Phase I Study to Evaluate the Tolerability, Efficacy, and Safety of Pazopanib in Combination with PCI-24781 in Patients with Metastatic Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 90
- 试验地点
- 1
- 主要终点
- Dose limiting toxicity (DLT)
研究概览
简要总结
This is a open-label non-randomized, dose escalation and expansion Phase Ia/Ib study to determine the safety, tolerability and maximum tolerated dose (MTD) of pazopanib in combination with PCI-24781 in patients with advanced solid tumors.
详细描述
Study rationale/purpose
Pazopanib is a potent, multi-targeted tyrosine kinase inhibitor44 of VEGFR-1, -2, -3, PDGFR-α and -β and c-kit approved for metastatic renal cell carcinoma based on phase III data showing a significant prolongation of progression-free survival (PFS) (5 mos in pretreated patients and 8.3 mos in treatment-naïve patients). In addition recent data was presented this year, but is not yet published, with treatment-refractory sarcoma patients that showed a PFS was significantly prolonged from a median of 20 vs. 7 weeks. As can occur with all antiangiogenic agents, resistance to pazopanib may develop. Epigenetic modification with HDAC inhibitors may overcome drug resistance by causing an increase in accessibility of DNA to chemotherapeutic agents and may therefore significantly potentiate their cytotoxicity. Combination trials with chemotherapy agents are ongoing (ClinicalTrials.gov) To our knowledge, a combination trial of HDACi with anti-angiogenesis agents has not yet been performed and represents an unmet medical need.
PCI-24781 is a pan HDAC inhibitor. In cell lines tested, up-regulation and down-regulation of genes known to result in changes with signal transduction, oxidation, metabolic changes, apoptosis, proliferation, differentiation and angiogenesis were seen. In addition, ongoing single agent and combination trials have shown the drug to be effective and well-tolerated.
Hypothesis
Combining an antiangiogenic agent, such as pazopanib, with an epigenetic modifier, such as histone deacetylase inhibitor (HDACi) PCI-24781, can increase the efficacy of pazopanib as well as overcome development of resistance to pazopanib.
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
- •Patients must provide written informed consent prior to performance of study-specific procedures or assessments, and must be willing to adhere with treatment and followup.
- •Age ≥ 18 years
- •Phase Ia: Patients must have histologically or cytologically documented metastatic solid tumor malignancies. Phase Ib: Patients must have histologically or cytologically confirmed locally advanced, solid tumor malignancies of one of the following tumor types:
- •Renal cell carcinoma (N = 20 patients) (Cohort A)
- •Non-anaplastic thyroid carcinoma (N = 20 patients) (Cohort B) Documentation of histology from a primary or metastatic site is allowed.
- •Soft tissue sarcoma (N = 20 patients) (Cohort C). Patients must have progressed in a prior line of therapy.
- •Ovarian carcinoma (N = 20 patients) (Cohort D)
- •Measurable disease by RECIST 1.1
- •Phase Ia: Patients may have de novo metastatic disease, or documented progression despite any number of prior therapies. Patients must have no curative or other effective therapeutic options available. Phase Ib: Patients may have had any number of prior treatments, or prior pazopanib.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
- •Resolution of all chemotherapy or radiation-related toxicities to Grade 1 severity or lower except for alopecia
- •Patient must be at least 4 weeks or five half-lives (whichever is shorter) from last standard or experimental therapy, except Patients who have received prior pazopanib are eligible but must not have received it in the last two weeks.
- •Patients must be at least 28 days from last radiation therapy dose, Peptide Receptor Radionuclide Therapy (PRRT), surgery, or tumor embolization prior to the first dose of pazopanib/PCI-24781
- •A female is eligible to enter and participate in this study if she is of:
- •Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who has had:
- •A hysterectomy
- •A bilateral oophorectomy (ovariectomy)
- •A bilateral tubal ligation
- •Is post-menopausal Subjects not using hormone replacement therapy (HRT) must have experienced total cessation of menses for ≥ 1 year and be greater than 45 years in age, or, in questionable cases, have a follicle stimulating hormone (FSH) value >40 milli-international units per millilitre (mIU/mL) and an estradiol value < 40pg/mL (<140 pmol/L). Subjects using HRT must have experienced total cessation of menses for >= 1 year and be greater than 45 years of age OR have had documented evidence of menopause based on FSH and estradiol concentrations prior to initiation of HRT
- •Childbearing potential, including any female who has had a negative serum pregnancy test within 2 weeks prior to the first dose of study treatment, preferably as close to the first dose as possible, and agrees to use adequate contraception. Novartis Pharmaceuticals acceptable contraceptive methods, when used consistently and in accordance with both the product label and the instructions of the physician, are as follow:
- •Complete abstinence from sexual intercourse for 14 days before exposure to investigational product, through the dosing period, and for at least 21 days after the last dose of investigational product
- •Oral contraceptive, either combined or progestogen alone
- •Injectable progestogen
- •Estrogenic vaginal ring
- •Percutaneous contraceptive patches
- •Intrauterine device (IUD) or intrauterine system (IUS) with a documented failure rate of less than 1% per year
- •Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study, and this male is the sole partner for that subject
- •Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository)
- •Female subjects who are lactating should discontinue nursing prior to the first dose of study drug and should refrain from nursing throughout the treatment period and for 14 days following the last dose of study drug.
- •Adequate organ system function as defined below
- •Absolute neutrophil count (ANC) 1.5 X 109/L
- •Hemoglobin 9 g/dL (5.6 mmol/L)
- •Platelets 100 X 109/L
- •Prothrombin time (PT) or international normalized ratio (INR) 1.2 X upper limit of normal (ULN)
- •Activated partial thromboplastin time (aPTT) 1.2 X ULN
- •Total bilirubin 1.5 X ULN
- •Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) 2.5 X ULN
- •Serum creatinine <1.5 x ULN Or, if >1.5 mg/dL: Calculated creatinine clearance 50 mL/min Urine Protein to Creatinine Ratio (UPC) e <1
- •Subjects may not have had a transfusion within 7 days of screening assessment.
- •Subjects receiving anticoagulant therapy are eligible if their INR is within the recommended range for the desired level of anticoagulation.
- •Patients with increased bilirubin due to Gilberts disease will not be excluded, if increased bilirubin is the only protocol exclusion criteria met.
- •Concomitant elevations in bilirubin and AST/ALT above 1.0 x ULN (upper limit of normal) are not permitted.
- •If UPC ≥1, then a 24-hour urine protein must be assessed. Subjects must have a 24-hour urine protein value <1 g to be eligible.
- •5.1.2 Exclusion Criteria
- •Patients with other primary malignancies receiving active treatment at the time of study entry, other than carcinoma in situ of the cervix, non-melanoma skin cancer, nonmuscle invasive bladder cancer.
- •History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis, except for individuals who have previously-treated CNS metastases.
- •Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding including, but not limited to:
- •Active peptic ulcer disease
- •Known intraluminal metastatic lesion/s with risk of bleeding
- •Inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease), or other gastrointestinal conditions with increased risk of perforation
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排除标准
- 未提供
研究组 & 干预措施
Panobinostat with PC124871
干预措施: PZP115891, PCI-24781 (Drug)
结局指标
主要结局
Dose limiting toxicity (DLT)
时间窗: up to 4 weeks
A dose limiting toxicity (DLT) will be defined as any predetermined adverse events occurring during Cycle 1 when association to therapy that is part of this study is related or possibly related
Maximum Tolerated Dose (MTD)
时间窗: up to 4 weeks
The maximum tolerated dose (MTD) will be defined as the highest tested dose level at which less than 33% of patients experience DLT in Cycle 1
次要结局
- Establish the half-life of PCI-24781, pazopanib and the combination of the two drugs.(up to 2 months)
- Establish the area under the curve (AUC) of PCI-24781, pazopanib and the combination of the two drugs.(up to 2 months)
- Objective response rate (ORR)(approximately 4 months)
- Establish the volume of distribution of PCI-24781, pazopanib and the combination of the two drugs.(up to 2 months)
- Establish the bioavailability of PCI-24781, pazopanib and the combination of the two drugs.(up to 2 months)
- Establish the clearance of PCI-24781, pazopanib and the combination of the two drugs.(up to 2 months)
- Overall survival (OS)(Up to 1 year)
- Duration of Response (DoR)(Up to 1 year)
- Clinical Benefit Rate (CBR)(approximately 4 months)
- Progression-free Survival (PFS)(Up to 1 year)
研究者
Pamela Munster
Professor, Department of Medicine (Hematology/Oncology), UCSF
University of California, San Francisco