Trial Review

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT03157128




Registration number
NCT03157128
Ethics application status
Date submitted
9/05/2017
Date registered
15/05/2017
Date last updated
12/02/2019

Titles & IDs
Public title
Phase 1/2 Study of LOXO-292 in Patients With Advanced Solid Tumors, RET Fusion-Positive Solid Tumors, and Medullary Thyroid Cancer
Scientific 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)
Secondary ID [1] 0 0
2017-000800-59
Secondary ID [2] 0 0
LOXO-RET-17001
Universal Trial Number (UTN)
Trial acronym
LIBRETTO-001
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Non-Small Cell Lung Cancer 0 0
Medullary Thyroid Cancer 0 0
Colon Cancer 0 0
Solid Tumor 0 0
Condition category
Condition code
Cancer 0 0 0 0
Lung - Mesothelioma
Cancer 0 0 0 0
Lung - Non small cell
Cancer 0 0 0 0
Lung - Small cell
Metabolic and Endocrine 0 0 0 0
Other endocrine disorders
Cancer 0 0 0 0
Bowel - Back passage (rectum) or large bowel (colon)
Cancer 0 0 0 0
Thyroid
Cancer 0 0 0 0
Neuroendocrine tumour (NET)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - LOXO-292

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


Treatment: Drugs: LOXO-292
Oral LOXO-292
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Phase 1: Maximum tolerated dose (MTD)
Timepoint [1] 0 0
The first 28 days of treatment (Cycle 1)
Primary outcome [2] 0 0
Phase 1: Recommended Phase 2 dose (RP2D)
Timepoint [2] 0 0
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)
Primary outcome [3] 0 0
Phase 2: Objective Response Rate - As assessed by RECIST v1.1 or RANO, as appropriate to tumor type, as assessed by independent review committee (IRC)
Timepoint [3] 0 0
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.
Secondary outcome [1] 0 0
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).
Timepoint [1] 0 0
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)
Secondary outcome [2] 0 0
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.
Timepoint [2] 0 0
Day 8 of Cycle 1 and Day 8 after Intra-patient Dose Escalation (Phase 1 only)
Secondary outcome [3] 0 0
Phase 1: ORR based on RECIST 1.1 or RANO, as appropriate to tumor type.
Timepoint [3] 0 0
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.
Secondary outcome [4] 0 0
Phase 2: ORR (by Investigator)
Timepoint [4] 0 0
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.
Secondary outcome [5] 0 0
Phase 2: best change in tumor size from baseline (by IRC and Investigator)
Timepoint [5] 0 0
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.
Secondary outcome [6] 0 0
Phase 2: DOR (by IRC and Investigator)
Timepoint [6] 0 0
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.
Secondary outcome [7] 0 0
Phase 2: CNS ORR (by IRC)
Timepoint [7] 0 0
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.
Secondary outcome [8] 0 0
Phase 2: CNS DOR (by IRC)
Timepoint [8] 0 0
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.
Secondary outcome [9] 0 0
Phase 2: time to any and best response (by IRC and Investigator)
Timepoint [9] 0 0
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.
Secondary outcome [10] 0 0
Phase 2: CBR (by IRC and Investigator)
Timepoint [10] 0 0
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.
Secondary outcome [11] 0 0
Phase 2: PFS (by IRC and Investigator)
Timepoint [11] 0 0
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.
Secondary outcome [12] 0 0
Phase 2: OS
Timepoint [12] 0 0
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.
Secondary outcome [13] 0 0
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.
Timepoint [13] 0 0
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)
Secondary outcome [14] 0 0
Phase 2: Plasma concentrations of LOXO-292 and PK parameters, including but not limited to AUC0-24, Cmax, and Tmax.
Timepoint [14] 0 0
Day 8 of Cycle 1 and Day 8 after Intra-patient Dose Escalation (Phase 2 only)

Eligibility
Key inclusion criteria
Key

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
Minimum age
12 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1/Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
9/05/2017
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/12/2019
Actual
Sample size
Target
870
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Peter MacCallum Cancer Institute - Melbourne
Recruitment hospital [2] 0 0
Royal North Shore Hospital - Saint Leonards
Recruitment postcode(s) [1] 0 0
3000 - Melbourne
Recruitment postcode(s) [2] 0 0
NSW 2065 - Saint Leonards
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Colorado
Country [3] 0 0
United States of America
State/province [3] 0 0
Georgia
Country [4] 0 0
United States of America
State/province [4] 0 0
Illinois
Country [5] 0 0
United States of America
State/province [5] 0 0
Louisiana
Country [6] 0 0
United States of America
State/province [6] 0 0
Maryland
Country [7] 0 0
United States of America
State/province [7] 0 0
Massachusetts
Country [8] 0 0
United States of America
State/province [8] 0 0
Michigan
Country [9] 0 0
United States of America
State/province [9] 0 0
New York
Country [10] 0 0
United States of America
State/province [10] 0 0
North Carolina
Country [11] 0 0
United States of America
State/province [11] 0 0
Ohio
Country [12] 0 0
United States of America
State/province [12] 0 0
Oregon
Country [13] 0 0
United States of America
State/province [13] 0 0
Pennsylvania
Country [14] 0 0
United States of America
State/province [14] 0 0
Tennessee
Country [15] 0 0
United States of America
State/province [15] 0 0
Texas
Country [16] 0 0
United States of America
State/province [16] 0 0
Utah
Country [17] 0 0
United States of America
State/province [17] 0 0
Wisconsin
Country [18] 0 0
France
State/province [18] 0 0
Bordeaux
Country [19] 0 0
France
State/province [19] 0 0
Lyon
Country [20] 0 0
France
State/province [20] 0 0
Marseille
Country [21] 0 0
France
State/province [21] 0 0
Montpellier
Country [22] 0 0
France
State/province [22] 0 0
Paris
Country [23] 0 0
France
State/province [23] 0 0
Villejuif
Country [24] 0 0
Hong Kong
State/province [24] 0 0
Shatin
Country [25] 0 0
Israel
State/province [25] 0 0
Be'er Sheva
Country [26] 0 0
Japan
State/province [26] 0 0
Chiba
Country [27] 0 0
Japan
State/province [27] 0 0
Akashi
Country [28] 0 0
Japan
State/province [28] 0 0
Fukuoka
Country [29] 0 0
Japan
State/province [29] 0 0
Osaka
Country [30] 0 0
Japan
State/province [30] 0 0
Tokyo
Country [31] 0 0
Japan
State/province [31] 0 0
Tottori
Country [32] 0 0
Korea, Republic of
State/province [32] 0 0
Goyang-si
Country [33] 0 0
Korea, Republic of
State/province [33] 0 0
Gyeonggi-do
Country [34] 0 0
Korea, Republic of
State/province [34] 0 0
Seoul
Country [35] 0 0
Singapore
State/province [35] 0 0
Singapore
Country [36] 0 0
Spain
State/province [36] 0 0
Barcelona
Country [37] 0 0
Spain
State/province [37] 0 0
Madrid
Country [38] 0 0
Switzerland
State/province [38] 0 0
Luzern

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Loxo Oncology, Inc.
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/show/NCT03157128
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
S. Michael Rothenberg, MD, PhD
Address 0 0
Loxo Oncology Medical Monitor, VP of R&D
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Patient Advocacy
Address 0 0
Country 0 0
Phone 0 0
855-RET-4-292 (855-738-4292)
Fax 0 0
Email 0 0
clinicaltrials@loxooncology.com
Contact person for scientific queries

No data has been provided for results reporting
Summary results
Not applicable