Window of Opportunity Study of Intratumoral CD40 Agonist (Mitazalimab) With or Without PD-1 Inhibitor (Nivolumab) in Patients With Resectable Breast Cancer (WINIT-BC)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 32
- 试验地点
- 1
- 主要终点
- Occurrence of Grade 3 or higher adverse events as assessed by CTCAE v5.0
研究概览
简要总结
The goal of this clinical trial is to study the safety, feasibility, histologic and immunological effects of Mitazalimab, a CD40 agonistic antibody, when administered either alone or in combination with PD-1 inhibition prior to surgical resection.
The investigator hypothesizes that preoperative administration of CD40 agonist with or without PD-1 inhibitor intratumorally will demonstrate an acceptable safety profile, will not result in an unplanned delay in surgery, and will lead to increased immune activation.
Subjects will receive a single intratumoral dose of CD40 agonist with or without PD-1 inhibitor 7 or more days prior to surgery and will be followed for safety, feasibility, immune, and pathologic responses.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Signed and dated written IRB-approved informed consent.
- •Age ≥18 years.
- •Body weight > 40kg
- •Stage I-III or recurrent resectable breast cancer to be treated with curative-intent
- •Planning to undergo upfront surgery as part of routine clinical care
- •Discussion with the treating or study medical oncologist re: the potential of sending an Oncotype evaluation (if ER+HER2-) on the core needle biopsy sample
- •Availability of the core needle biopsy sample for correlative studies
- •Surgery to be performed at a University of Pennsylvania Hospital
- •Life expectancy of at least 12 weeks.
- •Adequate bone marrow, hepatic, and renal function. ANC (Absolute Neutrophil Count) ≥ 1.5x109 cell/ml, platelets ≥75,000 /mm3, hemoglobin ≥9.0 g/dL, total serum bilirubin within 1.5 x upper limit of normal (ULN) unless Gilbert's, AST/ALT, within 2.5 x ULN, Albumin ≥3g/dL, and all tests performed within 4 weeks prior to administration of Study Treatment.
- •ECG with no clinically significant findings as assessed by the investigator.
- •ECOG (Eastern Cooperative Oncology Group) performance status of 0-
- •Female patients of childbearing potential who are not abstinent and intend to be sexually active with a non-sterilized male partner must use at least 1 highly effective method of contraception from the time of screening throughout the total duration of the drug treatment and the drug washout period (90 days after therapy). Non-sterilized male partners of a female patient of childbearing potential must use male condom plus spermicide throughout this period. Female patients should also refrain from breastfeeding throughout this period.
- •Able and willing to comply with all study procedures.
排除标准
- •Metastatic disease.
- •Planned neoadjuvant therapy, i.e., not undergoing upfront surgery.
- •Known history of hepatitis B or C with active viral replication.
- •Administration of any live vaccine within 28 days of first dose of study treatment.
- •Prior CD40 or anti-PD-1 agonist therapy.
- •Participation in another interventional clinical trial within 30 days before receiving first dose of study treatment. However, the subject may participate in observational studies.
- •Any illness or condition that in the opinion of the investigator may affect the safety of the subject or the evaluation of any study endpoint.
- •Current or prior use of immunosuppressive medication within 14 days before study treatment. The following are exceptions to this criterion:
- •Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
- •Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
- •Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP.
- •History of allogenic organ transplantation
- •Active or prior documented autoimmune disease. Examples include inflammatory bowel disease [e.g., colitis or Crohn's disease], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis], Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]. The following are exceptions to this criterion:
- •Patients with vitiligo or alopecia
- •Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement or type 1 DM controlled with insulin
- •Any chronic skin condition that does not require systemic therapy
- •Patients without active autoimmune disease in the last 5 years may be included but only after consultation with the study physician
- •Patients with celiac disease controlled by diet alone
- •Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent
- •History of another active malignancy except for non-melanoma skin cancer, lentigo maligna or other carcinoma in situ
- •History of active primary immunodeficiency
- •Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
- •Body weight > 110 kg.
- •Actively breastfeeding. -
研究组 & 干预措施
Mitazalimab 75 μg/kg + Nivolumab
Arm B, Dose Level 0 (DL0): Mitazalimab 75 μg/kg + Nivolumab
干预措施: Intratumoral Mitazalimab (Drug)
Mitazalimab 75 μg/kg + Nivolumab
Arm B, Dose Level 0 (DL0): Mitazalimab 75 μg/kg + Nivolumab
干预措施: Intratumoral Nivolumab (Drug)
Mitazalimab 200 μg/kg + Nivolumab
Arm B, Dose Level 1 (DL1): Mitazalimab 200 μg/kg + Nivolumab
干预措施: Intratumoral Mitazalimab (Drug)
Mitazalimab 22.5 μg/kg + Nivolumab
Arm B, Dose Level -1 (DL-1): Mitazalimab 22.5 μg/kg + Nivolumab. This dose level will only be explored if ≥ 2 DLTs occur at any time in DL1.
干预措施: Intratumoral Nivolumab (Drug)
Mitazalimab 22.5 μg/kg
Arm A, Dose Level -1 (DL-1): Mitazalimab 22.5 μg/kg. This dose level will only be explored if ≥ 2 DLTs occur at any time in DL1.
干预措施: Intratumoral Mitazalimab (Drug)
Mitazalimab 75 μg/kg
Arm A, Dose Level 0 (DL0): Mitazalimab 75 μg/kg
干预措施: Intratumoral Mitazalimab (Drug)
Mitazalimab 200 μg/kg
Arm A, Dose Level 1 (DL1): Mitazalimab 200 μg/kg
干预措施: Intratumoral Mitazalimab (Drug)
Mitazalimab 22.5 μg/kg + Nivolumab
Arm B, Dose Level -1 (DL-1): Mitazalimab 22.5 μg/kg + Nivolumab. This dose level will only be explored if ≥ 2 DLTs occur at any time in DL1.
干预措施: Intratumoral Mitazalimab (Drug)
Mitazalimab 200 μg/kg + Nivolumab
Arm B, Dose Level 1 (DL1): Mitazalimab 200 μg/kg + Nivolumab
干预措施: Intratumoral Nivolumab (Drug)
结局指标
主要结局
Occurrence of Grade 3 or higher adverse events as assessed by CTCAE v5.0
时间窗: Within 30 days of treatment
Type and severity of adverse events
Feasibility of CD40 agonist (Mitazalimab) with/without PD-1 inhibitor (Nivolumab) prior to surgery
时间窗: 14 days after planned surgical date
Number of successful surgical resection without unanticipated delay in surgery \> 14 days after planned surgical date due to treatment-related issues
次要结局
- Immunologic effects of CD40 agonist (Mitazalimab) with/without PD-1 inhibitor (Nivolumab)(Prior to treatment and up to 30 days post surgery)
- Tumor response rate(2 weeks after surgery)
- Recurrence of disease(up to 5 years post surgery)
- Event-free survival(up to 5 years post surgery)
- immunologic effects of CD40 agonist (Mitazalimab) with/without PD-1 inhibitor (Nivolumab)(Prior to treatment and up to 30 days post surgery)
- Number of participants with change in serum cytokine levels pre- and post-treatment(Prior to treatment and up to 30 days post surgery)
- Number of participants with changes in tumor immune cell number pre- and post-treatment(Prior to treatment and up to 30 days post surgery)
- Number of participants with changes in TCR repertoire in peripheral blood pre- and post-treatment(Prior to treatment and up to 30 days post surgery)
- Number of participants with changes in TCR repertoire in tumor pre- and post-treatment(Prior to treatment and up to 30 days post surgery)
- Number of patients with FDG PET/CT response or flair after treatment(between baseline and 1 week post-treatment)
研究者
Jennifer Zhang
Assistant Professor of Surgery at the Hospital of the University of Pennsylvania
University of Pennsylvania