A Study of LOXO-292 in Participants With Advanced Solid Tumors, RET Fusion-Positive Solid Tumors, and Medullary Thyroid Cancer

  • Interventional
  • Recruiting
  • NCT03157128
Eligibility Details Visit Clinicaltrials.gov

A 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)

This is an open-label, first-in-human study designed to evaluate the safety, tolerability, pharmacokinetics (PK) and preliminary anti-tumor activity of selpercatinib (also known as LOXO-292) administered orally to participants with advanced solid tumors, including rearranged during transfection (RET)-fusion-positive solid tumors, medullary thyroid cancer (MTC) and other tumors with RET activation.

This is an open-label, multi-center Phase 1/2 study in participants 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 - completed) and phase 2 (dose expansion). Participants 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 milligrams (mg) twice a day (BID) has been selected as the recommended phase 2 dose (RP2D). Approximately 950 participants with advanced solid tumors harboring a RET gene alteration in tumor and/or blood will be enrolled to one of seven phase 2 cohorts:

        - Cohort 1: Advanced RET fusion positive solid tumor for participants who progressed on or intolerant to first line therapy (open)

        - Cohort 2: Advanced RET fusion positive solid tumor for treatment naïve participants (open)

        - Cohort 3: Advanced RET-mutant MTC participants who progressed on or intolerant to first line therapy (closed)

        - Cohort 4: Advanced RET-mutant MTC participants who are treatment naïve (closed)

        - Cohort 5: Advanced RET-altered solid tumor for participants otherwise ineligible for cohorts 1-4. See details in inclusion/exclusion criteria (open)

        - Cohort 6: Participants otherwise eligible for Cohorts 1-5 who discontinued another RET inhibitor due to intolerance may be eligible with prior Sponsor approval (open)

        - Cohort 7: RET fusion positive early-stage non-small cell lung cancer (NSCLC) participants who are candidates for definitive surgery. Participants will receive selpercatinib in a neoadjuvant and adjuvant setting. Participants will be followed for disease recurrence for up to 5 years from the date of surgery (open in US only)

Gender
All

Age Group
12 Years and up

Accepting Healthy Volunteers?
No

Key Inclusion Criteria:

        For Phase 1:

         - Participants with a locally advanced or metastatic solid tumor that:

         - Has progressed on or is intolerant to standard therapy, or

         - For which 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 multikinase inhibitors (MKIs) with anti-RET activity are allowed

         - 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) greater than or equal to (≥) 40 percent (%) (age less than [<] 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 Cohort 1: Participants 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 and 2:

             - Enrollment will be restricted to participants with evidence of a RET gene alteration in tumor

             - At least one measurable lesion as defined by RECIST 1.1 or RANO, as appropriate to tumor type and not previously irradiated

         - Cohorts 3 and 4: Enrollment closed

         - Cohort 5:

             - Without measurable disease but otherwise meet criteria for Cohorts 1 and 2;

             - MTC syndrome spectrum cancers (e.g., MTC, pheochromocytoma), cancers with neuroendocrine features/differentiation, 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

         - Cohort 6: Participants who otherwise are eligible for Cohorts 1, 2 or 5 who discontinued another RET inhibitor due to intolerance may be eligible with prior Sponsor approval

         - Cohort 7: Participants must have a histologically confirmed stage IB-IIIA NSCLC by AJCC (The American Joint Committee on Cancer) version 8. The tumor must have been deemed resectable by a thoracic surgeon, the participant must be determined to be medically operable based on the determination of a thoracic surgeon, and the participant must not have received prior systemic therapy, including prior radiation therapy, for NSCLC.

        Key Exclusion Criteria (Phase 1 and Phase 2):

         - Phase 2 Cohorts 1 and 2: an additional known oncogenic driver

         - Cohorts 3 and 4: Enrollment closed

         - Cohorts 1, 2 and 5: prior treatment with a selective RET inhibitor Notes: Participants otherwise eligible for Cohorts 1, 2, and 5 who discontinued another selective RET inhibitor may be eligible for Phase 2 Cohort 6 with prior Sponsor approval

         - Investigational agent or anticancer therapy (including chemotherapy, biologic therapy, immunotherapy, anticancer Chinese medicine or other anticancer herbal remedy) within 5 half-lives or 2 weeks (whichever is shorter) prior to planned start of LOXO-292 (selpercatinib). In addition, no concurrent investigational anti-cancer therapy is permitted Note: Potential exception for this exclusion criterion will require a valid scientific justification and approval from the Sponsor

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

         - Radiotherapy with a limited field of radiation for palliation within 1 week of planned start of LOXO-292 (selpercatinib), with the exception of participants 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 Common Terminology Criteria for Adverse Events (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. Participants 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 (selpercatinib) 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 (selpercatinib) or prolongation of the QT interval corrected (QTcF) greater than (>) 470 milliseconds (msec)

         - Required treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers and certain prohibited concomitant medications

At a Glance

National Government IDNCT03157128

IRB#IRB17-0782

Lead SponsorLoxo Oncology, Inc.

Lead PhysicianChristine Bestvina

Collaborator(s)N/A

EligibilityAll
12 Years and up
Recruiting