| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Dose escalation: Male or female patients age 12 years or older with a locally advanced or metastatic solid tumor refractory to standard of care therapy, or for whom no standard of care therapy is available.
Dose expansion: 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. |
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| E.1.1.1 | Medical condition in easily understood language |
| Male or female patients age 12 years or older with refractory advanced or metastatic solid tumor (dose escalation) or with evidence of a RET gene alteration (dose expansion). |
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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 | 10065252 |
| E.1.2 | Term | Solid 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 | 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 | 20.0 |
| 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 |
Primary Objective (Phase 1):
• To determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of LOXO-292.
Primary Objective (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 for tumor type, as assessed by independent review committee (IRC).
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|
| E.2.2 | Secondary objectives of the trial |
Phase 1:
• To determine the safety profile and tolerability of LOXO-292.
• To characterize the pharmacokinetic (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 by determining:
o ORR based on RECIST 1.1 or RANO, as appropriate to tumor type, as assessed by Investigator;
o Best change in tumor size from baseline as assessed by IRC and Investigator;
o Duration of response (DOR) as assessed by IRC and Investigator;
o Central nervous system (CNS) ORR based on RECIST 1.1 or RANO, as appropriate to tumor type, as assessed by IRC (for patients with brain metastases);
For full list see protocol.
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|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion Criteria for 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 MKI(s) with anti-RET activity are allowed. Refer to Appendix A for examples of MKIs with anti-RET activity. However, prior treatment with a selective RET inhibitor(s) (including investigational selective RET inhibitor[s]) is prohibited. The specific agent(s), duration of treatment, clinical benefit and reason for discontinuation (e.g., progressive disease [PD], drug toxicity or intolerance) should be documented for all kinase inhibitors the patient has been exposed to.
3. A RET gene alteration is not required initially. Once adequate PK is achieved (see Phase 1 and Maximum Tolerated Dose Determination), evidence of a RET gene alteration in tumor and/or blood is required (e.g., gene rearrangement and/or mutation, excluding synonymous, frameshift, or nonsense mutations) as identified through molecular assays, as performed for clinical evaluation. The RET alteration result should be generated from a laboratory with CLIA, ISO/EIC, CAP, or other similar certification. The Sponsor should be contacted to discuss test results from labs where such certification is not clearly demonstrated to determine eligibility. A positive germline test for a RET mutation is acceptable for patients with MTC. In all cases, an anonymized/redacted Molecular Pathology Report or other report(s) describing tumor RET (and other) alteration analysis should be submitted to the Sponsor or designee during/prior to eligibility.
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 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.
• Patients who do not have adequate archival tumor tissue available should undergo a fresh tumor biopsy, if it is considered safe to perform prior to treatment (requirement may be waived with Sponsor approval).
• If archived tumor tissue was obtained prior to progression on the last MKI with anti-RET activity, the patient should undergo a fresh tumor biopsy, if it is considered safe to perform, prior to treatment (optional).
9. Adequate hematologic status, defined as:
• Absolute neutrophil count (ANC) ≥ 1.0 109/L not requiring growth factor support for at least 7 days prior to treatment, and
• Platelet count ≥ 75 109/L not requiring transfusion support for at least 7 days prior to treatment, and
• Hemoglobin (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 or AST ≤ 2.5 the upper limit of normal (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 mL/minute 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.
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; this may include barrier methods such as condom or diaphragm with spermicidal gel.
Inclusion Criteria for Phase 2:
As for phase 1 with the following modifications:
1. Required prior first line therapies for Cohorts 1 and 3 are listed in table 3 of the protocol.
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 2. However, a positive germline DNA test for a RET gene mutation as defined in Table 2 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 for 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.
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| E.4 | Principal exclusion criteria |
Exclusion Criteria for Phase 1 and Phase 2:
1. Phase 2, Cohorts 1-4, an additional validated oncogenic driver that could cause resistance to LOXO-292 treatment. See Appendix C for examples.
2. Prior treatment with a selective RET inhibitor(s) (including investigational selective RET inhibitor[s]).
3. Investigational agent or anticancer therapy 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. Refer to the Protocol for allowable concurrent therapies. LOXO-292 may be started within less than 5 half lives or 2 weeks of prior therapy if considered by the Investigator to be safe and within the best interest of the patient, with prior Sponsor approval.
4. Major surgery (excluding placement of vascular access) within 4 weeks prior to planned start of LOXO-292.
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. Patients are eligible if neurologically stable and without increase in steroid dose 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 LOXO 292 or prolongation of the QT interval corrected for heart rate using Fridericia’s formula (QTcF) > 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 clinically significant, active disease process which in the opinion of the Investigator makes it undesirable for the patient to participate in the trial. 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. Current treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers. For prohibited medications (Appendix D).
14. Current treatment with proton pump inhibitors (PPIs) (Appendix E).
Note:
Treatment with PPIs must be stopped 1 or more weeks prior to the first dose of LOXO-292. For recommended alternatives, refer to the Protocol.
15. Pregnancy or lactation.
16. Active second malignancy other than minor treatment of indolent cancers.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoint (Phase 1):
• MTD/RP2D.
Primary Endpoint (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 |
| First 28-day cycle of LOXO-292 treatment. |
|
| E.5.2 | Secondary end point(s) |
Secondary Endpoints (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).
• 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.
• ORR based on RECIST 1.1or RANO, as appropriate to tumor type.
Secondary Endpoints (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, 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.
Exploratory Endpoints:
• Differences in efficacy and safety based on LOXO-292 PK parameters.
• Changes in CEA and calcitonin (patients with MTC) thyroglobulin (non-MTC patients), ACTH and cortisol (patients with Cushing’s disease related to their cancer) with LOXO-292 treatment.
• Identity of RET gene fusions, mutations, and concurrently activated oncogenic pathways in tumor biopsies and cfDNA.
• Changes from baseline in disease-related symptoms and HRQoL, as measured by EORTC QLQ-C30 (adults), PedsQL for teens (ages 13-17 years), PedsQL for children (age 12 years), and patient bowel diaries (MTC patients only).
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Adverse drug reactions and serious adverse drug reactions, 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 D1&D8, Cycle3 D1, Cycle5 D5
• ORR (CR+PR), DOR, proportion of patients that have any tumor regression as a best response, CBR, PFS, OS: Cycle2 and higher |
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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 | 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) | No |
| 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 | 6 |
| 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 |
| Hong Kong |
| Italy |
| Korea, Republic of |
| Singapore |
| Spain |
| Switzerland |
| Taiwan |
| United Kingdom |
| United States |
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| 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
|
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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 | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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