Patient case: 72-year-old male with lung adenocarcinoma; genetic feature: EZR-ROS1 fusion

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

Summary: This is a Phase 1/2, open-label, first-in-human study designed to evaluate the safety, tolerability, pharmacokinetics (PK) and preliminary anti-tumor activity of LOXO-292 administered orally to patients with advanced solid tumors, including RET-fusion-positive solid tumors, medullary thyroid cancer (MTC) and other tumors with RET activation.

Detailed description: 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.

Eligibility: 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.

Relevance to patient case: not relevant