Phase Ia/Ib Open Label Dose-escalation and Expansion Study of TPST-1495 as a Single Agent and in Combination With Pembrolizumab in Subjects With Solid Tumors
Considering participating in a START clinical trial?
Study Summary
To evaluate the effect of TPST-1495 as monotherapy or in combination with anti-PD-1 mAb in multiple tumors dependent on the EP2/4 pathway, such as MSS colorectal cancer, bladder, head and neck and breast cancer
To evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity of TPST-1495 as a monotherapy and in combination with pembrolizumab.
To determine its MTD, safety, tolerability, pharmacokinetics (PD), pharmacodynamics (PK) and preliminary anti-tumor activity in subjects with advanced solid tumors
The primary objectives are to characterize the safety and tolerability (including dose limiting toxicities) and determine the recommended phase 2 dose (RP2D) of TPST-1495 as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors.
Expansion Stage cohorts will evaluate TPST-1495 at the selected RP2D and schedule for both monotherapy and combination in endometrial cancer, squamous cell carcinoma of the head and neck, and microsatellite stable colorectal cancer (combination only), as well as in a biomarker-specific cohort enrolling patients with pathogenic tumor PIK3CA gene mutation.
Monotherapy dose-finding employs a modified 3+3 design evaluating BID and QD TPST-1495 schedules along with continuous or intermittent (Days 1-5 every 7 days) dosing. For the pembrolizumab combination, the starting dose and schedule of TPST-1495 are determined by safety, PK and PD of monotherapy.
To characterize TPST-1495 pharmacodynamic activities, we quantified biomarkers associated with EP2 and EP4 blockade in pre- and post-treatment specimens
To assess inhibition of PGE2-mediated immune suppression by TPST-1495, whole blood samples collected prior to and 2- and 4-hours following the first dose were incubated with LPS in the presence or absence of exogenous PGE2 after which supernatants were assayed by TNF-α ELISA (Invitrogen, Inc.). PGE2 catabolism was measured by quantifying PGE2 metabolite (PGEM) in urine using a validated mass spectrometry assay. Biopsies were assessed for quantities of T cells, granzyme B+ cells, and cyclooxygenase-2 (COX-2) positive cells by immunohistochemistry
- Subjects must have a histologically-confirmed malignancy that is metastatic or unresectable for which there is no remaining standard therapy known to confer clinical benefit. While all solid tumor types are eligible for the dose-escalation and dose-finding portions of the study, there is a preference to enroll patients with colorectal cancer, squamous cell carcinoma of the head and neck, urothelial cancer, endometrial cancer, NSCLC, and gastric or gastroesophageal junction adenocarcinoma. The expansion cohorts are limited to the following tumor types: endometrial, SCCHN, CRC, and tumors with an activating mutation in PIK3Ca.
- Subjects must have a tumor that is at least 1 cm in a single dimension and is radiographically apparent on CT or MRI.
- Eastern Cooperative Oncology Group performance status of 0 or 1 at treatment initiation.
- Life expectancy estimated to be > or = 12 weeks
- Adequate organ and marrow function (subjects must not have received transfusions or growth factor support within 1 month prior to first dose of investigational product) as defined below:
- Albumin > orr = 3.0 g/dL
- Hemoglobin > or = 10.0 g/dL
- Absolute neutrophil count > or = 1,000/mm3
- Platelet count > or = 100,000/mm3
- Bilirubin < or = 1.5 × institutional upper limit of normal (ULN); for subjects with documented/suspected Gilbert's disease, bilirubin should be < or = 2 × ULN.
- Aspartate transaminase (AST) and alanine transaminase (ALT) < or = 2.5 × ULN; for subjects with liver metastases, AST or ALT < or = 5 × ULN
- Creatinine =< or =1.5×ULN OR calculated creatinine clearance (CrCl) > or = 60 mL/min for subjects with creatinine levels > 1.5× ULN.
- Concurrent enrollment in another clinical study, unless it is an observational (non interventional) clinical study, a specimen-collection study or the follow-up period of an interventional study.
- Received more than 4 doses of nonsteroidal anti-inflammatory drugs or COX-2 inhibitors within 2 weeks prior to study treatment initiation.
- History of allergy or hypersensitivity, GI bleed, or ulceration secondary to nonsteroidal anti-inflammatory drugs or COX-2 inhibitors.
- History of GI ulcer within 1 year of treatment initiation or history of untreated helicobacter pylori infection. Subjects with history of treated helicobacter pylori infection with confirmation of eradication are eligible
- History of diverticulitis or any GI bleed within 2 years of treatment initiation.
- Receipt of any anticancer therapy within the following windows:
- Small molecule tyrosine kinase inhibitor (TKI) therapy (including investigational) within 2 weeks or 5 half-lives prior to treatment initiation, whichever is longer
- Any type of anti-cancer antibody or cytotoxic chemotherapy within 4 weeks prior to treatment initiation
- Radiation therapy for bone metastasis within 2 weeks, any other external radiation therapy within 4 weeks before treatment initiation. Patients with clinically relevant ongoing complications from prior radiation therapy are not eligible
- Other investigational therapy within 2 weeks or 5 half-lives prior to dosing, whichever is longer
- Subjects with active or untreated central nervous system (CNS) metastases
- New York Heart Association Classification II, III or IV.
- Baseline QTcF > 470 milliseconds
- Receipt of live attenuated vaccines within 30 days prior to the first dose of investigational product. (Killed virus or other non-live vaccines are allowed (including most seasonal influenza vaccines, streptococcus pneumonia vaccines, and newly approved COVID-19 vaccines).
- Active autoimmune disease or inflammatory disorders including inflammatory bowel disease (e.g., ulcerative colitis or Crohn's disease) requiring systemic treatment (i.e., with use of disease modifying agents, systemic corticosteroids or immunosuppressive drug) within 2 years prior to treatment initiation.
- Known human immunodeficiency virus (HIV) infection, active Hepatitis B (HBV), or hepatitis C (HCV). Active HBV is defined as a known positive HBsAg result. Active HCV is defined by a known positive HCV antibody result and known quantitative HCV RNA results greater than the lower limits of detection of the assay. Patients receiving antiviral therapy for Hepatitis B or C also are not eligible
- Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations including a history of substance abuse that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
- Subjects who are receiving anti-coagulant therapy or who are considered to be at increased risk of bleeding (i.e bleeding disorder or coagulopathy).
Clinical Study Information for Healthcare Providers
By clicking the button below you will find in-depth information about this clinical trial, including study design, primary and secondary endpoints, and more. This information is intended for healthcare professionals seeking to review the scientific and operational aspects of the study.