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

Status: Active

Description

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.

Eligibility Criteria

Inclusion Criteria

  • 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.

Locations & Contacts

California

Duarte
City of Hope Comprehensive Cancer Center
Status: Active
Name Not Available
Los Angeles
UCLA / Jonsson Comprehensive Cancer Center
Status: In review
Contact: Kim Kelly
Phone: 310-206-8309
Email: kmkelly@mednet.ucla.edu
Orange
UC Irvine Health / Chao Family Comprehensive Cancer Center
Status: Active
Name Not Available
San Diego
University of California San Diego
Status: Active
Name Not Available
San Francisco
UCSF Medical Center-Mount Zion
Status: Active
Name Not Available

Georgia

Atlanta
Emory University Hospital / Winship Cancer Institute
Status: Active
Name Not Available

Illinois

Chicago
University of Chicago Comprehensive Cancer Center
Status: Active
Name Not Available

Maryland

Baltimore
University of Maryland / Greenebaum Cancer Center
Status: Active
Contact: Joann Alimurong
Phone: 410-328-2703
Email: joann.alimurong@umm.edu

Massachusetts

Boston
Brigham and Women's Hospital
Status: Active
Name Not Available
Dana-Farber Cancer Institute
Status: Active
Name Not Available
Massachusetts General Hospital Cancer Center
Status: Active
Name Not Available

Michigan

Ann Arbor
University of Michigan Comprehensive Cancer Center
Status: Approved
Name Not Available
Detroit
Wayne State University / Karmanos Cancer Institute
Status: Approved
Name Not Available

Missouri

Saint Louis
Siteman Cancer Center at Washington University
Status: Active
Name Not Available

New York

Buffalo
Roswell Park Cancer Institute
Status: Active
Name Not Available
New York
Laura and Isaac Perlmutter Cancer Center at NYU Langone
Status: Active
Name Not Available
Memorial Sloan Kettering Cancer Center
Status: Active
Name Not Available

North Carolina

Chapel Hill
UNC Lineberger Comprehensive Cancer Center
Status: Active
Name Not Available

Ohio

Cleveland
Case Comprehensive Cancer Center
Status: Active
Name Not Available
Columbus
Ohio State University Comprehensive Cancer Center
Status: Active
Name Not Available

Oregon

Portland
OHSU Knight Cancer Institute
Status: Active
Name Not Available

Tennessee

Nashville
Vanderbilt University / Ingram Cancer Center
Status: Active
Name Not Available

Texas

Dallas
UT Southwestern / Simmons Cancer Center-Dallas
Status: Active
Contact: Marcella West Aguilar
Phone: 214-648-1479
Email: marcella.aguilar@utsouthwestern.edu
Houston
M D Anderson Cancer Center
Status: Active
Name Not Available

Utah

Salt Lake City
Huntsman Cancer Institute / University of Utah
Status: Active
Name Not Available

Washington

Seattle
Fred Hutch / University of Washington Cancer Consortium
Status: In review
Name Not Available

Wisconsin

Madison
University of Wisconsin Hospital and Clinics
Status: Active
Name Not Available

Trial Objectives and Outline

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.

Trial Phase & Type

Trial Phase

Phase I/II

Trial Type

Treatment

Lead Organization

Lead Organization
Loxo Oncology, Inc.

Trial IDs

Primary ID LOXO-RET-17001
Secondary IDs NCI-2017-00976, 2017-000800-59
Clinicaltrials.gov ID NCT03157128