Phase 1a/1b Study of TPST-1495 Alone and With Pembrolizumab in Subjects With Solid Tumors

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Brief Title

Phase 1a/1b Study of TPST-1495 in Subjects With Solid Tumors

Official Title

Phase 1a/1b Open Label Dose-escalation and Expansion Study of TPST-1495 as a Single Agent 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 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 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.
    

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 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 administration schedules and determine an RP2D for
      the selected schedule. The Expansion stage will evaluate the activity of TPST-1495 at the
      selected schedule and dose in disease-specific cohorts.
    

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

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

117

Start Date

May 6, 2020

Completion Date

July 31, 2022

Primary Completion Date

August 31, 2021

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 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.

          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).

         15. Administration of the following substrates for drug transporters OATP1B1 and OATP1B3
             is prohibited while on study or within 7 days of treatment initiation: glyburide,
             digoxin, docetaxel, paclitaxel, pitavastatin, rosuvastatin, simvastatin or saquinavir
      

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

April 2021