A Phase 1, First-in-human, Multicenter, Open-label, Dose-escalation Study to Characterize the Safety and Tolerability of MP0317 in Patients With Relapsed/Refractory Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 46
- 试验地点
- 4
- 主要终点
- Incidence of dose-limiting toxicities (DLTs)
研究概览
简要总结
This study is investigating a new experimental therapy, MP0317, a DARPin® drug candidate targeting fibroblast activation protein (FAP) and CD40. Preclinical studies suggest that MP0317 may provide benefit for the treatment of tumors known to express high levels of FAP and for which approved therapies have been exhausted. This is the first study of MP0317 in humans and its main purpose is to test its safety and tolerability in patients with advanced solid tumors. This study will also examine the blood levels of MP0317 at several increasing dose levels and a recommended dose for further development will be determined. The recommended dose will be tested in a second part of the study to confirm safety and to further assess the preliminary biologic and anti-tumor activity.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 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
- •Has an advanced, histologically-proven solid tumor of one of the following types, and for which approved therapies have been exhausted or for which the Investigator considers the patient ineligible or unable to tolerate other treatments:
- •Colorectal cancer
- •Ovarian cancer
- •Endometrial cancer
- •Gastric cancer
- •Pancreatic cancer
- •Anal cancer
- •Cervical cancer
- •Head and neck squamous cell carcinoma (HNSCC)
- •Mesothelioma
- •Prostate cancer
- •Non-small cell lung cancer (NSCLC)
- •Urothelial/bladder cancer
- •Microsatellite instability high cancer of any type
- •Cutaneous squamous cell cancer
- •Breast cancer
- •Has signed and dated written informed consent before performing any study procedure, including screening
- •Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 1
- •Anticipated life expectancy ≥ 12 weeks by Investigator judgement
- •Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
- •Should agree to undergo mandatory paired (pre and on-treatment) tumor biopsies and be considered to have biopsiable disease. The biopsies should be performed as follows:
- •At least 1 tumor lesion ≥ 20 mm amenable to percutaneous biopsy other than the target lesion(s) used to follow response as defined by RECIST v1.
- •For cutaneous or subcutaneous lesions, tumors should be ≥ 5 mm in diameter amenable to biopsy by excisional or punch biopsies without unacceptable risk of a major procedural complication.
- •For core needle biopsy specimens, at least 3 to 6 cores with an 18-gauge needle should be collected.
- •The on-treatment tumor biopsy should be taken from the same lesion as the pre-treatment biopsy. The biopsied lesion should be large enough to take both biopsies ≥ 1 cm apart.
- •Should agree to undergo mandatory paired (pre and on-treatment) skin biopsies
- •At least 28 days must have elapsed between any prior major surgery and screening. The following procedures are not considered major:
- •Obtaining the pre-treatment tumor and skin biopsies as per protocol requirements
- •Placement of a port for central venous access
- •Needle, punch or excisional biopsy of a clinically or radiographically detected lesion
- •Laboratory parameters at screening:
- •a. Hematology: i. Platelet count ≥ 100,000 cells/mm3 ii. Absolute neutrophil count ≥ 1,000 cells/mm3 iii. Hemoglobin ≥ 9 g/dL b. Serum creatinine < 1.5 x upper limit of normal (ULN) or creatinine clearance > 50 mL/min on the basis of Cockcroft-Gault glomerular filtration rate estimation c. Coagulation: i. International normalized ratio (INR) < 1.5 ii. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless therapeutically warranted d. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x ULN e. Bilirubin normal, except for patients with known familial hyperbilirubinemia (such as Gilbert syndrome); for patients with documented Gilbert's syndrome (Gilbert-Meulengracht syndrome) total bilirubin ≤ 3 x ULN is acceptable f. Albumin > 2.8 g/dL or > 28 g/L, and without albumin transfusion for ≥ 7 days before screening
- •Is using highly effective contraception, for females of childbearing potential (FCBP) and for men, as follows:
- •Female: Is not pregnant, is not breastfeeding, and one of the following applies:
- •Not a FCBP
- •A FCBP who agrees and/or whose male partner agrees to follow the contraceptive guidance from screening, during the treatment period, and for at least 3 months after the last study drug administration. A FCBP must have a negative serum pregnancy test result at screening.
- •Male: Agreement to use a highly effective contraception method from screening, during the treatment period, and for at least 3 months after the last study drug administration and to refrain from donating sperm during this period.
- •Exclusion criteria:
- •Known hypersensitivity to excipients used in the MP0317 formulation
- •Autoimmune diseases, except autoimmune endocrinopathies that are stable with hormone replacement therapy
- •Inflammatory diseases such as arthritis, colitis, liver fibrosis, cirrhosis, interstitial fibrosis or chronic obstructive pulmonary disease (COPD) that may have elevated tissue fibroblast activation protein (FAP) expression unless approved after consultation with the Sponsor
- •Serious illness or concomitant non-oncological disease considered by the Investigator to be incompatible with participating in the protocol
- •Left ventricular ejection fraction of < 50% on echocardiographic exam or multi-gated acquisition (MUGA) scan at screening
- •History or evidence of clinically significant cardiovascular disease defined as at least one of the following criteria:
- •Evidence of poorly controlled arterial hypertension (systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg)
- •Myocardial infarction or instable angina pectoris within 6 months before screening
- •Heart failure (New York Heart Association Class III or IV)
- •Any cardiac arrhythmia that is not well controlled
- •QT corrected (QTc) prolongation ≥ Grade 2 (> 480 ms) at screening measured on 2 separate electrocardiograms (ECG) at least 10 minutes apart
- •Clinically significant valvular heart disease
- 另有 28 项未显示
排除标准
- 未提供
研究组 & 干预措施
Dose-escalation Cohorts (q3w)
The starting dose is 0.03 mg/kg every 3 weeks (q3w) and up to 6 dose levels are planned.
Study treatment will be administered as an intravenous (IV) infusion until progressive disease (PD), unacceptable toxicity, withdrawal of consent or other reasons to discontinue treatment occur, whichever comes first.
干预措施: MP0317, a tri-specific fibroblast activation protein (FAP) x CD40 DARPin® drug candidate (q3w regimen) (Drug)
Dose-escalation Cohorts (q1w)
The starting dose is 0,5 mg/kg every week (q1w) and up to 3 dose levels are planned.
Study treatment will be administered as an intravenous (IV) infusion until progressive disease (PD), unacceptable toxicity, withdrawal of consent or other reasons to discontinue treatment occur, whichever comes first.
干预措施: MP0317, a tri-specific fibroblast activation protein (FAP) x CD40 DARPin® drug candidate (q1w regimen) (Drug)
结局指标
主要结局
Incidence of dose-limiting toxicities (DLTs)
时间窗: 4 weeks after first study drug administration
DLTs will be reviewed as a subset of AEs that occur within 4 weeks after first study drug administration
Type, incidence and severity of AEs and serious adverse events (SAEs)
时间窗: From first study drug administration and until 28 days after the last study drug administration or end of study (EOS)
According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0
Recommended dose for expansion (RDE)
时间窗: From first study drug administration and until 28 days after the last study drug administration or end of study (EOS)
Based on incidence and nature of DLTs, and incidence, nature, and severity of AEs and SAEs
Maximum tolerated dose (MTD)
时间窗: From first study drug administration and until 28 days after the last study drug administration or end of study (EOS)
Based on occurrence of DLTs within an adaptive study design following Bayesian Logistic Regression Model (BLRM)
次要结局
- Overall response rate (ORR)(4.5 months)
- Progression-free survival (PFS)(4.5 months)
- Serum concentration-time profiles(4.5 months)
- Area under the serum curve (AUC)(4.5 months)
- Total clearance (CL)(4.5 months)
- Half-life (t1/2)(4.5 months)
- Volume of distribution at steady state (Vss)(4.5 months)
- Disease control rate (DCR)(4.5 months)
- Duration of response (DOR) of CR or PR(4.5 months)
- Time to progression (TTP)(4.5 months)
- Overall survival (OS)(12 months; including 4.5 months survival follow-up)