Advanced Breast Cancer
Conditions
Brief 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.
Interventions
DRUGOlaparib
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.
DRUGFulvestrant
Fulvestrant 500 mg on Days 1, 15, 29, and every 4 weeks thereafter
Sponsors
Seoul National University Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Single arm, phase II study
Eligibility
Sex/Gender
ALL
Age
19 Years to No maximum
Healthy volunteers
No
Inclusion 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. \<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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 6-month progression-free survival (PFS) rate | Duration of response is the time from response to progression or death from any cause whichever is earlier. | PFS rate is the number (%) of patients who are alive without any evidence of disease progression at 6 months. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free survival (PFS) | Duration of response is the time from response to progression or death from any cause whichever is earlier. | PFS is defined as the time from the initiation of the study treatment to disease progression or death from any cause whichever is earlier. Progression-free survival will be estimated using the Kaplan-Meier method with 95% CI(Confidence interval). |
| Objective response rate (ORR) | Duration of response is the time from response to progression or death from any cause whichever is earlier. | ORR is defined as the number (%) of patients with at least 1 visit response of CR(Complete Response) or PR (Partial Response) per RECIST 1.1. Data obtained up until progression, or last evaluable assessment in the absence of progression, will be included in the assessment of response rate. |
| Duration of response | Duration of response is the time from response to progression or death from any cause whichever is earlier. | Duration of response is the time from response to progression or death from any cause whichever is earlier. |
| Safety and toxicity according to CTCAE v5.0 | Duration of response is the time from response to progression or death from any cause whichever is earlier. | All safety analyses will be performed on the Safety Population. Safety and tolerability will be assessed in terms of AEs, deaths, laboratory data, vital signs and ECGs. These will be collected for all patients. Appropriate summaries of these data will be described. |
| Translational research using tumour and blood samples | Duration of response is the time from response to progression or death from any cause whichever is earlier. | Collected samples will be used for potential development of biomarkers for response/resistance and safety |
Countries
South Korea
Outcome results
None listed