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WO2008009927A1 - Utilisation de fulvestrant et d'un inhibiteur de l'aromatase pour traiter le cancer du sein - Google Patents

Utilisation de fulvestrant et d'un inhibiteur de l'aromatase pour traiter le cancer du sein Download PDF

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Publication number
WO2008009927A1
WO2008009927A1 PCT/GB2007/002708 GB2007002708W WO2008009927A1 WO 2008009927 A1 WO2008009927 A1 WO 2008009927A1 GB 2007002708 W GB2007002708 W GB 2007002708W WO 2008009927 A1 WO2008009927 A1 WO 2008009927A1
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Prior art keywords
treatment
breast cancer
dtc
patients
fulvestrant
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PCT/GB2007/002708
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Inventor
Michael Gnant
Raimund Jakesz
Richard Franz Greil
Hellmut Samonigg
Christian Marth
Stephan Braun
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AstraZeneca UK Ltd
AstraZeneca AB
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AstraZeneca UK Ltd
AstraZeneca AB
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to a method of treatment of breast cancer which comprises administration of fulvestrant and simultaneous, separate or sequential treatment with an aromatase inhibitor to a patient in need thereof wherein the patient has hormone receptor positive early breast cancer.
  • Fulvestrant (FASLODEX TM) is presently approved for the treatment of hormone receptor positive advanced breast cancer with disease progression following antioestrogen therapy. The approved dose is 250mg per month administered by intramuscular injection. Fulvestrant is not approved for treatment of early breast cancer.
  • the present invention provides a method of treatment of breast cancer which comprises administration of fulvestrant and simultaneous, separate or sequential treatment with an aromatase inhibitor to a patient in need thereof wherein the patient has hormone receptor positive early breast cancer.
  • fulvestrant is administered as a 450-550 mg intramuscular injection monthly. Preferably one additional 450-550 mg dose is administered at day 14 of the first month. Preferably the dose of fulvestrant is about 500mg.
  • the patient has hormone receptor positive early breast cancer and a biomarker indicative of a poor prognosis.
  • the biomarker indicative of a poor prognosis is the presence of disseminated tumour cells in the bone marrow.
  • the aromatase inhibitor is anastrozole, exemestane or letrozole.
  • the aromatase inhibitor is anastrozole.
  • Another aspect of the present invention provides fulvestrant in a package together with instructions for its use for treatment of hormone receptor positive early breast cancer with simultaneous, sequential or separate treatment with an aromatase inhibitor.
  • Another aspect of the present invention provides the use of fulvestrant for manufacture of a medicament for treatment of hormone receptor positive early breast cancer in a patient wherein the patient is receiving simultaneous, sequential or separate treatment with an aromatase inhibitor.
  • Another aspect of the present invention provides the use of fulvestrant for manufacture of a medicament in a package together with instructions for its use for treatment of hormone receptor positive early breast cancer with simultaneous, sequential or separate treatment with an aromatase inhibitor.
  • Early breast cancer is defined as cancer confined to the breast and/or local lymph nodes without inflammatory or metastatic breast cancer patients who have had their primary treatment with surgery, radiotherapy and/or chemotherapy and also those who are suitable for hormonal treatment before this happens (also called “neoadjuvant") or as a sole form of treatment.
  • "early breast cancer” is defined as cancer confined to the breast and/or local lymph nodes without inflammatory or metastatic breast cancer patients who have had their primary treatment with surgery, radiotherapy and/or chemotherapy.
  • the invention is exemplified by the following non-limiting Example.
  • NCI CTCAE Version 3 grade 3 or 4 Adverse Events (AE), and Serious Adverse Events (SAE) after 12 and 24 months of randomised treatment. All adverse events will be recorded.
  • Clinical recurrence Occurrence of locally, regionally recurrent breast cancer and / or distant metastases after primary surgical, systemic and / or radiologic treatment
  • Measurement An observation made on a variable using a measurement device.
  • Principal Investigator A person responsible for the conduct of a clinical study at an investigational study centre. Every investigational study centre has a principal investigator.
  • Breast cancer is one of the most common female cancers and the most common cause of cancer deaths in women. It comprises 18% of all female cancers worldwide (McPherson et al, 2000). The incidence varies among populations with about half of all cases occurring in North America and Western Europe. Oestrogen acts as an endocrine growth factor for at least one third of breast cancers. It has long been acknowledged that many cancers are hormone dependent and that hormonal manipulation can affect the progress of the disease. The effects of hormonal manipulation on metastatic breast cancer were observed as early as 1896 following removal of the oestrogenic stimulus by bilateral oophorectomy (Beatson, 1896). The most important factor determining response to hormonal manipulation is the presence of the oestrogen receptor in the target tissue (Fisher et al, 2001).
  • the anti-oestrogen tamoxifen (AstraZeneca, NolvadexTM) is the most widely used hormonal treatment for breast cancer in both pre- and postmenopausal women.
  • This drug has been used to treat patients with breast cancer in advanced disease, as an adjuvant therapy after surgery, and for the treatment of ductal carcinoma in situ (DCIS), and also to reduce the risk of breast cancer development in women at high risk (Fisher et al, 1998).
  • DCIS ductal carcinoma in situ
  • de novo resistance or acquired resistance may occur after prolonged treatment limiting the effectiveness of tamoxifen in many patients. In some patients the disease progresses during therapy because tumour growth may also be stimulated by tamoxifen (Weibe et al, 1993).
  • the third generation oral AIs i.e., anastrozole (ArimidexTM, AstraZeneca), letrozole (FemaraTM, Novartis, USA), and the steroidal, type I inhibitor, exemestane (AromasinTM, Pfizer, USA), have now been tested in phase III trials where each has been shown to be more effective than the progestin megestrol acetate (MegaceTM, Bristol-Myers Squibb, USA) (Buzdar et al, 1998, Buzdar et al, 2001, Dombernowsky et al, 1998, Kaufman et al, 2000) and two have been shown to be more effective than tamoxifen (Bonneterre et al, 2001, Mouridsen et al, 2001).
  • tumour cells outside the primary tumour and in organs relevant for subsequent metastasis formation would serve three purposes that could be clinically useful: i) as unambiguous evidence for an early occult spread of tumour cells (Braun et al, 2005; Pierga et al, 2004; Wiedswang et al, 2003; Gebauer et al, 2001; Gerber et al, 2001; Braun et al, 2000a; Mansi et al, 1999; Diel et al, 1996); ii) as a relevant risk factor for subsequent metastasis and, thus, a poor prognosis (Braun et al, 2005; Pierga et al, 2004; Wiedswang et al, 2003; Gebauer et al, 2001; Gerber et al, 2001; Braun et al, 2000a; Mansi et al, 1999; Diel et al, 1996); and iii) as a marker for monitoring treatment sus
  • genotyping and phenotyping of CTC and DTC should provide detailed insight into the metastatic process and permit direct exploration of targeted treatment strategies (Pantel & Brakenhoff, 2004).
  • markers are needed to improve selection of both low-risk patients with no need to up-scale systemic adjuvant treatment and high-risk patients with a clear need for improved control of microscopic residual disease, since they frequently recur despite the administration of recommended standard therapy.
  • the pooled analysis conclusively demonstrated that the presence of DTC predicts poor outcome of patients treated with (inadequate?) adjuvant chemotherapy or endocrine therapy (Braun et al, 2005).
  • Fulvestrant is a new ER antagonist, without known agonistic properties, that downregulates cellular levels of the ER in a dose-dependent manner (Howell et al, 2000, Robertson et al, 2001, Wakeling et al, 1991). Fulvestrant is well- tolerated and has demonstrated efficacy in women whose breast cancer has progressed following tamoxifen therapy (Howell et al, 2002. Osborne et al, 2002). The results from two phase III trials showed that fulvestrant, given at a dose of 250 mg every 28 days, was at least as effective for both Time To Progression (TTP) and Objective Response (OR) as anastrozole (1 mg/day).
  • TTP Time To Progression
  • OR Objective Response
  • DTC patients with DTC represent a subgroup of patients in high-risk for relapse, which justifies that they should be suitable for initial testing of fulvestrant in the adjuvant setting. Furthermore, as both the detection of DTC during and persistence of DTC after therapy identifies patients with poor prognosis, DTC can be tested as a surrogate marker for subsequent clinical relapses and consequently for evaluation of the efficacy of the anastrozole-fulvestrant combination.
  • the primary objective of this study is to compare the frequency of events (i.e., presence of DTC in BM, clinical recurrence and/or death) in patients treated with anastrozole-fulvestrant combination as compared to that in patients treated with anastrozole alone by assessment of the BM status (i.e., the presence or absence of DTC) and the occurrence of clinical recurrences and/or deaths after 12 months (with a diagnostic window of ⁇ 3 weeks) of randomised treatment.
  • events i.e., presence of DTC in BM, clinical recurrence and/or death
  • a secondary objective of this study is to assess the safety of the anastrozole-fulvestrant combination by evaluation of the rate of NCI CTCAE grade 3 and 4 adverse events (AE) and serious AE (SAE) after 12 and 24 months (with a diagnostic window of ⁇ 3 weeks) of randomised treatment. All adverse events will be recorded. 2.2.2 Efficacy (presence / absence of DTC after 24 months and outcome)
  • a secondary objective of the study is to compare the frequency of events (i.e., presence of DTC in BM, clinical recurrence and/or death) in patients treated with anastrozole-fulvestrant combination as compared to that in patients treated with anastrozole alone by assessment of the BM status (i.e., the presence or absence of DTC) and the occurrence of clinical recurrences and/or deaths after 24 months (with a diagnostic window of ⁇ 3 weeks) of randomised treatment.
  • events i.e., presence of DTC in BM, clinical recurrence and/or death
  • An exploratory objective of the study is to compare the numbers of DTC in patients before and after 12 months ⁇ 3 weeks and 24 months ⁇ 3 weeks of treatment with anastrozole- fulvestrant combination to that in patients before and after 12 months ⁇ 3 weeks and 24 months ⁇ 3 weeks of treatment with anastrozole by evaluating the degree of any DTC reduction in relation to clinical recurrences and/or deaths.
  • An exploratory objective of the study is to investigate the clinical utility (occurrence versus absence of clinical event) of a molecular approach for the assessment of disseminated ribonucleotides by utilizing a multi-marker RT-PCR and its concordance with the standard immunocytocheniical assay for the detection of DTC before and after 12 and 24 months of randomised treatment.
  • An exploratory objective of the study is to investigate the clinical utility (occurrence versus absence of clinical event) of a molecular approach for the assessment of circulating ribonucleotides by utilizing a multi-marker RT-PCR and its concordance with the standard immunocytochemical assay for the detection of DTC before and after 12 and 24 months of randomised treatment.
  • An exploratory objective of the study is to explore the clinical utility (occurrence versus absence of clinical event) of a molecular approach for the assessment of circulating tumour- cell derived methylated nucleotides (presence versus absence of ribonucleotides; e.g., RASSFl) and its concordance with the standard immunocytochemical assay for the detection of DTC before and after 12 and 24 months of randomised treatment.
  • RASSFl ribonucleotides
  • An exploratory objective of the study is to investigate the expression of hormone receptors, HER2 oncoprotein and broad stem cell characteristics (e.g., CD44, CD24) of DTC.
  • broad amplification of DTC genome is attempted to assess genetic changes, including loss of heterozygosity.
  • Other translational research projects may be initiated.
  • Figure 1 displays a brief overview of the study design.
  • a Cycle refers to fulvestrant injection q28 ⁇ 3 days, except first cycle with an additional application on day 14 and/or dispensing of anastrozole tablets; check, evaluation of safety and efficacy; EOS, End-of-Study visit (also if a patient is withdrawn from / discontinues study except for clinical events).
  • Fulvestrant at a dose of 250 mg every 28 days is the first oestrogen receptor antagonist shown to be at least as effective as a third-generation aromatase inhibitor in the second- line treatment of advanced breast cancer (Howell et al, 2002, Osborne et al, 2002). In these studies, overall survival was also similar between the fulvestrant and anastrozole treatment arms (Pippen et al, 2003). By using the fulvestrant 500 mg regimen, both earlier achievement and higher levels of steady-state plasma concentrations may contribute to lower treatment failures, especially if given in addition to peripheral aromatase-inhibition.
  • fulvestrant will be administered at a dose of 500 mg every 28 days plus an additional 500 mg dose on day 14 of the first month only in an attempt to decrease the time to achieve steady-state levels and increase efficacy.
  • Phase III pharmacokinetic (PK) sampling data has demonstrated that a 250 mg dose administered every 28 days requires 3 to 6 months (90 to 180 days) before approaching steady-state drug concentrations. Earlier achievement of steady-state plasma concentrations may be important to avoid earlier "progression events”.
  • the expected mean peak plasma concentration (C max ) is approximately 27 ng/niL, around day 32.
  • C max will be expected in the range of 26 — 28 ng/mL.
  • the trough plasma concentrations at steady state are expected to be approximately 15 ng/mL compared to approximately 7 ng/mL for the 250 mg every 28 days injection.
  • Figure 2 represents population-predicted profiles of fulvestrant 250 mg treatment and the planned 500 mg treatment regimen
  • anastrozole at a dose of 1 mg/day is an established treatment for postmenopausal patients with hormone-receptor expressing primary breast cancer.
  • anastrozole at a dose of 1 mg/day as compared to tamoxifen at a dose of 20 mg/day reduces but does not abolish breast cancer recurrence. Therefore, a subgroup among anastrozole-treated patients may be considered at (high-)risk of breast cancer recurrence despite an effective treatment.
  • an oestrogen antagonist such as fulvestrant (as originally intended by the combination of anastrozole and tamoxifen in the ATAC trial), will be able to modify such a high-risk status.
  • DTC may be used i) as a selection criterion of high-risk patients at the time of decision about adjuvant treatment, and ii) as a surrogate marker of therapeutic efficacy of the applied treatment in patients with no clinically detectable evidence of disease.
  • patients Before entering the study, patients will be assessed to ensure that they meet the eligibility criteria. Patients not meeting these criteria should not be entered into the study.
  • the investigator must keep a record of patients who were considered for enrolment but were never enrolled, e.g., patient screening log indicating the reason why they were not enrolled. This information is necessary to establish that the patient population was selected without bias.
  • the patient-screening log should be filed in the Investigator Study File at each centre. Note: The patient's signed and dated informed written consent must be obtained before conducting any procedure specifically for the study.
  • ER +ve and/or PgR +ve Documented positive hormone receptor status (ER +ve and/or PgR +ve) of paraffin- embedded primary tumour tissue (core needle biopsy or tumour excision), according to the local laboratory parameters.
  • a positive hormone receptor status in fine needle aspiration may be used for pre-selection of patients for intraoperative Screening BM aspiration; a positive hormone receptor status of the tumour excision is required for inclusion in the study. 5.
  • Postmenopausal woman defined as a woman fulfilling any one of the following criteria:
  • liver function tests In case of abnormal values, the liver function tests have to be repeated and meet above criteria within 3 days before study treatment.
  • EXCEPT • Patient had received adjuvant chemotherapy and has a DTC-positive Screening Phase BM aspiration in local anaesthesia up to 8 weeks after but not less than 2 weeks of completion of chemotherapy;
  • Fulvestrant (FaslodexTM) as a 5% w/v solution in clear neutral glass pre-filled syringes (PFS). Each syringe will contain 250 mg of fulvestrant in 5 niL (Formulation Number F6521).
  • the constituents of the solution are as follows: fulvestrant, ethanol 96%, benzyl alcohol, benzyl benzoate and castor oil.
  • the constituents of each tablet are as follows: anastrozole, lactose monohydrate, macrogol, magnesium stearate, hypromellose, povidone, sodium starch glycollate and titanium dioxide.
  • Each fulvestrant pre-filled syringe will be packed into a light excluding carton.
  • Anastrozole 1 mg tablets will be packed into tamper evident, high density polyethylene (HDPE) bottles with an induction seal child resistant cap. Each bottle will contain 35 tablets (sufficient for 28 days plus 7 days overage).
  • HDPE high density polyethylene
  • fulvestrant 500 mg regime [fulvestrant 500 mg im on days 0, 14 ( ⁇ 3), 28 ( ⁇ 3) and every 28 ( ⁇ 3) days thereafter] plus anastrozole 1 mg po once daily or, anastrozole 1 mg po once daily.
  • Study treatment is given for 24 months. In calculating days of treatment administration, the first day of treatment is considered as day 0. Therefore, if injections are given on a Monday, the Monday four weeks later will be considered day 28; a window of ⁇ 3 days is acceptable.
  • Fulvestrant will be provided as 250 mg in 5 mL as a pre-filled syringe. Each dose of fulvestrant will be administered as 500 mg, that is, two 5 mL intramuscular injections, one in each buttock. Injections will be given as 500 mg on days 0, 14 ( ⁇ 3 days), 28 ( ⁇ 3 days) and every 28 ( ⁇ 3 days) thereafter.
  • Anastrozole 1 mg will be administered as one tablet daily. Each bottle will contain 35 tablets, allowing for 28 days treatment, plus an additional 7 days if a patients' visit is delayed. Study treatments must be administered within 7 days of randomisation and will continue until disease progression or until considered by the investigator not in the best interest of the patient, (whichever occurs first). Reasons for treatment discontinuation will be collected. Otherwise study treatment will cease after 2 years of treatment. 3.4.3 Labelling
  • Labelling of the investigational product will be performed in accordance with GMP, Good Manufacturing Practice.
  • Concomitant anticancer treatments including concurrent trastuzumab treatment, except for postoperative radiotherapy of breast/chest wall with or without regional lymph nodes, are not permitted during the study. Such treatments are prohibited even if they were given for another indication (e.g., megestrol acetate for appetite stimulation, methotrexate for rheumatological disorders). Preceding adjuvant / neoadjuvant chemotherapy but not endocrine therapy are permitted (see Sections 3.3.2 and 3.3.3). Neoadjuvant trastuzumab treatment is allowed, but concurrent adjuvant trastuzumab treatment is prohibited.
  • Sex hormone containing drugs such as hormone-replacement therapy (HRT), progestational agents (megestrol acetate), DHEA, other androgens (e.g., oxandrolone) and SERMs (eg raloxifene (Evista)) are not permitted during the study.
  • HRT hormone-replacement therapy
  • progestational agents megestrol acetate
  • DHEA DHEA
  • other androgens e.g., oxandrolone
  • SERMs eg raloxifene (Evista)
  • vaginal rings e.g. Estring(R)
  • Estring(R) controlled-release vaginal rings
  • other drugs than those mentioned above which may affect sex hormone status or disease response, such as systemic ketoconazole, systemic corticosteroids and adrenocortical suppressants are not allowed to begin after randomisation in to the study. However, the patient can continue to receive such drugs if they were taken before randomisation and the investigator is satisfied that the patient's hormonal status is stable. Hormone antagonists and related agents (eg. soy isoflavones) are not allowed.
  • Topical applications inhaled sprays, eye drops, local injections and mouth- washes (if not swallowed) containing corticosteroids or ketoconazole are permitted during the study.
  • LMWH low molecular weight heparin
  • Anticoagulant therapy should be driven by the indication for which it is being administered.
  • Patients receiving antiplatelet therapy may be at increased risk of bleeding from intramuscular injection.
  • the investigator should decide whether that risk is outweighed by the possible benefits of continued treatment. It is advised to apply direct pressure to the injection site in these patients.
  • Therapeutic warfarin with its target INR > 2 is not allowed; subcutaneous application of fractionated heparins may be considered an alternative treatment (if appropriate for the underlying disease) to facilitate study enrolment.
  • Subsequent treatment for breast cancer will be at the discretion on the investigator. Continuation of anastrozole is recommended for a total of 5 years for patients in both treatment groups.
  • the fast assessment of superior efficacy may induce subsequent design of a phase III trial to examine the improved clinical outcome of patients using anastrozole-fulvestrant combination.
  • Primary outcome variables for efficacy are:
  • mDNA e.g., methylated RASSF-I
  • BM aspirates and peripheral blood obtained prior to randomisation, after 12 and 24 months (each ⁇ a 3 week diagnostic window)
  • CTC circulating ribonucleotides
  • An event for the primary and secondary efficacy endpoint is defined as:
  • the primary efficacy variable is an "event" as defined in Section 4.6. It constitutes of DTC measurement after 12 months of randomised treatment (as described in Section 4.6.2) AND / OR occurrence of a clinical event (as described in Section 4.6.3); either one alone is considered an event, despite that BM aspiration and peripheral blood draw are to be performed in the case of a clinical event (i.e., any disease recurrence of death). Events are measured as described in Sections 4.6.2 and 4.6.3. 4.6.2 Disseminated tumour cells in bone marrow
  • Bone marrow aspirates (preferably 5 mL up to a maximum of 10 mL from each iliac crest; also see Table 5) are obtained and shipped to the Innsbruck laboratory in charge of the central workup and analysis of the samples according to the standard operational procedure (SOP) attached in a Supplement to this protocol. Bone marrow aspirations are performed within 4 weeks prior to randomisation (as specified in Section 4.2) for screening and after 12 and 24 months of randomised treatment OR at the time of a clinical event. Of note, recurrent and recurrence-free patients will have three BM aspirates per protocol. Of further note, each BM aspiration will be bilateral, since the detection rate by bilateral aspiration as compared to unilateral is significantly higher, which in return results in a significant reduction of patients to be screened.
  • a "DTC-positive” result is defined as the presence of immunocytochemically positive cells with tumour cell-like morphology or cells with morphological overlap between haematopoietic cells and tumour cells after exclusion of plasma cells (known to directly bind alkaline phosphatase of the reporting antibody labelling), obvious skin squamous epithelial cells and cellular or debris artefacts among a total analysed volume of 4 x 10 6 mononucleated cells obtained from workup and immunostaining according to SOPs described in a Supplement to this protocol.
  • Clinical events are assessed by chest X-ray and liver ultrasound (alternatively by chest and abdominal CT scan) and whole body bone scan after 12 and 24 months of randomised treatment. Further tests rendering the diagnosis more precisely are at the individual investigator's discretion.
  • the date of recurrence is the date of the investigation/procedure (imaging, biopsy, etc) that led to the diagnosis of recurrence. If more than one investigation/procedure is performed, and assuming that more than one confirms recurrence, the date of recurrence is the date when the first investigation/procedure was performed.
  • the date of the recurrence in the case of a biopsy refers to the date of the biopsy itself and not the date of the pathology report. In the case of more than one procedure, where the first one had unclear results that have been confirmed later, that date of recurrence is the date of the investigation/procedure with clear, definitive results. Recurrence should not be backdated to the earlier procedure.
  • PAXgeneTM tubes are kept at room temperature (18-22°C) for 2-24 hrs (up to 96 hrs at room temperature are possible) and are then stored frozen at ⁇ -2O 0 C at Innsbruck Medical University, Department of Obstetrics and Gynecology, Laboratory for Biochemistry.
  • RNA will be isolated according to the manufacturer's recommendations using the PAXgeneTM Blood RNA Kit 50 (Qiagen, Hilden, Germany; #762134) for both BM and peripheral blood samples without further modifications (as described in a Supplement to this protocol).
  • RT-PCR for the detection of DTC and CTC in BM and peripheral blood, respectively are confidential intellectual property of Innsbruck Medical University, Department of Obstetrics and Gynecology, Laboratory for Biochemistry. Detection of mDNA will be performed as previously published (Muller et al, 2003; Widschwendter et al, 2004; Fiegl et al, 2005) and outlined in a Supplement to this protocol.
  • An adverse event is the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product.
  • An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram).
  • an AE can include an undesirable medical condition occurring at any time, including run-in or washout periods, even if no study treatment has been administered. Any events that are unequivocally because of progression of the disease under study must not be reported as an AE. Adverse events of bone pain that are not considered to be due to disease progression should be reported as an adverse event. Serious adverse event (SAE)
  • a SAE is an AE occurring during any study phase (i.e., run-in, treatment, washout, follow- up), and at any dose of the investigational product, comparator or placebo, that fulfils one or more of the following criteria:
  • OAEs will be identified by the Study Team Physician and, if applicable, by the Drug Safety Physician during the evaluation of safety data for the Clinical Study Report.
  • Significant adverse events of particular clinical importance, other than SAEs and those AEs leading to discontinuation of the patient from study treatment, will be classified as OAEs. Examples of these are marked haematological and other laboratory abnormalities, and certain events that lead to intervention (other than those already classified as serious), dose reduction or significant additional treatment.
  • OAE For each OAE, a narrative may be written and included in the
  • Stability limits for BM and blood obtained for primary and exploratory efficacy analyses, respectively, defined by the Innsbruck Laboratory will be applied to all analyses performed. Innsbruck Laboratory will not analyse samples that fall outside these stability limits. Analytical data will not be reported if found to have been derived from a sample that fell outside these stability limits.
  • the standards of procedure followed by Innsbruck Laboratory may be amended in accordance with its Standard Operating Procedures. Innsbruck Laboratory will inform ABCSG of the stability limits relevant to this study before the first patient gives informed consent to take part in the study.
  • Bone marrow samples in 50 mL tubes with EDTA are considered stable for a maximum of 72 hrs, however, best results are obtained after 24-48 hrs if the sample is kept at temperatures between +4°C and +22°C (i.e., room temperature 18-22°C is sufficient for transport).
  • PAXgene tubes with either BM or peripheral blood for the detection of disseminated or circulating mRNA markers are kept at room temperature (18-22°C) for a minimum of 2 hrs, an optimum of 24 hrs and a maximum of 120 hrs.
  • EDTA tubes containing peripheral blood (5 mL) for analysis of circulating methylated DNA are shipped together with PAXgene tubes and EDTA-bone marrow, and will be further processed in the Innsbruck Laboratory.
  • SAP Statistical Analysis Plan
  • Circulating ribonucleotides 12 and 24 months Circulating tumour-cell derived methylated nucleotides 12 and 24 months Frequency of expression of hormone receptors, HER2 oncoprotein and broad stem cell characteristics of DTC at 12 and 24 months
  • Efficacy data from this study will be analysed on an intention-to-treat basis using randomised treatment.
  • the safety data for this study will be summarised using treatment received.
  • the analysis population will consist of all randomised patients who received at least one dose of trial therapy.
  • a logistic regression analysis including treatment factor only, will be used to compare the proportion of "successes" between the two treatment groups.
  • the results of the analysis will be presented in terms of odds ratios together with associated confidence intervals and 2-sided p-values. The estimate of the difference in the "success” rates and the corresponding 2-sided
  • a Cox's proportional hazards regression model will also be performed as a secondary analysis.
  • the model will allow for the effect of treatment and will also include terms for preceding chemotherapy, hormone-receptor expression, country, axillary lymph-node metastases status, tumours ⁇ 2 vs. >2cm in diameter and differentiation grade of primary tumours.
  • the conclusion will be based on the unadjusted analysis, which is considered as primary. If the unadjusted analysis and the adjusted analysis yield different results, the consequences of the covariate adjustments will be explored.
  • a global test for the presence of the treatment by baseline covariate interactions will be performed at the 1% level of significance by including all the 2-way treatment by baseline covariate interactions in the model.
  • the assumptions of proportionality will also be investigated with a time-dependent exploratory variable, which is defined as treatment- ⁇ log(time to event) ⁇ . If the p- value from the WaId Chi-squared statistic for this variable is less than 5% there is evidence of a departure from the adjusted model assumptions.
  • Safety and tolerability data will be presented by treatment received. Appropriate summaries of these data will be presented. Safety and tolerability will be assessed in terms of AEs, laboratory data, and ECG changes, which will be collected for all patients. Data from all treatment periods will be combined in the presentation of safety data. AEs (both in terms of
  • ECG changes will be summarized for each treatment group. Vital signs data will be listed for each patient and changes in vital signs will be summarized
  • a logistic regression analysis including treatment factor only, will be used to compare the proportion of "successes" between the two treatment groups.
  • the results of the analysis will be presented in terms of odds ratios together with associated confidence intervals and 2-sided p-values. The estimate of the difference in the "success” rates and the corresponding 2-sided
  • the numbers of DTC in patients at baseline after 12 months ⁇ 3 weeks and after 24 months ⁇ 3 weeks of randomised treatment will be summarised descriptively, by treatment group, using standard summary statistics (mean, minimum, maximum, sd and N).
  • Fidler IJ Kripke ML. Metastasis results from pre-existing variant cells within a malignant tumour. Science 1977;197:337-42. Fiegl H, Millinger S, Mueller-Holzner E, et al. Circulating Tumor-Specific DNA: A Marker for Monitoring Efficacy of Adjuvant Therapy in Cancer Patients. Cancer Res 2005;65(4):l 141-5.
  • Fisher B Anderson S, Tan-Chiu E, et al. Tamoxifen and chemotherapy for axillary node- negative, oestrogen receptor-negative breast cancer findings from the National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol. 2001 ;19:931-942. Fisher B 5 Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Crothenin WM, et al. Tamoxifen for prevention of breast cancer: report of National Surgical Adjuvant Breast and Bowel Project P-I study. J Nat'l Cancer Inst 1998;90:1371-88.
  • Klein CA Blankenstein TJF, Schrnidt-Kittler O, et al. Genetic heterogeneity of single disseminated tumour cells in minimal residual cancer. The Lancet 2002a;360(9334):683-9.
  • Klein CA Seidl S, Petat-Dutter K, et al. Combined transcriptome and genome analysis of single micrometastatic cells. Nat Biotech 2002b;20:387-92.
  • Arimidex® anastrozole
  • Arimidex® for the treatment of advanced breast cancer: A prospective combined survival analysis of two multicenter trials.

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Abstract

L'invention concerne un procédé de traitement du cancer du sein, consistant à administrer du fulvestrant et, simultanément, de manière séparée ou séquentielle, un traitement à l'aide d'un inhibiteur de l'aromatase, tel que de l'anastrozole, par exemple, à un patient nécessitant un tel traitement, le patient présentant un cancer du sein hormonosensible au stade précoce.
PCT/GB2007/002708 2006-07-18 2007-07-18 Utilisation de fulvestrant et d'un inhibiteur de l'aromatase pour traiter le cancer du sein Ceased WO2008009927A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011014516A1 (fr) * 2009-07-28 2011-02-03 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Antagonistes d’Œstrogène en tant que traitements pour des troubles sclérosants
CN102600064A (zh) * 2012-03-31 2012-07-25 西安力邦制药有限公司 氟维司群或其衍生物缓释制剂及其制备方法
WO2023081748A1 (fr) * 2021-11-03 2023-05-11 The Regents Of The University Of California Procédés, dispositifs et systèmes pour déterminer la survie globale de patients atteints d'un cancer du sein
US20250170134A1 (en) * 2013-08-14 2025-05-29 Novartis Ag Combination therapy for the treatment of cancer

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WO2006065828A2 (fr) * 2004-12-13 2006-06-22 Schering Corporation Nouveaux inhibiteurs de la farnesyl proteine transferase et leur utilisation dans le traitement du cancer
WO2006069208A2 (fr) * 2004-12-21 2006-06-29 Schering Corporation Nouveaux inhibiteurs de farnesyl proteine transferase en tant qu'agent antitumoraux
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WO2006065828A2 (fr) * 2004-12-13 2006-06-22 Schering Corporation Nouveaux inhibiteurs de la farnesyl proteine transferase et leur utilisation dans le traitement du cancer
WO2006069208A2 (fr) * 2004-12-21 2006-06-29 Schering Corporation Nouveaux inhibiteurs de farnesyl proteine transferase en tant qu'agent antitumoraux

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HOWELL ET AL: "The future of fulvestrant ('Faslodex')", 2005, CANCER TREATMENT REVIEWS, SAUNDERS, US, PAGE(S) S26-S33, ISSN: 0305-7372, XP005140945 *
JOHNSTON ET AL: "Aromatase inhibitors: Combinations with fulvestrant or signal transduction inhibitors as a strategy to overcome endocrine resistance", May 2005, JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY, ELSEVIER SCIENCE LTD., OXFORD, GB, PAGE(S) 173-181, ISSN: 0960-0760, XP005040167 *
JOHNSTON S: "Fulvestrant and the sequential endocrine cascade for advanced breast cancer.", March 2004, BRITISH JOURNAL OF CANCER MAR 2004, VOL. 90 SUPPL 1, PAGE(S) S15 - S18, ISSN: 0007-0920, XP002454331 *
LEARY A ET AL: "Combination therapy with aromatase inhibitors: the next era of breast cancer treatment?", 18 September 2006, BRITISH JOURNAL OF CANCER 18 SEP 2006, VOL. 95, NR. 6, PAGE(S) 661 - 666, ISSN: 0007-0920, XP002454332 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011014516A1 (fr) * 2009-07-28 2011-02-03 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Antagonistes d’Œstrogène en tant que traitements pour des troubles sclérosants
US8969326B2 (en) 2009-07-28 2015-03-03 University of Pittsburgh—of the Commonwealth System of Higher Education Estrogen antagonists as treatments for sclerosing disorders
US9655869B2 (en) 2009-07-28 2017-05-23 University of Pittsburgh—of the Commonwealth System of Higher Education Estrogen antagonists as treatments for sclerosing disorders
CN102600064A (zh) * 2012-03-31 2012-07-25 西安力邦制药有限公司 氟维司群或其衍生物缓释制剂及其制备方法
US20250170134A1 (en) * 2013-08-14 2025-05-29 Novartis Ag Combination therapy for the treatment of cancer
WO2023081748A1 (fr) * 2021-11-03 2023-05-11 The Regents Of The University Of California Procédés, dispositifs et systèmes pour déterminer la survie globale de patients atteints d'un cancer du sein

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