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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 16, 2018
Sponsor:
Information provided by (Responsible Party):
Loxo Oncology, Inc.

May 9, 2017
May 17, 2017
August 16, 2018
May 9, 2017
August 2019   (Final data collection date for primary outcome measure)
  • Phase 1: Maximum tolerated dose (MTD) [ Time Frame: The first 28 days of treatment (Cycle 1) ]
  • 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) ]
  • 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)
Maximum tolerated dose (MTD) [ Time Frame: The first 28 days of treatment (Cycle 1) ]
Complete list of historical versions of study NCT03157128 on ClinicalTrials.gov Archive Site
  • 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) ]
  • 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) ]
  • 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. ]
  • 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. ]
  • 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. ]
  • 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. ]
  • 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. ]
  • 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. ]
  • 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. ]
  • 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. ]
  • 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. ]
  • 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. ]
  • 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) ]
  • 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) ]
  • Recommended dose for further study [ 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) ]
  • Number of participants with adverse events as assessed by CTCAE v4.03 [ 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) ]
  • Number of participants with serious adverse events [ 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) ]
  • Number of patients with changes in clinical laboratory results compared to baseline [ Time Frame: Day 1 (baseline) , Day 8 and Day 15 of Cycle 1 and every cycle (28 days) beginning with Cycle 2, for approximately 24 months (or earlier if the patient discontinues from the study), and through Safety Follow-up (28 days after the last dose) ]
  • Number of patients with changes upon physical examination compared to baseline [ Time Frame: Day 1 (baseline) , Day 8 and Day 15 of Cycle 1 and every cycle (28 days) beginning with Cycle 2, for approximately 24 months (or earlier if the patient discontinues from the study), and through Safety Follow-up (28 days after the last dose) ]
  • Number of patients with changes in vital signs compared to baseline [ Time Frame: Day 1 (baseline) , Day 8 and Day 15 of Cycle 1 and every cycle (28 days) beginning with Cycle 2, for approximately 24 months (or earlier if the patient discontinues from the study), and through Safety Follow-up (28 days after the last dose) ]
  • Number of patients with changes in ECGs compared to baseline [ Time Frame: Day 1 (baseline) , Day 8 and Day 15 of Cycle 1 and every cycle (28 days) beginning with Cycle 2, for approximately 24 months (or earlier if the patient discontinues from the study), and through Safety Follow-up (28 days after the last dose) ]
  • Area under the plasma concentration time curve from 0 to 24 hours (AUC0-24) of LOXO-292 [ Time Frame: Days 1 and 8 of Cycle 1 and Day 1 of Cycles 3 and 5 ]
  • Maximum plasma concentration (Cmax) of LOXO-292 [ Time Frame: Days 1 and 8 of Cycle 1 and Day 1 of Cycles 3 and 5 ]
  • Time to maximum plasma concentration (Tmax) of LOXO-292 [ Time Frame: Days 1 and 8 of Cycle 1 and Day 1 of Cycles 3 and 5 ]
  • Terminal half-life (t1/2) of LOXO-292 [ Time Frame: Days 1 and 8 of Cycle 1 and Day 1 of Cycles 3 and 5 ]
  • Degree of Accumulation of LOXO-292 [ Time Frame: Days 1 and 8 of Cycle 1 and Day 1 of Cycles 3 and 5 ]
  • Overall response rate [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose, and every 12 weeks 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
  • Duration of reponse [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose, and every 12 weeks after the last dose (for up to 2 years) in patients who have not progressed ]
    In patients with best overall response of complete response or partial response, as assessed by RECIST v1.1 or RANO, as appropriate to tumor type
  • Best change in tumor size from baseline [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose, and every 12 weeks after the last dose (for up to 2 years) in patients who have not progressed ]
  • Clinical benefit rate [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose, and every 12 weeks after the last dose (for up to 2 years) in patients who have not progressed ]
    Proportion of patients with complete response, partial response, or stable disease for at least 6 months while on LOXO-292, as assessed by RECIST v1.1 or RANO, as appropriate to tumor type
  • Median duration of progression-free survival following initiation of LOXO-292 [ Time Frame: Up to 2 years ]
  • Median overall survival following initiation of LOXO-292 [ Time Frame: Up to 2 years ]
  • 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 ]
  • 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. ]
  • 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) ]
  • 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) ]
  • 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) ]
  • Changes in serum tumor marker calcitonin compared to baseline (medullary thyroid cancer patients) [ Time Frame: Day 1 of Cycle 1 (baseline), Day 1 of Cycle 2, then Day 1 of every odd numbered cycle starting with Cycle 3, and 7 days after the last dose, for approximately 24 months (or earlier if the patient discontinues from the study) ]
  • Changes in serum tumor marker CEA compared to baseline (medullary thyroid cancer patients) [ Time Frame: Day 1 of Cycle 1 (baseline), Day 1 of Cycle 2, then Day 1 of every odd numbered cycle starting with Cycle 3, and 7 days after the last dose, for approximately 24 months (or earlier if the patient discontinues from the study) ]
  • RET gene status in DNA from tumor tissue [ Time Frame: Up to 28 days prior to Day 1 of Cycle 1 and 7 days after the last dose, for approximately 24 months (or earlier if the patient discontinues from the study) ]
  • RET gene status in plasma circulating free tumor DNA (cfDNA) [ Time Frame: Up to 28 days prior to Day 1 of Cycle 1, Day 15 of Cycle 1 , Day 1 of Cycle 2, then approximately every 8 weeks for one year, then every 12 weeks, and 7 days after last dose, for approximately 24 months (or earlier if patient discontinues from study). ]
 
Phase 1/2 Study of LOXO-292 in Patients With Advanced Solid Tumors, RET Fusion-Positive Solid Tumors, and Medullary Thyroid Cancer
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)
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.
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.
Interventional
Phase 1
Phase 2
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
  • Non-Small Cell Lung Cancer
  • Medullary Thyroid Cancer
  • Colon Cancer
  • Solid Tumor
Drug: LOXO-292
Oral LOXO-292
Experimental: LOXO-292
Phase 1 - Multiple doses of LOXO-292 Phase 2 - The maximum tolerated dose (MTD)/recommended dose from Phase 1
Intervention: Drug: LOXO-292
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
570
105
December 2019
August 2019   (Final data collection date for primary outcome measure)

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.
Sexes Eligible for Study: All
12 Years and older   (Child, Adult, Older Adult)
No
Contact: Patient Advocacy 855-RET-4-292 (855-738-4292) clinicaltrials@loxooncology.com
Australia,   France,   Hong Kong,   Japan,   Korea, Republic of,   Singapore,   Spain,   Switzerland,   United States
 
 
NCT03157128
LOXO-RET-17001
2017-000800-59 ( EudraCT Number )
No
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Plan to Share IPD: No
Loxo Oncology, Inc.
Loxo Oncology, Inc.
Not Provided
Study Director: S. Michael Rothenberg, MD, PhD Loxo Oncology Medical Monitor, VP of R&D
Loxo Oncology, Inc.
August 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP