A Phase 1/2 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)
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 857
- 试验地点
- 164
- 主要终点
- Phase 1: MTD
研究概览
简要总结
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.
详细描述
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)
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 12 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •(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.
研究组 & 干预措施
Phase 1: 40 mg Selpercatinib BID
Participants received Selpercatinib 40 milligrams (mg) administered orally twice daily (BID), in a 28-day treatment cycle. Treatment was continued until disease progression, unacceptable toxicity, or treatment discontinuation for other reasons.
干预措施: LOXO-292 (Drug)
Phase 1: 20 mg Selpercatinib BID
Participants received Selpercatinib 20 milligrams (mg) administered orally twice daily (BID), in a 28-day treatment cycle. Treatment was continued until disease progression, unacceptable toxicity, or treatment discontinuation for other reasons.
干预措施: LOXO-292 (Drug)
Phase 2, Cohort 1: RET Fusion Solid Tumor
Participants with Rearranged during transfection (RET) Fusion solid tumor progressed on/intolerant to standard first line therapy received Selpercatinib 160 milligrams (mg) administered orally twice daily (BID), in a continuous 28-day treatment cycle. Treatment was continued until disease progression, unacceptable toxicity, or treatment discontinuation for other reasons.
干预措施: LOXO-292 (Drug)
Phase 2, Cohort 2: RET Fusion Solid Tumor Without Standard Therapy
Participants with RET Fusion solid tumor without standard first line therapy received Selpercatinib 160 milligrams (mg) administered orally twice daily (BID), in a continuous 28-day treatment cycle. Treatment was continued until disease progression, unacceptable toxicity, or treatment discontinuation for other reasons.
干预措施: LOXO-292 (Drug)
Phase 2, Cohort 3: RET Mutant MTC
Participants with RET mutant medullary thyroid cancer (MTC) progressed on/intolerant to standard first line therapy received Selpercatinib 160 milligrams (mg) administered orally twice daily (BID), in a continuous 28-day treatment cycle. Treatment was continued until disease progression, unacceptable toxicity, or treatment discontinuation for other reasons.
干预措施: LOXO-292 (Drug)
Phase 2, Cohort 4: RET Mutant MTC Without Standard Therapy
Participants with RET mutant MTC without prior standard first line therapy or other kinase inhibitor(s) with anti-RET activity received Selpercatinib 160 milligrams (mg) administered orally twice daily (BID), in a continuous 28-day treatment cycle. Treatment was continued until disease progression, unacceptable toxicity, or treatment discontinuation for other reasons.
干预措施: LOXO-292 (Drug)
Phase 1: 60 mg Selpercatinib BID
Participants received Selpercatinib 60 milligrams (mg) administered orally twice daily (BID), in a 28-day treatment cycle. Treatment was continued until disease progression, unacceptable toxicity, or treatment discontinuation for other reasons.
干预措施: LOXO-292 (Drug)
Phase 1: 120 mg Selpercatinib BID
Participants received Selpercatinib 120 milligrams (mg) administered orally twice daily (BID), in a 28-day treatment cycle. Treatment was continued until disease progression, unacceptable toxicity, or treatment discontinuation for other reasons.
干预措施: LOXO-292 (Drug)
Phase 1: 80 mg Selpercatinib BID
Participants received Selpercatinib 80 milligrams (mg) administered orally twice daily (BID), in a 28-day treatment cycle. Treatment was continued until disease progression, unacceptable toxicity, or treatment discontinuation for other reasons.
干预措施: LOXO-292 (Drug)
Phase 1: 160 mg Selpercatinib QD
Participants received Selpercatinib 160 milligrams (mg) administered orally once daily (QD), in a 28-day treatment cycle. Treatment was continued until disease progression, unacceptable toxicity, or treatment discontinuation for other reasons.
干预措施: LOXO-292 (Drug)
Phase 1: 200 mg Selpercatinib BID
Participants received Selpercatinib 200 milligrams (mg) administered orally twice daily (BID), in a 28-day treatment cycle. Treatment was continued until disease progression, unacceptable toxicity, or treatment discontinuation for other reasons.
干预措施: LOXO-292 (Drug)
Phase 1: 160 mg Selpercatinib BID
Participants received Selpercatinib 160 milligrams (mg) administered orally twice daily (BID), in a 28-day treatment cycle. Treatment was continued until disease progression, unacceptable toxicity, or treatment discontinuation for other reasons.
干预措施: LOXO-292 (Drug)
Phase 1: 240 mg Selpercatinib BID
Participants received Selpercatinib 240 milligrams (mg) administered orally twice daily (BID), in a 28-day treatment cycle. Treatment was continued until disease progression, unacceptable toxicity, or treatment discontinuation for other reasons.
干预措施: LOXO-292 (Drug)
Phase 2, Cohort 6: RET Inhibitor-Discontinued Participants
Participants otherwise eligible for Cohorts 1-5 who discontinued other RET inhibitors received Selpercatinib 160 milligrams (mg) administered orally twice daily (BID), in a continuous 28-day treatment cycle. Treatment was continued until disease progression, unacceptable toxicity, or treatment discontinuation for other reasons.
干预措施: LOXO-292 (Drug)
Phase 2, Cohort 5: Advanced RET Altered Solid Tumor
Participants with RET altered solid tumor (cohorts 1-4, disease not measurable; MTC not eligible for Cohort 3 or 4; MTC syndrome spectrum cancer; circulating free tumor DNA [cfDNA+] for RET alteration not known to be present in tumor) received Selpercatinib 160 milligrams (mg) administered orally twice daily (BID), in a continuous 28-day treatment cycle. Treatment was continued until disease progression, unacceptable toxicity, or treatment discontinuation for other reasons.
干预措施: LOXO-292 (Drug)
Phase 1: 20 mg Selpercatinib QD
Participants received Selpercatinib 20 milligrams (mg) administered orally once daily (QD), in a 28-day treatment cycle. Treatment was continued until disease progression, unacceptable toxicity, or treatment discontinuation for other reasons.
干预措施: LOXO-292 (Drug)
结局指标
主要结局
Phase 1: MTD
时间窗: The first 28 days of treatment (Cycle 1)
Incidence rate and category of dose limiting toxicities (DLTs) during the first 28-day cycle of LOXO-292 (selpercatinib) treatment
Phase 1: RP2D
时间窗: The first 28 days of treatment (Cycle 1) and every cycle (28 days) for approximately 12 months (or earlier if the participant discontinues from the study)
Phase 1: RP2D
Phase 2: Objective Response Rate
时间窗: Approximately every 8 weeks for one year, then every 12 weeks, and 7 days after the last dose (for up to 2 years) in participants who have not progressed.
As assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or Response Assessment in Neuro-Oncology (RANO), as appropriate to tumor type, as assessed by independent review committee (IRC)
Phase 1: Maximum Tolerated Dose (MTD)
时间窗: 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)
时间窗: Cycle 1 (cycle length = 28 days)
Phase 1: RP2D
Phase 2: Objective Response Rate (ORR) Based on Independent Review Committee (IRC) Assessment
时间窗: 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.
次要结局
- Phase 1: Number of Participants with a Treatment-Related Adverse Event(s) (TRAE[s])(From the time of informed consent, for approximately 24 months (or earlier if the participant discontinues from the study), and through Safety Follow-up (28 days after the last dose))
- Phase 2: Overall Survival (OS)(Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in participants who have not progressed)
- Phase 1: Overall Response Rate (ORR) based on RECIST 1.1 or RANO, as Appropriate to Tumor Type(Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in participants who have not progressed)
- Phase 2: Best Change in Tumor Size from Baseline (by IRC and Investigator)(Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in participants who have not progressed)
- Phase 2: Time to Any and Best Response (by IRC and Investigator)(every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in participants who have not progressed)
- Phase 2: CBR (by IRC and Investigator)(Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in participants who have not progressed)
- Phase 1: Number of Participants with an Abnormal Laboratory or Physical Exam Result(s)(From the time of informed consent, for approximately 24 months (or earlier if the participant discontinues from the study), and through Safety Follow-up (28 days after the last dose))
- Phase 2: Duration of Response (DOR; by IRC and Investigator)(Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in participants who have not progressed)
- Phase 2: CNS DOR (by IRC)(Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in participants who have not progressed)
- Phase 1 and 2: PK: Maximum Concentration (Cmax) of LOXO-292 (Selpercatinib)(Cycle 1 Day 1 through Cycle 5 Day 1 (Cycle = 28 days))
- Phase 2: ORR (by Investigator)(Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in participants who have not progressed)
- Phase 2: Central Nervous System (CNS) ORR (by IRC)(Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in participants who have not progressed)
- Phase 2: PFS (by IRC and Investigator)(Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in participants who have not progressed)
- Phase 2: Percentage of Participants with any Serious Adverse Event (SAE[s])(From the time of informed consent, for approximately 24 months (or earlier if the participant discontinues from the study), and through Safety Follow-up (28 days after the last dose))
- Phase 1 and 2: Pharmacokinetics (PK): Area Under the Plasma Concentration-Time Curve of LOXO-292 (Selpercatinib)(Cycle 1 Day 1 through Cycle 5 Day 1 (Cycle = 28 days))
- Phase 1: Number of Participants With a Treatment-Related Adverse Event(s) (TRAE[s])(Up to 28 days)
- 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 (by Investigator)(Approximately for up to 9 years 8 months)
- Phase 2: Best Change in Tumor Size From Baseline (by IRC and Investigator)(Approximately for up to 9 years 8 months)
- Phase 2: Duration of Response (DOR; by IRC and Investigator)(Approximately for up to 9 years 8 months)
- Phase 2: Central Nervous System (CNS) ORR (by IRC)(Approximately for up to 9 years 8 months)
- Phase 2: CNS DOR (by IRC)(Approximately for up to 9 years 8 months)
- Phase 2: Time to Any and Best Response (by IRC and Investigator)(Approximately for up to 9 years 8 months)
- Phase 2: CBR (by IRC and Investigator)(Approximately for up to 9 years 8 months)
- Phase 2: PFS (by IRC and Investigator)(Approximately for up to 9 years 8 months)
- Phase 2: Overall Survival (OS)(Approximately for up to 9 years 8 months)
- Phase 2: Percentage of Participants With Any Serious Adverse Event (SAE[s])(Approximately for up to 9 years 8 months)
- 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: Maximum Concentration (Cmax) of LOXO-292 (Selpercatinib)(Cycle 5 Day 1 (Cycle = 28 days))
- 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))