JBCRG-M08(AMBER trial)

JRCT ID: jRCTs051220133

Registered date:14/12/2022

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: Hormone receptor-positive, HER2-negative inoperable or recurrent breast cancer
• Date of first enrollment: 14/12/2022
• Target sample size: 150
• Study type: Interventional

Intervention(s)

-_After the primary enrollment, AI + ABE will be administered with the same dosage and administration as those before the primary.
-_Patients who are confirmed not to have PD in the tumor evaluation at Week 12 after the primary enrollment and can continue AI + ABE will proceed to the secondary enrollment.
-_After the secondary enrollment, the following treatment will be performed according to the ESR1 mutation status in the results of ctDNA measurement for intervention at Week 8 after the primary enrollment.
-_ESR1 mutation-positive: FUL + ABE will be started.
-_ESR1 mutation-negative: AI + ABE will be continued, and the following treatment will be performed according to the ESR1 mutation status in the results of ctDNA measurement for intervention at Week 24 after the secondary enrollment.
-_ESR1 mutation-positive: FUL + ABE will be started.
-_ESR1 mutation-negative: AI + ABE will be continued, and the following treatment will be performed according to the ESR1 mutation status in the results of ctDNA measurement for intervention at Week 48 after the secondary enrollment.
-_ESR1 mutation-positive: FUL + ABE will be started.
-_ESR1 mutation-negative: AI + ABE will be continued.

-_Based on the ESR1 mutation status in the results of ctDNA measurement for intervention at Week 24 after the start of treatment with FUL + ABE, the following treatment will be performed.
-_ESR1 mutation-positive: FUL + ABE will be continued.
-_ESR1 mutation-negative: AI + ABE will be started.

Outcome(s)

• Primary Outcome: 2-year PFS rate from the secondary enrollment (all arms)

Secondary Outcome

(1)2-year PFS rate after the secondary enrollment (each arm): Key Secondary End Point
(2)Rate of disappearance of ESR1 mutations in ctDNA with FUL + ABE: Key Secondary End Point
(3)PFS from the secondary enrollment (all arms and each arm)
(4)PFS from FUL + ABE initiation (arm FUL + ABE, arm Re-AI + ABE, and both arms)
(5)PFS with Re-AI + ABE (arm Re-AI + ABE)
(6)Overall survival (OS) (all arms and each arm)
(7)Response rate and disease control rate (all arms and each arm)
(8)Safety
(9)Protocol treatment compliance rate

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Female

Include criteria

primary enrollment
(1) Histologically diagnosed with invasive breast cancer.
(2) Confirmed ER-positive or PgR-positive (>= 1% positive cells by IHC or an Allred score of >= 3).
(3) Confirmed HER2-negative (IHC 0 or 1, or FISH/DISH-negative).
(4) Diagnosed with advanced or metastatic breast cancer.
Note -Aromatase inhibitor + abemaciclib
combination therapy" includes LH-RH agonist
combination therapy based on menopausal status
prior to the start of treatment.
(5) Age >= 18 years at the time of informed consent.
(6) Women in menopause lasting more than 3
months (including in combination with LH-RH agonists).
(7) Performance status (PS) of 0 or 1 according to the ECOG criteria.
(8) Aromatase inhibitor + abemaciclib combination therapy has been administered as the first-line treatment for advanced metastatic breast cancer, and both drugs have been continued for >= 6 to < 12 months at the time of the primary enrollment. The patient should meet all of the following criteria (a) to (c).
(a) Each dose of abemaciclib is 150, 100, or 50 mg and has been taken twice daily.
(b) The aromatase inhibitor is letrozole or anastrozole.(Concomitant use of LH-RH agonists is acceptable depending on menopausal status).
(c) Aromatase inhibitor + abemaciclib combination therapy has been started under any of the following conditions:
- In the case of Stage IV (de novo) disease at diagnosis, drug therapy has not been administered.
- In the case of postoperative recurrence, drug ther apy has not been administered after recurrence. Inaddition, if postoperative therapy has been performed, it has to be recurrence at least 1 year after the completion of endocrine therapy as postoperative therapy, and the preoperative and postoperative therapy must not include CDK4/6 inhibitors.
(9) No evidence of progressive disease based on radiographic evaluation within 6 weeks before the day of enrollment.
(10) No active interstitial pneumonia confirmed byCT within 6 weeks before the day of enrollment.
(11) Non-hematologic toxicities (excluding alopecia) with aromatase inhibitor + abemaciclib
combination therapy controlled at Grade <= 2 according to CTCAE v 5.0.
(12) Meeting the following criteria in blood test within 28 days before the day of enrollment.
[1] Absolute neutrophil count (ANC) >=1,500/mm3(>=1.5 x 109/L)
[2] Hemoglobin >= 8.0 g/dL*
(*Patients may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator. Initial treatment must not begin earlier than the day after the erythrocyte transfusion.
[3] Platelet count >= 10 x 104/mm3 (100x109/L)
[4] Total bilirubin <= 1.5 mg/dL*1
*1 Patients with Gilbert's syndrome with a total bilirubin <=2.0 times ULN and direct bilirubin within normal limits are permitted.
[5] AST (GOT) <= 120 IU/L
[6] ALT (GPT) <= 120 IU/L
[7] Serum creatinine <= 2.0 mg/dL*
*Even if the above value is exceeded, the patient may be enrolled if the renal function is confirmed to be normal based on the measurement of serum cystatin C within 28 days before the day of primary enrollment.
(13) Patients who received chemotherapy must have recovered (Common Terminology Criteria for Adverse Events [CTCAE] Grade <=1) from the acute effects of chemotherapy except for residual alopecia or Grade 2 peripheral neuropathy prior to randomization. A washout period of at least 21 days is required between last chemotherapy dose and randomization (provided the patient did not receive radiotherapy)
(14) Patients who received radiotherapy must have completed and fully recovered from the acute effects of radiotherapy. A washout period of at least 14days is required between end of radiotherapy and randomization.
(15) The patient is able to swallow oral medications.
(16) Written consent for participation has been obtained from the patient herself.

secondary enrollment
(1) Both aromatase inhibitor and abemaciclib have been continued after the primary enrollment and are expected to be continued thereafter. (Each dose of abemaciclib is 150, 100, or 50 mg and has been taken twice daily.)
(2) No progression was confirmed by tumor evaluation at Week 12 after the primary enrollment.
(3) Performance status (PS) of 0 or 1 according to the ECOG criteria.
(4) The patient meets the following criteria in a blood test performed within 28 days before the day of secondary enrollment.
[1] Absolute neutrophil count (ANC) >=1,000/mm3(>=1.0 x 109/L)
[2] Hemoglobin >= 8.0 g/dL
[3] Platelet count >= 7.5 x 104/mm3 (75 x 109/L)
[4] Total bilirubin <= 1.5 mg/dL *1
*1 If the patient has been diagnosed with Gilbert's syndrome, total bilirubin should be <= 3.0 mg/dL.
[5] AST (GOT) <= 120 IU/L
[6] ALT (GPT) <= 120 IU/L
[7] Serum creatinine <= 2.0 mg/dL*
* Even if the above value is exceeded, the patient may be enrolled if the renal function is confirmed to
be normal based on the measurement of serum cystatin C within 28 days before the day of secondary enrollment.

Exclude criteria

primary enrollment
(1) The patient has concurrent or history of interstitial lung disease (ILD)/pneumonitits, including lung fibrosis.
(2) Patients with central nervous system metastases or carcinomatous meningitis, either active or inactive.
(3) Patients with active double cancer (synchronous or metachronous with disease-free period within 2years before the day of primary enrollment) other than breast cancer. However, even if the disease-free period is < 2 years before the day of primary enrollment, a history of the following will not be included in the active double cancer: laryngeal cancer in clinical stage 0 or I for which complete response was achieved by radiotherapy; and cancers for which 5-year relative survival is >= 95% such as those in the following pathological stages that were totally resected:
- Gastric cancer "adenocarcinoma (common type)," stage 0 to I; colon cancer (adenocarcinoma), stage 0 to I; rectal cancer (adenocarcinoma), stage 0 to I;esophageal cancer (squamous cell carcinoma, adenosquamous carcinoma, basaloid carcinoma), stage 0; and endometrial cancer
- (Endometrioid adenocarcinoma and mucinous adenocarcinoma), stage I; cervical cancer (squamous cell carcinoma), stage 0; thyroid cancer (papillary carcinoma and follicular carcinoma), stages I, II, and III; renal cancer (clear cell carcinoma and chromophobe cell carcinoma), stage I; and other lesions equivalent to intramucosal carcinoma
- In principle, staging will follow the UICC TNM 7th
edition or equivalent cancer handling rules.
(4) Patients with a history of breast cancer other than hormone receptor-positive, HER2-negative breast cancer that is synchronous or for which the disease-free period is < 5 years before the day of primary enrollment (excluding curatively resected non-invasive cancer).
(5) The patient has active systemic bacterial infection (requiring intravenous [IV] antibiotics at time of initiating study treatment), fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity or with known active hepatitis B or C [for example, hepatitis B surface antigen positive]. Screening is not required forenrollment.
(6) Patients with known infection with HBV or HCV or HIV. HBV infection is defined as HBs antigen-positive, or HBs antigen-negative and HBc antibody- or HBs antibody-positive with the quantified HBV-DNA level being equal to or higher than the detection sensitivity.
However, confirmation at screening is not essential for these assessments. It is desirable that HBV and HCV are confirmed to be negative regardless of the timing of test.
(7) Patients with a complication or history of heart failure of NYHA class II to IV, ischemic heart disease, or arrhythmia requiring treatment (excluding paroxysmal supraventricular tachycardia and atrial fibrillation with a resting rate of <= 100 bpm).
(8) The patient has a personal history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest.
(9) Patients with poorly controlled diabetes mellitus(casual blood glucose level of >= 300 mg/dL or HbA1c of >= 8.0%).
(10) Patients with poorly controlled hypertension (systolic blood pressure >= 160 mmHg or diastolicblood pressure >= 100 mmHg).
(11) Patients with symptoms of dyspnea at rest.
(12) Patients with pleural effusion, ascites, or cardiac effusion requiring drainage.
(13) Women who intend to become pregnant, women who cannot give consent for contraception, pregnant women or lactating women.
(14) Patients who do not wish to continue abemaciclib.
(15) The patient has had major surgery within 14 days prior to randomization.
(16) The patient has received an experimental treatment in a clinical trial within the last 30 days or 5 half-lives, whichever is longer, prior to randomization, or is currently enrolled in any other type of medical research (for example: medical device) judged by the sponsor not to be scientifically or medically compatible with this study.
(17) Patients who are participating or plan to participate in other clinical researches.
(18) History of hypersensitivity to letrozole, anastrozole, fulvestrant, or abemaciclib, or to leuprorelin or goserelin if menopausal status requires concomitant use. (except for a history of hypersensitivity to letrozole and anastrozole or leuprorelin and goserelin, whichever is not planned to be used)
(19) The patient has serious and/or uncontrolled preexisting medical condition(s) that in the judgement of the investigator, would preclude participation in this study.
(20) Patients who are judged by the investigator or subinvestigator to be inappropriate to participate in this research.

secondary enrollment
(1) Patients with accompanying active infection requiring systemic treatment.
(2) Patients who do not wish to continue abemaciclib.
(3) Patients who are judged by the investigator or subinvestigator to be inappropriate to continue this research.

Related Information

• Primary Sponsor: Yoshinami Tetsuhiro
• Source(s) of Monetary Support: Eli Lilly Japan K.K