Clinical Trial - NCT03157128

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

Recruiting

Sponsor: Loxo Oncology, Inc.

Collaborators:

Information provided by (Responsible party): Sponsor

ClinicalTrials.gov Identifier: NCT03157128

Protocol Info

Short Description: Phase 1 LOXO-292 in Advanced Solid Tumors
Long Description: 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)
MGH Status: Open
Sponsor: Loxo Oncology Inc.
Disease Program: Head & Neck

Next Steps


If you are interested in this protocol or in other treatment options at Massachusetts General Hospital, please Request a Consultation.




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.
Condition Title Intervention Phase
Non-Small Cell Lung Cancer Medullary Thyroid Cancer Colon Cancer Solid Tumor LOXO-292 Phase 1/Phase 2
Study Type Interventional
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)

Primary Outcome Measures

Phase 1: Maximum tolerated dose (MTD) [Time Frame: The first 28 days of treatment (Cycle 1)] [Designated as safety issue: ]

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)] [Designated as safety issue: ]

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.] [Designated as safety issue: ]


Secondary Outcome Measures

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)] [Designated as safety issue: ]

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)] [Designated as safety issue: ]

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.] [Designated as safety issue: ]

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.] [Designated as safety issue: ]

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.] [Designated as safety issue: ]

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.] [Designated as safety issue: ]

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.] [Designated as safety issue: ]

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.] [Designated as safety issue: ]

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.] [Designated as safety issue: ]

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.] [Designated as safety issue: ]

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.] [Designated as safety issue: ]

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.] [Designated as safety issue: ]

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)] [Designated as safety issue: ]

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)] [Designated as safety issue: ]

Estimated Enrollment: 870
Study Start Date: May 2017
Estimated Study Completion Date: December 2019
Estimated Primary Completion Date: August 2019
Arms Assigned Interventions

Experimental:LOXO-292

Phase 1 - Multiple doses of LOXO-292 Phase 2 - The maximum tolerated dose (MTD)/recommended dose for Phase 2 (RP2D)
Drug:LOXO-292
Oral LOXO-292

Eligibility

Ages Eligible for Study: N/A-N/A

Genders Eligible for Study: All

Accepts Healthly Volunteers: No

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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT03157128

Locations

  • United States, Arizona
    • Mayo Clinic - Scottsdale Scottsdale, Arizona, United States, 85259
  • United States, California
    • City of Hope Duarte, California, United States, 91010
    • UCSD Medical Center La Jolla, California, United States, 92093-0698
    • University of California, Los Angeles (UCLA) - Medical Center Los Angeles, California, United States, 90095
    • Hoag Memorial Hospital Presbyterian Newport Beach, California, United States, 92663
    • Kaiser Permanente of Oakland Oakland, California, United States, 94612
    • University of California - Irvine Medical Center Orange, California, United States, 92868
    • Kaiser Permanente- Sacramento Sacramento, California, United States, 95814
    • Kaiser Permanente - San Francisco San Francisco, California, United States, 94115
    • University of California, San Francisco (UCSF) - Helen Diller Family Comprehensive Cancer Center San Francisco, California, United States, 94115
    • Kaiser Permanente - Santa Clara, CA Santa Clara, California, United States, 95051
    • Kaiser Permanente- Vallejo Vallejo, California, United States, 94589
  • United States, Colorado
    • Sarah Cannon Research Institute at HealthONE Denver, Colorado, United States, 80218
  • United States, Connecticut
    • Yale University School of Medicine - Yale Cancer Center New Haven, Connecticut, United States, 06510
  • United States, Florida
    • Mayo Clinic - Jacksonville Jacksonville, Florida, United States, 32224
    • Memorial Hospital Pembroke Pines, Florida, United States, 33028
  • United States, Georgia
    • Emory University School of Medicine Atlanta, Georgia, United States, 30322
  • United States, Illinois
    • University of Chicago Medicine Chicago, Illinois, United States, 60637
  • United States, Louisiana
    • Ochsner Clinic Foundation New Orleans, Louisiana, United States, 70121
  • United States, Maryland
    • University of Maryland Medical Center Baltimore, Maryland, United States, 21201
  • United States, Massachusetts
    • Massachusetts General Hospital Boston, Massachusetts, United States, 02114
    • Dana-Farber Cancer Institute Boston, Massachusetts, United States, 02115
  • United States, Michigan
    • University of Michigan Ann Arbor, Michigan, United States, 48109
    • Henry Ford Health System Detroit, Michigan, United States, 48202
    • South Texas Accelerated Research Therapeutics (START) Midwest Grand Rapids, Michigan, United States, 49503
  • United States, Minnesota
    • Mayo Clinic - Rochester Rochester, Minnesota, United States, 55905
  • United States, Missouri
    • Washington University School of Medicine Saint Louis, Missouri, United States, 63110
  • United States, Nevada
    • Comprehensive Cancer Centers of Nevada Las Vegas, Nevada, United States, 89169
  • United States, New York
    • Roswell Park Comprehensive Cancer Center Buffalo, New York, United States, 14263
    • New York Cancer and Blood Specialists East Setauket, New York, United States, 11733
    • New York University (NYU) Langone Medical Center New York, New York, United States, 10016
    • Memorial Sloan Kettering Cancer Center New York, New York, United States, 10065
  • United States, North Carolina
    • University of North Carolina (UNC) - Chapel Hill Chapel Hill, North Carolina, United States, 27599
  • United States, Ohio
    • Cleveland Clinic Cleveland, Ohio, United States, 44195
    • The James Cancer Hospital and Solove Research Institute, The Ohio State University Comprehensive Cancer Center Columbus, Ohio, United States, 43221
  • United States, Oregon
    • Oregon Health & Science University (OHSU) Portland, Oregon, United States, 97239
  • United States, Pennsylvania
    • University of Pennsylvania Philadelphia, Pennsylvania, United States, 19104
  • United States, Tennessee
    • Sarah Cannon Research Institute, LLC Nashville, Tennessee, United States, 37203
    • Vanderbilt University School of Medicine Nashville, Tennessee, United States, 37232
  • United States, Texas
    • University of Texas Southwestern Medical Center Dallas, Texas, United States, 75390
    • MD Anderson Cancer Center Houston, Texas, United States, 77030
  • United States, Utah
    • Huntsman Cancer Institute Salt Lake City, Utah, United States, 84112
  • United States, Virginia
    • Virginia Cancer Specialists Fairfax, Virginia, United States, 22031
  • United States, Wisconsin
    • University of Wisconsin - Carbone Cancer Center Madison, Wisconsin, United States, 53792
  • Australia,
    • Peter MacCallum Cancer Institute Melbourne, , Australia, 3000
    • Royal North Shore Hospital Saint Leonards, , Australia, NSW 2065
  • Canada, British Columbia
    • British Columbia Cancer Agency Vancouver, British Columbia, Canada, VSZ 4E6
  • Denmark,
    • The Finsen Centre Copenhagen, , Denmark, 2100
  • France,
    • Institut Bergonie Bordeaux, , France, 33076
    • Centre Leon Berard Lyon, , France, 69008
    • Hospital La Timone Marseille, , France, 13005
    • ICM - Institut Regional du Cancer de Montpellier Montpellier, , France, 34298
    • Hopital Europeen Georges Pompidou Paris, , France, 75015
    • Gustave Roussy Villejuif, , France, 94805
  • Hong Kong,
    • Prince of Wales Hospital - Department of Clinical Oncology Shatin, , Hong Kong,
  • Israel,
    • Soroka University Medical Center - Dept. of Oncology Be'er Sheva, , Israel, 8410101
    • Hadassah Hebrew University Medical Center Ein Karem Jerusalem, , Israel, 9112001
  • Italy,
    • Istituto Nazionale Tumori - National Cancer Institute Milano, , Italy, 20133
  • Japan, Chiba
    • National Cancer Center Hospital East Kashiwa, Chiba, Japan, 277-8577
  • Japan,
    • Hyogo Cancer Center Akashi, , Japan, 673-8558
    • National Hospital Organization Kyushu Cancer Center Fukuoka, , Japan,
    • Hokkaido University Hospital Hokkaido, , Japan, 060-8648
    • Kanazawa University Hospital Kanazawa City, , Japan, 920-8641
    • Okayama University Hospital Okayama, , Japan, 700-8558
    • Osaka City General Hospital Osaka, , Japan, 5340021
    • Shizuoka Cancer Center Shizuoka, , Japan, 411-8777
    • National Cancer Center Hospital Tokyo, , Japan, 104-0045
    • Cancer Institute Hospital of JFCR Tokyo, , Japan, 135-8550
    • Tottori University Hospital Tottori, , Japan, 683-8504
  • Korea, Republic of,
    • National Cancer Center Goyang-si, , Korea, Republic of, 10408
    • Seoul National University Bundang Hospital Gyeonggi-do, , Korea, Republic of, 13620
    • Severance Hospital, Yonsei University Health System Seoul, , Korea, Republic of, 03722
    • Asan Medical Center Seoul, , Korea, Republic of, 05505
    • Samsung Medical Center Seoul, , Korea, Republic of, 06351
  • Singapore,
    • National Cancer Centre Singapore, , Singapore, 169610
  • Spain,
    • Hospital Universitario Vall d'Hebron Barcelona, , Spain, 08035
    • Fundacion Jimenez Diaz, START-Madrid Madrid, , Spain, 28040
    • START Madrid, Hospital Universitario HM Sanchinarro Madrid, , Spain, 28050
  • Switzerland,
    • Luzerner General Hospital Luzern, , Switzerland, 6000
  • Taiwan,
    • National Taiwan University Hospital Taipei City, , Taiwan, 10002 R.O.C

Sponsors and Collaborators

Loxo Oncology, Inc.

More Information

No publications provided

Responsible Party: Sponsor
ClinicalTrials.gov Identifier: NCT03157128
Other Study ID Numbers: 2017-000800-59
Study First Received:
Last Updated:
Health Authority:

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

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

Additional relevant MeSH terms:

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Thyroid Diseases

Colonic Neoplasms

Thyroid Neoplasms

Carcinoma, Neuroendocrine

Next Steps


If you are interested in this protocol or in other treatment options at Massachusetts General Hospital, please Request a Consultation.







ClinicalTrials.gov processed this data on May 30, 2019