A Phase 1 study on the effects of LOXO-292 (study drug) in patients with advanced solid tumors

Phase 1

• Conditions: MedDRA version: 20.0Level: PTClassification code 10027105Term: Medullary thyroid cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 20.0Level: PTClassification code 10061873Term: Non-small cell lung cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]; MedDRA version: 20.0Level: LLTClassification code 10065252Term: Solid tumorSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); 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.

• Registration Number: EUCTR2017-000800-59-NL
• Lead Sponsor: oxo Oncology, Inc.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2018-09-03
• Last Update Posted: 9 November 2020

Recruitment & Eligibility

• Status: A
• Sex: All
• Target Recruitment: 570

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 functio

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.

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified