E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
NTRK fusion cancers previously treated with a TRK inhibitor |
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E.1.1.1 | Medical condition in easily understood language |
Solid tumors of all type, including primary CNS tumors |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10049516 |
E.1.2 | Term | Malignant tumor |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10007958 |
E.1.2 | Term | Central nervous system neoplasm |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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. |
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E.2.2 | Secondary objectives of the trial |
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).
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 be combined with an additional contraceptive method because of a potential interaction with the study drug. The same rules are valid for male patients involved in this study if they have a partner of childbirth potential. Male patients must always to use a condom. c.Male patients with a non-pregnant female partner of child-bearing potential and woman of child-bearing potential, should provide agreement (by patients and/or partner) to use a highly effective form of contraception that results in a low failure rate of less than 1% per year when used consistently and correctly. d.Male sterility will be defined as only men sterilized surgically. e.For male patients with a pregnant partner, a condom should be used for contraception. 16.Ability to swallow capsules or liquid solution orally or receive liquid enterally via a naso- or gastro-feeding tube, and comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation. 17.Parent/guardian of child or adolescent subjects has the ability to understand, agree to, and sign the study ICF and applicable Pediatric Assent Form before initiation of any protocol related procedures; subject has the ability to give assent, as applicable, at the time of parental/guardian consent.
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E.4 | Principal 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
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E.5 End points |
E.5.1 | 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. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase 1: Every cohort from baseline until disease progression,unacceptable toxicity, patient's withdrawal of consent, or death. Phase 2: Approximately every 8 weeks for the first 12 cycles, then every 12 weeks while on treatment, and every 12 weeks after the last dose (for up to 2 years) in patients who have not progressed. |
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E.5.2 | 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) defined as the number of months from the initiation of LOXO 195 to the date of death due to any cause. Clinical benefit rate (CBR) defined by best overall response of confirmed CR, PR, or stable disease lasting 12 or more weeks following the initiation of LOXO-195.
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E.5.2.1 | 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. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 7 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Denmark |
France |
Germany |
Italy |
Korea, Republic of |
Singapore |
Spain |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |