Any Solid Tumor, Colon Cancer, Medullary Thyroid Cancer, Non-Small Cell Lung Cancer
Conditions
Keywords
LOXO-292, KIF5B-RET, M918T, CCDC6-RET, RET-PTC1, NCOA4-RET, RET-PTC, RET-PTC3, RET-PTC4, PRKAR1A-RET, RET-PTC2, GOLGA5-RET, RET-PTC5, ERC1-RET, KTN1-RET, RET-PTC8, HOOK3-RET, PCM1-RET, TRIM24-RET, RET-PTC6, TRIM27-RET, TRIM33-RET, RET-PTC7, AKAP13-RET, FKBP15-RET, SPECC1L-RET, TBL1XR1-RET, BCR-RET, FGRF1OP-RET, RFG8-RET, RET-PTC9, ACBD5-RET, MYH13-RET, CUX1-RET, KIAA1468-RET, FRMD4A-RET, SQSTM1-RET, AFAP1L2-RET, PPFIBP2-RET, EML4-RET, PARD3-RET, G533C, C609F, C609G, C609R, C609S, C609Y, C611F, C611G, C611S, C611Y, C611W, C618F, C618R, C618S, C620F, C620R, C620S, C630R, C630Y, D631Y, C634F, C634G, C634R, C634S, C634W, C634Y, K666E, E768D, L790F, V804L, V804M, A883F, S891A, R912P, CLIP1-RET, Y806C, RET fusion, RET alteration, RET mutation, RET rearrangement, RET translocation, Neoplasms by Site, Neoplasms, Non-Small Cell Lung Cancer, Lung Neoplasms, Carcinoma, Non-Small-Cell Lung, Cancer of Lung, Cancer of the Lung, Lung Cancer, Neoplasms, Lung, Neoplasms, Pulmonary, Pulmonary Cancer, Pulmonary Neoplasms, Respiratory Tract Neoplasms, Lung Diseases, Respiratory Tract Diseases, Carcinoma, Bronchogenic, Bronchial Neoplasms, Medullary Thyroid Cancer, Papillary Thyroid Cancer, Thyroid Diseases, Thyroid Neoplasms, Cancer of the Thyroid, Cancer of Thyroid, Neoplasms, Thyroid, Thyroid Ademona, Thyroid Cancer, Thyroid Carcinoma, Endocrine System Diseases, Endocrine Gland Neoplasms, Head and Neck Neoplasms, Thoracic Neoplasms, CNS tumor, Primary CNS tumor, Cancer of Colon, Cancer of the Colon, Colon Cancer, Colon Neoplasms, Colonic Cancer, Neoplasms, Colonic, Malignant tumor of Breast, Mammary Cancer, Mammary Carcinoma, Human, Mammary Neoplasm, Human, Neoplasms, Breast, Tumors, Breast, Human Mammary Carcinoma, Malignant Neoplasm of Breast, Breast Carcinoma, Breast Tumors, Cancer of the Breast, Breast Neoplasms, Breast Cancer, RET Inhibitor, MTC, NSCLC, selpercatinib, neo-adjuvant treatment in early stage NSCLC
Brief summary
This is an open-label, first-in-human study designed to evaluate the safety, tolerability, pharmacokinetics (PK) and preliminary anti-tumor activity of selpercatinib (also known as LOXO-292) administered orally to participants with advanced solid tumors, including rearranged during transfection (RET)-fusion-positive solid tumors, medullary thyroid cancer (MTC) and other tumors with RET activation.
Detailed description
This is an open-label, multi-center Phase 1/2 study in participants with advanced solid tumors, including RET fusion-positive solid tumors, MTC, and other tumors with RET activation. The trial will be conducted in 2 parts: Phase 1 (dose escalation - completed) and phase 2 (dose expansion). Participants with advanced cancer are eligible if they have progressed on or are intolerant to available standard therapies, or no standard or available curative therapy exists, or in the opinion of the Investigator, they would be unlikely to tolerate or derive significant clinical benefit from appropriate standard of care therapy, or they declined standard therapy. A dose of 160 milligrams (mg) twice a day (BID) has been selected as the recommended phase 2 dose (RP2D). Approximately 875 participants with advanced solid tumors harboring a RET gene alteration in tumor and/or blood will be enrolled to one of six phase 2 cohorts: * Cohort 1: Advanced RET fusion positive solid tumor other than NSCLC or thyroid cancer for participants who progressed on or intolerant to first line therapy (open) * Cohort 2: Advanced RET fusion positive solid tumor other than NSCLC or thyroid cancer for treatment naïve participants (open) * Cohort 3: Advanced RET-mutant MTC participants who progressed on or intolerant to first line therapy (closed) * Cohort 4: Advanced RET-mutant MTC participants who are treatment naïve (closed) * Cohort 5: Advanced RET-altered solid tumor for participants other than NSCLC or thyroid cancer and RET-mutant MEN2 spectrum tumors (e.g. pheochromocytoma) otherwise ineligible for cohorts 1-4. See details in inclusion/exclusion criteria (open) * Cohort 6: Participants otherwise eligible for Cohorts 1-5 who discontinued another RET inhibitor due to intolerance may be eligible with prior Sponsor approval (closed)
Interventions
DRUGLOXO-292
Oral LOXO-292
Sponsors
Eli Lilly and Company
Loxo Oncology, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 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 (≥) 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 Key
Exclusion criteria
(Phase 1 and Phase 2): * Phase 2 Cohorts 1 and 2: 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 2 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) * 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Maximum Tolerated Dose (MTD) | Cycle 1 (cycle length = 28 days) | The MTD is defined as the highest dose level at which none of the first 3 treated patients, or not more than 1 of the first 6 treated patients, experiences a DLT. A DLT is any adverse events that starts on or after first administration of study drug, as defined by National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. * Any Grade(G) ≥3 nonhematologic toxicity, excluding * G3 AST, ALT, and/or total bilirubin elevation for \<7 days. * G3 neutropenia \<7 days * G3 thrombocytopenia without clinically significant bleeding * G3 or G4 lymphopenia. * First occurrence of G3 or G4 electrolyte abnormalities * G3 fatigue, weakness, nausea; other manageable constitutional symptom * G3 or G4 vomiting or diarrhea that lasts for \<48hours with antiemetic/antidiarrheal medication in case of G3 and \<24 hours in case of G4 * G4 manageable constitutional symptom. |
| Phase 1: Recommended Phase 2 Dose (RP2D) | Cycle 1 (cycle length = 28 days) | Phase 1: RP2D |
| Phase 2: Objective Response Rate (ORR) Based on Independent Review Committee (IRC) Assessment | Approximately for up to 7 years 8 months | Objective Response Rate was defined as the percentage of participants with best overall response of confirmed response (CR), or Partial response (PR). Response was confirmed by a repeat assessment no less than 28 days. * CR is defined as disappearance of all target lesions. * PR is defined as at least a 30% decrease in the sum of diameter (LD for non-nodal lesions and short axis diameter \[SAD\] for nodal lesions) of target lesions, taking as reference the baseline sum LD. ORR was assessed by independent review committee (IRC) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. 95% confidence interval was calculated using Clopper-Pearson method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Number of Participants With a Treatment-Related Adverse Event(s) (TRAE[s]) | Up to 28 days | Phase 1: Number of Participants with a TRAE(s) is reported. |
| Phase 1: Number of Participants With an Abnormal Laboratory Values | Up to 28 days | — |
| Phase 2: Overall Response Rate (ORR) Based on RECIST 1.1 or RANO, as Appropriate to Tumor Type | Approximately for up to 9 years 8 months | Phase 2: ORR based on RECIST 1.1 or RANO, as Appropriate to Tumor Type |
| Phase 2: ORR (by Investigator) | Approximately for up to 9 years 8 months | Phase 2: ORR (by Investigator) |
| Phase 2: Best Change in Tumor Size From Baseline (by IRC and Investigator) | Approximately for up to 9 years 8 months | Phase 2: Best Change in Tumor Size from Baseline (by IRC and Investigator) |
| Phase 2: Duration of Response (DOR; by IRC and Investigator) | Approximately for up to 9 years 8 months | Phase 2: DOR (by IRC and Investigator) |
| Phase 2: Central Nervous System (CNS) ORR (by IRC) | Approximately for up to 9 years 8 months | Phase 2: CNS ORR (by IRC) |
| Phase 2: CNS DOR (by IRC) | Approximately for up to 9 years 8 months | Phase 2: CNS DOR (by IRC) |
| Phase 2: Time to Any and Best Response (by IRC and Investigator) | Approximately for up to 9 years 8 months | Phase 2: Time to Any and Best Response (by IRC and Investigator) |
| Phase 2: CBR (by IRC and Investigator) | Approximately for up to 9 years 8 months | Phase 2: CBR (by IRC and Investigator) |
| Phase 2: PFS (by IRC and Investigator) | Approximately for up to 9 years 8 months | Phase 2: PFS (by IRC and Investigator) |
| Phase 2: Overall Survival (OS) | Approximately for up to 9 years 8 months | Phase 2: OS |
| Phase 2: Percentage of Participants With Any Serious Adverse Event (SAE[s]) | Approximately for up to 9 years 8 months | Phase 2: Percentage of Participants with any SAE(s) |
| Phase 2: Pharmacokinetics (PK): Area Under the Plasma Concentration-Time Curve of LOXO-292 (Selpercatinib) | Cycle 5 Day 1 (Cycle = 28 days) | Phase 2: PK: AUC of LOXO-292 (Selpercatinib) |
| Phase 2: PK: Maximum Concentration (Cmax) of LOXO-292 (Selpercatinib) | Cycle 5 Day 1 (Cycle = 28 days) | Phase 2: PK: Cmax of LOXO-292 (Selpercatinib) |
| Phase 1: Pharmacokinetics (PK): Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours | Cycle 1 Day 8: Predose, 1, 2, 4, 8, 24 hours post dose (cycle length = 28 days) | — |
| Phase 1: Pharmacokinetics (PK): Maximum Plasma Concentration (Cmax) | Cycle 1 Day 8: Predose, 1, 2, 4, 8, 24 hours post dose (cycle length = 28 days) | — |
Countries
Australia, Canada, Denmark, France, Germany, Hong Kong, Israel, Italy, Japan, Singapore, South Korea, Spain, Switzerland, Taiwan, United Kingdom, United States
Contacts
STUDY_DIRECTORCall 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)
Eli Lilly and Company
Participant flow
Recruitment details
This study includes two parts: * Phase 1 (dose escalation) and; * Phase 2 (dose expansion) In Phase 1, participants received selpercatinib, with dosing based on body surface area. The Phase 2 portion of the study was opened after confirmation of the RP2D of 160 mg BID.
Pre-assignment details
In Phase 2, participants were assigned to one of six tumor-based groups: RET Fusion Solid Tumor, RET Fusion Solid Tumor Without Standard Therapy, RET Mutant MTC, RET Mutant MTC Without Standard Therapy, Advanced RET Altered Solid Tumor, RET Inhibitor-Discontinued Participants and received selpercatinib at the RP2D. The current results reported are for the primary completion date (i.e., up to 7 years 9 months). Additional results will be reported at the time of final results reporting.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 298 Participants |
| Age, Categorical Between 18 and 65 years | 556 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 27 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 27 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 580 Participants |
| Sex: Female, Male Female | 421 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk | EG015 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 10 | 0 / 16 | 0 / 12 | 0 / 1 | 0 / 20 | 0 / 19 | 0 / 764 | 0 / 3 | 0 / 6 | 147 / 307 | 27 / 74 | 67 / 143 | 18 / 116 | 83 / 201 | 8 / 16 |
| other Total, other adverse events | 6 / 6 | 10 / 10 | 16 / 16 | 12 / 12 | 1 / 1 | 20 / 20 | 19 / 19 | 764 / 764 | 3 / 3 | 6 / 6 | 307 / 307 | 74 / 74 | 143 / 143 | 116 / 116 | 201 / 201 | 16 / 16 |
| serious Total, serious adverse events | 4 / 6 | 8 / 10 | 9 / 16 | 7 / 12 | 1 / 1 | 13 / 20 | 11 / 19 | 380 / 764 | 3 / 3 | 3 / 6 | 187 / 307 | 39 / 74 | 93 / 143 | 65 / 116 | 114 / 201 | 8 / 16 |
Outcome results
None listed