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Targeted Treatment for RET Fusion-Positive Advanced Non-Small Cell Lung Cancer (A LUNG-MAP Treatment Trial)

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ClinicalTrials.gov Identifier: NCT04268550
Recruitment Status : Active, not recruiting
First Posted : February 13, 2020
Last Update Posted : December 7, 2023
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
SWOG Cancer Research Network

Study Description
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Brief Summary:
This phase II LUNG-MAP treatment trial studies how well selpercatinib works in treating patients with RET fusion-positive non-small cell lung cancer that is stage IV or has come back (recurrent). Selpercatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition or disease Intervention/treatment Phase
Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Cancer AJCC v8 Stage IVA Lung Cancer AJCC v8 Stage IVB Lung Cancer AJCC v8 Drug: Selpercatinib Phase 2

Detailed Description:

PRIMARY OBJECTIVE:

I. To evaluate the objective response rate (ORR) (confirmed complete or partial response) by blinded independent centralized review (BICR) associated with selpercatinib (LOXO-292) in patients with previously-treated stage IV or recurrent RET fusion-positive non-small cell lung cancer (NSCLC).

SECONDARY OBJECTIVES:

I. To evaluate the duration of BICR-assessed response among BICR responders. II. To evaluate the frequency and severity of toxicities. III. To evaluate the investigator-assessed objective response rate (confirmed complete or partial response).

IV. To evaluate duration of investigator-assessed response among patients with a response as determined by the local investigator.

V. To evaluate investigator-assessed progression-free survival (IA-PFS). VI. To evaluate BICR-assessed PFS. VII. To evaluate overall survival (OS).

VIII. Among patients with brain metastases at baseline:

VIIIa. To evaluate the central nervous system (CNS) response rate (confirmed complete response [CR]).

VIIIb. To evaluate the duration of intracranial response among patients with a CNS response.

TRANSLATIONAL MEDICINE OBJECTIVES:

I. To collect, process, and bank cell-free deoxyribonucleic acid (cfDNA) at baseline, progression, and end of treatment for future development of a proposal to evaluate comprehensive next-generation sequencing of circulating tumor deoxyribonucleic acid (ctDNA).

II. To establish a tissue/blood repository from patients with refractory non-small cell lung cancer (NSCLC).

OUTLINE:

Patients receive selpercatinib orally (PO) twice daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for 2 years and then at the end of 3 years from date of sub-study registration.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 124 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of LOXO-292 in Patients With RET Fusion-Positive Stage IV or Recurrent Non-Small Cell Lung Cancer (LUNG-MAP Sub-Study)
Actual Study Start Date : April 8, 2020
Estimated Primary Completion Date : May 1, 2024
Estimated Study Completion Date : May 1, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer

Arms and Interventions
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Arm Intervention/treatment
Experimental: Treatment (selpercatinib)
Patients receive selpercatinib orally PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
 Drug: Selpercatinib
Given PO
Other Names:
  • LOXO-292
  • RET Kinase Inhibitor LOXO-292


Outcome Measures
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Primary Outcome Measures :
  1. Response rate by blinded independent centralized review (BICR) [ Time Frame: Up to 3 years from date of sub-study registration ]
    A response will be confirmed by a complete response (CR) or partial response (PR). Proportions and associated confidence intervals will be calculated.


Secondary Outcome Measures :
  1. Incidence of adverse events [ Time Frame: Up to 3 years from date of sub-study registration ]
    Will be assessed using Common Terminology Criteria for Adverse Event version 5.0.

  2. BICR-progression-free survival (PFS) [ Time Frame: From date of sub-study registration to date of first documentation of progression assessed by BICR or symptomatic deterioration, or death due to any cause, assessed up to 3 years from date of sub-study registration ]
    Will be estimated using the method of Kaplan-Meier. The Brookmeyer-Crowley method will be used to estimate confidence intervals for the median using Greenwood's formula and based on a log-log transformation applied on the survival function for landmark times

  3. Investigator-assessed (IA) PFS [ Time Frame: From date of sub-study registration to date of first documentation of progression assessed by local review or symptomatic deterioration, or death due to any cause, assessed up to 3 years from date of sub-study registration ]
    Will be estimated using the method of Kaplan-Meier. The Brookmeyer-Crowley method will be used to estimate confidence intervals for the median using Greenwood's formula and based on a log-log transformation applied on the survival function for landmark times

  4. Overall survival [ Time Frame: Up to 3 years from date of sub-study registration ]
    Will be estimated using the method of Kaplan-Meier. The Brookmeyer-Crowley method will be used to estimate confidence intervals for the median using Greenwood's formula and based on a log-log transformation applied on the survival function for landmark times

  5. BICR-duration of response (DOR) [ Time Frame: From date of first documentation of confirmed response (CR or PR) to date of first documentation of progression assessed by BICR or symptomatic deterioration, or death due to any cause among patients who achieve, assessed at 6 and 12 months ]
    Will be evaluated among patients who achieve a confirmed response. Will be estimated using the method of Kaplan-Meier. The Brookmeyer-Crowley method will be used to estimate confidence intervals for the median using Greenwood's formula and based on a log-log transformation applied on the survival function for landmark times. The median DOR and percentage with DOR at landmark times at 6 and 12 months after documentation of confirmed response will be estimated.

  6. Central nervous system (CNS) response rate [ Time Frame: Baseline ]
    Will be assessed among patients with brain metastases. Will be estimated using the method of Kaplan-Meier. The Brookmeyer-Crowley method will be used to estimate confidence intervals for the median using Greenwood's formula and based on a log-log transformation applied on the survival function for landmark times

  7. Duration of intracranial response among patients with a CNS response [ Time Frame: Baseline ]
    Will be assessed among patients with brain metastases. Will be estimated using the method of Kaplan-Meier. The Brookmeyer-Crowley method will be used to estimate confidence intervals for the median using Greenwood's formula and based on a log-log transformation applied on the survival function for landmark times


Eligibility Criteria
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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have been assigned to S1900B based on biomarker analysis of tissue and/or blood and determined to have RET fusion-positive NSCLC as defined here:

    • Patients must have RET fusion-positive NSCLC as determined by the Foundation Medicine (FMI) tissue-assay, other tumor-based assays such as next-generation sequencing (NGS), polymerase chain reaction (PCR), or follicular in situ hybridization (FISH), or by cfDNA blood assay. Patients with RET fusions detected by immunohistochemistry (IHC) alone are not eligible. The testing must be done within a laboratory with Clinical Laboratory Improvement Act (CLIA), International Organization for Standardization (ISO/International Electrotechnical Commission (IEC), College of American Pathologists (CAP), or similar certification. Presence of RET fusions detected on tests performed outside of LUNGMAP must have been confirmed by the study biomarker review panel
  • For patients whose prior therapy was for stage IV or recurrent disease, the patient must have received at least one line of a platinum-based chemotherapy regimen. For patients whose prior systemic therapy was for stage I-III disease only (i.e. patient has not received any treatment for stage IV or recurrent disease), disease progression on platinum-based chemotherapy must have occurred within one year from the last date that the patient received that therapy. Prior anti-PD-1/PD-L1 therapy, alone or in combination (e.g. nivolumab, pembrolizumab, or durvalumab) is allowed

  • Patients must be negative for all additional validated oncogenic drivers that could cause resistance to LOXO-292 treatment. This includes EGFR sensitizing mutations, EGFR T790M, ALK gene fusion, ROS1 gene fusion, KRAS activating mutation, BRAF V600E mutation and MET exon 14 skipping mutation or high-level amplification and expression

    • Note: EGFR, ALK, ROS, KRAS, and BRAF testing is performed as part of the LUNGMAP screening/pre-screening FoundationOne test. If prior data is not available, results from the FMI testing must be obtained prior to sub-study registration
  • Patients must have measurable disease documented by computed tomography (CT) or magnetic resonance imaging (MRI). The CT from a combined positron emission tomography (PET)/CT may be used to document only non-measurable disease unless it is of diagnostic quality. Measurable disease must be assessed within 28 days prior to sub-study registration. Pleural effusions, ascites and laboratory parameters are not acceptable as the only evidence of disease. Non-measurable disease must be assessed within 42 days prior to sub-study registration. All disease must be assessed and documented on the Baseline Tumor Assessment Form. Patients whose only measurable disease is within a previous radiation therapy port must demonstrate clearly progressive disease (in the opinion of the treating investigator) prior to registration. CT and MRI scans must be submitted for central review via transfer of images and data (TRIAD)
  • Patients must have a CT or MRI scan of the brain to evaluate for CNS disease within 42 days prior to sub-study registration
  • Patients with evidence of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load on suppressive therapy within 28 days prior to registration
  • Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. Patients with HCV infection who are currently on treatment must have an undetectable HCV viral load within 28 days prior to registration
  • Patients with known human immunodeficiency virus (HIV) infection are eligible, provided they are on effective anti-retroviral therapy and have undetectable viral load at their most recent viral load test and within 6 months prior to registration
  • Patients must be able to swallow capsules
  • Patients must have progressed (in the opinion of the treating physician) following the most recent line of therapy
  • Patients must have recovered (=< grade 1) from any side effects of prior therapy. Patients must not have received any radiation therapy within 14 days prior to sub-study registration
  • Absolute neutrophil count (ANC) >= 1,500/mcl (obtained within 28 days prior to sub-study registration)
  • Platelet count >= 100,000 mcl (obtained within 28 days prior to sub-study registration)
  • Serum bilirubin =< institutional upper limit of normal (IULN) (within 28 days prior to sub-study registration). For patients with liver metastases, bilirubin must be =< 5 x IULN
  • Either alanine aminotransferase (ALT) or aspartate aminotransferase (AST) =< 2 x IULN (within 28 days prior to sub-study registration) (if both ALT and AST are done, both must be =< 2 IULN). For patients with liver metastases, bilirubin and either ALT or AST must be =< 5 x IULN (if both ALT and AST are done, both must be =< 5 x IULN)
  • Serum creatinine =< the IULN or calculated creatinine clearance >= 50 mL/min using the following Cockcroft-Gault formula (within 28 days prior to sub-study registration)
  • Patients must have Zubrod performance status 0-1 documented within 28 days prior to sub-study registration
  • Pre-study history and physical exam must be obtained within 28 days prior to sub-study registration
  • No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years
  • Patients must have electrolytes and blood urea nitrogen (BUN) performed within 14 days prior to sub-study registration
  • Patients must agree to have blood specimens submitted for circulating tumor DNA (ctDNA)
  • Patients must also be offered participation in banking and in the correlative studies for collection and future use of specimens
  • Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines
  • As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system
  • Patients with impaired decision-making capacity are eligible as long as their neurological or psychological condition does not preclude their safe participation in the study (e.g., tracking pill consumption and reporting adverse events to the investigator)

Exclusion Criteria:

  • Patients must not have received any prior treatment with selective anti-RET inhibitors (anti-RET multikinase inhibitors are permitted)
  • Patient must not have leptomeningeal disease, spinal cord compression or brain metastases unless: (1) metastases have been locally treated and have remained clinically controlled and asymptomatic for at least 14 days following treatment, and prior to registration, AND (2) patient has no residual neurological dysfunction and has been off corticosteroids for at least 24 hours prior to sub-study registration
  • Patients must not have received any prior systemic therapy (systemic chemotherapy, immunotherapy or investigational drug) within 14 days prior to sub-study registration
  • Patients must not be planning to receive any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment while receiving treatment on this study. Concurrent use of hormones for non-cancer-related conditions (e.g., insulin for diabetes and hormone replacement therapy) is acceptable
  • Patient must not have had a major surgery within 14 days prior to sub-study registration. Patient must have fully recovered from the effects of prior surgery in the opinion of the treating investigator
  • Patients must not have any grade III/IV cardiac disease as defined by the New York Heart Association Criteria (i.e., patients with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort), unstable angina pectoris, and myocardial infarction within 6 months, or serious uncontrolled cardiac arrhythmia
  • Patients must not have a QT interval by Fridericia (QTcF) > 470 msec based on the electrocardiogram (ECG) within 28 days prior to registration. It is suggested that a local cardiologist review the QTcF intervals

  • Patients must not have any clinically significant uncontrolled systemic illness, including but not limited to uncontrolled infection, requiring intravenous antibiotics, unstable angina pectoris, myocardial infarction within the past 6 months, uncontrolled cardiac arrhythmias, uncontrolled hypertension, or uncontrolled diabetes mellitus

    • Uncontrolled diabetes: Patients who have a diagnosis of diabetes must have an hemoglobin (Hb) A1C < 7% within 28 days prior to registration. The same criterion will be used in patients with confirmed diagnosis of diabetes mellitus who have been on a stable dietary or therapeutic regimen for this condition in the last three months
    • Uncontrolled blood pressure and hypertension: All blood pressure measurements within the 28 days prior to registration must be systolic blood pressure (SBP) =< 180 and diastolic blood pressure (DBP) =< 100. An exception can be made by a healthcare provider for a patient with a single blood pressure elevation who upon rechecking has a blood pressure within the parameters above
  • Patients must not have any impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of LOXO-292 (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or active peptic ulcer disease)
  • Patients must not be planning to receive any strong inhibitors or inducers of CYP3A4 at least 14 days prior to sub-study registration and throughout protocol treatment
  • Patients must not be planning to use proton pump inhibitors (PPIs) at least one week prior to sub-study registration and throughout protocol treatment
  • Patients must not be pregnant or nursing. Women study patients of reproductive potential and fertile men study patients and their partners must abstain or use effective contraception (including barrier method) while receiving study treatment and for at least 3 months after the last dose of LOXO-292. Male study patients must agree not to donate sperm for 6 months after the last dose of LOXO-292. A woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation. However, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04268550


Locations
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Sponsors and Collaborators
SWOG Cancer Research Network
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Yasir Y Elamin SWOG Cancer Research Network
More Information
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Responsible Party: SWOG Cancer Research Network
ClinicalTrials.gov Identifier: NCT04268550    
Other Study ID Numbers: S1900B
NCI-2019-08097 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
S1900B ( Other Identifier: SWOG )
S1900B ( Other Identifier: CTEP )
U10CA180888 ( U.S. NIH Grant/Contract )
First Posted: February 13, 2020    Key Record Dates
Last Update Posted: December 7, 2023
Last Verified: December 2023

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
 Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms