IRB Study Number 23-397
Status Recruiting
Institute Taussig Cancer Institute
Description
2.1 Primary Objectives
• 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)
2.2 Secondary Objectives
• To characterize the safety and tolerability of TYRA-300 in participants with advanced cancer (Phase 1, Parts A and B, and Phase 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)
• To characterize ORR in participants with activating FGFR3 gene alterations (Phase 1, Part B)
• To characterize DOR (Phase 1, Part B and Phase 2)
• To characterize DCR >12 weeks (Phase 1, Part B and Phase 2)
• To characterize TTR (Phase 1, Part B and Phase 2)
• To characterize PFS in participants treated with TYRA-300 in specific tumor expansion cohorts (Cohorts 1 and 2 of Phase 2 only)
Inclusion Criteria
5.1.1 Phase 1, Part A
Male and female participants who are 18 years of age or older on the day of signing the ICF.
Life expectancy >12 weeks.
Ability to understand and sign the ICF and comply with study procedures.
Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤1.
Note: Refer to Appendix 14.4 for ECOG PS.
Participants with any histologically confirmed advanced solid tumor who have exhausted standard therapeutic options.
Ability to swallow capsules.
Disease evaluable by RECIST v1.1.
Adequate organ and bone marrow function as demonstrated by the following:
a. ANC ≥1500/mm3.
b. Platelet count ≥75,000/mm3.
c. International normalized ratio (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 (≤5 × 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 Cockroft-Gault formula.
Note: Refer to Appendix 14.5 for the GFR formula.
- 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 120 days after the last dose of TYRA-300.
Note: Refer to Appendix 14.6 for details of acceptable contraceptive methods.
- Negative test result for COVID-19 by either a PCR-based test within 48 hours or a rapid-antigen test within 24 hours prior to starting TYRA-300; 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.
Note: Refer to Appendix 14.7 for COVID-19 vaccination-related information.
5.1.2 Phase 1, Part B
Male and female participants who are 18 years of age or older on the day of signing the ICF.
Life expectancy >12 weeks.
Ability to understand and sign the ICF and comply with study procedures.
ECOG PS ≤1.
Note: Refer to Appendix 14.4 for ECOG PS.
- 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 diagnosed by any authorized/approved or CLIA (or regional equivalent) validated local test performed in a certified laboratory facility.
b. A specimen must be submitted for analysis using the CTA, but the results of the CTA do not need to be available before starting TYRA-300.
c. Any number of prior therapies, including prior FGFR inhibitors, are permitted.
d. At the MTD, up to 10 participants with metastatic urothelial carcinoma with eligible FGFR3 gene alterations identified by the CTA or any authorized/approved CLIA (or regional equivalent) validated local test who have not received a prior FGFR inhibitor.
Ability to swallow capsules.
At least 1 measurable lesion by RECIST v1.1.
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 (≤5 × 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 Cockroft-Gault formula.
Note: Refer to Appendix 14.5 for the GFR formula.
- 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 120 days after the last dose of TYRA-300.
Note: Refer to Appendix 14.6 for details of acceptable contraceptive methods.
- Negative test result for COVID-19 by either a PCR-based test within 48 hours or a rapid-antigen test within 24 hours prior to starting TYRA-300; 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.
Note: Refer to Appendix 14.7 for COVID-19 vaccination-related information.
5.1.3 Phase 2
Male and female participants who are 12 years of age or older on the day of signing the ICF.
Life expectancy >12 weeks.
Ability to understand and willingness to sign the ICF. For participants under 18 years of age (or country equivalent), a parent/legal guardian with the ability to understand and sign the informed consent and the child with the ability to understand and sign the Assent Form.
ECOG PS 0 to 2. KPS >70 for participants aged 12 to 17 years.
Note: Refer to Appendix 14.4 for ECOG PS and Appendix 14.8 for KPS.
- 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 the CTA or an FDA authorized/approved CDx or a CLIA (or regional equivalent) validated local test performed in a certified laboratory.
b. Urothelial carcinoma with an eligible FGFR3 gene mutation or rearrangement identified by the central CTA or an FDA authorized/approved CDx or a CLIA (or regional equivalent) validated local test performed in a certified laboratory who have not received a prior FGFR inhibitor.
c. Any solid tumor with an eligible FGFR3 gene mutation or rearrangement identified via an authorized/approved or CLIA (or regional equivalent) validated local test result in a certified 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.
Ability to swallow capsules.
At least 1 measurable lesion by RECIST v1.1.
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 (≤5 × 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 Cockroft-Gault formula.
Note: Refer to Appendix 14.5 for the GFR calculation formula.
- 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 120 days after the last dose of TYRA-300.
Note: Refer to Appendix 14.6 for details of acceptable contraceptive methods.
- Negative test result for COVID-19 by either a PCR-based test within 48 hours or a rapid-antigen test within 24 hours prior to starting TYRA-300; 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.
Note: Refer to Appendix 14.7 for COVID-19 vaccination-related information.
Exclusion Criteria
Participant received chemotherapy, targeted therapy, immunotherapy, or an investigational therapy within 2 weeks or 5 half-lives (within 6 weeks for nitrosoureas and mitomycin) before the first dose of study drug.
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).
Had major surgery within 4 weeks prior to enrollment.
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.
Females who are pregnant, breastfeeding, or planning to become pregnant within 120 days after the last dose of TYRA-300 and males who plan to father a child while enrolled in this study or within 120 days after the last dose of TYRA-300.
Has impaired wound healing capacity defined as skin/decubitus ulcers, chronic leg ulcers, known gastric ulcers, or unhealed incisions.
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.
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).
- 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.
- Active, symptomatic, or untreated brain metastases.
a. Prior brain metastases treated at least 3 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.
Gastrointestinal disorders that will affect oral administration or absorption of TYRA-300.
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 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.
c. Participants with hepatitis C infection previously treated with antiviral therapy and negative for hepatitis C virus by PCR are allowed.
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).
Known allergy to TYRA-300 or any excipients of the formulated product.
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.
Note: Refer to Appendix 14.9 for a list of strong CYP3A4 inhibitors and inducers.
