A Study to Compare Standard Therapy to Treat Hodgkin Lymphoma to the Use of Two Drugs, Brentuximab Vedotin and Nivolumab

תקציר

This phase III trial compares the effect of adding immunotherapy (brentuximab vedotin and nivolumab) to standard treatment (chemotherapy with or without radiation) to the standard treatment alone in improving survival in patients with stage I and II classical Hodgkin lymphoma. Brentuximab vedotin is in a class of medications called antibody-drug conjugates. It is made of a monoclonal antibody called brentuximab that is linked to a cytotoxic agent called vedotin. Brentuximab attaches to CD30 positive lymphoma cells in a targeted way and delivers vedotin to kill them. A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs such as doxorubicin hydrochloride, bleomycin sulfate, vinblastine sulfate, dacarbazine, and procarbazine hydrochloride work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Cyclophosphamide is in a class of medications called alkylating agents. It works by damaging the cell's deoxyribonucleic acid (DNA) and may kill cancer cells. It may also lower the body's immune response. Etoposide is in a class of medications known as podophyllotoxin derivatives. It blocks a certain enzyme needed for cell division and DNA repair and may kill cancer cells. Vincristine is in a class of medications called vinca alkaloids. It works by stopping cancer cells from growing and dividing and may kill them. Prednisone is in a class of medications called corticosteroids. It is used to reduce inflammation and lower the body's immune response to help lessen the side effects of chemotherapy drugs. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Adding immunotherapy to the standard treatment of chemotherapy with or without radiation may increase survival and/or fewer short-term or long-term side effects in patients with classical Hodgkin lymphoma compared to the standard treatment alone.

זכאות

תכנון המחקר

מדדי תוצאה

1. מדד תוצאה ראשוני

   Progression-free survival (PFS) in rapid early responder (RER) patients

   Will compare the PFS of RER patients randomized to immunotherapy (IO) therapy (brentuximab vedotin-nivolumab) against those randomized to standard therapy. PFS curves will be estimated separately by arm using Kaplan Meier methodology, and the test will be a 1-sided log-rank test between the (pooled) IO and standard arms, stratified according to the stratification factors at randomization and including all eligible and evaluable randomized patients.

   מסגרת זמן From the time of randomization to the earliest time of disease relapse, progression, or death due to any cause, assessed up to 3 years after the randomization of the last patient or when reaching 124 events, whichever comes first

2. מדד תוצאה ראשוני

   PFS in slow-early responder (SER) patients

   Will compare PFS among SER patients randomized to IO therapy and involved-site radiation therapy against arms containing standard therapy. PFS curves will be estimated separately by arm using Kaplan Meier methodology, and the test will be a 1-sided log-rank test between the (pooled) IO and standard arms, stratified according to the stratification factors at randomization and including all eligible and evaluable randomized patients.

   מסגרת זמן From the time of randomization to the earliest time of disease relapse, progression, or death due to any cause, assessed up to 3 years after the randomization of the last patient or when reaching 71 events, whichever comes first

3. מדד תוצאה משני

   Overall survival (OS) in RER patients

   The non-inferiority of IO therapy to standard therapy will be tested in the randomized and eligible RER cohort using a confidence interval approach performed 12 years after the last patient not lost to follow-up has reached more than 12 years of follow-up (patients are followed up to 13 years).

   מסגרת זמן Time from randomization to death due to any cause, assessed up to 12 years after the last enrollment

4. מדד תוצאה משני

   OS in SER patients

   Will be compared between a standard chemotherapy approach and an IO therapy approach among the SER patients.

   מסגרת זמן Time from randomization to death due to any cause, assessed up to 12 years after the last enrollment

5. מדד תוצאה משני

   OS for entire patient population

   Will be based on a confidence interval approach conducted after the last patient not lost to follow-up has been followed for at least 12 years from randomization. Twelve-year OS and its corresponding 90% confidence interval will be estimated with the Kaplan-Meier method for each study arm within the entire randomized and evaluable trial population.

   מסגרת זמן Time from randomization to death due to any cause, assessed at 12 years after the last enrollment

6. מדד תוצאה משני

   PFS for favorable risk patients

   Will be estimated in patients with favorable features at diagnosis. PFS and a corresponding confidence interval will be estimated using the Kaplan-Meier approach. PFS will also be compared between the (pooled) IO therapy and standard therapy arms using stratified log-rank tests within each cohort.

   מסגרת זמן Up to 12 years

7. מדד תוצאה משני

   PFS for unfavorable risk patients

   Will be estimated in patients with unfavorable features at diagnosis. PFS and a corresponding confidence interval will be estimated using the Kaplan-Meier approach. PFS will also be compared between the (pooled) IO therapy and standard therapy arms using stratified log-rank tests within each cohort.

   מסגרת זמן Up to 12 years

8. מדד תוצאה משני

   PFS for entire population

   PFS and a corresponding confidence interval will be estimated using the Kaplan-Meier approach. PFS will also be compared between the (pooled) IO therapy and standard therapy arms using stratified log-rank tests within each cohort.

   מסגרת זמן Up to 12 years

9. מדד תוצאה משני

   Event-free survival (EFS)

   Pooling IO treatment arms and standard treatment arms, EFS and corresponding confidence intervals will be estimated with the Kaplan-Meier approach for patients assigned versus (vs.) not assigned to receive radiaton therapy (RT), and compared using the log-rank test.

   מסגרת זמן Time from randomization to the earliest of progression, relapse, second malignancy, or death due to any cause, assessed up to 12 years from last enrollment

10. מדד תוצאה משני

    Incidence of adverse events (AEs)

    Will use the American Society of Clinical Oncology and the Society for Immunotherapy of Cancer guidelines to capture immune-related AEs. Physician-reported treatment related AEs will be reported for all grades using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Rates of individual toxicities with grades greater or equal to 3 will be compared between the pooled IO and standard arms using exact binomial tests. The maximum grade for each toxicity will be recorded for each patient. The rates and confidence intervals for these toxicities will be provided. Comparison of AEs will also be conducted for physician-reported treatment-related AEs between RT and non-RT patients.

    מסגרת זמן Assessed up to 12 years from last enrollment

11. מדד תוצאה משני

    Patient reported outcomes (PRO)-CTCAE

    Targeted patient-reported AEs will be collected at each time point using the PRO-CTCAE for patients 7 years and older. For youth (7-17 years) the Pediatric PRO-CTCAE form will be used and for those 18 years and older adult the PRO-CTCAE form will be used. For information collected by each of the above forms, the scores for each attribute together with frequency, severity and/or interference will be presented descriptively using summary statistics at each assessment time. Additionally, the worst severity and/or interference over the entire course will be summarized. The changes among main time points will be calculated. The results will be provided for the whole population and compared between subpopulations by arms and by age groups. Regression models based on longitudinal measurements can be constructed by considering the following covariates besides age groups: baseline demographics, clinical risk factors, and study arms.

    מסגרת זמן Assessed up to 12 years from last enrollment

12. מדד תוצאה משני

    Patient-reported fatigue

    Will be measured by validated short forms from the Patient Reported Outcomes Measurement Information System initiatives. Domain scores will be converted to T-scores with an established standard deviation of 10 points with an average score normalized to 50 within the healthy adult population. The minimal clinically important difference (MCID) in these PRO measures has been accepted to be 2-3 points of the standard deviation (SD = 10) of the measure. To account for the dual primary PRO outcomes of fatigue and cognitive deficits, we will consider Bonferroni correction of p-values. Primary interests will be differences in T-scores between IO and chemotherapy arms at 1-year post completion of therapy.

    מסגרת זמן Baseline up to 1 year from end of study treatment

13. מדד תוצאה משני

    Patient-reported cognitive deficits

    Will be measured by validated short forms from the Neuro-QoL initiative. Domain scores will be converted to T-scores with an established standard deviation of 10 points with an average score normalized to 50 within the healthy adult population. The MCID in these PRO measures has been accepted to be 2-3 points of the standard deviation (SD = 10) of the measure. To account for the dual primary PRO outcomes of fatigue and cognitive deficits, we will consider Bonferroni correction of p-values. Primary interests will be differences in T-scores between IO and chemotherapy arms at 1-year post completion of therapy.

    מסגרת זמן Baseline up to 1 year from end of study treatment

14. מדד תוצאה משני

    Patient-reported health-related quality of life

    Domain scores will be converted to T-scores with an established standard deviation of 10 points with an average score normalized to 50 within the healthy adult population. The MCID in these PRO measures has been accepted to be 2-3 points of the standard deviation (SD = 10) of the measure. To account for the dual primary PRO outcomes of fatigue and cognitive deficits, we will consider Bonferroni correction of p-values. Primary interests will be differences in T-scores between IO and chemotherapy arms at 1-year post completion of therapy.

    מסגרת זמן Baseline up to 1 year from end of study treatment

15. מדד תוצאה משני

    Incidence of self-reported late morbidities

    Will be collected by using validated measures from the St. Jude Life Cohort. The cumulative incidence of late-morbidities (e.g., cardiovascular, pulmonary and endocrine) will be compared between the standard chemotherapy and the IO therapy and among different age groups (7-14; 15-40 and 41-60) with K-sample method. The frequencies of selected organ toxicities will be compared between two treatment arms, among the three age groups and between RT and non-RT with chi-square tests.

    מסגרת זמן Assessed up to 12 years from last enrollment

16. מדד תוצאה משני

    Effect of metabolic tumor burden (MTV) on PFS

    MTV will be measured at baseline using fludeoxyglucose F-18 (FDG)-PET. The Kaplan-Meier curves of PFS will be compared between the two levels with log-rank tests.

    מסגרת זמן At baseline prior to initiation of therapy

17. מדד תוצאה משני

    Effect of total lesion glycolysis (TLG) on PFS

    TLG will be measured at baseline using FDG-PET. The Kaplan-Meier curves of PFS will be compared between the two levels with log-rank tests.

    מסגרת זמן At baseline prior to initiation of therapy

18. מדד תוצאה משני

    Contribution of social determinants of health (SDOH) to PET2 response by race and ethnicity

    PET2 Response will be compared by race and ethnicity using Fisher exact tests.

    מסגרת זמן After Cycle 2 of treatment (1 cycle = 28 days)

19. מדד תוצאה משני

    Contribution of SDOH to PFS by race and ethnicity

    Kaplan-Meier (K-M) curves of PFS will be generated by racial/ethnic groups (e.g., non-Hispanic white \[NHW\], non-Hispanic black \[NHB\], Hispanic). The p values for the K-M curve comparison will be obtained from log-rank tests. Associations between race/ethnicity and PFS will be evaluated with univariable and multivariable Cox proportional hazard models by considering other covariates such as baseline clinical conditions, toxicities, SDOH, and treatment arm (standard vs. IO). Backward selection will be used to select those factors with p-value \< 0.2, which will be included in final multivariable models.

    מסגרת זמן Assessed up to 12 years after last enrollment

20. מדד תוצאה משני

    Contribution of SDOH to OS by race and ethnicity

    K-M curves of OS will be generated by racial/ethnic groups (e.g., NHW, NHB, Hispanic). The p values for the K-M curve comparison will be obtained from log-rank tests. Associations between race/ethnicity and OS will be evaluated with univariable and multivariable Cox proportional hazard models by considering other covariates such as baseline clinical conditions, toxicities, SDOH, and treatment arm (standard vs. IO). Backward selection will be used to select those factors with p-value \< 0.2, which will be included in final multivariable models.

    מסגרת זמן Assessed up to 12 years after last enrollment

21. מדד תוצאה אחר

    PFS comparison between treatment arms for each age group

    Will be compared between a standard chemotherapy approach and an IO therapy approach within different age groups (ages 5-11 years, 12-21 years, 22-39 years, 40-60 years) using log-rank tests. Cox regression models will be constructed to evaluate the treatment effects for different age groups while considering the impact of other potentially prognostic variables including baseline demographics and clinical risk factors. PFS and corresponding confidence intervals for each age group will be estimated with the Kaplan-Meier method, overall and by treatment arms. In additional models, age may be evaluated as a continuous variable with potentially non-linear effects on PFS.

    מסגרת זמן Up to 12 years

22. מדד תוצאה אחר

    Concordance and discordance of 5-point score (PS) visual PET assessments

    The concordance and discordance of 5-PS visual PET assessment from rapid central review and local institutional review will be evaluated at each of the timepoints. Will collect and retrospectively review local vs. central review concordance rates. For discordant cases, will document the differences in treatments if only local review or only central review were performed

    מסגרת זמן At baseline, post cycle 2, and at end of systemic therapy

23. מדד תוצאה אחר

    Association between FDG PET parameters obtained by automated measurements and PFS

    The association between FDG PET parameters obtained by automated measurements using convolutional neural networks and PFS will be evaluated in this aim. The PET parameters of interest are total MTV and TLG, tumor standardized uptake value change. PET parameters will be obtained based on artificial intelligence (AI) based measurements. The effect of these PET measurements will be evaluated by Cox regression models.

    מסגרת זמן At baseline, post cycle 2, and at the end of therapy

24. מדד תוצאה אחר

    Agreement between AI derived FDG-PET measurement extraction and physician-based manual quantitative PET measurement

    Will compare AI derived automated quantitative FDG-PET measurement extraction and physician-based manual quantitative PET measurement with Spearman rank correlation coefficients for each extracted PET metric.

    מסגרת זמן At baseline, post cycle 2, and at the end of therapy

25. מדד תוצאה אחר

    Incidence of patient reported adverse events and provider adverse event reporting

    Will be collected by PRO-CTCAE and Ped-PRO-CTCAE. The patient reported AEs will be compared to provider reported AEs reported descriptively.

    מסגרת זמן Assessed up to 12 years

26. מדד תוצאה אחר

    Association between self-reported race/ethnicity and dimensional SDOH

    Will be evaluated by Chi-square tests or Fisher exact tests for sparse data. Will also calculate the area deprivation index (derived from patient-reported address and zip code to census block-group data for patients treated in the United States, and the Canadian Index of Multiple Deprivation for patients treated in Canada) and investigate its association with race/ethnicity and SDOH.

    מסגרת זמן Assessed up to 12 years

27. מדד תוצאה אחר

    Post-relapse/post-progression OS by race/ethnicity and select SDOH measures

    The K-M curves will be presented together with p-values via log-rank tests across the different race/ethnicity groups for each treatment arm. Cox proportional hazard models to evaluate the relationship between race/ethnicity and post-relapse OS will be constructed.

    מסגרת זמן Assessed up to 12 years

28. מדד תוצאה אחר

    Completion rate of PRO and health-related quality of life contact forms

    Will be evaluated for the first 450 eligible participants.

    מסגרת זמן At 1 year off treatment

תאריכים

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