Informations générales (source: ClinicalTrials.gov)
A Randomised Trial of Early Detection of Molecular Relapse With Circulating Tumour DNA Tracking and Treatment With Palbociclib Plus Fulvestrant Versus Standard Endocrine Therapy in Patients With ER Positive HER2 Negative Breast Cancer
Interventional
Phase 2
Royal Marsden NHS Foundation Trust (Voir sur ClinicalTrials)
mars 2022
septembre 2030
28 août 2025
Detection of molecular relapse with circulating tumour DNA analysis can identify which
patients with ER positive breast cancer are relapsing on adjuvant endocrine therapy. This
trial will aim to demonstrate that palbociclib and fulvestrant, can defer or prevent
relapse in patients with ctDNA detected molecular relapse.
The TRAK-ER trial will have two phases, a ctDNA surveillance phase and a randomised
therapy trial in patients with positive ctDNA.
The TRAK-ER trial will establish a ctDNA screening programme for patients with ER
positive breast cancer receiving adjuvant endocrine therapy with at least a further three
years of standard adjuvant endocrine therapy planned. Patients recruited into the TRAK-ER
study will have high-risk clinical features to identify patients at higher risk of future
relapse.
ctDNA assays will be used to identify which people are at very high risk of relapse (i.e.
those with a positive ctDNA result), and randomise this high risk population between
standard endocrine therapy versus palbociclib plus fulvestrant for up to two years.
Etablissements
| Les établissements d'Île-de-France ayant mis à jour leurs données Origine et niveau de fiabilité des données | |||||
|---|---|---|---|---|---|
| CLCC INSTITUT GUSTAVE ROUSSY | Fabrice ANDRE | 19/06/2024 12:29:11 | Contacter | ||
| Les établissements sans correspondance certaine dans le répertoire FINESS dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| Centre Antoine Lacassagne - 06189 - Nice - France | PI: Dr Caroline Bailleux | Contact (sur clinicalTrials) | |||
| Centre Eugène Marquis - 25042 - Rennes - France | Dr Fanny Le Du | Contact (sur clinicalTrials) | |||
| Centre George François Leclerc - 21079 - Dijon - France | Sylvain Ladoire | Contact (sur clinicalTrials) | |||
| Centre Henri Becquerel - 76038 - Rouen - France | Marianne Leheurteur | Contact (sur clinicalTrials) | |||
| Centre Hospitalier Annecy Genevois_Site d'Annecy - 90074 - Annecy - France | PI, Dr Marie Vallee | Contact (sur clinicalTrials) | |||
| Centre Hospitalier Simone Veil de Blois - 41016 - Blois - France | Oliver Arsene | Contact (sur clinicalTrials) | |||
| Centre Hospitalier Universitaire de Limoges - 87042 - Limoges - France | Elise Deluche | Contact (sur clinicalTrials) | |||
| Centre Jean Perrin - 63011 - Clermont Ferrand - France | PI: Dr Xavier Durando | Contact (sur clinicalTrials) | |||
| Centre Léon Bérard - 69373 - Lyon - France | Dr Thomas Bachelot | Contact (sur clinicalTrials) | |||
| CHU de Saint Etienne-Institut de Cancérologie - 42270 - Saint-Priest-en-Jarez - France | Gilles Freyer | Contact (sur clinicalTrials) | |||
| Clinique Chénieux - 87000 - Limoges - France | Dominque Genet | Contact (sur clinicalTrials) | |||
| Groupe Hospitalier Mutualiste de Grenoble - 38000 - Grenoble - France | Elise Bonnet | Contact (sur clinicalTrials) | |||
| Hôpital Américain de Paris - Paris - France | Contact (sur clinicalTrials) | ||||
| Institut Bergonié - Bordeaux - France | Monica Arnedos | Contact (sur clinicalTrials) | |||
| Institut Claudius Regaud - 31059 - Toulouse - France | Dr Florence Dolenc | Contact (sur clinicalTrials) | |||
| Institut de Cancérologie de l'Ouest - 44805 - Nantes - France | PI: Dr Marie Robert | Contact (sur clinicalTrials) | |||
| Institut de Cancérologie de l'Ouest - 49055 - Angers - France | Anne Patsouris | Contact (sur clinicalTrials) | |||
| Institut du Cancer Avignon Sainte Catherine - 84000 - Avignon - France | Dr Julien Grenier | Contact (sur clinicalTrials) | |||
| Institut Godinot - 51726 - Reims - France | Dr Christelle Jouannaud | Contact (sur clinicalTrials) | |||
| Institut Paoli Calmettes - 13273 - Marseille - France | Dr Renaud Sabatier | Contact (sur clinicalTrials) | |||
Critères
Tous
Inclusion Criteria for ctDNA Surveillance:
1. Written informed consent to participate in the trial and to donation of tissue and
blood samples
2. Male or female patients aged 18 years or older
3. ECOG performance status 0, 1 or 2 (see
https://ecog-acrin.org/resources/ecog-performance-status)
4. Histologically proven primary ER+ (Allred score 6/8 or greater, or stain in ≥10% of
cancer cells) and HER2- (immunohistochemistry 0/1+ and/or negative by in situ
hybridization) breast cancer as determined by local laboratory
5. Patients with high risk early stage breast cancer according to at least one of the
following criteria:
Primary surgery (no other treatment prior to surgery) A. Four or more involved
axillary lymph nodes or positive supraclavicular lymph node at diagnosis, or
B. Tumour size > 5 cm, regardless of lymph node status, or
C. 1-3 involved axillary lymph nodes and at least one of the following; i) Tumour
size > 3 cm, ii) histological grade 3 iii) high genomic risk defined as Oncotype Dx
Recurrence Score >=26, Prosigna score >=60, EPclin risk score >=4.0, or Mammaprint
high risk category, or
Neoadjuvant chemotherapy (chemotherapy prior to surgery)
D. At least one lymph node positive (micrometastasis or macrometastasis) after
chemotherapy
E. Lymph node negative and tumour size > 3 cm after chemotherapy
Neoadjuvant endocrine therapy (endocrine based therapy prior to surgery) Use the
primary surgery criteria - staging tumour size and lymph node status may be either
the pathological staging after endocrine therapy or on the initial clinical staging
prior to neoadjuvant therapy
6. Available tissue from one archival tumour tissue sample (either from diagnostic
biopsy, primary surgery or where available residual disease post-neoadjuvant
chemotherapy)
7. No evidence of macroscopic distant metastatic disease or incurable locally advanced
disease on staging scans conducted at any time since initial diagnosis.
8. Patients receiving standard endocrine therapy with aromatase inhibitors (letrozole,
anastrazole, exemestane), tamoxifen, or combination of such for a minimum of 6
months* and maximum of 7 years duration with an additional three years of endocrine
therapy planned. Pre- or peri-menopausal patients may also receive GnRH analogues.
* patients may enrol during the first 6 months of standard endocrine therapy, and
wait until at least 6 months of endocrine therapy has been received prior to
starting ctDNA surveillance
9. Patients must have had surgery achieving clear margins (as per local guidelines)
10. Female and male patients of reproductive potential must be willing to use an
adequate method of contraception for the first three years of the trial, if
randomised to standard endocrine therapy for the duration of trial treatment through
to at least 4 weeks after the last dose of trial treatment, and if randomised to
fulvestrant and palbociclib to 2 years after the last dose of fulvestrant (see
section 4.6). Note: Abstinence is acceptable if this is the usual lifestyle and
preferred contraception for the patient.
11. Patients willing to have frequent blood tests.
Inclusion Criteria for Interventional phase:
1. Signed informed consent for treatment
2. ECOG performance status 0, 1 or 2
3. Women of childbearing potential should have a negative serum pregnancy test prior to
randomisation. If randomisation occurs more than 72 hours prior to receiving the
first dose of treatment the test must be repeated before treatment.
4. Female and male patients of childbearing potential must be willing to use an
adequate method of contraception (section 4.6), starting with the first dose of
treatment through 4 weeks after the last dose of treatment if randomised to standard
endocrine therapy and 2 years after the last dose of fulvestrant if randomised to
fulvestrant and palbociclib. Note: Abstinence is acceptable if this is the usual
lifestyle and preferred contraception for the patient. Female patients will be
deemed not of childbearing potential if they are postmenopausal or have had
irreversible sterilisation
5. Patient has adequate bone marrow and organ function as defined by the following
laboratory values:
1. Absolute Neutrophil Count (ANC) ≥ 1.5 × 109/L
2. Platelets ≥ 100 × 109/L
3. Haemoglobin ≥ 100 g/L
4. INR ≤1.5
5. Creatinine <1.5 x ULN and creatinine clearance ≥30ml/min
6. Total bilirubin < ULN except for patients with Gilbert's syndrome who may only
be included if the total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 ×
ULN.
7. Alanine aminotransferase (ALT) < 2.5 x ULN
8. Aspartate aminotransferase (AST) < 2.5 × ULN
6. Patients must be post-menopausal OR
Pre- or peri-menopausal patients or men may be enrolled if they have ovarian/gonadal
suppression with licensed GnRH analogues. Patients must have commenced licensed GnRH
analogues at least 2 weeks prior to Cycle 1 Day 1 and continue throughout the study if
randomised to fulvestrant and palbociclib.
Post-menopausal female patients, as defined by at least one of the following:
- Age ≥60 years;
- Age <60 years and cessation of regular menses for at least 12 consecutive months
with no alternative pathological or physiological cause, and serum estradiol and FSH
levels within the institutional laboratory's reference range for post-menopausal
females;
- Documented bilateral oophorectomy;
Exclusion Criteria for ctDNA Surveillance:
1. Any concurrent or planned treatment for the current diagnosis of breast cancer other
than adjuvant endocrine therapy or a bisphosphonate.
2. Patients with prior exposure to a CDK 4/6 inhibitor as part of standard of care may
enrol only after at least 12 months from completing CDK4/6 therapy.
3. Prior exposure to therapeutic dose of fulvestrant is not permitted. One
subtherapeutic dose of fulvestrant is permitted.
4. Prior diagnosis of cancer including prior diagnosis of breast cancer in the previous
5 years, other than for non-melanoma carcinoma of the skin or cervical carcinoma in
situ
5. Patients previously entered into a therapeutic trial where experimental therapy is
continued post-surgery. Patients who have entered a clinical trial of a CDK4/6
inhibitor in the adjuvant setting are not eligible. Patients who received a CDK4/6
inhibitor only before an operation, with no post-operative adjuvant use, are
eligible.
6. Treatment with an unlicensed or investigational product within 4 weeks prior
registration to trial
7. Patient has not recovered to ≤ grade 1 (except alopecia or certain other toxicities,
which in the opinion of the Investigator should not exclude the patient) from
related side effects of any prior antineoplastic therapy, not including side-effects
of endocrine therapy
8. Patient with impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of oral medication (e.g. Crohn's disease,
ulcerative diseases, uncontrolled nausea, vomiting, diarrhoea, malabsorption
syndrome, or small bowel resection)
9. Patient has any other concurrent severe and/or uncontrolled medical condition that
would, in the Investigator' opinion cause unacceptable safety risks, contraindicate
patient participation in the clinical trial or compromise compliance with the
protocol.
10. Clinically significant uncontrolled heart disease including any of the following:
1. History of myocardial infarction (MI), angina pectoris, symptomatic
pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to
trial entry
2. Symptomatic congestive heart failure
3. Long QT syndrome or family history of idiopathic sudden death or congenital
long QT syndrome.
4. Cardiac arrhythmia.
11. History of pneumonitis, interstitial lung disease or pulmonary fibrosis
12. Known history of Human Immunodeficiency Virus (HIV) (testing not required as part of
study screening)
13. Known active Hepatitis B or Hepatitis C (testing not required as part of study
screening)
14. Females who are known to be pregnant or breastfeeding
15. History of bleeding diathesis (i.e. disseminated intravascular coagulation, clotting
factor deficiency), other known abnormalities in coagulation or treatment with
anticoagulants. Low molecular weight heparin (LMWH), low dose aspirin or clopidogrel
are permitted.
16. Child-Pugh class C hepatic impairment or creatinine clearance < 30ml/min.
17. Patient with bilateral tumours, or unilateral multifocal cancers with multiple
separate primary cancers.(Multifocal cancer that reflects a single primary cancer,
in the opinion of the investigator, are eligible)
Exclusion Criteria for Interventional phase:
1. Evidence of recurrent disease (metastatic or local, see section 6.6 for management
of patients with potentially curable local recurrences) on staging scans conducted
since positive ctDNA result
2. Known hypersensitivity to the excipients of palbociclib plus fulvestrant
3. Any anti-cancer treatment since enrolling in the TRAK-ER study other than hormonal
therapy or a bisphosphonate. Prior exposure to fulvestrant is not permitted.
4. Diagnosis of an alternative cancer since enrolment in the trial other than
non-melanoma cancer of the skin or cervical carcinoma in situ
5. Patient has had major surgery within 4 weeks prior to starting trial treatment or
has not recovered from major side effects of such procedure
6. Patient is currently receiving warfarin or other coumarin derived anti-coagulant,
for treatment, prophylaxis or otherwise. Therapy with unfractionated heparin, low
molecular weight heparin (LMWH), or a direct-acting oral anticoagulant (DOAC such as
rivaroxaban or fondaparinux) is allowed
7. Patient has not recovered to ≤ grade 1 (except alopecia or certain other toxicities,
which in the opinion of the Investigator should not exclude the patient) from
related side effects of any prior antineoplastic therapy, not including side-effects
of endocrine therapy
8. Patient with impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of oral medication (e.g. Crohn's disease,
ulcerative diseases, uncontrolled nausea, vomiting, diarrhoea, malabsorption
syndrome, or small bowel resection)
9. Patient has any other concurrent severe and/or uncontrolled medical condition that
would, in the Investigator' opinion cause unacceptable safety risks, contraindicate
patient participation in the clinical trial or compromise compliance with the
protocol.
10. Clinically significant uncontrolled heart disease including any of the following:
1. History of myocardial infarction (MI), angina pectoris, symptomatic
pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to
trial entry
2. Symptomatic congestive heart failure
3. Long QT syndrome or family history of idiopathic sudden death or congenital
long QT syndrome.
4. Cardiac arrhythmia.
11. Patient is currently receiving any of the following substances and cannot be
discontinued 7 days prior to Cycle 1 Day 1:
- Medications that are strong inducers or inhibitors of CYP3A4 (section 8.5.2)
- Herbal preparations/medications, dietary supplements, fruits (e.g grapefruit,
pomelos, starfruit, Seville oranges) and their juice
12. History of pneumonitis, interstitial lung disease or pulmonary fibrosis
13. Known history of HIV (testing not required as part of study screening)
14. Known active Hepatitis B or Hepatitis C (testing not required as part of study
screening)
15. Patient has a history of non-compliance to medical regimen
16. History of bleeding diathesis (i.e. disseminated intravascular coagulation, clotting
factor deficiency), other known abnormalities in coagulation or treatment with
anticoagulants. Low molecular weight heparin (LMWH), low dose aspirin or clopidogrel
are permitted.
17. Females who are known to be pregnant or breastfeeding.
1. Written informed consent to participate in the trial and to donation of tissue and
blood samples
2. Male or female patients aged 18 years or older
3. ECOG performance status 0, 1 or 2 (see
https://ecog-acrin.org/resources/ecog-performance-status)
4. Histologically proven primary ER+ (Allred score 6/8 or greater, or stain in ≥10% of
cancer cells) and HER2- (immunohistochemistry 0/1+ and/or negative by in situ
hybridization) breast cancer as determined by local laboratory
5. Patients with high risk early stage breast cancer according to at least one of the
following criteria:
Primary surgery (no other treatment prior to surgery) A. Four or more involved
axillary lymph nodes or positive supraclavicular lymph node at diagnosis, or
B. Tumour size > 5 cm, regardless of lymph node status, or
C. 1-3 involved axillary lymph nodes and at least one of the following; i) Tumour
size > 3 cm, ii) histological grade 3 iii) high genomic risk defined as Oncotype Dx
Recurrence Score >=26, Prosigna score >=60, EPclin risk score >=4.0, or Mammaprint
high risk category, or
Neoadjuvant chemotherapy (chemotherapy prior to surgery)
D. At least one lymph node positive (micrometastasis or macrometastasis) after
chemotherapy
E. Lymph node negative and tumour size > 3 cm after chemotherapy
Neoadjuvant endocrine therapy (endocrine based therapy prior to surgery) Use the
primary surgery criteria - staging tumour size and lymph node status may be either
the pathological staging after endocrine therapy or on the initial clinical staging
prior to neoadjuvant therapy
6. Available tissue from one archival tumour tissue sample (either from diagnostic
biopsy, primary surgery or where available residual disease post-neoadjuvant
chemotherapy)
7. No evidence of macroscopic distant metastatic disease or incurable locally advanced
disease on staging scans conducted at any time since initial diagnosis.
8. Patients receiving standard endocrine therapy with aromatase inhibitors (letrozole,
anastrazole, exemestane), tamoxifen, or combination of such for a minimum of 6
months* and maximum of 7 years duration with an additional three years of endocrine
therapy planned. Pre- or peri-menopausal patients may also receive GnRH analogues.
* patients may enrol during the first 6 months of standard endocrine therapy, and
wait until at least 6 months of endocrine therapy has been received prior to
starting ctDNA surveillance
9. Patients must have had surgery achieving clear margins (as per local guidelines)
10. Female and male patients of reproductive potential must be willing to use an
adequate method of contraception for the first three years of the trial, if
randomised to standard endocrine therapy for the duration of trial treatment through
to at least 4 weeks after the last dose of trial treatment, and if randomised to
fulvestrant and palbociclib to 2 years after the last dose of fulvestrant (see
section 4.6). Note: Abstinence is acceptable if this is the usual lifestyle and
preferred contraception for the patient.
11. Patients willing to have frequent blood tests.
Inclusion Criteria for Interventional phase:
1. Signed informed consent for treatment
2. ECOG performance status 0, 1 or 2
3. Women of childbearing potential should have a negative serum pregnancy test prior to
randomisation. If randomisation occurs more than 72 hours prior to receiving the
first dose of treatment the test must be repeated before treatment.
4. Female and male patients of childbearing potential must be willing to use an
adequate method of contraception (section 4.6), starting with the first dose of
treatment through 4 weeks after the last dose of treatment if randomised to standard
endocrine therapy and 2 years after the last dose of fulvestrant if randomised to
fulvestrant and palbociclib. Note: Abstinence is acceptable if this is the usual
lifestyle and preferred contraception for the patient. Female patients will be
deemed not of childbearing potential if they are postmenopausal or have had
irreversible sterilisation
5. Patient has adequate bone marrow and organ function as defined by the following
laboratory values:
1. Absolute Neutrophil Count (ANC) ≥ 1.5 × 109/L
2. Platelets ≥ 100 × 109/L
3. Haemoglobin ≥ 100 g/L
4. INR ≤1.5
5. Creatinine <1.5 x ULN and creatinine clearance ≥30ml/min
6. Total bilirubin < ULN except for patients with Gilbert's syndrome who may only
be included if the total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 ×
ULN.
7. Alanine aminotransferase (ALT) < 2.5 x ULN
8. Aspartate aminotransferase (AST) < 2.5 × ULN
6. Patients must be post-menopausal OR
Pre- or peri-menopausal patients or men may be enrolled if they have ovarian/gonadal
suppression with licensed GnRH analogues. Patients must have commenced licensed GnRH
analogues at least 2 weeks prior to Cycle 1 Day 1 and continue throughout the study if
randomised to fulvestrant and palbociclib.
Post-menopausal female patients, as defined by at least one of the following:
- Age ≥60 years;
- Age <60 years and cessation of regular menses for at least 12 consecutive months
with no alternative pathological or physiological cause, and serum estradiol and FSH
levels within the institutional laboratory's reference range for post-menopausal
females;
- Documented bilateral oophorectomy;
Exclusion Criteria for ctDNA Surveillance:
1. Any concurrent or planned treatment for the current diagnosis of breast cancer other
than adjuvant endocrine therapy or a bisphosphonate.
2. Patients with prior exposure to a CDK 4/6 inhibitor as part of standard of care may
enrol only after at least 12 months from completing CDK4/6 therapy.
3. Prior exposure to therapeutic dose of fulvestrant is not permitted. One
subtherapeutic dose of fulvestrant is permitted.
4. Prior diagnosis of cancer including prior diagnosis of breast cancer in the previous
5 years, other than for non-melanoma carcinoma of the skin or cervical carcinoma in
situ
5. Patients previously entered into a therapeutic trial where experimental therapy is
continued post-surgery. Patients who have entered a clinical trial of a CDK4/6
inhibitor in the adjuvant setting are not eligible. Patients who received a CDK4/6
inhibitor only before an operation, with no post-operative adjuvant use, are
eligible.
6. Treatment with an unlicensed or investigational product within 4 weeks prior
registration to trial
7. Patient has not recovered to ≤ grade 1 (except alopecia or certain other toxicities,
which in the opinion of the Investigator should not exclude the patient) from
related side effects of any prior antineoplastic therapy, not including side-effects
of endocrine therapy
8. Patient with impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of oral medication (e.g. Crohn's disease,
ulcerative diseases, uncontrolled nausea, vomiting, diarrhoea, malabsorption
syndrome, or small bowel resection)
9. Patient has any other concurrent severe and/or uncontrolled medical condition that
would, in the Investigator' opinion cause unacceptable safety risks, contraindicate
patient participation in the clinical trial or compromise compliance with the
protocol.
10. Clinically significant uncontrolled heart disease including any of the following:
1. History of myocardial infarction (MI), angina pectoris, symptomatic
pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to
trial entry
2. Symptomatic congestive heart failure
3. Long QT syndrome or family history of idiopathic sudden death or congenital
long QT syndrome.
4. Cardiac arrhythmia.
11. History of pneumonitis, interstitial lung disease or pulmonary fibrosis
12. Known history of Human Immunodeficiency Virus (HIV) (testing not required as part of
study screening)
13. Known active Hepatitis B or Hepatitis C (testing not required as part of study
screening)
14. Females who are known to be pregnant or breastfeeding
15. History of bleeding diathesis (i.e. disseminated intravascular coagulation, clotting
factor deficiency), other known abnormalities in coagulation or treatment with
anticoagulants. Low molecular weight heparin (LMWH), low dose aspirin or clopidogrel
are permitted.
16. Child-Pugh class C hepatic impairment or creatinine clearance < 30ml/min.
17. Patient with bilateral tumours, or unilateral multifocal cancers with multiple
separate primary cancers.(Multifocal cancer that reflects a single primary cancer,
in the opinion of the investigator, are eligible)
Exclusion Criteria for Interventional phase:
1. Evidence of recurrent disease (metastatic or local, see section 6.6 for management
of patients with potentially curable local recurrences) on staging scans conducted
since positive ctDNA result
2. Known hypersensitivity to the excipients of palbociclib plus fulvestrant
3. Any anti-cancer treatment since enrolling in the TRAK-ER study other than hormonal
therapy or a bisphosphonate. Prior exposure to fulvestrant is not permitted.
4. Diagnosis of an alternative cancer since enrolment in the trial other than
non-melanoma cancer of the skin or cervical carcinoma in situ
5. Patient has had major surgery within 4 weeks prior to starting trial treatment or
has not recovered from major side effects of such procedure
6. Patient is currently receiving warfarin or other coumarin derived anti-coagulant,
for treatment, prophylaxis or otherwise. Therapy with unfractionated heparin, low
molecular weight heparin (LMWH), or a direct-acting oral anticoagulant (DOAC such as
rivaroxaban or fondaparinux) is allowed
7. Patient has not recovered to ≤ grade 1 (except alopecia or certain other toxicities,
which in the opinion of the Investigator should not exclude the patient) from
related side effects of any prior antineoplastic therapy, not including side-effects
of endocrine therapy
8. Patient with impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of oral medication (e.g. Crohn's disease,
ulcerative diseases, uncontrolled nausea, vomiting, diarrhoea, malabsorption
syndrome, or small bowel resection)
9. Patient has any other concurrent severe and/or uncontrolled medical condition that
would, in the Investigator' opinion cause unacceptable safety risks, contraindicate
patient participation in the clinical trial or compromise compliance with the
protocol.
10. Clinically significant uncontrolled heart disease including any of the following:
1. History of myocardial infarction (MI), angina pectoris, symptomatic
pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to
trial entry
2. Symptomatic congestive heart failure
3. Long QT syndrome or family history of idiopathic sudden death or congenital
long QT syndrome.
4. Cardiac arrhythmia.
11. Patient is currently receiving any of the following substances and cannot be
discontinued 7 days prior to Cycle 1 Day 1:
- Medications that are strong inducers or inhibitors of CYP3A4 (section 8.5.2)
- Herbal preparations/medications, dietary supplements, fruits (e.g grapefruit,
pomelos, starfruit, Seville oranges) and their juice
12. History of pneumonitis, interstitial lung disease or pulmonary fibrosis
13. Known history of HIV (testing not required as part of study screening)
14. Known active Hepatitis B or Hepatitis C (testing not required as part of study
screening)
15. Patient has a history of non-compliance to medical regimen
16. History of bleeding diathesis (i.e. disseminated intravascular coagulation, clotting
factor deficiency), other known abnormalities in coagulation or treatment with
anticoagulants. Low molecular weight heparin (LMWH), low dose aspirin or clopidogrel
are permitted.
17. Females who are known to be pregnant or breastfeeding.