| 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 |
|
| E.1.1.1 | Medical condition in easily understood language |
| Solid tumors of all type, including primary CNS tumors |
|
| 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 | 21.0 |
| 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) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| 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) |
|
| 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 years and older and age < 12 years with previously treated neurotrophic tyrosine kinase (NTRK) fusion cancers.
Phase 2:
To assess objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), as determined by an independent review committee (IRC) in documented NTRK fusion cancer patients previously treated with a TRK inhibitor who have progressed. |
|
| E.2.2 | Secondary objectives of the trial |
Phase 1: Assessment of:
- PK properties of LOXO-195
- Safety and tolerability of LOXO-195.
- ORR according to best response by RECIST v1.1, as determined by an IRC, in patients with a documented NTRK fusion cancer previously treated with a TRK inhibitor.
- ORR determined by the Investigator using RANO in patients with primary CNS malignancies with NTRK fusion.
Phase 2: Assessment of:
- Safety and tolerability of LOXO-195 at the RP2D in patients age 12 and older and patients age < 12.
- ORR determined by an IRC in patients with NTRK fusion cancers who have discontinued prior TRK therapy due to intolerance and/or nonresponse
- ORR determined by RECIST v1.1 or RANO as appropriate by Investigator in patients with NTRK fusion cancers who have discontinued prior TRK therapy due to disease progression or intolerance and/or non response.
- additional parameters including: Duration of response (DOR), Progression-free survival (PFS), Overall survival (OS), Clinical benefit rate (CBR). |
|
| 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 years) or Lansky Performance Score (LPS) ≥ 40% (age<16 years). If enrolled with primary CNS tumor to be assessed by RANO, Karnofsky Performance Score (KPS) (age≥ 16 years) or LPS (age<16 years) 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 time points 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 years and older: Adequate renal function defined as serum creatinine ≤2.0 mg/dL or estimated glomerular filtration ≥ 30 mL/min using Cockcroft-Gault formula.
For patients up to age 18 years: 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 potential. Surgically sterilized women are exempt.
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 suspension 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.
|
|
| 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 or drugs associated with QT prolongation. The Investigator should review concomitant medications with their site pharmacist as the list can change frequently.
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.
7.Known hypersensitivity to any of the components of the investigational agent, LOXO-195 or Ora-Sweet® SF and OraPlus®, for patients who will take the LOXO-195 suspension
|
|
| 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 years and older and age < 12 years.
Phase 2:
ORR as determined by IRC using RECIST v1.1 in patients age 12 years and older and age < 12 years with documented NTRK fusion cancers and demonstration of progression following (or during receipt of) previous treatment with a TRK inhibitor. |
|
| 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. |
|
| 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.
ORR as determined by IRC, in patients with a documented NTRK fusion cancer previously treated with a TRK inhibitor.
ORR 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 years and older and age < 12 years
Changes from baseline in clinical safety laboratory values and vital signs.
ORR using RECIST v1.1 as determined by an IRC in Cohort 2
ORR using RECIST v1.1 or RANO criteria as appropriate by Investigator in Cohort 1 and Cohort 2
Duration or response (DOR) will be determined for patients with best overall response of confirmed CR or PR by 1) an IRC and 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) as determined by an IRC and Investigator.
Overall survival (OS) Clinical benefit rate (CBR) as determined by an IRC and Investigator.
|
|
| 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. |
|
| 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 |
|
| 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
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| 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 |
| Ireland |
| Italy |
| Korea, Republic of |
| Singapore |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 20 |
Print
