NTRK fusion cancers previously treated with a TRK inhibitor MedDRA version: 20.0 Level: LLT Classification code 10049516 Term: Malignant tumor System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 20.0 Level: PT Classification code 10007958 Term: Central nervous system neoplasm System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: LOXO-195
Product Code: LOXO-195
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: not available
CAS Number: 2097002-61-2
Current Sponsor code: LOXO-195
Other descriptive name: LOXO
Sponsors
Loxo Oncology, Inc
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1.Advanced solid tumor for which, in the opinion of the Investigator, no other standard therapy offers greater benefit. 2.A solid tumor diagnosis in the setting of: a.a documented NTRK fusion and a clinical history of relapse following a response to a prior TRK inhibitor b.a documented NTRK fusion unresponsive to a prior TRK inhibitor c.a documented NTRK fusion and a clinical history of intolerance to a prior TRK inhibitor 3.NTRK (NTRK1, NTRK2, and NTRK3) gene fusions will be identified in a CLIA certified (or equivalent) laboratory. 4.Performance Status: Eastern Cooperative Oncology Group (ECOG) score 3 (age 16) or Lansky Performance Score (LPS) 40% (age 16). If enrolled with primary CNS tumor to be assessed by RANO, Karnofsky Performance Score (KPS) (age 16) or LPS (age 16) 50%. 5.Evaluable and/or measurable disease by RECIST v1.1 or RANO. 6.Life expectancy 4 weeks. 7.At least 1 month of age. 8.Tissue submission. Samples from 2 timepoints are required if available 9.Adequate hematologic function, for patients without known bone marrow involvement, defined as: a.Hemoglobin (Hb) = 8.0 g/dL b.Absolute neutrophil count (ANC) = 1.0 × 109 /L c.Platelets (Plt) = 100 × 109 /L without need for regular transfusion support Patients with known bone marrow involvement will not be evaluable for hematologic DLT and can enroll with: a.Hb = 8.0 g/dL (transfusions allowed) b.ANC = 0.75 × 109 /L c.Plt = 50 × 109 /L (transfusions allowed) 10.Adequate hepatic function defined as: a.AST and ALT =2.5 × upper limit of normal (ULN) or =5 × ULN if in the setting of liver metastases b.Total bilirubin =1.5 × ULN or =3 × ULN if in the setting of liver metastases or Gilbert's disease; patients with higher total bilirubin levels due to Gilbert's disease or hepatic metastases may be enrolled with Sponsor approval 11.For patients age 18 and older: Adequate renal function defined as serum creatinine =2.0 or estimated glomerular filtration = 30 mL/min using Crockroft-Gault formula. For patients up to age 18: Estimated glomerular filtration rate = 30 mL/minute/1.73 m2 based on local institutional practice for determination OR a serum creatinine based on age/gender 12.At least 5 half-lives since most recent kinase inhibitor dose OR at least 7 days since last systemic anticancer therapy (whichever is shorter) and recovered to baseline from all toxicity of last cytotoxic chemotherapy dose. Alopecia and other non-acute toxicities are acceptable. 13.Patients with stable CNS primary tumor, brain metastases, or treated spinal cord compression are eligible if neurological symptoms have been stable for 7 days prior to the first dose of LOXO-195 and there has been no change in steroid dose, if taking steroids to manage CNS symptoms, for 7 days prior to the first dose of LOXO-195. The patient can be receiving any dose of steroids is as long as dosing meets specifications noted above. 14.Negative serum pregnancy test prior to C1D1 study drug if a woman of child-bearing age. Pregnancy test are not required for pre-pubertal (Tanner 1) girls. A post-menopausal woman will be defined as having no menses for 12 months without an alternative medical cause. 15.Agreement to adequate contraception in male and female patients with reproductive potential for the duration of treatment and for 6 months following study completion. a.Willingness to use double effective birth control methods, defined as one used by the patient and another by his/her partner. b.Oral contraception should always
Exclusion criteria
Exclusion criteria: 1.If received recent therapy, evidence of unstable organ dysfunction due to treatment. 2.Concurrent treatment with a strong CYP3A4 inhibitor or inducer. 3.Clinically significant active cardiovascular disease or history of myocardial infarction within 3 months prior to planned start of LOXO-195, cardiomyopathy; current or known history within the past 6 months of prolonged QTc interval >480 milliseconds. If there is a known explanation for a limited period of a prolonged QT interval (i.e., a medication known to cause prolonged QT interval was administered and has since been discontinued with clearly documented normal QT interval thereafter), that subject may be enrolled. 4.Major surgery within 7 days of enrollment. Catheter placement, endoscopic procedures, and dental surgery are not considered major surgery. 5.Uncontrolled systemic bacterial, fungal or viral infection. Infections treated with a stable dose of antimicrobial therapy for at least 7 days are allowed. 6.Pregnancy or lactation
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase 1: To determine the recommended dose for further study of oral LOXO-195 in 2 patient groups defined as age 12 and older and age < 12 with previously treated NTRK fusion cancers. Phase 2: To assess ORR by RECIST v1.1, as determined by independent radiology review in documented NTRK fusion cancer patients previously treated with a TRK inhibitor who have progressed. ;Secondary Objective: Phase 1: To characterize the PK properties of LOXO-195. To characterize the safety and tolerability of LOXO-195. To assess overall response rate (ORR) according to best response by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), as determined by independent radiology review, in patients with a documented NTRK fusion cancer previously treated with a TRK inhibitor. To assess the ORR determined by the treating Investigator using Response Assessment in Neuro-Oncology (RANO) in patients with primary CNS malignancies with NTRK fusion. Phase 2: To characterize the safety and tolerability of LOXO-195 at the RP2D in patients age 12 and older and patients age < 12. To assess ORR determined by RECIST v1.1 or RANO as appropriate in patients with NTRK fusion cancers who have discontinued prior TRK To assess additional parameters including: Duration of response (DOR), Progression-free survival (PFS), Overall survival (OS), Clinical benefit rate (CBR). ;Primary end point(s): Phase 1: Identification of MTD and/or recommended dose for further study of LOXO 195 in patients age 12 and older and age < 12. Phase 2: Best overall response of confirmed CR or PR as determined by independent radiology review committee using RECIST v1.1 in patients age 12 and older and age < 12 with documented NTRK fusion cancers and demonstration of progression following (or during receipt of) previous treatment with a TRK inhibitor. Confirmed CR or PR is defined as a repeat assessment performed no less than 28 days after the criteria for response is first met.;Timepoint(s) of ev | — |
Secondary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: Phase 1: PK properties of LOXO-195 will be determined between C1D6 and C1D8 Phase 1 and Phase 2: EORTC QLQ-C30 and EQ-5D or PedsQL should be conducted at the same cycle visits as the disease assessment.;Secondary end point(s): Phase 1: Incidence, severity, and duration of AEs, including all, serious, and those considered treatment related. Changes from baseline in clinical safety laboratory values and vital signs. Best overall response of confirmed CR or PR assessed by RECIST v1.1, as determined by independent radiology review, in patients with a documented NTRK fusion cancer previously treated with a TRK inhibitor. Best overall response of confirmed CR or PR as determined by the treating Investigator using RANO in patients with primary CNS malignancies. Overall survival (OS) defined as the number of months from the initiation of LOXO 195 to the date of death due to any cause. To characterize the PK properties of LOXO-195. Phase 2: Incidence, severity, and duration of AEs, including all, serious, and those considered treatment related in patients age 12 and older and age ?12. Changes from baseline in clinical safety laboratory values and vital signs. Best overall response of confirmed CR or PR using RECIST v1.1 or RANO criteria as appropriate in patients with documented NTRK fusion cancers who discontinued the previous TRK inhibitor due to intolerance. Duration or response (DOR) will be determined for patients with best overall response of confirmed CR or PR by 1) an independent radiology review committee and/or 2) the treating Investigator; DOR is defined as the number of months from the start of CR or PR (whichever response is recorded first) and subsequently confirmed to the first date that recurrent or progressive disease is documented, or death. Progression-free survival (PFS) defined as the number of months from the initiation of LOXO-195 to the earlier of PD or death due to any cause. Overall survival (OS) define | — |
Countries
Australia, Denmark, France, Germany, Italy, Korea, Republic of, Singapore, Spain, United States
Contacts
Public ContactMedpace Regulatory Submissions
Medpace
Outcome results
None listed