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Phase 1/2 Study of LOXO-292 in Patients With Advanced Solid Tumors, RET Fusion-Positive Solid Tumors, and Medullary Thyroid Cancer (LIBRETTO-001)

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ClinicalTrials.gov Identifier: NCT03157128
Recruitment Status : Recruiting
First Posted : May 17, 2017
Last Update Posted : August 9, 2018
Sponsor:
Information provided by (Responsible Party):
Loxo Oncology, Inc.

Brief 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.

Condition or disease Intervention/treatment Phase
Non-Small Cell Lung Cancer Medullary Thyroid Cancer Colon Cancer Solid Tumor Drug: LOXO-292 Phase 1 Phase 2

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 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.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 570 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : May 9, 2017
Estimated Primary Completion Date : August 2019
Estimated Study Completion Date : December 2019


Arm Intervention/treatment
Experimental: LOXO-292
Phase 1 - Multiple doses of LOXO-292 Phase 2 - The maximum tolerated dose (MTD)/recommended dose from Phase 1
Drug: LOXO-292
Oral LOXO-292




Primary Outcome Measures :
  1. Phase 1: Maximum tolerated dose (MTD) [ Time Frame: The first 28 days of treatment (Cycle 1) ]
  2. Phase 1: Recommended Phase 2 dose (RP2D) [ Time Frame: The first 28 days of treatment (Cycle 1) and every cycle (28 days) for approximately 12 months (or earlier if the patient discontinues from the study) ]
  3. Phase 2: Objective Response Rate [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, and 7 days after the last dose (for up to 2 years) in patients who have not progressed. ]
    As assessed by RECIST v1.1 or RANO, as appropriate to tumor type, as assessed by independent review committee (IRC)


Secondary Outcome Measures :
  1. Phase 1: Frequency, severity, and relatedness of TEAEs and serious adverse events (SAEs), changes in hematology and blood chemistry values, assessments of physical examinations, vital signs, and electrocardiograms (ECGs). [ Time Frame: From the time of informed consent, for approximately 24 months (or earlier if the patient discontinues from the study), and through Safety Follow-up (28 days after the last dose) ]
  2. Phase 1: Plasma concentration of LOXO-292 and PK parameters, including but not limited toarea under the curve from time 0 to 24 hours (AUC0-24), maximum drug concentration (Cmax), time to maximum plasma concentration (Tmax), and degree of accumulation. [ Time Frame: Day 8 of Cycle 1 and Day 8 after Intra-patient Dose Escalation (Phase 1 only) ]
  3. Phase 1: ORR based on RECIST 1.1 or RANO, as appropriate to tumor type. [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in patients who have not progressed. ]
  4. Phase 2: ORR (by Investigator) [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in patients who have not progressed. ]
  5. Phase 2: best change in tumor size from baseline (by IRC and Investigator) [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in patients who have not progressed. ]
  6. Phase 2: DOR (by IRC and Investigator) [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in patients who have not progressed. ]
  7. Phase 2: CNS ORR (by IRC) [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in patients who have not progressed. ]
  8. Phase 2: CNS DOR (by IRC) [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in patients who have not progressed. ]
  9. Phase 2: time to any and best response (by IRC and Investigator) [ Time Frame: every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in patients who have not progressed. ]
  10. Phase 2: CBR (by IRC and Investigator) [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in patients who have not progressed. ]
  11. Phase 2: PFS (by IRC and Investigator) [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in patients who have not progressed. ]
  12. Phase 2: OS [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in patients who have not progressed. ]
  13. Phase 2: Frequency, severity and relatedness of TEAEs and SAEs, changes in hematology and blood chemistry values, assessments of physical examinations, vital signs and ECGs. [ Time Frame: From the time of informed consent, for approximately 24 months (or earlier if the patient discontinues from the study), and through Safety Follow-up (28 days after the last dose) ]
  14. Phase 2: Plasma concentrations of LOXO-292 and PK parameters, including but not limited to AUC0-24, Cmax, and Tmax. [ Time Frame: Day 8 of Cycle 1 and Day 8 after Intra-patient Dose Escalation (Phase 2 only) ]

Other Outcome Measures:
  1. Differences in efficacy and safety based on LOXO-292 PK parameters. [ Time Frame: Day 8 of Cycle 1 and Day 8 after Intra-patient Dose Escalation ]
  2. Changes in CEA and calcitonin (patients with MTC) thyroglobulin (non-MTC thyroid cancer patients), ACTH and cortisol (patients with Cushing's disease related to their cancer) with LOXO-292 treatment. [ Time Frame: From the time of informed consent, Day 1 and Day 15 of Cycle 1, Day 1 of Cycle 2 and odd-numbered cycles, starting with Cycle 3, and 7 days after the last dose. ]
  3. Identity of RET gene fusions, mutations, and concurrently activated oncogenic pathways in tumor biopsies and cfDNA. [ Time Frame: Up to 28 days prior to C1D1, Day 1 & Day 15 of Cycle 1, Day 1 of Cycle 3, then approximately every 8 weeks for 1 year, then every 12 weeks, & 7 days after the last dose, for approximately 24 months (or earlier if the patient discontinues from the study) ]
  4. Changes from baseline in disease-related symptoms and HRQoL, as measured by EORTC QLQ-C30 (adults), PedsQL for teens (ages 13-17 years), and PedsQL for children (age 12 years). [ Time Frame: Day 1 of Cycle 1, then approximately every 8 weeks for one year, then every 12 weeks, and 7 days after the last dose, for approximately 24 months (or earlier if the patient discontinues from the study) ]
  5. Changes from baseline in disease-related symptoms and HRQoL, as measured by patient bowel diaries (MTC patients only). [ Time Frame: Day 1, Day 8, Day 15, and Day 22 of Cycle 1, and Day 1 of each cycle, and 7 days after the last dose, for approximately 24 months (or earlier if the patient discontinues from the study) ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   12 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03157128


Contacts
Contact: Patient Advocacy 855-RET-4-292 (855-738-4292) clinicaltrials@loxooncology.com

  Show 33 Study Locations
Sponsors and Collaborators
Loxo Oncology, Inc.
Investigators
Study Director: S. Michael Rothenberg, MD, PhD Loxo Oncology Medical Monitor, VP of R&D

Responsible Party: Loxo Oncology, Inc.
ClinicalTrials.gov Identifier: NCT03157128     History of Changes
Other Study ID Numbers: LOXO-RET-17001
2017-000800-59 ( EudraCT Number )
First Posted: May 17, 2017    Key Record Dates
Last Update Posted: August 9, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Loxo Oncology, Inc.:
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

Additional relevant MeSH terms:
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Colonic Neoplasms
Thyroid Diseases
Thyroid Neoplasms
Carcinoma, Neuroendocrine
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Endocrine System Diseases
Endocrine Gland Neoplasms
Head and Neck Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Adenocarcinoma