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A Phase 1/2 Study of Oral LOXO-292 in Patients with Advanced Solid Tumors, Including RET Fusion-Positive Solid Tumors, Medullary Thyroid Cancer, and Other Tumors with RET Activation (LIBRETTO-001)

Protocol Number:
Phase I/II
Benjamin Levy
Sibley Memorial Hospital
Johns Hopkins Bayview Medical Center
The main purposes of this research study include the following:-To determine whether selpercatinib is safe;-To identify which dose level of selpercatinib should be studied in future studies;- To identify which of the dose levels used in this study is the highest tolerated dose or the dose thatcauses side effects that are too severe to continue taking selpercatinib;-To evaluate how the body absorbs and processes different doses of selpercatinib by measuring thelevels of selpercatinib in the blood at different times (this is called pharmacokinetic (PK) testing);-To determine how well your cancer responds to selpercatinib;-To determine how long any benefits from selpercatinib last.
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 MKI(s) with anti-RET activity are allowed. Refer to Appendix A for examples of MKIs with anti-RET activity. The specific agent(s), duration of treatment, clinical benefit and reason for discontinuation (e.g., progressive disease [PD], drug toxicity or intolerance) should be documented for all kinase inhibitors the patient has been exposed to.Evidence of a RET gene alteration in tumor and/or blood is required (e.g., gene rearrangement and/or mutation, excluding synonymous, frameshift, or nonsense mutations) as identified through molecular assays, as performed for clinical evaluation. The RET alteration result should be generated from a laboratory with CLIA, ISO/IEC, CAP, or other similar certification. The Sponsor should be contacted to discuss test results from laboratories where such certification is not clearly demonstrated to determine eligibility. A positive germline test for a RET mutation is acceptable for patients with MTC. In all cases, an anonymized/redacted Molecular Pathology Report or other report(s) describing tumor RET (and other) alteration analysis should be submitted to the Sponsor or designee during/prior to eligibility.Measurable or non-measurable disease as determined by RECIST 1.1 or RANO as appropriate to tumor type.At least 18 years of ageEastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2 (age equal to 16 years) or Lansky Performance Score (LPS) equal to 40% (age less than 16 years) with no sudden deterioration 2 weeks prior to the first dose of study treatment.Life expectancy of at least 3 months.Archived tumor tissue sample available.• Patients who do not have adequate archival tumor tissue available should undergo a fresh tumor biopsy, if it is considered safe to perform prior to treatment (requirement may be waived with Sponsor approval).• If archived tumor tissue was obtained prior to progression on the last MKI with anti-RET activity, the patient should undergo a fresh tumor biopsy, if it is considered safe to perform, prior to treatment (optional).Adequate hematologic status, defined as:• Absolute neutrophil count (ANC) equal to 1.0× 109/L not requiring growth factor support for at least 7 days prior to treatment, and• Platelet count equal to 75 × 109/L not requiring transfusion support for at least 7 days prior to treatment, and• Hemoglobin (Hb) equal to 9 g/dL not requiring transfusion support or erythropoietin for at least 7 days prior to treatment.Adequate hepatic function, defined as:• ALT or AST equal to 2.5 × the upper limit of normal (ULN) or equal to 5 × ULN with documented liver involvement (such as liver metastasis or a primary biliary tumor) and• Total bilirubin equal to 1.5 × ULN or equal to 3 × ULN with documented liver involvement (patients with Gilbert’s Disease may be enrolled with prior Sponsor approval).Adequate renal function, with estimated glomerular filtration rate equal to 30 mL/minute (up to 6 patients with an estimated glomerular filtration rate (eGFR) equal to 15 and less than 30 mL/minute will be allowed to enroll with Sponsor approval).Ability to swallow capsules and comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation. If the liquid formulation is widely available, this requirement may be waived with Sponsor approval.
This study will be conducted in two parts: dose escalation and dose expansion (also called “phase 1”). Johns Hopkins will only be participating in Part 2, dose expansion (also called “phase 2”). A dose of 160 mg BID has been chosen for the dose expansion portion of the study. For this portion of the study, only patients with an alteration/activation in the RET gene/protein will be enrolled. Patients will be enrolled into one of six groups (i.e. expansion cohorts) depending on the type of cancer they have and if they have received previous treatment for the, you will be assigned to a group based on your cancer type and previous cancer treatment. As the dose escalation portion of the study is still ongoing, it is possible that the dose of 160 mg BID for the dose expansion portion of the study could be modified in the future based on the results of continued dose escalation.

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