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Testing the Use of Targeted Treatment for RET Positive Advanced Non-small Cell Lung Cancer

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ClinicalTrials.gov Identifier: NCT05364645
Recruitment Status : Recruiting
First Posted : May 6, 2022
Last Update Posted : June 11, 2024
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
SWOG Cancer Research Network

Tracking Information
First Submitted Date  ICMJE May 3, 2022
First Posted Date  ICMJE May 6, 2022
Last Update Posted Date June 11, 2024
Actual Study Start Date  ICMJE July 25, 2022
Actual Primary Completion Date June 27, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 3, 2022)
Investigator-assessed progression-free survival (PFS) [ Time Frame: From date of sub-study randomization 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 ]
Will be compared between the arms using a 1-sided log-rank test at the 0.10 level upon the observation of 55 PFS events or at a maximum follow-up duration (from closure of accrual of 15 months). Will be estimated using the method of Kaplan-Meier. Confidence intervals about median event times will be estimated using the Brookmeyer-Crowley method. For point estimates at landmark times, the associated 95% confidence interval (CI) will be calculated using Greenwood's formula and based on a log-log transformation applied on the survival function. Hazard ratios for these outcomes will be estimated using a Cox Proportional Hazards regression.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 3, 2022)
  • Incidence of grade 3 or higher non hematologic toxicity and grade 4 or higher hematologic toxicity [ Time Frame: During first cycle (1 cycle = 21 days) ]
  • Frequency and severity of adverse events [ Time Frame: Up to 3 years ]
  • Investigator-assessed objective response rate [ Time Frame: Up to 3 years ]
  • Overall survival [ Time Frame: From date of sub-study randomization to date of death due to any cause, assessed up to 3 years ]
    Will be estimated using the method of Kaplan-Meier. Confidence intervals about median event times will be estimated using the Brookmeyer-Crowley method. For point estimates at landmark times, the associated 95% CI will be calculated using Greenwood's formula and based on a log-log transformation applied on the survival function. Hazard ratios for these outcomes will be estimated using a Cox Proportional Hazards regression.
  • Duration of investigator-assessed response [ Time Frame: From date of first documentation of response (complete response [CR] or partial response [PR]) to date of first documentation of progression, or death due to any cause among participants who achieve a response (CR or PR), assessed up to 3 years ]
    Will be estimated using the method of Kaplan-Meier. Confidence intervals about median event times will be estimated using the Brookmeyer-Crowley method. For point estimates at landmark times, the associated 95% CI will be calculated using Greenwood's formula and based on a log-log transformation applied on the survival function. Hazard ratios for these outcomes will be estimated using a Cox Proportional Hazards regression.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Testing the Use of Targeted Treatment for RET Positive Advanced Non-small Cell Lung Cancer
Official Title  ICMJE A Randomized Phase II Study of Carboplatin and Pemetrexed w/ or w/o Selpercatinib in Participants With Non-Squamous RET Fusion-Positive Stage IV Non-Small Cell Lung Cancer and Progression of Disease on Prior RET Directed Therapy (Lung-MAP Sub-Study)
Brief Summary This phase II Lung-MAP treatment trial tests whether carboplatin and pemetrexed with or without selpercatinib works to shrink tumors in patients with RET fusion-positive non-small cell lung cancer that is stage IV or has not responded to previous RET directed therapy. Chemotherapy drugs, such as carboplatin and pemetrexed, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Selpercatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving selpercatinib in combination with carboplatin and pemetrexed may help lower the chance of the cancer growing and spreading.
Detailed Description

PRIMARY OBJECTIVE:

I. To compare investigator-assessed progression-free survival (IA-PFS) in participants with RET fusion-positive non-small cell lung cancer (NSCLC) with acquired selective RET inhibitor resistance randomized to carboplatin and pemetrexed with or without selpercatinib.

SECONDARY OBJECTIVES:

I. To evaluate if the combination of selpercatinib combined with carboplatin and pemetrexed during the first cycle of treatment has an acceptable toxicity rate.

II. To evaluate the frequency and severity of toxicities within the arms. III. To compare the investigator-assessed objective response rate (ORR) (complete or partial confirmed response) between the arms.

IV. To compare overall survival (OS) between the arms. V. To evaluate duration of investigator-assessed response among responders within each treatment arm.

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 participants with refractory non-small cell lung cancer (NSCLC).

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive carboplatin intravenously (IV) over 30 minutes and pemetrexed IV over 10 minutes on day 1. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also selpercatinib orally (PO) twice daily (BID) in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive carboplatin IV over 30 minutes and pemetrexed IV over 10 minutes on day 1. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients who had disease progression are followed up every 6 months for 2 years and then at 3 years. Patients who did not have disease progression are followed up every 12 weeks until disease progression.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Lung Non-Small Cell Carcinoma
  • Recurrent Lung Non-Small Cell Carcinoma
  • Stage IV Lung Cancer AJCC v8
  • Stage IVA Lung Cancer AJCC v8
  • Stage IVB Lung Cancer AJCC v8
Intervention  ICMJE
  • Drug: Carboplatin
    Given IV
    Other Names:
    • Blastocarb
    • Carboplat
    • Carboplatin Hexal
    • Carboplatino
    • Carboplatinum
    • Carbosin
    • Carbosol
    • Carbotec
    • CBDCA
    • Displata
    • Ercar
    • JM-8
    • Nealorin
    • Novoplatinum
    • Paraplatin
    • Paraplatin AQ
    • Paraplatine
    • Platinwas
    • Ribocarbo
  • Drug: Pemetrexed
    Given IV
    Other Names:
    • MTA
    • Multitargeted Antifolate
    • Pemfexy
  • Drug: Selpercatinib
    Given PO
    Other Names:
    • LOXO-292
    • RET Kinase Inhibitor LOXO-292
    • Retevmo
    • WHO 10967
Study Arms  ICMJE
  • Experimental: Arm A (carboplatin, pemetrexed, selpercatinib)
    Patients receive carboplatin IV over 30 minutes and pemetrexed IV over 10 minutes on day 1. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also selpercatinib PO BID in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: Carboplatin
    • Drug: Pemetrexed
    • Drug: Selpercatinib
  • Active Comparator: Arm B (carboplatin, pemetrexed)
    Patients receive carboplatin IV over 30 minutes and pemetrexed IV over 10 minutes on day 1. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: Carboplatin
    • Drug: Pemetrexed
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 3, 2022)
74
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 1, 2029
Actual Primary Completion Date June 27, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Participants must have stage IV or recurrent disease
  • Participants must have been assigned to S1900F based on biomarker analysis of tissue and/or blood and determined to have RET fusion-positive NSCLC as defined here:

    • Participants must have RET fusion-positive NSCLC as determined by the Foundation Medicine (FMI) tissue-assay or other tumor-based assays such as next generation sequencing (NGS), polymerase chain reaction (PCR), or fluorescent in situ hybridization (FISH), or by cfDNA blood assay as outlined in the LUNGMAP Screening Protocol. Participants previously tested for and determined to have RET-fusion-positive NSCLC outside of LUNGMAP, must also submit tissue for central FMI testing on the LUNGMAP Screening Protocol. Participants with RET fusions detected by 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
  • Participants must be negative for all additional validated oncogenic drivers that could cause resistance to selpercatinib treatment. This includes EGFR sensitizing mutations, EGFR T790M mutations, ALK gene fusions, ROS1 gene fusion, KRAS activating mutations, BRAF V600E mutation and MET exon 14 skipping mutations 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 randomization.
  • Participants 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 randomization. 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 randomization. All disease must be assessed and documented on the Baseline Tumor Assessment Form. Participants 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 randomization
  • Participants must have a CT or MRI scan of the brain to evaluate for central nervous system (CNS) disease within 42 days prior to sub-study randomization
  • Participants must have received and developed disease progression during or after an anti-RET inhibitors treatment. The anti-RET inhibitor therapy must be the most recent therapy
  • Participants must have progressed (in the opinion of the treating physician) following the most recent line of therapy
  • Participants must have recovered (=< grade 1) from any side effects of prior therapy. Participants must not have received any radiation therapy within 14 days prior to sub-study randomization
  • For participants with stage IV or recurrent disease, the participant must not have received a platinum-based chemotherapy regimen. For participants whose prior systemic therapy was for stage I-III disease only (i.e., participant has not received any treatment for stage IV or recurrent disease), disease progression on platinum-based chemotherapy must not have occurred within one year (365 days) from the last date that the participant received that therapy. Prior anti-PD-1/PD-L1 therapy, alone or in combination (e.g., nivolumab, pembrolizumab, or durvalumab) is allowed
  • Participants must have an electrocardiogram (ECG) performed within 28 days prior to sub-study randomization. It is suggested that a local cardiologist review the corrected QT by Fridericia's correction formula (QTcF) intervals
  • Absolute neutrophil count (ANC) >= 1.5 x 10^3/uL obtained within 28 days prior to sub-study randomization
  • Platelet count >= 100 x 10^3/uL obtained within 28 days prior to sub-study randomization
  • Hemoglobin >= 9 g/dL obtained within 28 days prior to sub-study randomization
  • Serum bilirubin =< institutional upper limit of normal (IULN) and either alanine aminotransferase (ALT) or aspartate aminotransferase (AST) =< 2 x IULN within 28 days prior to sub-study randomization (if both ALT and AST are done, both must be < 2 x IULN). For participants 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)
  • Participants must have a serum creatinine =< the IULN OR measured or calculated creatinine clearance >= 50 mL/min using the following Cockcroft-Gault Formula. This specimen must have been drawn and processed within 28 days prior to sub-study randomization
  • Participants must have Zubrod performance status 0-1 documented within 28 days prior to sub-study randomization
  • Participants must provide pre-study history and physical exam within 28 days prior to sub-study randomization
  • Participants with evidence of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load on suppressive therapy within 28 days prior to sub-study randomization
  • Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. Participants with HCV infection who are currently on treatment must have an undetectable HCV viral load within 28 days prior to sub-study randomization
  • Participants 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 sub-study randomization
  • Participants must be able to swallow capsules
  • Participants must agree to have blood specimens submitted for circulating tumor DNA (ctDNA)
  • Participants must also be offered participation in banking and in the correlative studies for collection and future use of specimens
  • Participants 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)
  • Participants 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

Exclusion Criteria:

  • Participants 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 sub-study randomization, AND (2) participant has no residual neurological dysfunction and has been off corticosteroids for at least 24 hours prior to sub-study randomization
  • Participants must not have received any prior systemic therapy (systemic chemotherapy, tyrosine kinase inhibitor [TKI], immunotherapy or investigational drug) within 14 days prior to sub-study randomization
  • Participants 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
  • Participants must not have a prior or concurrent malignancy whose natural history or treatment (in the opinion of the treating physician) has the potential to interfere with the safety or efficacy assessment of the investigational regimen
  • Participants must not have had a major surgery within 14 days prior to sub-study randomization. Participants must have fully recovered from the effects of prior surgery in the opinion of the treating investigator
  • Participants must not have any grade III/IV cardiac disease as defined by the New York Heart Association Criteria (i.e., participants 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
  • Participants must not be pregnant or nursing. Individuals who are of reproductive potential must have agreed to use an effective contraceptive method with details provided as a part of the consent process. A person who has had menses at any time in the preceding 12 consecutive months or who has semen likely to contain sperm is considered to be of "reproductive potential." In addition to routine contraceptive methods, "effective contraception" also includes refraining from sexual activity that might result in pregnancy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) including hysterectomy, bilateral oophorectomy, bilateral tubal ligation/occlusion, and vasectomy with testing showing no sperm in the semen
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT05364645
Other Study ID Numbers  ICMJE S1900F
NCI-2022-02517 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
S1900F ( Other Identifier: SWOG )
S1900F ( Other Identifier: CTEP )
U10CA180888 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party SWOG Cancer Research Network
Original Responsible Party Same as current
Current Study Sponsor  ICMJE SWOG Cancer Research Network
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Yasir Y Elamin SWOG Cancer Research Network
PRS Account SWOG Cancer Research Network
Verification Date June 2024

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP