PPhase-I Study to Evaluate the Safety, Tolerability and Preliminary Efficacy of the Bispecific PSMAxCD3 Antibody CC-1 as Single Agent and Combined With Checkpoint Blockade in Patients With Squamous Cell Carcinoma of the Lung
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 3
- 试验地点
- 2
- 主要终点
- Incidence and severity of adverse events (AEs) (CTCAE V5.0) over 22 days
研究概览
简要总结
This trial is a phase I study in patients with metastatic non-small-cell lung cancer (NSCLC) after failure of second line therapy aiming to evaluate safety and efficacy of CC-1, a bispecific antibody (bsAb) with PSMAxCD3 specificity developed within DKTK. CC-1 binds to human prostate-specific membrane antigen (PSMA) on tumor cells of squamous cell carcinoma of the lung (SCC) as well as to tumor vessels of SCC, thereby allowing for a dual mode of anti-cancer action. CC-1 was developed in a novel format which not only prolongs serum half-life but most importantly reduces off-target T cell activation with expected fewer side effects. Together with preemptive IL-6 receptor (IL-6R) blockade using tocilizumab, this allows for application of effective bsAb doses with expected high anticancer activity. The study comprises two phases: The first phase is a dose-escalation phase with concomitant prophylactic application of tocilizumab to evaluate the maximally tolerated dose (MTD) of CC-1. This is followed by a dose-expansion phase (also with prophylactic IL-6R blockade using tocilizumab). A translational research program comprising, among others, analysis of CC-1 half-life and the induced immune response as well as molecular profiling in liquid biopsies will serve to better define the mode of action of CC-1 and to identify biomarkers for further clinical development.
详细描述
SCC of the lung is an aggressive malignant disease with poor prognosis after failure of established therapies. Any drug employed after second-line treatment is associated with only limited clinical benefit. Therefore, there is a high medical need for new therapeutic approaches in this patient population. The clinical effects of immune checkpoint inhibitors in NSCLC have proven the potential of T-cell based immunotherapy in this entity. The rationale for the therapeutic use of CC-1 is based on its proposed mode of action as a bsAb being specifically designed to direct T cells via its CD3 binding part towards tumor target cells via its PSMA binding part. Furthermore, CC-1 also reacts with tumor vessels of NSCLC thereby allowing for a dual mode of anti-cancer action by also attacking tumor blood supply and allowing for improved influx of immune effector cells. Due to its unique ability to redirect T cells via CD3 for PSMA-expressing tumor cell lysis, CC-1 can elicit repeated target cell elimination by cytotoxic T cells and a polyclonal response of previously primed CD4+ and CD8+ T cells. Compared to other immunotherapeutics presently being approved or in development (bsAbs with alternative formats like the authorised bsAb blinatumomab or other antibodies or CAR T cells), CC-1 is expected to offer the following major advantages:
(i) Reduction of off-target T cell activation and thus reduction of side effects due to its optimized format (ii) The possibility to tightly steer anti-target activity via serum level-controlled antibody application which, in contrast to CAR T cells, allows for termination of activity if desired.
On the background of the poor prognosis of patients with SCC of the lung after second-line therapy, the bsAb CC-1 holds promise as a new treatment option of immunotherapy for these patients.
The planned study will include patients with SCC of the lung with detectable PSMA expression on tumor cells after second line treatment. PSMA expression is to be determined by central immunohistochemical assessment of fresh or kryopreserved tumor samples. Only patients with proven PSMA expression on tumor cells as defined by ≥10% positivity of tumor cells can be included. The requirement of ≥10% positivity of tumor cells for PSMA expression cells is in line with definitions of positivity for target antigen expression employed for other antibodies used in cancer treatment, for example the human epidermal receptor protein-2 (HER2)-specific antibodies trastuzumab and pertuzumab. Both antibodies are approved for the treatment of HER2-positive breast cancer, and HER2 positivity is given if ≥10% of tumor cells show staining for HER2 as assessed by immunohistochemistry .
PSMA-positivity is estimated for about 50% of screened patients with SCC of the lung.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- •• Existence of a written informed consent
- •Patient is able to understand and comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations
- •SCC of the lung with detectable PSMA expression by tumor cells after second line treatment. PSMA expression is to be determined by central immunohistochemical assessment of fresh or cryopreserved tumor samples. Only patients with proven PSMA expression by tumor cells as defined by ≥10% positivity of tumor cells can be included.
- •Life expectance of > 3 months
- •At least one measurable lesion that can be accurately assessed at baseline by CT or MRI and is suitable for repeated assessment
- •Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2
- •Patient aged ≥ 18, no upper age limit
- •Female patients of child bearing potential and male patients with partners of child bearing potential, who are sexually active, must agree to the use of two effective forms (at least one highly effective method) of contraception. This should be started from the signing of the informed consent and continue throughout period of taking study treatment and for 1 month (female patients) / 3 months (male patients) after last dose of study drug. Postmenopausal or evidence of non-childbearing status. For women of childbearing potential: negative urine or serum pregnancy test within 21 days prior to study treatment and confirmed prior to treatment on day
- •Postmenopausal or evidence of non-childbearing status 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 post menopausal 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)
- •Adequate bone marrow, renal, and hepatic function defined by laboratory tests within 14 days prior to study treatment:
- •Neutrophil count ≥ 1,500/mm3 Platelet count ≥ 100,000/µl Bilirubin ≤ 1.5 x upper limit of normal (ULN) ALT and AST ≤ 2.5 x ULN PT-INR/PTT ≤ 1.5 x ULN Creatine kinase ≤ 2.5 x ULN Serum creatinine ≤ 1.5 mg/dl or creatinine clearance ≥ 60 ml/min
排除标准
- •• Other malignancy within the last 5 years except: adequately treated non-melanoma skin cancer, carcinoma in situ of the cervix, carcinoma in situ of the breast, histological finding of prostate cancer of TNM stage T1
- •PSMA expression <10% by tumor cells
- •Concurrent or previous treatment within 30 days in another interventional clinical trial with an investigational anticancer therapy
- •Persistent toxicity (≥Grade 2 according to Common Terminology Criteria for Adverse Events [CTCAE] version 5.0) caused by previous cancer therapy, excluding alopecia and neurotoxicity (≤ 2 grade)
- •Clinical signs of active infection (> grade 2 according to CTCAE version 5.0)
- •Cerebral/Meningeal manifestation of the SCC of the lung
- •History of HIV infection
- •Immunocompromised patients
- •Viral active or chronic hepatitis (HBV or HCV)
- •History of autoimmune disease
- •History of relevant CNS pathology or current relevant CNS pathology (e.g. seizure, paresis, aphasia, cerebrovascular ischemia/hemorrhage, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, psychosis, coordination or movement disorder)
- •Epilepsy requiring pharmacologic treatment
- •Therapeutic anticoagulation therapy
- •Major surgery within 4 weeks of starting study treatment. Patients must have recovered from any effects of major surgery.
- •Patients receiving any systemic chemotherapy or radiotherapy within 2 weeks prior to study treatment or a longer period depending on the defined characteristics of the agents used
- •Heart failure NYHA III/IV
- •Severe obstructive or restrictive ventilation disorder
- •Known history of GI-perforation
- •Known intolerance to CC-1, tocilizumab or other immunoglobulin drug products as well as hypersensitivity to any of the excipients present in the respective drug products (CC-1, tocilizumab)
研究组 & 干预措施
Treatment with bispecific Ab CC-1
administration of bispecific PSAMxCD3 Ab CC-1.
干预措施: CC-1 and Toczilizumab (Drug)
结局指标
主要结局
Incidence and severity of adverse events (AEs) (CTCAE V5.0) over 22 days
时间窗: 10-72 patients. at least 1 cycle (for 22 day cycles) plus 21 days follow-up, but may vary depending on treatment-induced clinical benefit and optional additional cycles
Incidence and severity of adverse events (AEs) (CTCAE V5.0) over 22 days (i.e. until end of first treatment cycle) Full hematology assessments for safety hemoglobin, red blood cells, platelets, mean cell volume, mean cell hemoglobin concentration, mean cell hemoglobin, white blood cells, absolute differential white cell count and absolute neutrophil count or segmented neutrophil count and Band forms should be performed at each visit and when clinically indicated. Biochemistry assessments for safety: sodium, potassium, calcium, magnesium, glucose, creatinine, total bilirubin, gamma glutamyltransferase, alkaline phosphatase,aspartate transaminase, alanine transaminase, urea or blood urea nitrogen, total protein, albumin and lactic dehydrogenase are performed.
Dose expansion part
时间窗: 14 patients.at least 1 cycle (for 22 day cycles) plus 21 days follow-up, but may vary depending on treatment-induced clinical benefit and optional additional cycles
To define the recommended phase-II dose of CC-1 under preemptive IL-6R blockade I
次要结局
- Immunogenicity(day 15, day 43)
- Anti-tumor activity(End of safety follow up,day 22 of cycle 3 and 4)
- Survival(12 month after end of safety follow up)