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 selpercatinib
(also known as 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.
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
- Any Solid Tumor
Interventions
Drug | Synonyms | Arms |
---|
LOXO-292 | | LOXO-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
~850 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
Name | Type | Description | Interventions |
---|
LOXO-292 | Experimental | Phase 1 - Multiple doses of LOXO-292 Phase 2 - The maximum tolerated dose (MTD)/recommended dose for Phase 2 (RP2D) | |
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.
- 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), cancers with
neuroendocrine features/differentiation, 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.
- Cohort 6: Patients who otherwise are eligible for Cohorts 1-5 who discontinued another
RET inhibitor due to intolerance may be eligible with prior Sponsor approval.
Key Exclusion Criteria (Phase 1 and Phase 2):
- Phase 2 Cohorts 1-4: an additional known oncogenic driver.
- Cohorts 1-5: prior treatment with a selective RET inhibitor
Notes:
Patients otherwise eligible for Cohorts 1-5 who discontinued another selective RET
inhibitor may be eligible for Phase 2 Cohort 6 with prior Sponsor approval.
Notes:
Patients otherwise eligible for Cohorts 1-5 who discontinued another selective RET
inhibitor may be eligible for Phase 2 Cohort 6 with prior Sponsor approval.
Notes:
Patients otherwise eligible for Cohorts 1-5 who discontinued another selective RET
inhibitor may be eligible for Phase 2 Cohort 6 with prior Sponsor approval.
- Investigational agent or anticancer therapy (including chemotherapy, biologic therapy,
immunotherapy, anticancer Chinese medicine or other anticancer herbal remedy) 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.
Note:
Potential exception for this exclusion criterion will require a valid scientific
justification and approval from the Sponsor.
- 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.
- Required treatment with certain strong CYP3A4 inhibitors or inducers and certain
prohibited concomitant medications.
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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