The main purpose of this study is to learn more about the safety, side effects, and effectiveness of LOXO-260. LOXO-260 may be used to treat cancer that has a change in a particular gene (known as the RET gene). Participation could last up to 24 months (2 years) and possibly longer if the disease does not get worse.

Inclusion Criteria:

• Must be ≥ 18 years of age at the time of signing the informed consent (Phase 1a and Phase 1b). Patients 12 years and older may be enrolled in Phase 1b for countries and sites where approved.
• Must have evidence of a previously documented RET fusion (solid tumors) or RET mutation (MTC or MEN2-associated cancers) that is a histological or a cytological proven diagnosis of locally advanced, unresectable and/or metastatic cancer and meet cohort-specific criteria.
• Have received a prior selective RET inhibitor.
• Eastern Cooperative Oncology Group (ECOG) score of 0 to 1 (age > 16 years), Karnofsky Performance Status (KPS) ≥ 80 (age > 16 years), or Lansky Performance Status (LPS) ≥ 40% (age < 16 years).
• Have discontinued all previous treatments for cancer with resolution of any significant AEs, and of all clinically significant toxic effects of prior locoregional therapy, surgery, radiotherapy, or systemic anticancer therapy.
• Have adequate organ function.
• Phase 1b expansion: Patients must have measurable disease per RECIST v 1.1.
• Phase 1b expansion: Molecular Pathology Results (including RET and other genes) from a sample, blood or tissue, taken on or after RET selective treatment.

Exclusion Criteria:

• Disease suitable for local therapy administered with curative intent.
• Have an active fungal, bacterial, and/or active untreated viral infection.
• The patient has a serious pre-existing medical condition(s).
• Have symptomatic CNS malignancy or metastasis.
• Patients treated with drugs known to be strong inhibitors or inducers of cytochrome P450 3A (CYP3A).
• Progression of disease within 4 months of starting a prior selective RET inhibitor.
• Phase 1b expansion: Patients harboring known activating bypass alterations outside RET that may confer resistance to LOXO-260.