An Investigational Drug (TPST-1495) in Patients With Familial Adenomatous Polyposis

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.

EXPLORATORY OBJECTIVES:

I. Reduction in intestinal polyp burden as a function of immunohistochemical staining at baseline and end of intervention (6-months) of rectal and duodenal tissue samples for COX-2 expression level, beta-catenin, and Ki-67.

II. Proteomic profile of serum correlated to clinical response to therapy compared between baseline and end of intervention.

III. Biospecimen acquisition.

OUTLINE:

Patients receive TPST-1495 orally (PO) once daily (QD) for 6 months in the absence of unacceptable toxicity. Patients also undergo esophagogastroduodenoscopy (EGD) and gastrointestinal (GI) endoscopy with biopsy at baseline and end of treatment and undergo blood sample collection throughout the study.

After completion of study treatment, patients are followed up at 1 month.

• Biopsy Procedure (Procedure), also known as Biopsy, BIOPSY_TYPE, Bx: Undergo biopsy
• Biospecimen Collection (Procedure), also known as Biological Sample Collection, Biospecimen Collected, Sample Collection, Specimen Collection: Undergo blood sample collection
• EP2/EP4 Antagonist TPST-1495 (Drug), also known as Dual EP2/4 Antagonist TPST-1495, PGE2 EP2/EP4 Receptor Antagonist TPST-1495, Prostaglandin E2 Receptor EP2/EP4 Antagonist TPST-1495, TPST 1495, TPST-1495, TPST1495: Given PO
• Esophagogastroduodenoscopy (Procedure), also known as EGD, Upper Endoscopy: Undergo EGD
• Gastrointestinal Endoscopy (Procedure): Undergo GI endoscopy
• Questionnaire Administration (Other): Ancillary studies

Primary outcomes

• Percent change in duodenal polyp burden [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 [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.

Secondary outcomes

• Percent change in rectal/pouch polyp burden [Baseline to 6 months]: Will be assessed by comparing the lower GI endoscopies. Results will be presented using summary statistics and corresponding confidence intervals.

Other outcomes

• Percent change in immunohistochemical staining levels [Baseline to 6 months]: Will assess rectal and duodenal tissue samples for COX-2 expression level, beta-catenin, and Ki-67. Mean percent change in immunohistochemical staining levels will be associated with intestinal polyp burden using a scatterplot of the two variables and evaluated using a Spearman rank correlation statistic.
• Proteomic profile [Baseline to 6 months]: Will identify proteins that are statistically significantly differently expressed between patients after treatment. The proteomic profile of serum will be correlated to clinical response to therapy and compared between baseline and end of intervention. No formal statistical inference will be performed. Proteins will be described with summary statistics to assist in planning follow-up studies.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* 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
* Age ≥ 18. 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

Exclusion Criteria:

* 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

• Niloy J Samadder, Principal investigator, University of Wisconsin Carbone Cancer Center - University Hospital

NIH grants: P30CA014520, UG1CA242596, UG1CA242635