Brief Title
Phase 1a/1b Study of TPST-1495 as a Single Agent and in Combination With Pembrolizumab in Subjects With Solid Tumors
Official Title
Phase 1a/1b Open Label Dose-escalation and Expansion Study of TPST-1495 as a Single Agent and in Combination With Pembrolizumab in Subjects With Solid Tumors
Brief Summary
This is a first-in-human Phase 1a/1b, multicenter, open-label, dose-escalation, dose and
schedule optimization, and expansion study of TPST-1495 as a single agent and in combination
with pembrolizumab to determine its maximum tolerated dose (MTD) and or recommended Phase 2
dose (RP2D), safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary
anti-tumor activity in subjects with advanced solid tumors. Subjects with all histologic
types of solid tumors are eligible for the escalation and dose-finding portions of the study.
However, the preferred tumor types for enrollment are colorectal cancer (CRC), non-small cell
lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), urothelial cancer,
endometrial cancer, and gastroesophageal junction (GEJ) or gastric adenocarcinoma. Enrollment
in the expansion cohorts is limited to the following tumor types: endometrial, SCCHN, CRC,
and a basket cohort in subjects selected for an activating mutation in PIK3Ca.
Detailed Description
This is a first-in-human Phase 1a/1b, multicenter, open-label, dose-escalation, dose and
schedule optimization, and expansion study of TPST-1495 as a single agent 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. Subjects with all histologic types of solid tumors are eligible for the study.
However, the preferred tumor types for enrollment are colorectal cancer (CRC), non-small cell
lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), urothelial cancer,
endometrial cancer, and gastroesophageal junction (GEJ) or gastric adenocarcinoma. Tumor
prostaglandin production and downstream signaling in both tumor cells and other cell types,
including immune suppressive cell population in the tumor microenvironment, is thought to be
a principal driver of progression in each of these selected malignancies. To be eligible,
subjects must have no remaining standard therapy known to confer clinical benefit.
The study is composed of 3 stages. The Dose-Escalation stage will determine the MTD of
single-agent TPST-1495 administered twice a day (BID). The Schedule and Dose Optimization
stage will evaluate alternative TPST-1495 single-agent administration schedules and determine
an RP2D for the selected schedule. This arm will also evaluate TPST-1495 in combination with
pembrolizumab. The Expansion stage will evaluate the activity of TPST-1495 as a single agent
and in combination with pembrolizumab at the selected schedule and dose in disease-specific
cohorts and in a basket cohort in subjects selected for an activating mutation in PIK3Ca.
Study Phase
Phase 1
Study Type
Interventional
Primary Outcome
Determination of maximum tolerated dose and/or recommended Phase 2 dose (RP2D) and optimum dose schedule for TPST-1495 as a single agent and in combination with pembrolizumab
Secondary Outcome
Incidence of adverse events and serious adverse events as assessed by NCI-CTCAE v.5.0
Condition
Solid Tumor
Intervention
TPST-1495 twice daily
Study Arms / Comparison Groups
TPST-1495 monotherapy dose escalation
Description: Subjects will receive escalating doses of TPST-1495 administered orally twice daily until maximum tolerated dose is reached or until disease progression
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
175
Start Date
May 6, 2020
Completion Date
October 1, 2024
Primary Completion Date
April 1, 2024
Eligibility Criteria
Subjects must meet all the following inclusion criteria to be eligible:
1. 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.
2. Subjects must have a tumor that is at least 1 cm in a single dimension and is
radiographically apparent on CT or MRI.
3. Eastern Cooperative Oncology Group performance status of 0 or 1 at treatment
initiation.
4. Life expectancy estimated to be ≥ 12 weeks
5. 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 ≥ 3.0 g/dL
- Hemoglobin ≥ 10.0 g/dL
- Absolute neutrophil count ≥ 1,000/mm3
- Platelet count ≥ 100,000/mm3
- Bilirubin ≤ 1.5 × institutional upper limit of normal (ULN); for subjects with
documented/suspected Gilbert's disease, bilirubin should be ≤ 2 × ULN.
- Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 × ULN; for
subjects with liver metastases, AST or ALT ≤ 5 × ULN
- Creatinine ≤ 1.5×ULN OR calculated creatinine clearance (CrCl) ≥ 60 mL/min for
subjects with creatinine levels > 1.5× ULN.
Subjects who meet any of the following exclusion criteria will not be eligible to receive
investigational product:
1. 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.
2. Received more than 4 doses of nonsteroidal anti-inflammatory drugs or COX-2 inhibitors
within 2 weeks prior to study treatment initiation.
3. History of allergy or hypersensitivity, GI bleed, or ulceration secondary to
nonsteroidal anti-inflammatory drugs or COX-2 inhibitors.
4. 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
5. History of diverticulitis or any GI bleed within 2 years of treatment initiation.
6. 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
7. Subjects with active or untreated central nervous system (CNS) metastases
8. New York Heart Association Classification II, III or IV.
9. Baseline QTcF > 470 milliseconds
10. 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).
11. 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.
12. 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
13. 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.
14. Subjects who are receiving anti-coagulant therapy or who are considered to be at
increased risk of bleeding (i.e bleeding disorder or coagulopathy).
Gender
All
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Samuel Whiting, MD PhD, 415-798-8589, [email protected]
Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT04344795
Organization ID
TPST-1495-001
Responsible Party
Sponsor
Study Sponsor
Tempest Therapeutics
Study Sponsor
Samuel Whiting, MD PhD, Study Director, Tempest Therapeutics
Verification Date
January 2023