Trial Title:
Evaluating the Efficacy and Safety of Fulvestrant Plus DNA Damage Repair Inhibitors After a CDK4/6 Inhibitor
NCT ID:
NCT05536128
Condition:
Advanced Breast Cancer
Conditions: Official terms:
Breast Neoplasms
Fulvestrant
Olaparib
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Intervention model description:
Single arm, phase II study
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Olaparib
Description:
Olaparib tablet 300 mg taken orally twice daily Olaparib 500 mg on Days 1, 15, 29, and
every 4 weeks thereafter The treatment will continue till disease progression or
unacceptable toxicity or withdrawal of consent or another discontinuation criterion is
met.
Arm group label:
Olaparib,Fulvestrant
Other name:
(Lynparza Cap)
Intervention type:
Drug
Intervention name:
Fulvestrant
Description:
Fulvestrant 500 mg on Days 1, 15, 29, and every 4 weeks thereafter
Arm group label:
Olaparib,Fulvestrant
Other name:
Faslodex®
Summary:
Protocol Title: A Phase II open label, umbrella study evaluating the efficacy and safety
of Fulvestrant plus DNA damage repair inhibitors in hormone receptor-positive advanced
breast cancer after a CDK4/6 inhibitor
Detailed description:
Nearly 70% of breast cancers (BCs) express estrogen receptor and rely on estrogen binding
for growth and promotion of tumourigenesis. Endocrine therapy (ET), such as aromatase
inhibitors, are the mainstay initial therapy for hormone receptor-positive (HR+), human
epidermal growth factor receptor two-negative (HER2-) BC. Recently, the combination of ET
and cyclin-dependent kinase (CDK) 4/6 inhibitors has shown significant and meaningful
clinical benefit and has become the standard of care in this setting. So far, three
CDK4/6 inhibitors have been approved by both FDA and EMA(European Medicines Agency):
palbociclib (Ibrance, Pfizer, USA), ribociclib (vissali, Novartis, Switzerland) and
abemaciclib (Verzenio, Lilly, USA). All of these drugs are approved and are widely used
in 1st-line treatment for metastatic HR+/HER2- BC in Korea.
CDK4/6 inhibitors have revolutionized the treatment landscape of HR+ HER2- BC but
intrinsic or acquired resistance is inevitable. Fulvestrant, a selective estrogen
receptor degrader (SERD), is one of preferred agents as the 2nd line treatment after
failure of an aromatase inhibitor.
More data regarding treatment options and sequences after failure of CDK4/6 inhibitors
and endocrine treatments are needed. This is an umbrella study of treatments according to
the germline or somatic genetic alterations in this patient population. The main focus
would include, but not be limited to, DNA damage repair (DDR) inhibitors plus fulvestrant
combinations.
Criteria for eligibility:
Criteria:
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. Patients with known germline or somatic mutations of BRCA1 or BRCA2
14. 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.
Gender:
All
Minimum age:
19 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Seoul National University Hospital
Address:
City:
Seoul
Country:
Korea, Republic of
Contact:
Last name:
Seock-Ah Im
Phone:
82-2-2072-0850
Email:
moisa@snu.ac.kr
Investigator:
Last name:
Kyung-Hun Lee, MD
Email:
Sub-Investigator
Investigator:
Last name:
Dae-Won Lee, MD
Email:
Sub-Investigator
Start date:
December 31, 2022
Completion date:
December 31, 2025
Lead sponsor:
Agency:
Seoul National University Hospital
Agency class:
Other
Source:
Seoul National University Hospital
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05536128
