Phase 2 Study to Evaluate the Efficacy and Safety of TPST-1495 in Patients With Familial Adenomatous Polyposis (FAP)
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 38
- 试验地点
- 9
- 主要终点
- Percent change in duodenal polyp burden
研究概览
简要总结
This open-label phase II trial tests how well TPST-1495 works in reducing the number of polyps in the small bowel and colon in patients with familial adenomatous polyposis (FAP). FAP is an inherited condition in which numerous polyps (growths that protrude from mucous membranes) form on the inside walls of the colon and rectum. It increases the risk for colon cancer. TPST-1495 binds to specific prostaglandin receptors. TPST-1495 is a dual antagonist of the prostaglandin E2 (PGE2) receptor subtypes EP2 and EP4, while sparing the immune-stimulating EP1 and EP3 receptors. TPST-1495 may help reduce the number of polyps in the small bowel and colon in patients with FAP.
详细描述
PRIMARY OBJECTIVES:
I. To assess the activity of TPST-1495 in reducing duodenal polyp burden in patients with FAP.
II. To assess the safety of TPST-1495 in patients with FAP; we will evaluate the incidence of grade 2 or 3 adverse events.
SECONDARY OBJECTIVE:
I. The activity of TPST-1495 in reducing rectum/IPAA (ileal pouch-anal anastomosis) polyp burden in patients with FAP.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Prevention
- 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
- •Diagnosis of familial adenomatous polyposis (FAP), defined as at least one of the following:
- •Genetic diagnosis with confirmed APC mutation (clinical CLIA [clinical laboratory improvement amendments] certified lab or research testing)
- •Obligate carrier
- •Clinical diagnosis of classic FAP with ≥ 100 colorectal adenomas status post colectomy or a sub-total colectomy and a family history of FAP
- •Clinical diagnosis of FAP, based on personal and family history. Note: This criterion requires documented review and agreement from either the study chair or the MW consortium lead investigator
- •Previously underwent prophylactic colectomy or sub-total colectomy with IRA (ileo-rectal or ileo-colonic anastomosis) or IPAA at least 12 months before pre-registration evaluation and without ongoing surgical complication
- •Willing to discontinue taking non-steroidal anti-inflammatory drugs (NSAIDs) 5 days prior to initiation of study treatment and limit frequency of NSAID dosing during study treatment
- •Because no dosing or adverse event (AE) data are currently available on the use of TPST-1495 in participants < 18 years of age, children and adolescents are excluded from this study but will be eligible for future pediatric trials, if applicable
- •Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%)
- •Leukocytes (white blood count [WBC]) ≥ 3,000/uL (≥ 2,500/uL for African American participants)
- •Platelet count ≥ 100 x 10^9/L
- •Hemoglobin ≥ 11.5 g/dL
- •Total bilirubin ≤ 1.5 x institutional upper limit normal (ULN) (unless patient has Gilbert's)
- •Alkaline phosphatase ≤ 1.5 x institutional ULN
- •Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) ≤ 2 x institutional ULN
- •Alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (SGPT) ≤ 2 x institutional ULN
- •Creatinine ≤ institutional ULN
- •Urinary testing results within institutional limits of normal or deemed clinically insignificant
- •Individuals on chronic suppressive antiviral therapy for herpes simplex virus (HSV) are eligible
- •Presence of Spigelman 2 or 3 duodenal polyposis stage assessed by endoscopy
- •Not pregnant: The effects of TPST-1495 on the developing human fetus at the recommended therapeutic dose are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation or for 90 days after stopping study agent. Additionally, men should not donate sperm for the purpose of reproduction during the study and for a minimum of 90 days after receiving the last dose of study agent. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately
- •Not currently breastfeeding
- •Ability to understand and the willingness to sign a written informed consent document
- •Helicobacter (H.) pylori negative confirmed with gastric biopsy (at time of screening EGD). If positive for H. pylori the patient can be offered full course of approved therapy with confirmation of eradication and re-assessment for trial participation with likely need to repeat baseline endoscopies if > 45 days since date of baseline procedures
排除标准
- •Use of any other investigational agents ≤ 12 weeks prior to pre-registration
- •History of gastric or intestinal ulceration due to NSAID therapy
- •Uncontrolled intercurrent illness or recent surgical procedure that in the opinion of the investigative team would limit compliance with study requirements
- •History of invasive malignancy ≤ 3 years prior to pre-registration (exception: adequately treated carcinoma of the cervix, carcinoma in situ, or basal or squamous cell carcinomas of the skin)
- •History of any upper GI surgery that does not permit access to or evaluation of a 10 cm segment of the duodenum that includes the duodenal bulb, i.e. Whipple procedure or similar
- •Any histologically confirmed high grade dysplasia (HGD) or cancer, gastrointestinal bleeding and requirement for anticoagulation therapy after study start except for use of low dose aspirin
- •Exclusion of patients utilizing strong a moderate inhibitors of CYP2D6 and CYP3A4
- •Individuals with evidence of human immunodeficiency virus (HIV) infection will be excluded from the study even if the HIV viral load is undetectable on suppressive therapy. Many of the HIV suppression anti-viral medications are moderate/strong inhibitors of CYP2D6 and CYP3A4 and are exclusions based on above
- •Individuals with evidence of chronic hepatitis B virus (HBV) or C virus (HCV) infection will be excluded from the study, even if the HBV/HCV viral load is undetectable on suppressive therapy. Many of the HBV/HCV suppression anti-viral medications are moderate/strong inhibitors of CYP2D6 and CYP3A4 and are exclusions based on above
- •Individuals with active H. pylori infection that is untreated or refractory to standard antibiotic therapy
- •Patients with prior history of peptic ulcers complicated by bleeding, New York Heart Association (NYHA) Classification II-IV, active autoimmune diseases, on anticoagulants at risk of bleeding or abnormal corrected QT interval (QTc) prolongation will also be excluded. Patients enrolled in this trial are status post colectomy or subtotal colectomy (with either IPAA or IRA or ileo-colonic anastomosis) and thus would not be expected to be at significant risk of diverticulitis
研究组 & 干预措施
Prevention (TPST-1495)
Patients receive TPST-1495 PO QD for 6 months in the absence of unacceptable toxicity. Patients also undergo EGD and GI endoscopy with biopsy at baseline and end of treatment and undergo blood sample collection throughout the study.
干预措施: Biopsy Procedure (Procedure)
Prevention (TPST-1495)
Patients receive TPST-1495 PO QD for 6 months in the absence of unacceptable toxicity. Patients also undergo EGD and GI endoscopy with biopsy at baseline and end of treatment and undergo blood sample collection throughout the study.
干预措施: Biospecimen Collection (Procedure)
Prevention (TPST-1495)
Patients receive TPST-1495 PO QD for 6 months in the absence of unacceptable toxicity. Patients also undergo EGD and GI endoscopy with biopsy at baseline and end of treatment and undergo blood sample collection throughout the study.
干预措施: EP2/EP4 Antagonist TPST-1495 (Drug)
Prevention (TPST-1495)
Patients receive TPST-1495 PO QD for 6 months in the absence of unacceptable toxicity. Patients also undergo EGD and GI endoscopy with biopsy at baseline and end of treatment and undergo blood sample collection throughout the study.
干预措施: Questionnaire Administration (Other)
Prevention (TPST-1495)
Patients receive TPST-1495 PO QD for 6 months in the absence of unacceptable toxicity. Patients also undergo EGD and GI endoscopy with biopsy at baseline and end of treatment and undergo blood sample collection throughout the study.
干预措施: Esophagogastroduodenoscopy (Procedure)
Prevention (TPST-1495)
Patients receive TPST-1495 PO QD for 6 months in the absence of unacceptable toxicity. Patients also undergo EGD and GI endoscopy with biopsy at baseline and end of treatment and undergo blood sample collection throughout the study.
干预措施: Gastrointestinal Endoscopy (Procedure)
结局指标
主要结局
Percent change in duodenal polyp burden
时间窗: Baseline to 6 months
Will be determined based on the sum of diameters from all polyps. Will be assessed by comparing upper gastrointestinal (GI) endoscopies respectively. Will be described using a two-sided 95% confidence interval and examined for difference from zero with a one-side paired t-test.
Incidence of adverse events
时间窗: Up to 7 months
Will examine the proportion of patients with grade 2 or 3 adverse events according to the Common Terminology Criteria for Adverse Events version 6.0. Will be summarized as a proportion with a 1-sided 90% confidence interval.
次要结局
- Percent change in rectal/pouch polyp burden(Baseline to 6 months)