A Multicenter, Open-label Phase 1/2 Study of TYRA 300 in Advanced Urothelial Carcinoma and Other Solid Tumors

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Tyra Biosciences Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

28 Jul 2023 → 3 Mar 2026

Decision date (initial)

2024-06-25

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Tyra Biosciences, Inc.

External identifiers

EU CT number

2023-507589-22-00

EudraCT number

2022-001596-14

ClinicalTrials.gov

NCT05544552

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Pharmacokinetic, Dose response, Safety, Pharmacodynamic, Efficacy, Pharmacogenomic

• To determine the optimal and MTDs, and RP2D of TYRA-300 in participants with advanced solid tumors (Phase 1, Parts A and B)
• To evaluate the preliminary antitumor activity of TYRA-300 at the RP2D in participants in selected tumor expansion cohorts with activating FGFR3 gene alterations (Phase 2)

Secondary objectives 7

1. To characterize the safety and tolerability of TYRA-300 in participants with advanced cancer (Phase 1, Parts A and B, and Phase 2)
2. To conduct a preliminary characterization of the pharmacokinetics (PK) and pharmacodynamics in participants treated with TYRA-300 (Phase 1, Parts A and B, and Phase 2)
3. To characterize ORR in participants with activating FGFR3 gene alterations (Phase 1, Part B)
4. To characterize DOR (Phase 1, Part B and Phase 2)
5. To characterize DCR >12 weeks (Phase 1, Part B and Phase 2)
6. To characterize TTR (Phase 1, Part B and Phase 2)
7. To characterize PFS in participants treated with TYRA-300 in specific tumor expansion cohorts (Cohorts 1 and 2 of Phase 2 only)

Conditions and MedDRA coding

Advanced Urothelial Carcinoma and Other Solid Tumors with Activating FGFR3 Gene Alterations

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 30

1. PHASE 1 PART A (1-10): Male and female participants who are 18 years of age or older on the day of signing the ICF.
2. Life expectancy >12 weeks.
3. Ability to understand and sign the ICF and comply with study procedures.
4. ECOG PS ≤1.
5. Participants with any histologically confirmed advanced solid tumor who have exhausted standard therapeutic options. For doses of TYRA-300 above 120 mg QD or BID dose levels, participants must have an eligible FGFR3 gene mutation or fusion (see Appendix 14.3.1 and 14.3.2) diagnosed by any authorized/approved or validated local test performed in a CLIA-certified (or regional equivalent) laboratory.
6. Ability to swallow oral formulations.
7. Disease evaluable by RECIST v1.1.
8. Adequate organ and bone marrow function as demonstrated by the following: a. Absolute neutrophil count (ANC) ≥1500/mm3. b. Platelet count ≥75,000/mm3. c. International normalized ratio (INR) ≤1.5 × upper limit of normal (ULN). i. Participants treated with anticoagulants (eg, warfarin or heparin) will be allowed to participate provided no prior evidence of an underlying abnormality in these parameters exists. Close monitoring of at least weekly evaluations will be performed until INR is stable based on a predose measurement as defined by the local standard of care. d. Total bilirubin ≤1.5 × ULN. Documented Gilbert syndrome is allowed if total bilirubin is mildly elevated (<6 mg/dL). e. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN (≤3 × ULN for participants with liver involvement of their cancer). f. Serum albumin >2 g/dL. g. Glomerular filtration rate (GFR) ≥60 mL/min/1.73 m2 either directly measured via 24-hour urine collection or calculated using the CKD-EPI formula for adults.
9. Participants and their partners should practice contraception and reproduction restrictions of the study, as follows: a. Female participants of non-childbearing potential (ie, surgically sterile with a hysterectomy and/or bilateral oophorectomy; or chemically sterile; or ≥12 months of amenorrhea in the absence of chemotherapy, anti-estrogens, or ovarian suppression) do not need to undergo pregnancy testing. b. Female participants of child-bearing potential must have a documented negative pregnancy test within 7 days prior to starting TYRA-300. c. Female participants of child-bearing potential and all male participants must agree to use highly effective contraception prior to study entry and up to 180 days after the last dose of TYRA-300.
10. Coronavirus disease 2019 (COVID-19) testing per local standards and regulations, and fulfills COVID-19 vaccination requirements as per local site regulations (if any). Participants with a positive test result for COVID-19 infection at Screening who fulfil all other study eligibility criteria can be rescreened following test normalization and clinical recovery.
11. PHASE 1 PART B (11-20): Male and female participants who are 18 years of age or older on the day of signing the ICF.
12. Life expectancy >12 weeks.
13. Ability to understand and sign the ICF and comply with study procedures.
14. ECOG PS ≤1.
15. Participants with any histologically confirmed advanced solid tumor who have exhausted standard therapeutic options. a. The tumor must have an eligible FGFR3 gene mutation or fusion (see Appendix 14.3.1 and 14.3.2) diagnosed by any authorized/approved or validated local test performed in a CLIA-certified (or regional equivalent) laboratory. i. When tissue is not available to perform a validated local test at a CLIA-certified (or regional equivalent) laboratory, and prior NGS testing has not been performed, a central test, performed at a CLIA-certified laboratory, or a locally validated or approved assay, may be used to identify eligible mutations in ctDNA in plasma. b. A specimen must be submitted for analysis for central ctDNA testing, but the results of the test do not need to be available before starting TYRA-300. c. Any number of prior therapies, including prior FGFR inhibitors, are permitted. d. The BID dose cohorts opened in Part B will enroll participants with locally advanced/metastatic FGFR3 mutation positive urothelial carcinoma who have not received a prior FGFR inhibitor. Participants with metastatic urothelial carcinoma who have received a prior FGFR inhibitor and have an eligible FGFR3 resistance mutation, or participants with other solid tumors with eligible FGFR3 alterations, may be enrolled with medical monitor approval.
16. Ability to swallow oral formulations.
17. At least 1 measurable lesion by RECIST v1.1.
18. Adequate organ and bone marrow function as demonstrated by the following: a. ANC ≥1500/mm3. b. Platelet count ≥75,000/mm3. c. INR ≤1.5 × ULN. i. Participants treated with anticoagulants (eg, warfarin or heparin) will be allowed to participate provided no prior evidence of an underlying abnormality in these parameters exists. Close monitoring of at least weekly evaluations will be performed until INR is stable based on a predose measurement as defined by the local standard of care. d. Total bilirubin ≤1.5 × ULN. Documented Gilbert syndrome is allowed if total bilirubin is mildly elevated (<6 mg/dL). e. ALT and AST ≤2.5 × ULN (≤3 × ULN for participants with liver involvement of their cancer). f. Serum albumin >2 g/dL. g. GFR ≥45 mL/min/1.73 m2 either directly measured via 24-hour urine collection or calculated using CKD-EPI formula for adults.
19. Participants and their partners should practice contraception and reproduction restrictions of the study, as follows: a. Female participants of non-childbearing potential (ie, surgically sterile with a hysterectomy and/or bilateral oophorectomy; or chemically sterile; or ≥12 months of amenorrhea in the absence of chemotherapy, anti-estrogens, or ovarian suppression) do not need to undergo pregnancy testing. b. Female participants of child-bearing potential must have a documented negative pregnancy test within 7 days prior to starting TYRA-300. c. Female participants of child-bearing potential and all male participants must agree to use highly effective contraception prior to study entry and up to 180 days after the last dose of TYRA-300.
20. COVID-19 testing per local standards and regulations, and fulfils COVID-19 vaccination requirements as per local site regulations (if any). Participants with a positive test result for COVID-19 infection at Screening who fulfil all other study eligibility criteria can be rescreened following test normalization and clinical recovery.
21. PHASE 2 (21-30): Male and female participants who are 18 years of age or older on the day of signing the ICF.
22. Life expectancy >12 weeks.
23. Ability to understand and willingness to sign the ICF.
24. ECOG PS 0 to 2.
25. Participants must have a histologically confirmed locally advanced/metastatic tumor in 1 of the following categories: a. Urothelial carcinoma with an eligible FGFR3 gene mutation or rearrangement who have progressed on a prior FGFR inhibitor and presence of a resistance mutation or other kinase domain mutation likely to respond to TYRA-300 identified using an FDA authorized/approved CDx or a validated local test performed in a CLIA-certified (or regional equivalent) laboratory. When tissue to perform a validated local test (at a CLIA or regional equivalent certified laboratory) is not available, a central laboratory assay, performed at a CLIA-certified laboratory, or locally validated or approved assay, may be used to identify eligible mutations in ctDNA in plasma. b. Urothelial carcinoma with an eligible FGFR3 gene mutation or rearrangement identified by an FDA authorized/approved CDx or a CLIA (or regional equivalent) validated local test performed in a certified laboratory, who has not received a prior FGFR inhibitor. When tissue to perform a validated local test (at a CLIA or regional equivalent certified laboratory) is not available, a central laboratory assay, or a locally validated or approved assay, may be used to identify eligible mutations in ctDNA in plasma. c. Any solid tumor with an eligible FGFR3 gene mutation or rearrangement identified via an authorized/approved or validated local test in a CLIA-certified (or regional equivalent) laboratory. i. With medical monitor approval, participants who progressed on a prior FGFR inhibitor may be enrolled if they have a documented FGFR3 resistance mutation or other kinase domain mutation for which TYRA-300 is likely to be active based on preclinical studies. Note for France only: Participants with metastatic urothelial carcinoma should have previously received approved therapies, including platinum-based chemotherapy, an immune checkpoint inhibitor, and an antibody-drug conjugate. Participants with metastatic urothelial carcinoma may also be enrolled if they are not candidates for any of the approved therapies. Participants with other tumor types should either have received approved standard therapies for their tumor type or not be candidates for such therapies. Note for Spain only: Participants with metastatic urothelial carcinoma should have previously received approved therapies, including platinum-based chemotherapy, an immune checkpoint inhibitor, and an antibody-drug conjugate. Participants with metastatic urothelial carcinoma may also be enrolled if they are not candidates for any of the approved therapies or if they refuse these therapies. Participants with other tumor types should either have received approved standard therapies for their tumor type, not be candidates for such therapies, or have refused these therapies.
26. Ability to swallow oral formulations.
27. At least 1 measurable lesion by RECIST v1.1.
28. Adequate organ and bone marrow function as demonstrated by the following: a. ANC ≥1500/mm3. b. Platelet count ≥75,000/mm3. c. INR ≤1.5 × ULN. i. Participants treated with anticoagulants (eg, warfarin or heparin) will be allowed to participate provided no prior evidence of an underlying abnormality in these parameters exists. Close monitoring of at least weekly evaluations will be performed until INR is stable based on a predose measurement as defined by the local standard of care. d. Total bilirubin ≤1.5 × ULN. Documented Gilbert syndrome is allowed if total bilirubin is mildly elevated (<6 mg/dL). e. ALT and AST ≤2.5 × ULN (≤3 × ULN for participants with liver involvement of their cancer). f. Serum albumin >2 g/dL. g. GFR ≥45 mL/min/1.73 m2 either directly measured via 24-hour urine collection or calculated using the CKD-EPI formula for adults.
29. Participants and their partners should practice contraception and reproduction restrictions of the study, as follows: a. Female participants of non-childbearing potential (ie, surgically sterile with a hysterectomy and/or bilateral oophorectomy; or chemically sterile; or ≥12 months of amenorrhea in the absence of chemotherapy, anti-estrogens, or ovarian suppression) do not need to undergo pregnancy testing. b. Female participants of child-bearing potential must have a documented negative pregnancy test within 7 days prior to starting TYRA-300. c. Female participants of child-bearing potential and all male participants must agree to use highly effective contraception prior to study entry and up to 180 days after the last dose of TYRA-300.
30. COVID-19 testing per local standards and regulations, and fulfils COVID-19 vaccination requirements as per local site regulations (if any). Participants with a positive test result for COVID-19 infection at Screening who fulfil all other study eligibility criteria can be rescreened following test normalization and clinical recovery.

Exclusion criteria 16

1. Participant received chemotherapy, targeted therapy, immunotherapy, or an investigational therapy within 4 weeks or 5 half-lives, whichever is shorter, before the first dose of study drug (within 6 weeks for nitrosoureas and mitomycin).
2. Participant has not recovered from reversible toxicity of prior anticancer therapy (except toxicities that are not clinically significant including, but not limited to, alopecia, skin discoloration, or Grade 1 neuropathy).
3. Had major surgery within 4 weeks prior to enrollment.
4. Any reason that, in the view of the investigator, would substantially impair the ability of the participant to comply with study procedures and increase the risk to the participant. Examples include poorly controlled diabetes (glycated hemoglobin [HbA1c] >8%) and ongoing active infection requiring intravenous (IV) antibiotics.
5. Females who are pregnant, breastfeeding, or planning to become pregnant within 180 days after the last dose of TYRA-300 and males who plan to father a child while enrolled in this study or within 180 days after the last dose of TYRA-300.
6. Has impaired wound healing capacity defined as skin/decubitus ulcers, chronic leg ulcers, known gastric ulcers, or unhealed incisions.
7. Has a serum phosphorus level >ULN during screening (within 14 days of treatment and prior to Cycle 1, Day 1) that remains >ULN despite medical management with phosphate binders.
8. Any ocular condition likely to increase the risk of eye toxicity, including: a. History of or current evidence of central serous retinopathy (CSR; including ≥Grade 2 CSR while receiving a prior FGFR inhibitor) or retinal vascular occlusion (RVO). b. Active wet, age-related macular degeneration (AMD). c. Diabetic retinopathy with macular edema. d. Uncontrolled glaucoma (per local standard of care).
9. History of or current uncontrolled cardiovascular disease including: a. Unstable angina, myocardial infarction, or known congestive heart failure Class II to IV within the preceding 12 months. b. Cerebrovascular accident or transient ischemic attack within the preceding 3 months. c. Pulmonary embolism within the preceding 2 months.
10. MRI of the brain must be performed at screening for all patients and, if untreated/newly diagnosed brain metastases are identified, the candidate is not eligible. a. The candidate may rescreen for the study after definitive treatment of brain metastases. b. Prior brain metastases treated at least 4 weeks prior to signing the full-study ICF or that are clinically and radiographically stable for at least 1 month prior to Cycle 1, Day 1 and do not require chronic corticosteroid treatment are allowed.
11. Gastrointestinal disorders that will affect oral administration or absorption of TYRA-300.
12. Known history of human immunodeficiency virus (HIV) infection, or active hepatitis B or C infection. a. Participants with a history of HIV on antiviral therapy with undetectable viral load by polymerase chain reaction (PCR) are allowed. b. Participants with a history of hepatitis B virus infection with positive hepatitis B surface antibody, or positive hepatitis B core antibody with a negative PCR test, are allowed. i. Participants positive for hepatitis B surface antibody, who have received the HBV vaccine, have no history of HBV infection, and who are negative for hepatitis B core antibody are allowed. c. Participants with hepatitis C infection previously treated with antiviral therapy and negative for hepatitis C virus by PCR are allowed.
13. History of a second primary malignancy within 3 years of signing the ICF (except definitively treated early-stage cancer such as resected skin cancers and/or completely resected prostate cancer).
14. Known allergy to TYRA-300 or any excipients of the formulated product.
15. Participants taking strong inhibitors and/or inducers of CYP3A4 enzymes are prohibited. a. Participants who can switch to a similar medication without a CYP3A4 interaction will require a washout period of 2 weeks prior to starting TYRA-300.
16. Participant discontinued a prior anti-FGFR therapy due to significant toxicity, defined as hepatotoxicity ≥Grade 3 or any Grade 4 toxicity according to Common Terminology Criteria for Adverse Events v5.0.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Phase 1 (Parts A and B): Incidence of DLT events during the DLT evaluation period (Cycle 1 [28 days]).
2. Phase 2: Investigator-assessed ORR, defined as either a CR or PR by RECIST v1.1.

Secondary endpoints 9

1. Incidence of AEs characterized by study phase, cohort, seriousness, relationship to study drug, timing, and severity
2. Changes in clinical laboratory parameters, vital signs, electrocardiogram (ECG) parameters, and physical examination status.
3. Single-dose and steady-state PK parameters, including but not limited to accumulation ratio, Cmax, Tmax, AUC0-last, AUCTau, AUC0-∞(after first dose only), Vd/F, CL/F, and t1/2
4. Additional secondary endpoint for Phase 1, Part B only: ORR
5. Additional secondary endpoints for Phase 1, Part B and Phase 2: DOR, DCR, defined as CR, PR, or SD for >12 weeks, TTR.
6. Additional secondary endpoint for Phase 2 only: PFS in Cohorts 1 and 2.
7. Exploratory Endpoint: Biomarkers of TYRA-300 activity, safety, and efficacy. These biomarkers may include, but are not limited to, FGF23, parathyroid hormone, calcitriol, FGF19, and tumor-derived exosomes.
8. Exploratory Endpoint: Evaluate concordance between tissue-based NGS results and ctDNA results from a sponsor-designated central assay for detection of FGFR3 gene alterations in participants enrolled in Cohorts 1 and 2 of Phase 2.
9. Exploratory EndPoint: Estimate OS in Cohorts 1 and 2 of Phase 2.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Tyra Biosciences Inc.

Sponsor organisation

Tyra Biosciences Inc.

Address

2656 State Street

City

Carlsbad

Postcode

92008-1626

Country

United States

Scientific contact point

Organisation

Tyra Biosciences Inc.

Contact name

Doug Warner

Public contact point

Organisation

Tyra Biosciences Inc.

Contact name

Doug Warner

Third parties 13

Locations

3 EU/EEA countries · 7 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 3 · Art. 38 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 31 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications