| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Male or female patients age 12 years or older with a locally advanced or metastatic solid tumor with evidence of a RET gene alteration in tumor and/or blood |
|
| E.1.1.1 | Medical condition in easily understood language |
| Male or female patients age 12 years or older with locally advanced or metastatic solid tumor (phase 1) and with evidence of a RET gene alteration (phase 2). |
|
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065252 |
| E.1.2 | Term | Solid 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10027105 |
| E.1.2 | Term | Medullary thyroid cancer |
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase 1
To determine the MTD/recommended phase 2 dose (RP2D) of LOXO-292
Phase 2
To assess, for each phase 2 expansion cohort, the anti-tumor activity of LOXO-292 by determining ORR using RECIST 1.1 or RANO, as appropriate to tumor type, as assessed by independent review committee (IRC). |
|
| E.2.2 | Secondary objectives of the trial |
Phase 1
•To determine the safety profile and tolerability of LOXO-292.
•To characterize the PK properties of LOXO-292.
•To assess the anti-tumor activity of LOXO-292 by determining objective response rate (ORR) using Response Evaluation in Solid Tumors Version 1.1 (RECIST 1.1) or Response Assessment in Neuro-Oncology (RANO), as appropriate to tumor type
Phase 2
•To assess, for each expansion cohort, the anti-tumor activity of LOXO-292
•To determine the safety profile and tolerability of LOXO-292.
•To characterize the PK properties of LOXO-292
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Phase 1
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.
2.Prior MKIs with anti-RET activity are allowed.
3.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
4.Measurable or non-measurable disease as determined by RECIST 1.1 or RANO as appropriate to tumor type.
5.At least 18 years of age.
•For countries and sites where approved, patients as young as 12 years of age may be enrolled.
6.Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2 (age ≥ 16 years) or Lansky Performance Score (LPS) ≥ 40% (age < 16 years) with no sudden deterioration 2 weeks prior to the first dose of study treatment.
7.Life expectancy of at least 3 months.
8.Archived tumor tissue sample available.
9.Adequate hematologic status, defined as:
•Absolute neutrophil count (ANC) ≥ 1.0.10^9/L not requiring growth factor support for at least 7 days prior to treatment, and
•Platelet count ≥ 75.10^9/L not requiring transfusion support for at least 7 days prior to treatment, and
•Hb ≥ 9 g/dL not requiring transfusion support or erythropoietin for at least 7 days prior to treatment.
10.Adequate hepatic function, defined as:
•ALT and AST ≤ 2.5 ULN or ≤ 5 ULN with documented liver involvement (such as liver metastasis or a primary biliary tumor); and
•Total bilirubin ≤ 1.5 ULN or ≤ 3 ULN with documented liver involvement (patients with Gilbert’s Disease may be enrolled with prior Sponsor approval).
11.Adequate renal function, with estimated glomerular filtration rate ≥ 30 mL/minute (up to 6 patients with an estimated glomerular filtration rate (eGFR) ≥ 15 and < 30 will be allowed to enroll with Sponsor approval).
12.Ability to swallow capsules and comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation. If the liquid formulation is widely available the requirement may be waived with Sponsor approval.
13.Willingness of men and women of reproductive potential to observe conventional and effective birth control for the duration of treatment and for 3 months following the last dose of study treatment.
Phase 2
As for phase 1 with the following modifications:
1.Cohorts 1 and 3: failed or intolerant to standard of care. Cohorts 2 and 4 without prior standard first line therapy.
2.Cohorts 1-4: enrollment will be restricted to patients with evidence of a RET gene alteration in tumor (i.e., not just blood) as defined in Table 3 3. However, a positive germline DNA test for a RET gene mutation as defined in Table 3 3 is acceptable in the absence of tumor tissue testing for patients with MTC.
3.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 (unless PD for the irradiated lesion[s] has been radiographically documented).
4.Cohort 4: radiographic PD within the previous 14 months.
5. 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.
Note: Examples of RET inhibitors may include TPX0046, pralsetinib (BLU-667), or BOS172739. |
|
| E.4 | Principal exclusion criteria |
1.Phase 2 Cohorts 1-4: an additional validated oncogenic driver that could cause resistance to LOXO-292 treatment. See Appendix C (Table 11 3) for examples.
2.Cohorts 1 to 5: Prior treatment with a selective RET inhibitor(s) (including investigational selective RET inhibitor[s]).
3.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 Selpercatinib. In addition, no concurrent investigational anti-cancer therapy is permitted.
4.Major surgery (excluding placement of vascular access) within 4 weeks prior to planned start of Selpercatinib.
5.Radiotherapy with a limited field of radiation for palliation within 1 week of the first dose of study treatment, 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.
6.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.
7.Symptomatic primary CNS tumor, metastases, leptomeningeal carcinomatosis, or untreated spinal cord compression.
Exception:
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).
8.Clinically significant active cardiovascular disease or history of myocardial infarction within 6 months prior to planned start of Selpercatinib or prolongation of the QT interval corrected for heart rate using Fridericia’s formula (QTcF) interval > 470 msec on at least 2/3 consecutive electrocardiograms (ECGs) and mean QTcF > 470 msec on all 3 ECGs during Screening. Correction of suspected drug-induced QTcF prolongation may be attempted at the Investigator’s discretion if clinically safe to do so.
9.Active uncontrolled systemic bacterial, viral, or fungal infection or seriour ongoing intercurrent illness, such as hupertension or diabetes, despite optimal treatment. Screening for chronic conditions is not required.
10.Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal absorption of the study drug.
11.Uncontrolled symptomatic hyperthyroidism or hypothyroidism.
12.Uncontrolled symptomatic hypercalcemia or hypocalcemia.
13.Pregnancy or lactation.
14.Active second malignancy other than minor treatment of indolent cancers.
15.History of hypersensitivity to LOXO-292 or any of its capsule or liquid formulation components, or any of the liquid suspension components (for patient that cannot swallow capsules).
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1
MTD/RP2D
Phase 2
ORR based on RECIST 1.1 or RANO, as appropriate to tumor type, assessed by IRC |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
MTD/RP2D: at each end of dose escalation cohort
ORR: Every 8 weeks (±7 days) starting with D1 C3 through D1 C13. Every 12 weeks (±7 days) thereafter. During long-term follow-up: approximately every 3 months (±1 month) for up to two years after the last dose of study drug. |
|
| E.5.2 | Secondary end point(s) |
Phase 1
•Frequency, severity, and relatedness of TEAEs and SAEs, changes in hematology and blood chemistry values, assessments of physical examinations, vital signs, and ECGs
•Plasma concentrations of LOXO-292 and PK parameters, including but not limited to area under the concentration versus time curve from time 0 to 24 hours (AUC0-24), maximum drug concentration (Cmax), time to maximum plasma concentration (Tmax), and degree of accumulation
•ORR based on RECIST 1.1 or RANO, as appropriate to tumor type
Phase 2
•Parameters of anti-tumor activity/clinical benefit, including: ORR (by Investigator), best change in tumor size from baseline (by IRC and Investigator), DOR (by IRC and Investigator), CNS ORR (by IRC), CNS DOR (by IRC), time to any and best response (by IRC and Investigator), CBR (by IRC and Investigator), PFS (by IRC and Investigator), and OS
•Frequency, severity, and relatedness of TEAEs and SAEs, changes in hematology and blood chemistry values, and assessments of physical examinations, vital signs, and ECGs
•Plasma concentrations of LOXO-292 and PK parameters, including but not limited to AUC0-24, Cmax, and Tmax
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Frequency, severity, and relatedness of TEAEs and SAEs, changes in hematology and blood chemistry values, assessments of physical examinations, vital signs, and ECGs: throughout trial
Plasma concentration of LOXO-292 and PK parameters : Cycle1 D8
ORR, Parameters of anti-tumor activity/clinical benefit: Every 8 weeks (±7 days) starting with D1 C3 through D1 C13. Every 12 weeks (±7 days) thereafter. During long-term follow-up: approximately every 3 months (±1 month) for up to two years after the last dose of study drug. |
|
| 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 | No |
| 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 | No |
| 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 | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| 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
| 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 | 24 |
| 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 |
| Canada |
| Denmark |
| France |
| Germany |
| Hong Kong |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Netherlands |
| Poland |
| Singapore |
| Spain |
| Switzerland |
| Taiwan |
| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 28 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| 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 | 28 |
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