TT-4 As a Single Agent in Subjects with Advanced Selected Solid Tumors

NCT04976660 | Withdrawn Phase 1 FDA Drug

• 1 other identifier: TT-4-101
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

The purpose of this study is to evaluate the safety and tolerability of orally administered TT-4 in subjects with advanced selected solid tumors. The dose escalation portion of the study will determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of TT-4.

Conditions

Colorectal Cancer; Gastric Cancer; Hepatocellular Carcinoma; Pancreatic Cancer

Keywords

failed or not eligible for standard of care; Advanced Selected Solid Tumors; TT-4; Adenosine; Adenosine Antagonist; A2B; A2BR Inhibitor

Outcome Measures

Primary Outcomes (3)

• Number of subjects with Dose Limiting Toxicities (DLTs) of TT-4 during the dose escalation phase

  All toxicities will be graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0

  28 Days

• Define the maximum tolerated dose (MTD) or phase 2 recommended dose of TT-4during the dose escalation phase

  Up to 1 year

• Overall Response Rate (ORR)

  This is defined as complete response (CR) or PR according to RECIST 1.1 and from the first dose until documented confirmed disease progression.

  From study enrollment until participant discontinuation, first occurrence of progressive disease, or death from any cause, whichever occurs first (approximately 2 years)

Secondary Outcomes (6)

• Incidence of treatment-emergent adverse events (TEAEs) overall and by severity, seriousness and relatedness.

  Through study completion, an average of 1 year

• Duration of Response (DoR)

  From study enrollment until participant discontinuation, first occurrence of progressive disease, or death from any cause, whichever occurs first (approximately 2 years)]

• Progression Free Survival (PFS)

  From study enrollment until participant discontinuation, first occurrence of progressive disease, or death from any cause, whichever occurs first (approximately 2 years)]

• Peak serum concentration (Cmax) of TT-4

  Predose, 0.5, 1, 2, 4, 6, 8, 24 hours post-dose

• Area under the serum concentration versus time curve (AUC) of TT-4

  Predose, 0.5, 1, 2, 4, 6, 8, 24 hours post-dose

Study Arms (1)

Multiple Ascending Dose

EXPERIMENTAL

3+3 Dose escalation until MTD and/or R2PD of TT-4 is determined

Drug: TT-4

Interventions

TT-4 DRUG

TT-4 orally administered QD starting at 200 mg and will be increased to 800 mg (dosing may be increased to BID, if appropriate based on emerging safety, PK or PD data).

Multiple Ascending Dose

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects must be ≥18 years of age.
• Subjects or their legal representative must be able to provide written informed consent to participate in the trial prior to the performance of any study-specific procedures.
• Diagnosis of histologically or cytologically confirmed advanced selected solid tumors
• Cohort A dose escalation: Colorectal Cancer, Gastric cancer, Hepatocellular Carcinoma and locally advanced, unresectable, or metastatic Pancreatic Cancer, who have failed or are not eligible for standard of care treatment.
• Cohort B: Advanced colorectal cancer (CRC), who have failed or not eligible for standard of care
• Cohort C: Advanced Gastric cancer (GC), who have failed or not eligible for standard of care
• Cohort D: Advanced Hepatocellular Carcinoma (HCC), who have failed or not eligible for standard of care
• Cohort E: Locally advanced, unresectable, or metastatic Pancreatic Cancer (PANC), who have failed or not eligible for standard of care
• ECOG performance status (PS) score 0-1
• Have measurable disease per RECIST 1.1 or (for subjects in the expansion cohorts) iRECIST as assessed by the local site investigator/radiology. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
• Subjects must have locally advanced, recurrent or metastatic neoplastic disease that is not curable by currently available therapies.
• Failure to respond to standard therapy, or for whom no appropriate therapies are available (based on the judgment of the Investigator)
• Life expectancy of ≥ 3 months
• Subjects must have adequate hematologic function based on the following:
• Absolute neutrophil count ≥ 1.5 x 109/L

You may not qualify if:

• Subjects are to be excluded from the study if they meet any of the following criteria:
• Major surgery within 4 weeks prior to Screening
• Anti-cancer therapy, such as chemotherapy, immunotherapy, hormonal therapy, targeted therapy, or investigational agents within five half-lives or four weeks, whichever is shorter, prior to administration of the first dose of study treatment.
• Subjects with active central nervous system (CNS) metastases; however, subjects who have undergone radiation and/or surgery for the treatment of CNS metastases, who are neurologically stable, and who are no longer taking pharmacologic doses of corticosteroids are eligible; subjects with leptomeningeal metastases are not eligible.
• Has received prior radiotherapy within 2 weeks of start of study treatment. Subjects must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
• Primary CNS malignancy
• HIV-infected subjects with a history of Kaposi sarcoma and/or Multicentric Castleman Disease.
• Subjects who are hepatitis B surface antigen positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to enrollment.
• Note: Subjects should remain on antiviral therapy throughout study intervention and follow local guidelines for HBV antiviral therapy post completion of study intervention.
• Hepatitis B screening tests are not required unless:
• Known history of HBV infection
• As mandated by local health authority.
• Subjects with a history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at screening. Note: Subjects must have completed curative antiviral therapy at least 4 weeks prior to enrollment.
• Hepatitis C screening tests are not required unless:
• Known history of HCV infection

Sponsors & Collaborators

• Tarus Therapeutics, Inc.: lead

Related Publications (11)

• Antonioli L, Blandizzi C, Pacher P, Hasko G. Immunity, inflammation and cancer: a leading role for adenosine. Nat Rev Cancer. 2013 Dec;13(12):842-57. doi: 10.1038/nrc3613. Epub 2013 Nov 14.

  PMID: 24226193 BACKGROUND

• Cekic C, Sag D, Li Y, Theodorescu D, Strieter RM, Linden J. Adenosine A2B receptor blockade slows growth of bladder and breast tumors. J Immunol. 2012 Jan 1;188(1):198-205. doi: 10.4049/jimmunol.1101845. Epub 2011 Nov 23.

  PMID: 22116822 BACKGROUND

• Aherne CM, Kewley EM, Eltzschig HK. The resurgence of A2B adenosine receptor signaling. Biochim Biophys Acta. 2011 May;1808(5):1329-39. doi: 10.1016/j.bbamem.2010.05.016. Epub 2010 May 28.

  PMID: 20546702 BACKGROUND

• Allard B, Allard D, Buisseret L, Stagg J. The adenosine pathway in immuno-oncology. Nat Rev Clin Oncol. 2020 Oct;17(10):611-629. doi: 10.1038/s41571-020-0382-2. Epub 2020 Jun 8.

  PMID: 32514148 BACKGROUND

• Zhou Y, Chu X, Deng F, Tong L, Tong G, Yi Y, Liu J, Tang J, Tang Y, Xia Y, Dai Y. The adenosine A2b receptor promotes tumor progression of bladder urothelial carcinoma by enhancing MAPK signaling pathway. Oncotarget. 2017 Jul 25;8(30):48755-48768. doi: 10.18632/oncotarget.17835.

  PMID: 28548944 BACKGROUND

• Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, Lin NU, Litiere S, Dancey J, Chen A, Hodi FS, Therasse P, Hoekstra OS, Shankar LK, Wolchok JD, Ballinger M, Caramella C, de Vries EGE; RECIST working group. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 2017 Mar;18(3):e143-e152. doi: 10.1016/S1470-2045(17)30074-8. Epub 2017 Mar 2.

  PMID: 28271869 BACKGROUND

• Horigome E, Fujieda M, Handa T, Katayama A, Ito M, Ichihara A, Tanaka D, Gombodorj N, Yoshiyama S, Yamane A, Yamada K, Horiguchi J, Shinozuka K, Oyama T, Nishiyama M, Rokudai S. Mutant TP53 modulates metastasis of triple negative breast cancer through adenosine A2b receptor signaling. Oncotarget. 2018 Oct 2;9(77):34554-34566. doi: 10.18632/oncotarget.26177. eCollection 2018 Oct 2.

  PMID: 30349649 BACKGROUND

• Vecchio EA, Tan CY, Gregory KJ, Christopoulos A, White PJ, May LT. Ligand-Independent Adenosine A2B Receptor Constitutive Activity as a Promoter of Prostate Cancer Cell Proliferation. J Pharmacol Exp Ther. 2016 Apr;357(1):36-44. doi: 10.1124/jpet.115.230003. Epub 2016 Jan 20.

  PMID: 26791603 BACKGROUND

• Lan J, Lu H, Samanta D, Salman S, Lu Y, Semenza GL. Hypoxia-inducible factor 1-dependent expression of adenosine receptor 2B promotes breast cancer stem cell enrichment. Proc Natl Acad Sci U S A. 2018 Oct 9;115(41):E9640-E9648. doi: 10.1073/pnas.1809695115. Epub 2018 Sep 21.

  PMID: 30242135 BACKGROUND

• Ma DF, Kondo T, Nakazawa T, Niu DF, Mochizuki K, Kawasaki T, Yamane T, Katoh R. Hypoxia-inducible adenosine A2B receptor modulates proliferation of colon carcinoma cells. Hum Pathol. 2010 Nov;41(11):1550-7. doi: 10.1016/j.humpath.2010.04.008.

  PMID: 20619442 BACKGROUND

• Ryzhov S, Novitskiy SV, Zaynagetdinov R, Goldstein AE, Carbone DP, Biaggioni I, Dikov MM, Feoktistov I. Host A(2B) adenosine receptors promote carcinoma growth. Neoplasia. 2008 Sep;10(9):987-95. doi: 10.1593/neo.08478.

  PMID: 18714400 BACKGROUND

MeSH Terms

Conditions

Colorectal Neoplasms; Stomach Neoplasms; Carcinoma, Hepatocellular; Pancreatic Neoplasms

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Stomach Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Liver Neoplasms; Liver Diseases; Endocrine Gland Neoplasms; Pancreatic Diseases; Endocrine System Diseases

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 3+3 Design

Study Record Dates

• First Submitted: July 6, 2021
• First Posted: July 26, 2021
• Study Start: December 15, 2022
• Primary Completion: June 1, 2023
• Study Completion: September 30, 2023
• Last Updated: March 18, 2025

Record last verified: 2025-03