Summary

for people ages 12 years and up (full criteria)
at La Jolla, California and other locations
study started
estimated completion:

Description

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.

Official Title

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)

Details

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 450 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.

Keywords

Non-Small Cell Lung Cancer Medullary Thyroid Cancer Colon Cancer Solid Tumor LOXO-292 KIF5B-RET M918T CCDC6-RET RET-PTC1 NCOA4-RET RET-PTC RET-PTC3 RET-PTC4 PRKAR1A-RET RET-PTC2 GOLGA5-RET RET-PTC5 ERC1-RET KTN1-RET RET-PTC8 HOOK3-RET PCM1-RET TRIM24-RET RET-PTC6 TRIM27-RET TRIM33-RET RET-PTC7 AKAP13-RET FKBP15-RET SPECC1L-RET TBL1XR1-RET BCR-RET FGRF1OP-RET RFG8-RET RET-PTC9 ACBD5-RET MYH13-RET CUX1-RET KIAA1468-RET FRMD4A-RET SQSTM1-RET AFAP1L2-RET PPFIBP2-RET EML4-RET PARD3-RET G533C C609F C609G C609R C609S C609Y C611F C611G C611S C611Y C611W C618F C618R C618S C620F C620R C620S C630R C630Y D631Y C634F C634G C634R C634S C634W C634Y K666E E768D L790F V804L V804M A883F S891A R912P CLIP1-RET Y806C RET fusion RET alteration RET mutation RET rearrangement RET translocation Neoplasms by Site Neoplasms Lung Neoplasms Carcinoma, Non-Small-Cell Lung Cancer of Lung Cancer of the Lung Lung Cancer Neoplasms, Lung Neoplasms, Pulmonary Pulmonary Cancer Pulmonary Neoplasms Respiratory Tract Neoplasms Lung Diseases Respiratory Tract Diseases Carcinoma, Bronchogenic Bronchial Neoplasms Papillary Thyroid Cancer Thyroid Diseases Thyroid Neoplasms Cancer of the Thyroid Cancer of Thyroid Neoplasms, Thyroid Thyroid Ademona Thyroid Cancer Thyroid Carcinoma Endocrine System Diseases Endocrine Gland Neoplasms Head and Neck Neoplasms Thoracic Neoplasms CNS tumor Primary CNS tumor Cancer of Colon Cancer of the Colon Colon Neoplasms Colonic Cancer Neoplasms, Colonic Malignant tumor of Breast Mammary Cancer Mammary Carcinoma, Human Mammary Neoplasm, Human Neoplasms, Breast Tumors, Breast Human Mammary Carcinoma Malignant Neoplasm of Breast Breast Carcinoma Breast Tumors Cancer of the Breast Breast Neoplasms Breast Cancer RET Inhibitor MTC NSCLC Colonic Neoplasms Carcinoma, Neuroendocrine

Eligibility

For people ages 12 years and up

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.
  • 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 50 patients):

  • Cohorts 1-4 without measurable disease;
  • MTC not meeting the requirements for Cohorts 3 or 4;
  • Other RET-altered solid tumor or other RET alteration/activation (any solid tumor,excluding synonymous, frameshift, or nonsense mutations);
  • 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 neurologically stable and without increase in steroid dose 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.
  • 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

  • UCSD Medical Center accepting new patients
    La Jolla California 92093-0698 United States
  • City of Hope accepting new patients
    Duarte California 91010 United States

Details

Status
accepting new patients
Start Date
Completion Date
(estimated)
Sponsor
Loxo Oncology, Inc.
ID
NCT03157128
Phase
Phase 1/2
Study Type
Interventional
Last Updated
August 8, 2018