Phase 1/2 Study of LOXO-292 in Patients With Advanced Solid Tumors, RET Fusion-Positive Solid Tumors, and Medullary Thyroid Cancer

This is an open-label, multi-center Phase 1/2 study in patients with advanced solid tumors,
including RET fusion-positive solid tumors, MTC, and other tumors with RET activation. The
trial will be conducted in 2 parts: phase 1 (dose escalation) and phase 2 (dose expansion).
Patients with advanced cancer are eligible if they have progressed on or are intolerant to
available standard therapies, or no standard or available curative therapy exists, or in the
opinion of the Investigator, they would be unlikely to tolerate or derive significant
clinical benefit from appropriate standard of care therapy, or they declined standard
therapy. A dose of 160 mg BID has been selected as the recommended phase 2 dose (RP2D). Up to
~750 patients with advanced solid tumors harboring a RET gene alteration in tumor and/or
blood will be enrolled to one of five phase 2 cohorts.

Key Inclusion Criteria:

For Phase 1

- Patients with a locally advanced or metastatic solid tumor who:

- have progressed on or are intolerant to standard therapy, or

- no standard therapy exists, or in the opinion of the Investigator, are not
candidates for or would be unlikely to tolerate or derive significant clinical
benefit from standard therapy, or

- decline standard therapy

- Prior MKIs with anti-RET activity are allowed. However, prior treatment with a
selective RET inhibitor(s) is prohibited.

- A RET gene alteration is not required initially. Once adequate PK exposure is
achieved, evidence of RET gene alteration in tumor and/or blood is required as
identified through molecular assays, as performed for clinical evaluation.

- Measurable or non-measurable disease as determined by RECIST 1.1 or RANO as
appropriate to tumor type.

- Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2 or Lansky Performance
Score (LPS) ≥ 40% (age < 16 years) with no sudden deterioration 2 weeks prior to the
first dose of study treatment.

- Adequate hematologic, hepatic and renal function.

- Life expectancy of at least 3 months.

For Phase 2

As for phase 1 with the following modifications:

- For Cohorts 1 and 3 Subjects must have received prior standard therapy appropriate for
their tumor type and stage of disease, or in the opinion of the Investigator, would be
unlikely to tolerate or derive clinical benefit from appropriate standard of care
therapy.

- Cohorts 1-4: enrollment will be restricted to patients with evidence of a RET gene
alteration in tumor. However, a positive germline DNA test for a RET gene mutation is
acceptable in the absence of tumor tissue testing for patients with MTC.

- Cohorts 1-4: at least one measurable lesion as defined by RECIST 1.1 or RANO, as
appropriate to tumor type and not previously irradiated.

- Cohort 4: radiographic PD within the previous 14 months.

Note: Patients otherwise eligible for cohort 4 who do not demonstrate radiographic PD
within the previous 14 months may be enrolled to cohort 5 if a compelling rationale is
provided by the investigator and approved by the Sponsor.

Cohort 5: (up to 150 patients):

- Cohorts 1-4 without measurable disease;

- MTC not meeting the requirements for Cohorts 3 or 4; (a known RET mutation is not
required)

- MTC syndrome spectrum cancers (e.g. MTC, pheochromocytoma) or poorly differentiated
thyroid cancers with other RET alteration/activation may be allowed with prior Sponsor
approval;

- cfDNA positive for a RET gene alteration not known to be present in a tumor sample.

Key Exclusion Criteria (Phase 1 and Phase 2):

- Phase 2 Cohorts 1-4: an additional known oncogenic driver.

- Prior treatment with a selective RET inhibitor

- Investigational agent or anticancer therapy within 5 half-lives or 2 weeks (whichever
is shorter) prior to planned start of LOXO-292. In addition, no concurrent
investigational anti-cancer therapy is permitted. LOXO-292 may be started within less
than 5 half-lives or 2 weeks of prior therapy if considered by the Investigator to be
safe and within the best interest of the patient, with prior Sponsor approval.

- Major surgery (excluding placement of vascular access) within 4 weeks prior to planned
start of LOXO-292.

- Radiotherapy with a limited field of radiation for palliation within 1 week of planned
start of LOXO-292, with the exception of patients receiving radiation to more than 30%
of the bone marrow or with a wide field of radiation, which must be completed at least
4 weeks prior to the first dose of study treatment.

- Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of
starting study treatment with the exception of alopecia and Grade 2, prior
platinum-therapy related neuropathy.

- Symptomatic primary CNS tumor, metastases, leptomeningeal carcinomatosis, or untreated
spinal cord compression. Patients are eligible if neurological symptoms and CNS
imaging are stable and steroid dose is stable for 14 days prior to the first dose of
LOXO-292 and no CNS surgery or radiation has been performed for 28 days, 14 days if
stereotactic radiosurgery [SRS].

- Clinically significant active cardiovascular disease or history of myocardial
infarction within 6 months prior to planned start of LOXO-292 or prolongation of the
QT interval corrected (QTcF) > 470 msec on all 3 ECGs during Screening.

- Required treatment with certain strong CYP3A4 inhibitors or inducers.