Cholangio and Biliary

Key Eligibility Criteria:
Inclusion Criteria:
1. Histologic diagnosis of locally advanced or metastatic solid tumor malignancy (except CNS primary malignancy, for example, glioma), and where applicable, with an FGFR3 pathway alteration listed in Section 10.8, on molecular testing in tumor or blood sample that is deemed as actionable, as defined below per specified cohort.
2. Cohort B: Locally Advanced or Metastatic Urothelial Carcinoma
a. B1: LOXO-435 monotherapy- mUC, ≥2 prior regimens, including erdafitinib and EV
b. B2: LOXO-435 monotherapy- mUC, Qualifying FGFR3 alterations, ≥1 prior regimen, FGFR inhibitor naïve
c. B4: LOXO-435 monotherapy- mUC, ≥2 prior regimens, including erdafitinib; EV naïve
d. B5: LOXO-435 + Pembrolizumab + EV- mUC, Qualifying FGFR3 alterations, No prior systemic therapy
3. Cohort C: Locally Advanced or Metastatic Solid Tumors (Non-Urothelial Carcinoma)
a. C1: LOXO-435 monotherapy- Qualifying FGFR3 alterations, Progressed/intolerant to available standard therapies, FGFR inhibitor naïve
4. Have adequate tumor tissue sample available. Participants with inadequate tissue sample availability may still be considered for enrollment upon review

Exclusion Criteria:
1. Current evidence of corneal keratopathy or retinal disorder. Individuals with asymptomatic ophthalmic conditions may be eligible.
2. For Cohort B5 only, individuals with known uncontrolled diabetes.
3. For Cohorts B3 and B5 only, individuals with a history of non-infectious pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
4. Individuals with uncontrolled hypercalcemia <14 days to C1D1.


For pre-screening, please contact: Individual disease research teams.

Key Eligibility Criteria:

Inclusion Criteria:
1. Dose Expansion only:
a. Patients who have at least one measurable lesion, not previously irradiated and not chosen for biopsy during the study screening period, that can be accurately measured at baseline >/=10 mm in the longest diameter.
b. Mandatory provision of tumor tissue sample from a recent biopsy in a quantity sufficient to allow for analysis
c. All patients with biliary tract cancer or other solid tumor malignancies should have HER2 testing performed using a local laboratory
d. Cohort 1
i. Confirmed HER2-positive (IHC3+, or IHC2+ and ISH*+), locally advanced/unresectable or metastatic biliary tract cancer, including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer, and ampullary adenocarcinoma (*ISH: FISH, SISH, or DISH)
ii. Failed or intolerant to at least 1 prior gemcitabine- and/or cisplatin-based therapy with/without immune checkpoint inhibitors as per available local standards
e. Cohort 2
i. Pathologically confirmed HER2-positive (IHC3+, or IHC2+ and ISH*+), locally advanced/unresectable or metastatic solid tumor malignancy other than breast and gastric or gastroesophageal junction adenocarcinoma and biliary tract cancer (*ISH: FISH, SISH, or DISH)
ii. Patients who have received all available standard therapies known to provide clinical benefit, and have no currently available treatment options due to disease progression, intolerance or other reasons

Exclusion Criteria:
1. History of (non-infectious) interstitial lung disease (ILD) or pneumonitis that required steroids, or any evidence of current ILD or pneumonitis.
2. Systemic steroid therapy (>10 mg daily prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment.
3. Previous treatment with a 4-1BB/CD137-modulating agent.

For pre-screening, please contact: Your disease specific research team.