| Eligibility |
1.1 Inclusion criteria
Patients are eligible to be included in the study only if all of the following inclusion
criteria and none of the exclusion criteria apply:
Informed consent
1. Capable of giving signed informed consent which includes compliance with the
requirements and restrictions listed in the informed consent form (ICF) and in this
protocol.
2. Provision of signed and dated, written informed consent form prior to any mandatory
study specific procedures, sampling, and analyses.
Age
3. Subject must be 19 years of age or older at the time of signing the informed consent
form.
Type of patient and disease characteristics
4. Patients with HR+/HER2- metastatic or inoperable breast cancer
5. Disease progression following treatment with endocrine therapy(ies) and CDK4/6
inhibitor
6. Patients must have normal organ and bone marrow function measured within 28 days prior
to administration of study treatment as defined below
- Hemoglobin = 10.0 g/dL. Red blood cell/plasma transfusion is not permitted within
2 week prior to screening assessment.
- Absolute neutrophil count (ANC) = 1.5 x 109/L. Granulocyte colony-stimulating
factor administration is not permitted within 1 week prior to screening
assessment.
- Platelet count = 100 x 109/L. Platelet transfusion is not permitted within 1 week
prior to screening assessment.
- Total bilirubin = 1.5 x institutional upper limit of normal (ULN) if no liver
metastases; or = 3 × ULN in the presence of documented Gilbert's syndrome
(unconjugated hyperbilirubinemia) or liver metastases at baseline.
- Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT))
/ Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) =
2.5 x institutional upper limit of normal unless liver metastases are present in
which case they must be = 5x ULN
- Patients must have creatinine clearance estimated of =51 mL/min using the
Cockcroft-Gault equation or based on a 24 hour urine test :
Estimated creatinine clearance = (140-age [years]) x weight (kg) (x F)a serum
creatinine (mg/dL) x 72 a where F=0.85 for females and F=1 for males.
7. Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
8. Patients must have a life expectancy = 16 weeks.
9. At least one lesion (measurable and/or non-measurable) that can be accurately assessed
at baseline by CT or MRI and is suitable for repeated assessment.
Reproduction
10. Postmenopausal or evidence of non-childbearing status for women of childbearing
potential.
Postmenopausal is defined as:
- Amenorrhoeic for 1 year or more following cessation of exogenous hormonal
treatments
- Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the
postmenopausal range for women under 50
- radiation-induced oophorectomy with last menses >1 year ago
- chemotherapy-induced menopause with >1 year interval since last menses
- surgical sterilisation (bilateral oophorectomy or hysterectomy) OR
Pre/peri-menopausal, ie, not meeting the criteria for being post-menopausal.
- Pre-/peri-menopausal women can be enrolled if amenable to be treated with monthly
LHRH agonists (goserelin or leuprorelin). Participants must have concomitant
treatment with LHRH agonists (goserelin or leuprorelin) - which must have been
started 3 weeks before Cycle 1 Day 1 - and must be willing to continue on it for
the duration of the study.
11. Negative pregnancy test (urine and/or serum) for women of childbearing potential
within 28 days of study treatment and confirmed prior to treatment on day 1.
12. Male patients must use a condom during treatment and for 3 months after the last dose
of olaparib when having sexual intercourse with a pregnant woman or with a woman of
childbearing potential. Female partners of male patients should also use a highly
effective form of contraception if they are of childbearing potential Specific
criteria for each cohort
13. <For cohort A> Patients with known germline or somatic mutations of BRCA1 or BRCA2
14. <For cohort B> Patients with known somatic mutations of BRCA1, BRCA2, or other DDR
genes (including ATM(ataxia telangiectasia mutated), ATR, BRIP1, PALB2, CHEK1, CHEK2,
FANC family, RAD51 family, etc.) Patients with alteration in other DDR genes can be
discussed with the principal investigator at the molecular tumour board.
1.2 Exclusion criteria Medical conditions
1. As judged by the investigator, any evidence of condition or illness which in the
investigator's opinion makes it undesirable for the patient to participate in the
trial.
2. Other malignancy unless curatively treated with no evidence of disease for =5 years
except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer
of the cervix, ductal carcinoma in situ (DCIS), Stage 1, grade 1 endometrial
carcinoma.
3. Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as
judged by the investigator (eg., unstable ischemia, uncontrolled symptomatic
arrhythmia, congestive heart failure, QTcF prolongation >500 ms, electrolyte
disturbances, etc.), or patients with congenital long QT syndrome.
4. Persistent toxicities (>Common Terminology Criteria for Adverse Event (CTCAE) v5.0
grade 2) caused by previous cancer therapy, excluding alopecia grade 2.
5. Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features
suggestive of MDS(myelodysplastic syndrome)/AML(Acute Myelogenous Leukemia )
6. Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence
of brain metastases is not required. The patient can receive a stable dose of
corticosteroids (up to 10 mg prednisone/day or equivalent) before and during the study
as long as these were started at least 4 weeks prior to treatment. Patients with
spinal cord compression unless considered to have received definitive treatment for
this and evidence of clinically stable disease for 28 days.
7. Patients considered a poor medical risk due to a serious, uncontrolled medical
disorder, non-malignant systemic disease or active, uncontrolled infection. Examples
include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3
months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal
cord compression, superior vena cava syndrome, extensive interstitial bilateral lung
disease on High Resolution Computed Tomography (HRCT) scan or any psychiatric disorder
that prohibits obtaining informed consent.
8. Patients unable to swallow orally administered medication and patients with
gastrointestinal disorders likely to interfere with absorption of the study
medication.
9. Immunocompromised patients, e.g., patients who are known to be serologically positive
for human immunodeficiency virus (HIV).
10. Patients with known active hepatitis (i.e. Hepatitis B or C).
- Active hepatitis B virus (HBV) infection is defined by a positive HBV surface
antigen (HBsAg) and positive titer for HBV DNA.result. Patients with a past or
resolved HBV infection (defined as the presence of hepatitis B core antibody and
absence of HBsAg or deoxyribonucleic acid [DNA]-negative) are eligible.
- Patients positive for hepatitis C virus (HCV) antibody are eligible only if
polymerase chain reaction is negative for HCV RNA.
11. Underweight populations - =30kg
12. History of bleeding diathesis (ie, disseminated intravascular coagulation, clotting
factor deficiency) or long-term anticoagulant therapy (although patients treated with
anti-platelet therapy and low dose warfarin or other anticoagulant agents such as
acenocoumarol are eligible providing they have an international normalised ratio
[INR(international normalized ratio)] of =1.6) Prior/concomitant therapy
13. Any previous treatment with fulvestrant, other study drugs (including olaparib or
study drugs in each arms), or other investigational agents directly targeting DNA
damage response.
14. Patients receiving any systemic chemotherapy or radiotherapy (except for palliative
reasons) within 3 weeks prior to study treatment
15. Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin,
clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,
saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg.
ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout
period prior to starting the study treatments is 2 weeks.
16. Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin,
rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or
moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout
period prior to starting the study treatments is 5 weeks for enzalutamide or
phenobarbital and 3 weeks for other agents.
17. Major surgery within 2 weeks of starting study treatment and patients must have
recovered from any effects of any major surgery.
18. Previous allogenic bone marrow transplant or double umbilical cord blood
transplantation (dUCBT).
Prior/concurrent clinical study experience
19. Participation in another clinical study with an investigational product administered
in the last 4 weeks or 5 half-lives (whichever is longest)
20. Patients with a known hypersensitivity to fulvestrant or any of the excipients of the
product.
21. Patients with a known hypersensitivity to olaparib or study drugs in each arms, or any
of the excipients of the product.
Other exclusions
22. Involvement in the planning and/or conduct of the study
23. Judgment by the investigator that the patient should not participate in the study if
the patient is unlikely to comply with study procedures, restrictions and
requirements.
24. Previous enrolment in the present study.
25. Breast feeding women.
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