Are you entitled to go to Belgium?
Martine Piccart-Gebhart is widely respected as one if the foremost oncologists expert in her2+ breast cancer.
Perhaps she knows or can find out who is/are among France's foremost interventional radiologists to do the biopsy and/or whether putting you on a different combination of drugs first & re-imaging the node to see if it responds seems reasonable.
She speaks at all major international breast cancer conferences, led the international BIG studies that got Herceptin approved and is a thoughtful person (even to the point of considering prophylactic brain MRIs of early her2+ patients when she feels they are warranted)
I have no idea if this is feasible in the EU, but do know that MD Anderson, Stanford and others have means to do second pathologic opinions on the biopsy, if one is done and can provide links on how to proceed to get these.
So, as usual, no advice, as I am not qualified in anyway to provide advice, but am happy to my best to provide referrals to those I know are experts (through both my reading of the literature & my attendance at international conferences)--I believe she should be able to guide you to la creme de la creme (sorry for the lack of accents circonflexe!)
The French her2 expert from SABCS is Fabrice Andre(no accent aigu, either).... I have not heard him speak as often or as candidly--But for outspoken thoughtfulness as well as almost unparallelled expertise Dr Piccart seems the way to go.
Institut Gustave Roussy
Villejuif, France, 94805
Contact: Fabrice André, MD
Fabrice.ANDRE@gustaveroussy.fr
Principal Investigator: Fabrice André, MD
Both Dr. Piccart's institution the Institutes Jules Bourdet in Brussels & Dr. Andre's are participation in the PANACEA trial & he is the one of 2 chairs of the trial, combining herceptin with anti-PD-1 immunotherapy, . It appearsDr. Andre runs ithe trial for his institution as well:
Anti-PD-1 Monoclonal Antibody in Advanced, Trastuzumab-resistant, HER2-positive Breast Cancer (PANACEA)
This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2015 by International Breast Cancer Study Group
Sponsor:
International Breast Cancer Study Group
Information provided by (Responsible Party):
International Breast Cancer Study Group
ClinicalTrials.gov Identifier:
NCT02129556
First received: April 24, 2014
Last updated: October 6, 2015
Last verified: October 2015
Purpose
A significant amount of preclinical and correlative clinical data suggest that HER2-positive breast cancer could be amenable to immune¬therapeutic approaches. The presence of HER2-overexpression in breast cancers is associated with higher levels of proliferation, high histologic grade and higher levels of tumor infiltrating lymphocytes (TILs) compared with HER2-negative tumors. The investigators therefore hypothesize that for HER2-positive tumors, avoidance of destruction by the host immune system must be an important mechanism contributing to tumor growth and progression.
The term "immune evasion" refers to the ability of the tumor to suppress and change host anti-tumor immune reactions. The programmed cell death 1 (PD-1) pathway represents a major immune control switch which may be engaged by tumor cells to overcome active T-cell immune surveillance. The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in various tumors. High expression of PD-L1 on tumor cells (and to a lesser extent of PD-L2) has been found to correlate with poor prognosis and survival in various other solid tumor types. Furthermore, PD-1 has been suggested to regulate tumor-specific T-cell expansion in patients with malignant melanoma. These observations suggest that the PD-1/PD-L1 pathway plays a critical role in the tumor immune evasion and could be considered an attractive target for therapeutic intervention in several solid organ types.
MK-3475 (previously known as SCH 900475) is a potent and highly-selective humanized mAb of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. MK-3475 strongly enhances T lymphocyte immune responses in cultured blood cells from healthy human donors, cancer patients, and primatesMK-3475 also modulates the level of interleukin-2 (IL-2), tumor necrosis factor alpha (TNFα), interferon gamma (IFNγ), and other cytokines.
The investigators therefore propose to evaluate if the addition of an immunotherapy can reverse trastuzumab resistance and improve clinical outcomes in HER2-positive disease. In this study the investigators will determine if a monoclonal antibody targeted against PD-1, a T cell negative regulator, can reverse trastuzumab resistance in patients previously progressing on trastuzumab.
Condition Intervention Phase
Metastatic Breast Cancer
Drug: MK-3475
Phase 1
Phase 2
Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase Ib/II Trial Evaluating the Efficacy of MK-3475 and Trastuzumab in Patients With Trastuzumab-resistant, HER2-positive Metastatic Breast Cancers
Resource links provided by NLM:
Genetics Home Reference related topics: breast cancer
MedlinePlus related topics: Breast Cancer Cancer
Drug Information available for: Trastuzumab Pembrolizumab
U.S. FDA Resources
Further study details as provided by International Breast Cancer Study Group:
Primary Outcome Measures:
recommended dose of MK-3475 in combination with trastuzumab [ Time Frame: within the first 21 days ] [ Designated as safety issue: Yes ]
Determination of dose-limiting toxicity (DLT) which is defined as an adverse event or abnormal laboratory value assessed as suspected to be trial treatment related (possible, probable or definite) and unrelated to disease or disease Progression. Toxicities and lab values will be graded according to the NCI CTCAE (v4.0).
efficacy and safety profile of MK-3475 combined with trastuzumab [ Time Frame: Clinical and radiological tumor assessment will be performed by CT scan or MRI at progression or 6 months after stop of treatment, whichever occurs first. ] [ Designated as safety issue: Yes ]
At the time of each restaging, patients will be classified as achieving complete Response (CR), partial response (PR), stable disease (SD), progressive disease (PD), or non-evaluable for response according to RECIST (Version 1.1) criteria.
Secondary Outcome Measures:
Safety and Tolerability [ Time Frame: Adverse events are reported from the date of first dose of trial treatment until 90 days following treatment completion which occur after a maximum of 24 months. ] [ Designated as safety issue: Yes ]
The incidence of Events that are new or worsening will be summarized according to system organ class and/or preferred term, severity (based on CTCAE V4.0 grade), type of adverse event, and relation to study treatment.
Disease control (DC) [ Time Frame: from the start of trial treatment until confirmed CR, PR, or SD lasting for 24 weeks or longer ] [ Designated as safety issue: No ]
Disease control (DC) defined as best overall response of confirmed CR, PR, or SD lasting for 24 weeks or longer.
Duration of Response (DoR) [ Time Frame: from date of first documentation of objective response until first documentation of progressive disease, up to 6 months after stop of treatment (=30 months) ] [ Designated as safety issue: No ]
Duration of response (DoR) is defined among patients with objective response (confirmed CR or PR as best overall response) as the interval between dates of first documentation of objective response and first documentation of progressive disease. In the absence of documented progressive disease, follow-up will be censored at date of last disease assessment.
Time to Progression (TTP) [ Time Frame: from the first trial treatment until first documentation of progressive disease up to 6 months after stop of treatment (=30 months) ] [ Designated as safety issue: No ]
Time to progression (TTP) defined as the interval between the dates of the start of trial treatment and first documentation of progressive disease. In the absence of documented progressive disease, follow-up will be censored at date of last disease assessment
Progression-free survival (PFS) [ Time Frame: from the date of first treatment dose until documented disease progression or death from any cause. whichever occur first, assessed up to 30 months ] [ Designated as safety issue: No ]
For patients without progression, followup will be censored at the date of last disease assessment without progression, unless death occurs within 12 weeks following the date last known progressionfree, in which case the death will be counted as a PFS event. Patients who discontinue or initiate non-protocol treatment prior to documented disease progression will be followed for disease progression
Overall survival (OS) [ Time Frame: time from start of trial treatment to death from any cause, assessed up to 30 months ] [ Designated as safety issue: Yes ]
For patients who are lost to follow-up or who have no documentation of death at the time of final analysis, follow-up will be censored at the date of last assessment of vital status.
Estimated Enrollment: 46
Study Start Date: December 2014
Estimated Study Completion Date: December 2023
Estimated Primary Completion Date: December 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: MK-3475 with trastuzumab
MK-3475 at the dose of 1 mg/kg, 2 mg/kg, or 10 mg/kg once every 3 weeks by venous Infusion together with trastuzumab 6mg/kg by venous infusion once every 3 weeks.
A dose of 8mg/kg trastuzumab will be used at the first treatment if your prior treatment with trastuzumab was stopped more than 3 months before.
Drug: MK-3475
The phase Ib trial will determine the recommended phase to dose from three MK-3475 dose levels: 1mg/kg, 2 mg/kg or 10 mg/kg.
Eligibility
Ages Eligible for Study: 18 Years and older
Genders Eligible for Study: Female
Accepts Healthy Volunteers: No
Criteria
Inclusion criteria for screening:
Female gender
Age ≥ 18 years
Histologically confirmed breast adenocarcinoma that is unresectable loco-regional, or metastatic.
Locally confirmed HER2-positivity (immunohistochemistry score 3+) or ERBB2-amplification (Ratio ERBB2/centromeres ≥2.0 or mean gene copy number ≥ 6) of primary tumor or from metastatic or locally advanced biopsy.
Must have demonstrated progression of disease while on-treatment with trastuzumab. Progression must have been demonstrated by radiological or clinical assessment, with the presence of at least one measurable lesion as defined by RECIST 1.1.
If a patient has received a subsequent anti-HER2 therapy, she must also have progressed on the subsequent therapy. Progression must have been demonstrated by radiological or clinical assessment, with the presence of at least one measurable lesion as defined by RECIST 1.1.
LVEF ≥55%
Patient agrees to submit an FFPE tumor biopsy for central confirmation of HER2 positivity and central assessment of PD-L1 status. This can be from archival tissue sample from unresectable loco-regional or metastatic disease obtained ≤1 year prior to enrollment or new tissue material from a recently obtained surgical or diagnostic biopsy. Tissue obtained for the biopsy must not have been previously irradiated.
Note: Central Pathology Review on a tumor biopsy is mandatory for this trial, and patients will be evaluated centrally for eligibility.
Written Informed Consent (IC) for screening procedures and trial participation must be signed and dated by the patient and the Investigator prior to screening.
Written consent to biological material submission, indicating the patient has been informed of and agrees to tissue and blood material use, transfer and handling, must be signed and dated by the patient and the investigator prior to any procedures specific for this trial, including consent to translational research on FFPE and fresh frozen tumor biopsies in case the patient is enrolled into the trial.
The patient has been informed of and agrees to data transfer and handling, in accordance with national data protection guidelines.
Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1
Life expectancy >3 months.
Hematopoietic status:
Absolute neutrophil count ≥ 1.0 × 109/L,
Platelet count ≥ 100 × 109/L,
Hemoglobin ≥ 9 g/dL
Hepatic status:
Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN). In the case of known Gilbert's syndrome, a higher serum total bilirubin (< 2 × ULN) is allowed.
AST and ALT ≤ 2.5 × ULN; if the patient has liver metastases, ALT and AST must be ≤ 5 × ULN.
Renal status:
Creatinine ≤ 1.5 ×ULN or creatinine clearance > 60 ml/min
Proteinuria <1 g/day
International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 × ULN unless patient is receiving anticoagulant therapy as long as PT or PTT (partial thromboplastin time) is within therapeutic range of intended use of anticoagulant.
Inclusion criteria for enrollment:
All inclusion criteria for screening, plus:
Central lab confirmation on a metastatic biopsy (or biopsy from unresectable loco-regional disease) of:
HER2-positivity (immunohistochemistry score 3+) or ERBB2- amplification (Ratio ERBB2/centromer ≥2.0 or mean gene copy number ≥ 6),
Presence of PD-L1 expression assessed by IHC.
Patient agrees to submit tumor tissue for translational research:
tissue biopsy from unresectable loco-regional or metastatic disease obtained ≤1 year prior to enrollment or new tissue material from a recently obtained surgical or diagnostic biopsy.
if available: FFPE tumor block from primary surgery or diagnostic biopsy.
if available: pre-treatment fresh frozen tumor biopsy.
if feasible: FFPE tumor block from post-treatment biopsy will be taken at time of disease progression or end of all treatment if ended prior to progression. This re-biopsy is strongly advised.
if feasible: fresh frozen tumor biopsy from post-treatment biopsy will be taken at time of disease progression or end of all treatment if ended prior to progression.
Patient agrees to submit baseline (pre-treatment) blood and serial plasma for translational research, as detailed in Table 11 (see body of the protocol).
For patient of childbearing potential, negative serum pregnancy test. Pregnancy test has to be repeated within 72h before treatment start.
All anti-cancer treatment including endocrine therapy, with the exception of trastuzumab, must stop 3 weeks prior to first dose of trial treatment.
Exclusion criteria for screening:
Prior therapy with other anti-PD-1, anti- PD-L1, L2 or anti-CTLA4 therapy.
More than three lines of anti-HER2 treatment in the metastatic setting (multiple lines of endocrine therapy allowed).
No FFPE material to centrally assess HER2-positivity and PD-L1 expression.
Known Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies), or positive for Hepatitis B (HBsAg reactive) or Hepatitis C (HCV RNA [qualitative]).
Interstitial lung disease
Active central nervous system metastases, as indicated by clinical symptoms, cerebral edema, and/or progressive growth (patients with history of CNS metastases or spinal cord compression are eligible if they are clinically stable for at least 4 weeks before first dose of investigational product and do not require high-dose steroid treatment).
History of clinically significant or uncontrolled cardiac disease, including congestive heart failure (New York Heart Association functional classification ≥3), angina, myocardial infarction or ventricular arrhythmia.
Previous severe hypersensitivity reaction to treatment with another monoclonal antibody.
Active infection requiring systemic therapy.
Chronic systemic therapy with immunosuppressive agents including cortico¬steroids.
Concurrent disease or condition that would make the patient inappropriate for trial participation or any serious medical disorder that would interfere with the patient's safety.
Known history of uncontrolled hypertension (≥ 180/110), unstable diabetes mellitus, dyspnea at rest, or chronic therapy with oxygen.
Dementia, altered mental status, or any psychiatric condition that would prevent the understanding or rendering of Informed Consent.
Treatment with an investigational agent in the 4 weeks before enrollment.
Active autoimmune disease or a documented history of autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Patients with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Patients that require intermittent use of bronchodilators or local steroid injections would not be excluded from the trial. Patients with hypothyroidism stable on hormone replacement or Sjögren's syndrome will not be excluded from the trial.
Chemotherapy, radioactive therapy, and/or biological cancer therapy within 3 weeks prior to the first trial dose and has not recovered to CTCAE v.4 grade 1 or better from adverse events.
Pregnant or lactating women; lactation has to stop before enrollment.
The patient of childbearing potential who is unwilling to use effective contraception during treatment and up to 120 days after stop of trial treatment. Acceptable are barrier methods - condoms, diaphragm - also in conjunction with spermicidal jelly, or total abstinence. Oral, injectable, or implant hormonal contraceptives are not allowed.
Unresolved or unstable, serious adverse events from prior administration of another investigational drug.
Active or uncontrolled infection CTCAE v.4 grade 2 or higher.
Live vaccines within 30 days prior to the first dose of trial therapy and during trial treatment.
Exclusion criteria for enrollment:
All exclusion criteria for screening apply for enrollment as well. Excluded are especially patients who have received any of the treatments below:
Live vaccines within 30 days prior to the first dose of trial therapy and during trial treatment.
History of CNS metastases or spinal cord compression if they have not been clinically stable for at least 4 weeks before first dose of investigational product and require high-dose steroid treatment.
Treatment with an investigational agent in the 4 weeks before enrollment.
Patient has not recovered to CTCAE v.4 grade 1 or better from adverse events of prior therapy.
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: NCT02129556
Locations
Australia
Peter MacCullum Cancer Centre Not yet recruiting
Victoria, Australia, 3002
Contact: Sherene Loi, MD
Principal Investigator: Sherene Loi, MD
Royal Melbourne Hospital Not yet recruiting
Victoria, Australia, 3050
Contact: Sherene Loi, MD
Principal Investigator: Sherene Loi, MD
Austria
Medical University of Vienna Not yet recruiting
Vienna, Austria, 1090
Contact: Rupert Bartsch, MD +43 (0)1 40 160 0
Principal Investigator: Rupert Bartsch, MD
Belgium
Jules Bordet Institute Recruiting
Brussels, Belgium, 1000
Contact: Andrea Gombos, MD
andrea.gombos@bordet.be
Principal Investigator: Andrea Gombos, MD
CHU Sart Tilman Recruiting
Liège, Belgium, 4000
Contact: G Jerusalem, MD,PhD +32 43 667 664
g.jerusalem@hu.ulg.ac.be
Principal Investigator: Guy Jerusalem, MD,PhD
France
Institut de Cacérologie de l`OUEST Not yet recruiting
Anger, France
Contact: Mario Campone, MD 02 40 67 99 77
Principal Investigator: Mario Campone, MD
Centre Leon Berard Not yet recruiting
Lyon, France, 69008
Contact: Thomas Bachelot, MD 04 78 78 26 54
thomas.bachelot@lyon.unicancer.fr
Principal Investigator: Thomas Bachelot, MD
Institut Gustave Roussy Recruiting
Villejuif, France, 94805
Contact: Fabrice André, MD
Fabrice.ANDRE@gustaveroussy.fr
Principal Investigator: Fabrice André, MD
Italy
Istituto Europeo di Oncologia Not yet recruiting
Milan, Italy, 435
Contact: Giuseppe Curigliano, MD 02 57489 258
Principal Investigator: Giuseppe Curigliano, MD
Azienda USL4 Prato Not yet recruiting
Prato, Italy, 59100
Contact: Laura Biganzoli, MD 0574434334
lbiganzoli@usl4.toscana.it
Principal Investigator: Laura Biganzoli, MD
Sponsors and Collaborators
International Breast Cancer Study Group
Investigators
Study Chair: Sherene Loi, MD Department of Medical Oncology,Peter MacCallum Cancer Centre,East Melbourne, Victoria, Australia
Study Chair: Fabrice André, Prof. Department of Medical Oncology Institut Gustave Roussy,Villejuif,France
More Information
Publications:
Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001 Mar 15;344(11):783-92.
Hurvitz SA, Betting DJ, Stern HM, Quinaux E, Stinson J, Seshagiri S, Zhao Y, Buyse M, Mackey J, Driga A, Damaraju S, Sliwkowski MX, Robert NJ, Valero V, Crown J, Falkson C, Brufsky A, Pienkowski T, Eiermann W, Martin M, Bee V, Marathe O, Slamon DJ, Timmerman JM. Analysis of Fcγ receptor IIIa and IIa polymorphisms: lack of correlation with outcome in trastuzumab-treated breast cancer patients. Clin Cancer Res. 2012 Jun 15;18(12):3478-86. doi: 10.1158/1078-0432.CCR-11-2294. Epub 2012 Apr 13.
Denkert C, Loibl S, Noske A, Roller M, Müller BM, Komor M, Budczies J, Darb-Esfahani S, Kronenwett R, Hanusch C, von Törne C, Weichert W, Engels K, Solbach C, Schrader I, Dietel M, von Minckwitz G. Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol. 2010 Jan 1;28(1):105-13. doi: 10.1200/JCO.2009.23.7370. Epub 2009 Nov 16. Erratum in: J Clin Oncol. 2010 Feb 1;28(4):708.
Loi S, Sirtaine N, Piette F, Salgado R, Viale G, Van Eenoo F, Rouas G, Francis P, Crown JP, Hitre E, de Azambuja E, Quinaux E, Di Leo A, Michiels S, Piccart MJ, Sotiriou C. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol. 2013 Mar 1;31(7):860-7. doi: 10.1200/JCO.2011.41.0902. Epub 2013 Jan 22.
Responsible Party: International Breast Cancer Study Group
ClinicalTrials.gov Identifier: NCT02129556 History of Changes
Other Study ID Numbers: IBCSG 45-13/BIG 4-13 2013-004770-10
Study First Received: April 24, 2014
Last Updated: October 6, 2015
Health Authority: Belgium: Federal Agency for Medicinal Products and Health Products
Italy: The Italian Medicines Agency
France: Agence Nationale de Sécurité du Médicament et des produits de santé
Austria: Agentur für Gesundheit und Ernährungssicherheit
Keywords provided by International Breast Cancer Study Group:
Metastatic
Breast
trastuzumab-resistant
PD-L1 expressing
HER2-positive
Additional relevant MeSH terms:
Breast Neoplasms
Breast Diseases
Neoplasms
Neoplasms by Site
Skin Diseases
Trastuzumab
Antineoplastic Agents
Pharmacologic Actions
Therapeutic Uses
ClinicalTrials.gov processed this
Hope this helps!
Node biopsy. What should I ask?
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