Clinical Trials /

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

NCT03157128

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.

Related Conditions:
  • Malignant Solid Tumor
  • Non-Small Cell Lung Carcinoma
  • Thyroid Gland Medullary Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: LOXO-RET-17001
  • SECONDARY ID: 2017-000800-59
  • NCT ID: NCT03157128

Conditions

  • Non-Small Cell Lung Cancer
  • Medullary Thyroid Cancer
  • Colon Cancer
  • Solid Tumor

Interventions

DrugSynonymsArms
LOXO-292LOXO-292

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
LOXO-292ExperimentalPhase 1 - Multiple doses of LOXO-292 Phase 2 - The maximum tolerated dose (MTD)/recommended dose for Phase 2 (RP2D)
  • LOXO-292

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:12 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 1: Maximum tolerated dose (MTD)
Time Frame:The first 28 days of treatment (Cycle 1)
Safety Issue:
Description:As assessed by RECIST v1.1 or RANO, as appropriate to tumor type, as assessed by independent review committee (IRC)

Secondary Outcome Measures

Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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.
Safety Issue:
Description:
Measure: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.
Safety Issue:
Description:
Measure: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.
Safety Issue:
Description:
Measure: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.
Safety Issue:
Description:
Measure: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.
Safety Issue:
Description:
Measure: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.
Safety Issue:
Description:
Measure: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.
Safety Issue:
Description:
Measure: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.
Safety Issue:
Description:
Measure: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.
Safety Issue:
Description:
Measure: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.
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Loxo Oncology, Inc.

Trial Keywords

  • 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
  • Non-Small Cell Lung Cancer
  • 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
  • Medullary Thyroid Cancer
  • 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 Cancer
  • 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

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