A Phase I/II Study of Oral Selpercatinib (LOXO-292) in Patients With Advanced Solid Tumors, Including RET Fusion-Positive Solid Tumors, Medullary Thyroid Cancer, and Other Tumors With RET Activation (LIBRETTO-001)
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Study Summary
To evaluate LOXO-292 in patients with cancers.
To evaluate the safety, efficacy, tolerability, pharmacokinetics (PK) and preliminary anti-tumor activity of LOXO-292 administered orally to patients with advanced solid tumors, including RET-fusion-positive solid tumors, medullary thyroid cancer (MTC) and other tumors with RET activation.
To determine whether LOXO-292 is safe;
To identify which dose level of LOXO-292 should be studied in future studies;
To identify which of the dose levels used in this study is the highest tolerated dose or the dose that causes side effects that are too severe to continue treatment with LOXO-292;
To evaluate how the body absorbs and processes different doses of LOXO-292 by measuring the levels of LOXO-292 in the blood at different times (this is called pharmacokinetics (PK) testing);
Part 1: To find the highest tolerable dose of LOXO-292 that can be given to patients with non-small cell lung cancer (NSCLC), medullary thyroid cancer, and any other tumors that have the RET mutation (a type of genetic change).
Part 2: To learn if the dose of LOXO-292 found in Part 1 can help to control the disease.
The safety of LOXO-292 will also be studied in both parts.
To report an update on the efficacy, including tumor assessment by blinded independent review committee, and the safety of selpercatinib in patients with RET-mutant medullary thyroid cancer (MTC) or RET fusion+ thyroid cancer.
Dose expansion phase will further characterize the overall response rate, durability of response, and safety of LOXO-292 in predefined groups of patients with activating RET alterations.
Patients with MTC completed the validated European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 and modified Systemic Therapy-Induced Diarrhea Assessment Tool (mSTIDAT). The QLQ-C30 was completed prior to initiating study treatment (baseline) and corresponding with radiologic disease assessments, approximately every 8 weeks, until end of study treatment. QLQ-C30 subscales are scored 0-100; higher scores indicate better functioning or more severe symptoms. A clinically meaningful difference was pre-defined as > or = 10-point change from baseline.
The efficacy analysis set consisted of patients enrolled > or = 6 months (mo) prior to the cut-off date. If a pt achieved response, an additional > or = 6 mo follow-up from the initial response was required. There was no additional follow-up required for non-responders.
Cohort 7 of the study evaluates efficacy and safety of neoadjuvant selpercatinib in patients with resectable stage IB-IIIA RET fusion-positive NSCLC
To investigate the efficacy and safety of selpercatinib in a diverse group of patients with RET fusion-positive non-lung or thyroid advanced solid tumours (ie, a tumour-agnostic population).
To report patient-reported outcomes for non-small cell lung cancer (NSCLC), medullary thyroid cancer (MTC), non-MTC thyroid cancer (TC) (15 Jun 2021, data cut-off date) and tumor agnostic (TA) cohorts (24 Sep 2021, data cut-off date).
Patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (QLQ-C30) at baseline (BL), approximately every 8 weeks until cycle 13, and then every 12 weeks until end of treatment (EoT). Subscales were scored 0–100; higher scores indicate better functioning or more severe symptoms based on the subscale. Proportion of patients with improved, stable, or worsened status post-BL was assessed.
To describe patient-reported symptoms and HRQoL in selpercatinib-treated patients with RET-activated cancers
To provide an efficacy and safety update with more pts and longer follow-up in pts with RET fusion+ solid tumors other than NSCLC /thyroid cancer.
The efficacy analysis set (EAS) consisted of pts who received ≥1 dose of selpercatinib and had ≥6 months (mo) of follow-up from the first dose of selpercatinib until data cutoff.
- For Phase 1:
- Participants with a locally advanced or metastatic solid tumor that:
- Has progressed on or is intolerant to standard therapy, or
- For which 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
- Prior multikinase inhibitors (MKIs) with anti-RET activity are allowed
- 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 as identified through molecular assays, as performed for clinical evaluation
- Measurable or non-measurable disease as determined by RECIST 1.1 or RANO as appropriate to tumor type
- Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2 or Lansky Performance Score (LPS) greater than or equal to (> or =) 40 percent (%) (age less than [<] 16 years) with no sudden deterioration 2 weeks prior to the first dose of study treatment
- Adequate hematologic, hepatic and renal function
- Life expectancy of at least 3 months
- For Phase 2: As for phase 1 with the following modifications:
- For Cohort 1: Participants must have received prior standard therapy appropriate for their tumor type and stage of disease, or in the opinion of the Investigator, would be unlikely to tolerate or derive clinical benefit from appropriate standard of care therapy
- Cohorts 1 and 2:
- Enrollment will be restricted to participants with evidence of a RET gene alteration in tumor
- At least one measurable lesion as defined by RECIST 1.1 or RANO, as appropriate to tumor type and not previously irradiated
- Cohorts 3 and 4: Enrollment closed
- Cohort 5:
- Cohorts 1-4 without measurable disease
- MCT not meeting the requirements for Cohorts 3 or 4
- MTC syndrome spectrum cancers (e.g., MTC, pheochromocytoma), cancers with neuroendocrine features/differentiation, or poorly differentiated thyroid cancers with other RET alteration/activation may be allowed with prior Sponsor approval;
- cfDNA positive for a RET gene alteration not known to be present in a tumor sample
- Cohort 6: Participants who otherwise are eligible for Cohorts 1, 2 or 5 who discontinued another RET inhibitor may be eligible with prior Sponsor approval
- Cohort 7: Participants with a histologically confirmed stage IB-IIIA NSCLC and a RET fusion; determined to be medically operable and tumor deemed resectable by a thoracic surgical oncologist, without prior systemic treatment for NSCLC
- Pts with locally advanced/metastatic RET-altered solid tumors, including pts with RET mutations in tumors other than MTC.
- Phase 2 Cohorts 1-4: an additional known oncogenic driver.
- Cohorts 3 and 4: Enrollment closed
- Cohorts 1, 2 and 5: prior treatment with a selective RET inhibitor Notes: Participants otherwise eligible for Cohorts 1, 2, and 5 who discontinued another selective RET inhibitor may be eligible for Phase 2 Cohort 6 with prior Sponsor approval
- 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 LOXO-292 (selpercatinib). In addition, no concurrent investigational anti-cancer therapy is permitted Note: Potential exception for this exclusion criterion will require a valid scientific justification and approval from the Sponsor
- Major surgery (excluding placement of vascular access) within 4 weeks prior to planned start of LOXO-292 (selpercatinib)
- Radiotherapy with a limited field of radiation for palliation within 1 week of planned start of LOXO-292 (selpercatinib), with the exception of participants 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
- Any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 at the time of starting study treatment with the exception of alopecia and Grade 2, prior platinum-therapy related neuropathy
- Symptomatic primary CNS tumor, metastases, leptomeningeal carcinomatosis, or untreated spinal cord compression. Participants 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 (selpercatinib) and no CNS surgery or radiation has been performed for 28 days, 14 days if stereotactic radiosurgery (SRS)
- Clinically significant active cardiovascular disease or history of myocardial infarction within 6 months prior to planned start of LOXO-292 (selpercatinib) or prolongation of the QT interval corrected (QTcF) greater than (>) 470 milliseconds (msec)
- Required treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers and certain prohibited concomitant medications
- Clinically significant active cardiovascular disease or history of myocardial infarction within 6 months prior to planned start of LOXO-292 (selpercatinib) or prolongation of the QT interval corrected (QTcF) greater than (>) 470 milliseconds (msec)
- Participants with implanted pacemakers may enter the study without meeting QTc criteria due to nonevaluable measurement if it is possible to monitor for QT changes.
- Participants with bundle branch block may be considered for study entry if QTc is appropriate by a formula other than Fridericia's and if it is possible to monitor for QT changes.
- Required treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers and certain prohibited concomitant medications
- Phase 2 Cohort 7 (neoadjuvant treatment): Participant must not have received prior systemic therapy for NSCLC.
Clinical Study Information for Healthcare Providers
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