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Adjuvant Avelumab in Merkel Cell Cancer (ADAM)

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ClinicalTrials.gov Identifier: NCT03271372
Recruitment Status : Recruiting
First Posted : September 5, 2017
Last Update Posted : November 18, 2020
Sponsor:
Collaborators:
National Cancer Institute (NCI)
EMD Serono
Information provided by (Responsible Party):
University of Washington

Tracking Information
First Submitted Date  ICMJE August 31, 2017
First Posted Date  ICMJE September 5, 2017
Last Update Posted Date November 18, 2020
Actual Study Start Date  ICMJE December 19, 2017
Estimated Primary Completion Date August 30, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 25, 2017)
Relapse-free survival [ Time Frame: From the date of randomization and the date of first recurrence or death (whatever the cause), whichever occurs first, assessed for up to 5 years ]
The Kaplan-Meier technique will be used to obtain estimates.
Original Primary Outcome Measures  ICMJE
 (submitted: August 31, 2017)
Relapse-free survival [ Time Frame: From the date of randomization and the date of first recurrence (local, regional or distant metastasis) or death (whatever the cause), whichever occurs first, assessed for up to 5 years ]
The Kaplan-Meier technique will be used to obtain estimates. Medians will be presented with a 90% confidence interval based on the Brookmeyer and Crowley method (Kalbfleisch J.D., 2002). The comparison of the cause-specific hazards of failure between the two treatment arms will be done using the log-rank test stratified by primary tumor status (known primary versus unknown primary) as indicated at randomization. The hazard ratio of failure and the corresponding 95% confidence interval, of avelumab to placebo, will be estimated using a Cox proportional hazards model, stratified by primary tumor
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 24, 2018)
  • Disease-specific survival [ Time Frame: From the date of randomization and the date of death from Merkel cell carcinoma, assessed for up to 5 years ]
    Cumulative incidence estimates will be used to summarize the probabilities of disease-specific survival.
  • Distant-metastases free survival [ Time Frame: From the date of randomization and the date of first distant metastasis or date of death (any cause), whichever occurs first, assessed for up to 5 years ]
    The Kaplan-Meier technique will be used to obtain estimates.
  • Incidence of adverse events [ Time Frame: Throughout the duration of the treatment (up to 2 years after randomization) ]
    Graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.
  • Overall survival [ Time Frame: From the date of randomization and the date of death, assessed for up to 5 years ]
    The Kaplan-Meier technique will be used to obtain estimates.
Original Secondary Outcome Measures  ICMJE
 (submitted: August 31, 2017)
  • Disease-specific survival [ Time Frame: From the date of randomization and the date of death from Merkel cell carcinoma, assessed for up to 5 years ]
    Cumulative incidence estimates will be used to summarize the probabilities of disease-specific survival, where death due to non-Merkel cell carcinoma causes will be regarded as a competing risk. Medians will be presented with a 90% confidence interval based on the Brookmeyer and Crowley method (Kalbfleisch J.D., 2002). The comparison of the cause-specific hazards of failure between the two treatment arms will be done using the log-rank test stratified by primary tumor status (known primary versus unknown primary) as indicated at randomization. The hazard ratio of failure and the corresponding
  • Distant-metastases free survival [ Time Frame: From the date of randomization and the date of first distant metastasis or date of death (any cause), whichever occurs first, assessed for up to 5 years ]
    The Kaplan-Meier technique will be used to obtain estimates. Medians will be presented with a 90% confidence interval based on the Brookmeyer and Crowley method (Kalbfleisch J.D., 2002). The comparison of the cause-specific hazards of failure between the two treatment arms will be done using the log-rank test stratified by primary tumor status (known primary versus unknown primary) as indicated at randomization. The hazard ratio of failure and the corresponding 95% confidence interval, of avelumab to placebo, will be estimated using a Cox proportional hazards model, stratified by primary tumor
  • Incidence of adverse events graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 [ Time Frame: From the date of randomization and the date of first distant metastasis or date of death (any cause), whichever occurs first, assessed for up to 5 years ]
    Will be presented overall and when appropriate, by phase (induction and maintenance).
  • Overall survival [ Time Frame: From the date of randomization and the date of death, assessed for up to 5 years ]
    The Kaplan-Meier technique will be used to obtain estimates. Medians will be presented with a 90% confidence interval based on the Brookmeyer and Crowley method (Kalbfleisch J.D., 2002). The comparison of the cause-specific hazards of failure between the two treatment arms will be done using the log-rank test stratified by primary tumor status (known primary versus unknown primary) as indicated at randomization. The hazard ratio of failure and the corresponding 95% confidence interval, of avelumab to placebo, will be estimated using a Cox proportional hazards model, stratified by primary tumor
Current Other Pre-specified Outcome Measures
 (submitted: December 26, 2017)
  • AMERK serology [ Time Frame: Up to 5 years ]
    Blood test to predict recurrence in those patients who had a positive titer at baseline.
  • Biomarker exploration in tumor and peripheral blood samples [ Time Frame: Up to 5 years ]
    Tumor and peripheral blood samples.
Original Other Pre-specified Outcome Measures
 (submitted: August 31, 2017)
  • AMERK serology as a predictor of recurrence in those patients who had a positive titer at baseline [ Time Frame: Up to 5 years ]
    Cox regression models will be used to assess the association of biomarkers with the risk of failure for each endpoint as well as the potential interaction of treatment (avelumab versus placebo) with each biomarker.
  • Biomarkers such as MCPyV viral status, MCPyV T-antigen serology (AMERK test), tumor PD-L1 expression, intratumoral-CD8 T-cell infiltration score, immunogenicity markers in peripheral blood and potentially other novel biomarkers [ Time Frame: Up to 5 years ]
    Cox regression models will be used to assess the association of biomarkers with the risk of failure for each endpoint as well as the potential interaction of treatment (avelumab versus placebo) with each biomarker.
 
Descriptive Information
Brief Title  ICMJE Adjuvant Avelumab in Merkel Cell Cancer
Official Title  ICMJE A Multicenter, Randomized, Double-Blinded, Placebo-Controlled, Phase 3 Trial of Adjuvant Avelumab (Anti-PDL-1 Antibody) in Merkel Cell Carcinoma Patients With Lymph Node Metastases
Brief Summary This randomized phase III trial studies how well avelumab works in treating patients with Merkel cell cancer that has spread to the lymph nodes and have undergone surgery and/or radiation therapy. Immunotherapy with monoclonal antibodies, such as avelumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.
Detailed Description

OUTLINE:

Patients are randomized to 1 of 2 arms.

ARM I: Patients receive avelumab intravenously (IV) over 1 hour once every 15 days for the first 120 days (Induction Phase 1), once every 30 days for the next 120 days (Induction Phase 2), and then once every 120 days (Maintenance Phase) for a maximum of 720 days (approximately 24 months or 2 years total) in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive placebo IV over 1 hour once every 15 days for the first 120 days (Induction Phase 1), once every 30 days for the next 120 days (Induction Phase 2), and then once every 120 days (Maintenance Phase) for a maximum of 720 days (approximately 24 months or 2 years total) in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for 3 years for a minimum of 5 years from randomization.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE
  • Stage III Merkel Cell Carcinoma AJCC v8
  • Stage IIIB Merkel Cell Carcinoma AJCC v8
  • Stage IIIA Merkel Cell Carcinoma AJCC v8
Intervention  ICMJE
  • Drug: Avelumab
    Given IV
    Other Names:
    • Bavencio
    • MSB-0010718C
    • MSB0010718C
  • Other: Peripheral Blood Collection
    Correlative studies
  • Other: Placebo
    Given IV
    Other Names:
    • placebo therapy
    • PLCB
    • normal saline solution
Study Arms  ICMJE
  • Experimental: Arm I (avelumab)
    Patients receive avelumab IV over 1 hour once every 15 days for the first 120 days (Induction Phase 1), once every 30 days for the next 120 days (Induction Phase 2), and then once every 120 days (Maintenance Phase) for a maximum of 720 days (approximately 24 months or 2 years total) in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: Avelumab
    • Other: Peripheral Blood Collection
  • Placebo Comparator: Arm II (placebo)
    Patients receive placebo IV over 1 hour once every 15 days for the first 120 days (Induction Phase 1), once every 30 days for the next 120 days (Induction Phase 2), and then once every 120 days (Maintenance Phase) for a maximum of 720 days (approximately 24 months or 2 years total) in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Other: Peripheral Blood Collection
    • Other: Placebo
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: August 31, 2017)
100
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE August 30, 2024
Estimated Primary Completion Date August 30, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Histologically confirmed MCC metastases in regional lymph node(s)

    • Confirmation of the MCC diagnosis in the regional lymph node(s) is mandatory for trial participation
    • (NOTE: In-transit metastases without regional nodal involvement could be allowed, but only after written approval of the medical monitor)
  • Must have completed definitive treatment for primary MCC and regional lymphatic metastases that included surgical removal (with/without adjuvant radiation therapy) or primary radiation therapy as determined by the treating investigator
  • Estimated life expectancy greater than 3 years
  • Must start the study treatment no more than 120 days from the start date of definitive therapy (the date of surgical removal of nodal metastases or the date of initiation of definitive radiation therapy, as applicable)
  • Eastern Co-Operative Group (Eastern Cooperative Oncology Group [ECOG]) performance score of 0 or 1
  • Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L
  • Platelet count ≥ 100 x 10^9/L
  • Hemoglobin ≥ 9 g/dL (may have been transfused)
  • Total bilirubin level ≤ 1.5 x the upper limit of normal (ULN) range
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels ≤ 2.5 x ULN
  • Estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula or by 24-hour urine collection for creatinine clearance or according to local institutional standard
  • Women of childbearing potential must have a negative serum or urine pregnancy test at screening
  • Both male and female subjects must be willing to use highly effective contraception (that is, methods with a failure rate of less than 1% per year) throughout the study and for at least 30 days after last avelumab treatment administration if the risk of conception exists

    * (NOTE: The effects of the study treatment on the developing human fetus are unknown; thus, women of childbearing potential and men must agree to use highly effective contraception, as stipulated in national or local guidelines. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, the treating physician should be informed immediately.)

  • Must have an ability to understand and the willingness to sign a written informed consent document
  • Must consent to allow the acquisition of existing formalin-fixed paraffin-embedded (FFPE) tumor tissue, either a block or unstained slides, for performance of correlative studies

Exclusion Criteria:

  • Clinical or radiologic suspicion of residual MCC at the time of enrollment
  • Suspicion or known history of distant metastatic MCC, which is not classifiable as local recurrence or regional metastasis
  • Any prior systemic therapy (e.g. adjuvant, neo-adjuvant or concurrent use of chemotherapy, immunotherapy or an investigational agent) for MCC at any time
  • Any prior intra-lesional MCC therapy within 180 days from day 1 of study treatment
  • Residual toxicity from prior therapy grade > 1 (National Cancer Institute [NCI]-Common Terminology Criteria for Adverse Events [NCI-CTCAE v 5.0]) that could interfere with study endpoints or put patient safety at risk
  • Previous malignant disease (other than Merkel cell carcinoma) diagnosed within 3 years from day 1 of study treatment that could interfere with study endpoints or put patient safety at risk

    * (NOTE: Exception will be made for adequately treated basal or squamous cell carcinoma of the skin or carcinoma in situ [skin, bladder, cervical, colorectal, breast] or low grade prostatic intraepithelial neoplasia or Grade 1 prostate cancer; any other neoplasm, which is adjudged by the treating investigator to have a low risk of recurrence during the study, could be enrolled only after written approval from the medical monitor)

  • Use of any systemic immunosuppressive treatments including corticosteroids, cyclosporine, mycophenolate mofetil et cetera, ongoing or within the last 3 months prior to day 1 of treatment

    * (NOTE: Patients on physiologic dose of corticosteroids [≤ 10 mg/day of prednisone or equivalent] for long-term hormone-replacement therapy or those requiring short, intermittent courses of corticosteroids for hypersensitivity prophylaxis [such as for iodinated computed tomography (CT) contrast prophylaxis] or those using intranasal, inhaled, topical steroids, or local steroid injection [e.g., intra-articular injection] can be allowed)

  • Immunosuppressed status due to known human immunodeficiency virus (HIV) infection, severe uncontrolled diabetes, concurrent hematological malignancy, or other comorbidities
  • Uncontrolled intercurrent illness including, but not limited to, active serious infection, active hepatitis B or hepatitis C infection, uncontrolled seizure disorder, substance abuse disorder, or psychiatric illness/social situations that would limit compliance with study requirements or would put the patient at increased risk of complications during the study period
  • Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication
  • Active or history of any serious autoimmune disease, prior organ transplantation, including allogeneic stem-cell transplantation or immune-deficiencies that required treatment with systemic immunosuppressive drugs and could flare-up during study treatment

    * (NOTE: Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible)

  • Other severe acute or chronic medical conditions including immune-mediated colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study
  • Known prior severe hypersensitivity to investigational product or any component in its formulations that could interfere with study endpoints or put patient safety at risk
  • Pregnant or breast-feeding women
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: ADAM Trial Coordinator 206-606-1795 adamtrial@seattlecca.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03271372
Other Study ID Numbers  ICMJE 9820
NCI-2017-00998 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
RG1717054 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
P30CA015704 ( 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
Plan to Share IPD: No
Responsible Party University of Washington
Study Sponsor  ICMJE University of Washington
Collaborators  ICMJE
  • National Cancer Institute (NCI)
  • EMD Serono
Investigators  ICMJE
Principal Investigator: Shailender Bhatia Fred Hutch/University of Washington Cancer Consortium
PRS Account University of Washington
Verification Date November 2020

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