TT-10 as a Single Agent in Subjects With Advanced Selected Solid Tumors

Non Small Cell Lung Cancer Clinical Trial

Official title:

Phase I/II First-in-Human Study of TT-10 as a Single Agent in Subjects With Advanced Selected Solid Tumors

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04969315
• Other study ID #: TT-10-101
• Secondary ID: ADPORT-601
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: June 23, 2023
• Est. completion date: August 14, 2025

Study information

• Verified date: April 2024
• Source: Portage Biotech
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate the safety and tolerability of orally administered TT-10 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-10.

Description:

Multicenter, open-label dose-escalation Phase I/II clinical study, designed to evaluate the safety, tolerability, PK, PD, anti-tumor activity, and efficacy of TT-10 in subjects diagnosed with advanced Renal cell cancer (RCC), castrate resistant prostate cancer (CRPC) and Non-small cell lung cancer (NSCLC); who have failed or are not eligible for standard of care treatment.

The study will be conducted in two phases. Dose escalation (Phase 1) will be to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D), safety and tolerability of TT-10 in subjects with advanced subjects diagnosed with advanced Renal cell cancer (RCC), castrate resistant prostate cancer (CRPC) and Non-small cell lung cancer (NSCLC); who have failed or are not eligible for standard of care treatment. Dose expansion (Phase 2) will be to further explore the safety and tolerability of the MTD and/or RP2D, PK, PD, anti-tumor activity, and efficacy of TT-10.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 90
• Est. completion date: August 14, 2025
• Est. primary completion date: May 14, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria

1. Participants must be = 18 years of age.

2. Participants or their legal representative must be able to provide written informed consent to participate in the study prior to the performance of any study-specific procedures.

3. Diagnosis of histologically or cytologically confirmed advanced selected solid tumors

• Cohort A dose escalation: RCC, CRPC and NSCLC who have failed or are not eligible for standard of care treatment.

• Cohort B: Metastatic RCC who have failed or are not eligible for standard of care treatment.

• Cohort C: Metastatic CRPC who have failed or are not eligible for standard of care treatment.

• Cohort D: Metastatic NSCLC who have failed or are not eligible for standard of care treatment.

• Cohort E: Exploratory Biopsy - Inclusive of participants with RCC, CRPC and/or NSCLC who have failed or are not eligible for standard of care treatment and have an accessible tumor for pre- and post dose biopsies.

4. Eastern Cooperative Oncology Group performance status score 0 - 1

5. Have measurable disease per RECIST 1.1 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.

6. Failure to respond to standard therapy, or for whom no appropriate therapies are available (based on the judgment of the investigator)

7. Cohort E Only: Fresh tissue sample obtained prior to treatment initiation and agree to on-treatment biopsy from same lesion.

8. Life expectancy of = 3 months

9. Participants must have adequate hematologic function based on the following:

• Absolute neutrophil count = 1.5 x 109/L

• Platelet count = 100 x 109/L

• Hemoglobin = 9.0 g/dL

10. Participants must have adequate hepatic function based on the following:

• Total bilirubin < 1.5 x upper limit of normal (ULN) (unless elevated due to Gilbert's syndrome)

• Alanine aminotransferase/aspartate aminotransferase = 2.5 x ULN (= 5 x ULN for participants with known hepatic metastases)

11. Participants must have adequate renal function based on the following:

• Serum creatinine = 1.5 x ULN; or

• Serum creatinine clearance = 60 mL/min, as determined by Cockcroft-Gault equation

Exclusion Criteria:

1. Major surgery within 4 weeks prior to Screening

2. Participants with active central nervous system (CNS) metastases; however, participants 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; participants with leptomeningeal metastases are not eligible.

3. Has received prior radiotherapy within 2 weeks of start of study intervention. Participants 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.

4. Prior anti-cancer therapy within 4 weeks prior to the start of study intervention. A 2 week washout is acceptable for short-acting drugs (eg, tyrosine kinase inhibitors). Any treatment-related toxicities must be resolved to Grade 0 - 1.

5. Human immunodeficiency virus-infected participants

6. Participants 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: Participants 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

7. Participants with a history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at Screening. Note: Participants 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

• As mandated by local health authority

8. Participants who require immunosuppressive therapy including, but not limited to, treatment with corticosteroids in pharmacologic doses (equivalent to = 10 mg prednisone daily), cyclosporine, mycophenolate, azathioprine, methotrexate, adalimumab, infliximab, vedolizumab, tofacitinib, dupilumab, rituximab, etc. or systemic steroids (except for steroid use as cortisol replacement therapy in documented adrenal insufficiency)

9. Participants requiring administration of drugs known to be strong inhibitors or inducers of CYP3A4, 2C9 or 2C19

10. Participants requiring drugs that modify gastric pH, such as proton-pump inhibitors, H2 blockers or antacids (eg, calcium, magnesium or aluminum containing over-the-counter medications)

11. Ongoing systemic bacterial, fungal or viral infections at Screening

• NOTE: Participants on antimicrobial, antifungal or antiviral prophylaxis are not specifically excluded if all other inclusion/exclusion criteria are met

12. Administration of a live vaccine within 6 weeks of first dose of study intervention. Messenger ribonucleic acid vaccines for the prevention of Coronavirus Disease 2019 (COVID-19) infection are permitted.

13. Baseline QT interval corrected with Fridericia's method (QTcF) > 470 ms (average of triplicate readings)

• NOTE: Criterion does not apply to participants with a right or left bundle branch block.

14. Prior surgery or gastrointestinal dysfunction that may affect drug absorption (eg, gastric bypass surgery, gastrectomy)

15. Female participants who are pregnant or breastfeeding

16. Concurrent active malignancy other than non-melanoma skin cancer, carcinoma in situ of the cervix or prostate intraepithelial neoplasia

17. Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease

18. History of peptic ulcer and/or gastrointestinal bleed within the past 6 months prior to Screening

19. History of stroke, unstable angina, myocardial infarction or ventricular arrhythmia requiring medication or mechanical control within the last 6 months prior to Screening

20. Unstable or severe uncontrolled medical condition (eg, unstable cardiac function, unstable pulmonary condition including pneumonitis and/or interstitial lung disease, uncontrolled diabetes) or any important medical illness or abnormal laboratory finding that would, in the investigator's judgment, increase the risk to the participant associated with his or her participation in the study

Related Conditions & MeSH terms

• Carcinoma, Renal Cell
• Castrate Resistant Prostate Cancer
• Head and Neck Squamous Cell Carcinoma
• Non Small Cell Lung Cancer
• Renal Cell Cancer
• Squamous Cell Carcinoma of Head and Neck

Intervention

Drug:
• TT-10
TT-10 orally administered BID starting at 10 mg and will be increased to 200 mg (additional dose levels maybe explored, if appropriate based on emerging safety, PK or PD data).

Locations

Country	Name	City	State
United States	Sarah Cannon Research Institute Denver	Denver	Colorado
United States	Virginia Cancer Specialists	Fairfax	Virginia
United States	The University of Texas MD Anderson Cancer Center	Houston	Texas
United States	USC Norris Comprehensive Cancer Center	Los Angeles	California
United States	Norton Cancer Institute	Louisville	Kentucky
United States	Jefferson Health-Thomas Jefferson University Hospitals	Philadelphia	Pennsylvania
United States	Washington University	Saint Louis	Missouri
United States	University of California San Francisco UCSF	San Francisco	California

Sponsors (2)

Lead Sponsor	Collaborator
Portage Biotech	Tarus Therapeutics, Inc.

Country where clinical trial is conducted

United States, 

References & Publications (12)

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. Erratum In: Nat Rev Clin Oncol. 2020 Jul 17;: — View Citation

Beavis PA, Henderson MA, Giuffrida L, Mills JK, Sek K, Cross RS, Davenport AJ, John LB, Mardiana S, Slaney CY, Johnstone RW, Trapani JA, Stagg J, Loi S, Kats L, Gyorki D, Kershaw MH, Darcy PK. Targeting the adenosine 2A receptor enhances chimeric antigen receptor T cell efficacy. J Clin Invest. 2017 Mar 1;127(3):929-941. doi: 10.1172/JCI89455. Epub 2017 Feb 6. — View Citation

Helms RS, Powell JD. Rethinking the adenosine-A2AR checkpoint: implications for enhancing anti-tumor immunotherapy. Curr Opin Pharmacol. 2020 Aug;53:77-83. doi: 10.1016/j.coph.2020.07.003. Epub 2020 Aug 9. — View Citation

Kamai T, Kijima T, Tsuzuki T, Nukui A, Abe H, Arai K, Yoshida KI. Increased expression of adenosine 2A receptors in metastatic renal cell carcinoma is associated with poorer response to anti-vascular endothelial growth factor agents and anti-PD-1/Anti-CTLA4 antibodies and shorter survival. Cancer Immunol Immunother. 2021 Jul;70(7):2009-2021. doi: 10.1007/s00262-020-02843-x. Epub 2021 Jan 8. — View Citation

Schwarzacher SW, Krammer EB. Complex anomalies of the human aortic arch system: unique case with both vertebral arteries as additional branches of the aortic arch. Anat Rec. 1989 Nov;225(3):246-50. doi: 10.1002/ar.1092250310. — View Citation

Sek K, Molck C, Stewart GD, Kats L, Darcy PK, Beavis PA. Targeting Adenosine Receptor Signaling in Cancer Immunotherapy. Int J Mol Sci. 2018 Dec 2;19(12):3837. doi: 10.3390/ijms19123837. — View Citation

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. Erratum In: Lancet Oncol. 2019 May;20(5):e242. — View Citation

Steingold JM, Hatfield SM. Targeting Hypoxia-A2A Adenosinergic Immunosuppression of Antitumor T Cells During Cancer Immunotherapy. Front Immunol. 2020 Sep 29;11:570041. doi: 10.3389/fimmu.2020.570041. eCollection 2020. — View Citation

Vigano S, Alatzoglou D, Irving M, Menetrier-Caux C, Caux C, Romero P, Coukos G. Targeting Adenosine in Cancer Immunotherapy to Enhance T-Cell Function. Front Immunol. 2019 Jun 6;10:925. doi: 10.3389/fimmu.2019.00925. eCollection 2019. — View Citation

Vijayan D, Young A, Teng MWL, Smyth MJ. Targeting immunosuppressive adenosine in cancer. Nat Rev Cancer. 2017 Dec;17(12):709-724. doi: 10.1038/nrc.2017.86. Epub 2017 Oct 23. Erratum In: Nat Rev Cancer. 2017 Nov 22;17 (12 ):765. — View Citation

Willingham SB, Hotson AN, Miller RA. Targeting the A2AR in cancer; early lessons from the clinic. Curr Opin Pharmacol. 2020 Aug;53:126-133. doi: 10.1016/j.coph.2020.08.003. Epub 2020 Sep 29. — View Citation

Zhang J, Yan W, Duan W, Wuthrich K, Cheng J. Tumor Immunotherapy Using A2A Adenosine Receptor Antagonists. Pharmaceuticals (Basel). 2020 Sep 8;13(9):237. doi: 10.3390/ph13090237. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of subjects with Dose Limiting Toxicities (DLTs) of TT-10 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
Primary	Define the maximum tolerated dose (MTD) or phase 2 recommended dose of TT-10 during the dose escalation phase	To confirm the maximum tolerated dose (MTD) of TT-10, defined as the highest dose level at which <2 out of 6 participants experience a dose-limiting toxicity	Through study completion, an average of 1 year
Primary	Expansion cohort primary objective - safety	Incidence and severity of treatment-related adverse events (TRAEs) in participants treated at the recommended phase 2 dose in the expansion phase	Through study completion, an average of 1 year
Secondary	Overall Response Rate (ORR)	ORR is to be reported as the proportion of patients who have a Complete Response or Partial Response per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1	From study enrollment until participant discontinuation, first occurrence of progressive disease, or death from any cause, whichever occurs first (approximately 2 years)
Secondary	Duration of Response (DoR)	Defined as the time from first documented objective response per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 to the date of first documented radiographic progression of disease (PD) or death.	From study enrollment until participant discontinuation, first occurrence of progressive disease, or death from any cause, whichever occurs first (approximately 2 years)
Secondary	Progression Free Survival (PFS)	Time from first dose to the date of the first confirmed documented progression per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1	From study enrollment until participant discontinuation, first occurrence of progressive disease, or death from any cause, whichever occurs first (approximately 2 years)
Secondary	Peak serum concentration (Cmax) of TT-10	PK Parameter	Predose, 0.5, 1, 2, 4, 6, 8, 24 hours post-dose
Secondary	Area under the serum concentration versus time curve (AUC) of TT-10	PK Parameter	Predose, 0.5, 1, 2, 4, 6, 8, 24 hours post-dose
Secondary	Half-life of TT-10	PK Parameter	Predose, 0.5, 1, 2, 4, 6, 8, 24 hours post-dose