A phase II study of combination of radiotherapy and Atezolizumab/nab-paclitaxel for inoperable or recurrent PD-L1 positive triple negative breast cancer

JRCT ID: jRCTs021210010

Registered date:04/06/2021

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: inoperable or recurrent PD-L1 positive triple negative breast cancer
• Date of first enrollment: 14/04/2022
• Target sample size: 20
• Study type: Interventional

Intervention(s)

(1) Radiotherapy
The following treatments are given to lesions for which local radiotherapy is an indication. In general, radiotherapy should be given before the start of the second course of drug therapy. However, depending on the patient's condition, it can be performed before the start of the first course or before the start of the third course.
Once a day, 6Gy for 5 days (30Gy / 5 times / 5 days in total)
However, if the spinal cord (10 cm or more) or the brain (whole) is the planned irradiation site, these tolerable doses of 4.5 Gy for 5 days (22.5 Gy / 5 times / 5 days in total) are chosen.
(2) Atezolizumab / nab-paclitaxel
Atezolizumab: 840 mg (fixed dose) given by intravenous drip on days 1 and 15 of the 28-day cycle.
Nab-paclitaxel: 100 mg / m2 is infused intravenously on days 1, 8 and 15 of the 28-day cycle. Administration of Nab-paclitaxel should not be given more frequently than every 7 days.
The interval from the date of administration of the drug therapy to the irradiation is 4 days or more and the interval from the date of irradiation to the date of administration of the drug therapy is 3 days or more.
Continue the above treatments until discontinuation due to exacerbations or adverse events.

Outcome(s)

Primary Outcome

Primary Endpoints
Incidence rate of pre-specified adverse events of interest (PAEIs) when the combination of atezolizumab/nab-paclitaxel is combined with local radiation therapy
<PAEI>
The following adverse events* occurred within 3 months after completion of irradiation
-Grade 3-4 non-hematologic, non-dermal, non-pulmonary related toxicity
-Fever over 38.5 degree with ANC<1,000/muL
-Neutrophil count reduction of <500/muL lasting longer than 5 days
-Significant bleeding with platelet count <40,000/muL or platelet count <20,000/muL
-Grade 4 skin disorder
-Development of radiation pneumonitis outside the radiation range, regardless of grade
-All Grade 2 pulmonary events that do not recover to Grade 1 or lower within 12 weeks
-Grade 2 pulmonary event, once recovered, but with a recurrence of a Grade 2 pulmonary event (relapse)
-All pulmonary events of Grade 3-4
Encephalitis or meningitis of any grade

Secondary Outcome

safety
overall survival time
progression-free survival
Response rate
Percentage of disease control
(Irradiated lesion) Percentage of local control
duration of effect

Key inclusion & exclusion criteria

• Age minimum: >= 20age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

(1) Written informed consent has been obtained from the patient himself / herself.
(2) Age 20 years / over
(3) Histologically confirmed inoperable or recurrent triple-negative breast cancer (without HER2, ER, PR expression, with PD-L1 expression).
-HER2-negative is evaluated in the each institution according to one of the following definitions.
-No amplification in in situ hybridization (ISH), or IHC 0 or IHC 1+
-ER and PR negative are defined as less than 10% of hormone receptor-expressing cells in IHC analysis.
-PD-L1 positive means that the PD-L1 score in the tumor tissue is IC 1 or higher in the IHC analysis using the SP142 antibody.
(4) Within 2 regimens of chemotherapy or systemic targeted therapy for the breast cancer
(5) ECOG Performance Status 0-2
(6) Patients who can be expected to survive for 12 weeks or more
(7) Patients with lesions for which local radiotherapy is an indication
(8) The latest L/D within 14 days before registration satisfies all of the following.
White blood cell count <= 12,000 / muL
Neutrophil count => 1500 / muL
Lymphocyte count => 500 / muL
Platelet count => 100,000 / muL
Hemoglobin => 9.0 g / dL
AST, ALT, <= 2.5 x upper limit of normal value (ULN)
(patients with liver metastasis: AST and ALT <= 5 x ULN are allowed)
Alkaline phosphatase <= 2.5 x upper limit of normal value (ULN)
(patients with liver or bone metastasis: Alkaline phosphatase <= 5 x ULN is allowed)
Serum bilirubin <= 1.25 x ULN
(in Gilbert's syndrome, serum bilirubin level <= 3 x ULN is allowed)
INR and aPTT <= 1.5 x ULN
Estimated creatinine clearance => 30 mL / min

Exclude criteria

1) V20 (ratio of lung volume irradiated above 20 Gy to total lung volume) is expected to exceed 20%
2) Heterozygous / synchronous double cancer (excluding cervical carcinoma in situ, well-treated basal cell carcinoma of the skin, intramucosal cancer of the digestive tract, and malignant tumors treated more than 5 years ago without recurrence)
3) Patients with a history of hypersensitivity to the ingredients of atezolizumab preparations, patients with a history of hypersensitivity to Nab-paclitaxel or additives. And, have a history of high hypersensitivity reaction to other antibody preparations (if it develops before 2 years and there is no recurrence, it can be registered).
4) Receive continuous systemic administration (oral or intravenous) of steroids or other immunosuppressive drugs. However, temporary use or use of low doses of prednisolone or prednisolone equivalent less than 15 mg / day can be registered.
5) Patients with or with a history of recurrent autoimmune disease. However, it does not include the patients with hypothyroidism that can be controlled by hormone replacement therapy and skin diseases that do not require systemic management (white spots, psoriasis, alopecia, etc.).
6) Have one or more of interstitial pneumonia, pulmonary fibrosis, severe emphysema diagnosed by diagnostic imaging (preferably diagnosed by CT) or clinical findings. A history of radiation pneumonitis (fibrosis) in the irradiation field is acceptable.
7) Have the following serious illnesses or conditions
-Significant nutritional disorders
-Transient ischemic attack, cerebrovascular attack, thrombosis, or thrombotic embolism within 180 days before full registration
-Congestive heart failure (NYHA Class III or IV)
-Unstable angina or myocardial infarction within 6 months
-Severe arrhythmia requiring medication and AV block exceeding the second degree
-Uncontrollable high blood pressure
-Cirrhosis (Child Class B or above)
-Mental disorders that may interfere with compliance with this study implementation plan
-Diabetes under treatment or uncontrolled due to continuous use of insulin
-Uncontrollable pericardial fluid, ascites or pleural effusion
-Anticoagulant therapy (excluding antiplatelet therapy such as low-dose aspirin) is required
-Uncontrolled, valvular disease, dilated cardiomyopathy, hypertrophic cardiomyopathy
8) Pregnant or lactating women
9) Women of childbearing potential who are not willing to contracept, and partner men who are fertile and unwilling to contracept for 7 months after the end of study.
10) Have the following pretreatment history within 56 days from the registration date:
Radiopharmaceuticals (excluding radiopharmaceuticals for testing and diagnosis)
Within 28 days from the registration date:
Systemic corticosteroid
(Excluding temporary use, prednisolone or prednisolone equivalent less than 15 mg / day)
Immunosuppressant
Antineoplastic agents (chemotherapy, molecular targeted therapy, immunotherapy, etc.)
Adhesion of the pleura or pericardium
Surgical therapy with general anesthesia
Administration of unapproved drugs
Within 14 days from the registration date:
Surgical therapy with local or surface anesthesia(CV port placement, dental treatment, etc. which do not affect the primary endpoint, are not included.)
11) Participating in other clinical trials or clinical studies (excluding trials without intervention)
12) Positive for HIV antigen / antibody test or HTLV-1 antibody test
13)In the past, anti-PD-L2 antibody, anti-CD137 antibody,Anti-CTLA-4 antibody or other antibody therapy or drug therapy aimed at controlling T cells Has a history of pretreatment.If the subjects have using anti-PD-1 antibodies or anti-PD-L1 antibodies previously, they can register, but in that case, 6 weeks have need passed since the last administration before the start of research treatment. In that case, the attending physician must have determined that there will be no problem with the safety or evaluation of participation.
14) Cases in which the investigator determined that participation in this study was inappropriate
15) Have a fever of 38 degrees or higher at the time of registration
16) HBsAg / antibody positive or HCV antibody positive

Related Information

• Primary Sponsor: Suzuki Yoshiyuki
• Source(s) of Monetary Support: none