, MD         
Institut de Cancérologie de l'Ouest/ René Gauducheau Recruiting
Nantes, France
Contact: Mario Campone, MD       mario.campone@ico.unicancer.fr   
Principal Investigator: Mario Campone, MD         
Centre Antoine Lacassagne Recruiting
Nice, France
Contact: Jean-Marc Ferrero, MD       jean-marc.ferrero@nice.unicancer.fr   
Principal Investigator: Jean-Marc Ferrero, MD         
Institut Curie Recruiting
Paris, France
Contact: Marie-Paule Sablin, MD       mariepaule.sablin@curie.fr   
Principal Investigator: Marie-Paule Sablin, MD         
Centre Eugène Marquis Recruiting
Rennes, France
Contact: Claudia Lefeuvre-Plesse, MD       c.lefeuvre@rennes.unicancer.fr   
Principal Investigator: Claudia Lefeuvre-Plesse, MD         
Centre Henri Becquerel Recruiting
Rouen, France
Contact: Jean-Christophe Théry, MD       jean-christophe.thery@chb.unicancer.fr   
Principal Investigator: Jean-Christophe Théry, MD         
Institut Curie Recruiting
Saint-Cloud, France
Contact: Florence COUSSY, MD       florence.coussy@curie.fr   
Principal Investigator: Florence COUSSY, MD         
Hopitaux Universitaire de Strasbourg - Hopital Civil Not yet recruiting
Strasbourg, France
Contact: Philippe BARTHELEMY, MD       philippe.barthelemy@chru-strasbourg.fr   
Principal Investigator: Philippe BARTHELEMY, MD         
Institut Claudius Regaud Recruiting
Toulouse, France
Contact: Florence Dalenc, MD       dalenc.florence@iuct-oncopole.fr   
Principal Investigator: Florence Dalenc, MD         
Gustave Roussy Recruiting
Villejuif, France
Contact: Monica Arnedos, MD       Monica.ARNEDOS@gustaveroussy.fr   
Principal Investigator: Monica Arnedos, MD         
Sub-Investigator: Fabrice André, MD         
Sponsors and Collaborators
UNICANCER
Fondation ARC
AstraZeneca
Investigators
Principal Investigator: Fabrice ANDRE, Pr Gustave Roussy, Villejuif
  More Information

Additional Information:
Responsible Party: UNICANCER
ClinicalTrials.gov Identifier: NCT02299999     History of Changes
Other Study ID Numbers: UC-0105/1304  2013-001652-36 
Study First Received: October 1, 2014
Last Updated: February 19, 2016
Health Authority: France: Agence Nationale de Sécurité du Médicament et des produits de santé
Individual Participant Data  
Plan to Share IPD: Undecided

Additional relevant MeSH terms:
Methotrexate
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Paclitaxel
Vincristine
Vinorelbine
Vinblastine
Docetaxel
Vinca Alkaloids
Gemcitabine
Liposomal doxorubicin
Olaparib
Taxane
Bicalutamide
Albumin-Bound Paclitaxel
Cisplatin
Bevacizumab
Cyclophosphamide
Carboplatin
Capecitabine
Doxorubicin
Mitomycins
Mitomycin
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents

ClinicalTrials.gov processed this record on July 25, 2016