evt_NCT03584009_v19_v20_83d6534c93d2

{
  "changed_paths": [
    "/protocolSection/identificationModule/acronym",
    "/protocolSection/statusModule/statusVerifiedDate",
    "/protocolSection/statusModule/lastUpdateSubmitDate",
    "/protocolSection/statusModule/lastUpdatePostDateStruct/date",
    "/protocolSection/descriptionModule/briefSummary",
    "/protocolSection/armsInterventionsModule/armGroups/0/description",
    "/protocolSection/armsInterventionsModule/armGroups/1/description",
    "/protocolSection/armsInterventionsModule/interventions/0/description",
    "/protocolSection/outcomesModule/primaryOutcomes/0/measure",
    "/protocolSection/outcomesModule/primaryOutcomes/0/timeFrame",
    "/protocolSection/outcomesModule/secondaryOutcomes/0/timeFrame",
    "/protocolSection/outcomesModule/secondaryOutcomes/1/timeFrame",
    "/protocolSection/outcomesModule/secondaryOutcomes/2/timeFrame",
    "/protocolSection/outcomesModule/secondaryOutcomes/3/timeFrame",
    "/protocolSection/outcomesModule/secondaryOutcomes/4/measure",
    "/protocolSection/outcomesModule/secondaryOutcomes/4/timeFrame",
    "/protocolSection/outcomesModule/secondaryOutcomes/5/measure",
    "/protocolSection/outcomesModule/secondaryOutcomes/5/timeFrame",
    "/protocolSection/outcomesModule/secondaryOutcomes/6/timeFrame",
    "/protocolSection/outcomesModule/secondaryOutcomes/7/timeFrame",
    "/protocolSection/outcomesModule/secondaryOutcomes/8/timeFrame",
    "/protocolSection/eligibilityModule/eligibilityCriteria"
  ],
  "citation_text": "TrialDiff Evidence Record evt_NCT03584009_v19_v20_83d6534c93d2. ClinicalTrials.gov NCT03584009, versions 19-20. Evidence version 1.",
  "claims_not_supported": [
    "That the amendment was scientifically unjustified.",
    "That the change constitutes misconduct or wrongdoing.",
    "That sponsor intent can be inferred from this registry change.",
    "That the change caused or altered the trial's results.",
    "That the change was or was not disclosed in a manuscript.",
    "That TrialDiff determines regulatory compliance or non-compliance.",
    "That the outcome change was inconsistent with the protocol or statistical analysis plan.",
    "That event-class membership is a validated global review-priority ranking."
  ],
  "claims_supported": [
    "TrialDiff compared ClinicalTrials.gov record version 19 to version 20 for NCT03584009.",
    "The JSON Patch for this comparison has hash 1a39a795ad2b5442dd8e9f98761ab287329ce64cc5187f99db00e9bafdf60c5c.",
    "The active deterministic rule set hash was 318445b9ad266f51fd10ef378645c753ba7a098e3e4395c3c457750dc5f88d86.",
    "The deterministic triage label was critical; before timing adjustment it was critical.",
    "The triage label is uncalibrated metadata, not a validated review-priority finding.",
    "The patch satisfied these deterministic event-class predicates: primary_endpoint_changed_after_primary_completion_without_results_reconciliation.",
    "A registry field under the primary outcome module changed between ClinicalTrials.gov versions 19 and 20.",
    "The timing context for the from-version record was late_recruitment.",
    "The deterministic rules that fired were: arms_or_interventions_change, eligibility_criteria_change, primary_outcome_any_change, secondary_outcome_any_change.",
    "The changed JSON Pointer paths were: /protocolSection/identificationModule/acronym, /protocolSection/statusModule/statusVerifiedDate, /protocolSection/statusModule/lastUpdateSubmitDate, /protocolSection/statusModule/lastUpdatePostDateStruct/date, /protocolSection/descriptionModule/briefSummary, /protocolSection/armsInterventionsModule/armGroups/0/description, /protocolSection/armsInterventionsModule/armGroups/1/description, /protocolSection/armsInterventionsModule/interventions/0/description, /protocolSection/outcomesModule/primaryOutcomes/0/measure, /protocolSection/outcomesModule/primaryOutcomes/0/timeFrame, /protocolSection/outcomesModule/secondaryOutcomes/0/timeFrame, /protocolSection/outcomesModule/secondaryOutcomes/1/timeFrame, /protocolSection/outcomesModule/secondaryOutcomes/2/timeFrame, /protocolSection/outcomesModule/secondaryOutcomes/3/timeFrame, /protocolSection/outcomesModule/secondaryOutcomes/4/measure, /protocolSection/outcomesModule/secondaryOutcomes/4/timeFrame, /protocolSection/outcomesModule/secondaryOutcomes/5/measure, /protocolSection/outcomesModule/secondaryOutcomes/5/timeFrame, /protocolSection/outcomesModule/secondaryOutcomes/6/timeFrame, /protocolSection/outcomesModule/secondaryOutcomes/7/timeFrame, /protocolSection/outcomesModule/secondaryOutcomes/8/timeFrame, /protocolSection/eligibilityModule/eligibilityCriteria.",
    "A primary outcome definition field changed after primary completion between versions 19 and 20, without a results-posting co-occurrence signal."
  ],
  "classification": {
    "calibration_status": "uncalibrated",
    "categories": [
      "primary_outcome_change",
      "arm_intervention_change",
      "secondary_outcome_change",
      "eligibility_change"
    ],
    "category": "primary_outcome_change",
    "deterministic_rules": [
      "arms_or_interventions_change",
      "eligibility_criteria_change",
      "primary_outcome_any_change",
      "secondary_outcome_any_change"
    ],
    "event_class_rule_set_hash": "07957f8b90549d4f42387f51b471ecde9901b6db63bbc27b84c73631603407c0",
    "event_classes": [
      "primary_endpoint_changed_after_primary_completion_without_results_reconciliation"
    ],
    "rule_set_hash": "318445b9ad266f51fd10ef378645c753ba7a098e3e4395c3c457750dc5f88d86",
    "severity": "critical",
    "severity_pre_timing": "critical",
    "timing_context": "late_recruitment",
    "triage_label": "critical",
    "triage_rule_set_hash": "af5e5835e00a5fcfe2a17fd02b5fc244c2564104f93f78a1d77d7889f12a178b",
    "value_signals": []
  },
  "event_id": "evt_NCT03584009_v19_v20_83d6534c93d2",
  "evidence_version": 1,
  "patch": [
    {
      "op": "add",
      "path": "/protocolSection/identificationModule/acronym",
      "value": "Veronica"
    },
    {
      "op": "replace",
      "path": "/protocolSection/statusModule/statusVerifiedDate",
      "value": "2020-11"
    },
    {
      "op": "replace",
      "path": "/protocolSection/statusModule/lastUpdateSubmitDate",
      "value": "2020-11-09"
    },
    {
      "op": "replace",
      "path": "/protocolSection/statusModule/lastUpdatePostDateStruct/date",
      "value": "2020-11-12"
    },
    {
      "op": "replace",
      "path": "/protocolSection/descriptionModule/briefSummary",
      "value": "This is a Phase II, multicenter, open-label, randomized study to compare the efficacy of venetoclax in combination with fulvestrant compared with fulvestrant alone in women with ER+, HER2-negative, locally advanced or Metastatic Breast Cancer (MBC) who experienced disease recurrence or progression during or after treatment with CDK4/6i therapy for at least 8 weeks.\nAs of 9th October 2020, participants in the Venetoclax + Fulvestrant arm, have all discontinued Venetoclax treatment and have continued on Fulvestrant treatment alone."
    },
    {
      "op": "replace",
      "path": "/protocolSection/armsInterventionsModule/armGroups/0/description",
      "value": "As of 9th October 2020, Participants in the Venetoclax + Fulvestrant arm, have all discontinued Venetoclax treatment and have continued on Fulvestrant treatment alone.\nFulvestrant study treatment will continue until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined end of the study (2 years after the last participant is enrolled) which ever occur first."
    },
    {
      "op": "replace",
      "path": "/protocolSection/armsInterventionsModule/armGroups/1/description",
      "value": "Participants will receive fulvestrant administered as IM (intramuscular) injections.\nNo crossover to the venetoclax arm is permitted.\nStudy treatment will continue until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined end of the study (2 years after the last participant is enrolled) which ever occur first."
    },
    {
      "op": "replace",
      "path": "/protocolSection/armsInterventionsModule/interventions/0/description",
      "value": "Venetoclax will be administered orally, 800-mg tablet beginning on Cycle 1 Day 1 until the 9th October 2020."
    },
    {
      "op": "replace",
      "path": "/protocolSection/outcomesModule/primaryOutcomes/0/measure",
      "value": "Clinical benefit defined as Complete Response (CR), Partial Response (PR) or Stable Disease (SD) lasting >= 24 weeks, as determined by the Investigator according to RECIST v1.1"
    },
    {
      "op": "replace",
      "path": "/protocolSection/outcomesModule/primaryOutcomes/0/timeFrame",
      "value": "Randomization in participants with measurable disease at baseline through the end of study (2 years after the last participant is enrolled)"
    },
    {
      "op": "replace",
      "path": "/protocolSection/outcomesModule/secondaryOutcomes/0/timeFrame",
      "value": "Randomization to the first occurrence of disease progression as determined by the investigator according to (RECIST v1.1 ) or death from any cause, until the end of study (2 years after the last participant is enrolled)"
    },
    {
      "op": "replace",
      "path": "/protocolSection/outcomesModule/secondaryOutcomes/1/timeFrame",
      "value": "Objective Response defined as Complete Response (CR) or Partial response (PR), as determined by the investigator according to RECIST v1.1 from Randomization of participant until end of the study (2 years after the last participant enrolled)"
    },
    {
      "op": "replace",
      "path": "/protocolSection/outcomesModule/secondaryOutcomes/2/timeFrame",
      "value": "Time from first occurrence of a documented Objective response to the time of the first documented disease progression or death from any cause, whichever occurs first, until end of the study (2 years after the last participant is enrolled)"
    },
    {
      "op": "replace",
      "path": "/protocolSection/outcomesModule/secondaryOutcomes/3/timeFrame",
      "value": "Randomization to death from any cause, through the end of study (2 years after the last participant is enrolled)"
    },
    {
      "op": "replace",
      "path": "/protocolSection/outcomesModule/secondaryOutcomes/4/measure",
      "value": "Percentage of Participants with Adverse Events (AEs)"
    },
    {
      "op": "replace",
      "path": "/protocolSection/outcomesModule/secondaryOutcomes/4/timeFrame",
      "value": "Baseline to end of study (2 years after the last participant is enrolled)"
    },
    {
      "op": "replace",
      "path": "/protocolSection/outcomesModule/secondaryOutcomes/5/measure",
      "value": "Plasma concentration of Venetoclax and fulvestrant"
    },
    {
      "op": "replace",
      "path": "/protocolSection/outcomesModule/secondaryOutcomes/5/timeFrame",
      "value": "At pre-defined intervals from Cycle 1, Day 1, through end of treatment (2 years after the last participant is enrolled)."
    },
    {
      "op": "replace",
      "path": "/protocolSection/outcomesModule/secondaryOutcomes/6/timeFrame",
      "value": "Baseline, cycle 1 day 1, and all subsequent cycles through at the end of treatment/discontinuation visit (2 years after the last participant is enrolled)"
    },
    {
      "op": "replace",
      "path": "/protocolSection/outcomesModule/secondaryOutcomes/7/timeFrame",
      "value": "Baseline through end of study (2 years after the last participant is enrolled)"
    },
    {
      "op": "replace",
      "path": "/protocolSection/outcomesModule/secondaryOutcomes/8/timeFrame",
      "value": "Baseline through the end of study (2 years after the last participant is enrolled)"
    },
    {
      "op": "replace",
      "path": "/protocolSection/eligibilityModule/eligibilityCriteria",
      "value": "<p>Inclusion Criteria:</p><ul><li>Histological or cytological confirmation of estrogen receptor-positive (ER+) invasive carcinoma of the breast.\nER+, HER2- negative invasive carcinoma of the breast with evaluable sample for BCL-2 IHC value at the time of screening.\nParticipants who were originally diagnosed with HER2-positive breast cancer that converted to HER2-negative MBC are not eligible.</li><li>Evidence of metastatic or locally advanced disease not amenable to surgical or local therapy with curative intent.</li><li>Be postmenopausal or pre- or perimenopausal women amenable to being treated with the luteinizing hormone-releasing hormone (LHRH) agonist goserelin.</li><li>Participants must not have received more than two prior lines of hormonal therapy in the locally advanced or metastatic setting.\nIn addition, at least one line of treatment must be a CDK4&#x2F;6i AND participants must have experienced disease recurrence or progression during or after CDK4&#x2F;6i therapy, which must have been administered for a minimum of 8 weeks prior to progression.</li><li>Participants for whom endocrine therapy (e.g., fulvestrant) is recommended and treatment with cytotoxic chemotherapy is not indicated at the time of entry into the study, as per national or local treatment guidelines.</li><li>Women of childbearing potential (i.e., not postmenopausal for at least 12 months or surgically sterile) must have a negative serum pregnancy test result at screening, within 14 days prior to the first study drug administration.</li><li>For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use non-hormonal contraceptive methods with a failure rate of &lt;1% per year during the treatment period and for up to 2 years after the last dose of study drug (or based on the local prescribing information for fulvestrant).\nWomen must refrain from donating eggs during this same period.</li><li>Willing to provide tumor biopsy sample.</li><li>Have at least one measurable lesion via RECIST v1.1.</li><li>Have an Eastern Cooperative Oncology Group (ECOG) Performance Score of 0-1.</li><li>Have adequate organ and marrow function.</li><li>Have a life expectancy &gt; 3 months.</li><li>To full fill the coagulation requirements for patient with or without therapeutic anticoagulation.</li></ul><p>Exclusion criteria:</p><ul><li>Prior treatment with fulvestrant or other selective estrogen receptor degraders (SERDs), venetoclax, or any agent whose mechanism of action is to inhibit BCL-2.</li><li>Pregnant, lactating, or intending to become pregnant during the study.</li><li>Known untreated or active Central Nervous System (CNS) metastases (progressing or requiring anticonvulsants or corticosteroids for symptomatic control.</li><li>Prior chemotherapy in the locally advanced or metastatic setting regardless of the duration of the treatment.</li><li>Any anti-cancer therapy received within 21 days of the first dose of study drug, including chemotherapy, radiotherapy, hormonal therapy, immunotherapy, antineoplastic vaccines, or other investigational therapy.\n(Radiotherapy with palliative intent to non-target sites is allowed).</li><li>Concurrent radiotherapy to any site or prior radiotherapy within 21 days of Cycle 1 Day 1 or previous radiotherapy to the target lesion sites (the sites that are to be followed for determination of a response) or prior radiotherapy to &gt; 25% of bone marrow.</li><li>Current severe, uncontrolled, systemic disease (e.g., clinically significant cardiovascular, pulmonary, metabolic or infectious disease.</li><li>Any major surgery within 28 days of the first dose of study drug or anticipation of the need for major surgery during the course of study treatment.</li><li>Consumption of one or more of the following within 3 days prior to the first dose of study drug: Grapefruit or grapefruit products; Seville oranges including marmalade containing Seville oranges; Star fruit (carambola).</li><li>Administration within 7 days prior first dose of study treatment of Steroid therapy for anti-neoplastic intent, Strong or moderate CYP3A inhibitors or Strong or moderate CYP3A inducers.</li><li>Need for current chronic corticosteroid therapy (&gt; 10 mg of prednisone per day or an equivalent dose of other anti-inflammatory corticosteroids).</li><li>Known infection with (human immunodeficiency virus) HIV or human T-cell leukemia virus 1.</li><li>Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 4 weeks prior to Cycle 1 Day).</li><li>Positive test results for hepatitis B core antibody (HBcAb) or hepatitis C virus (HCV) antibody at screening.\nParticipants who are positive for HCV antibody must be negative for HCV by PCR to be eligible for study participation.\nParticipants with a past or resolved hepatitis B virus (HBV) infection (defined as having a positive total HBcAb and negative hepatitis B surface antigen [HbsAg]) may be included if HBV DNA is undetectable.\nThese participants must be willing to undergo monthly DNA testing.</li><li>Participants who have a positive HCV antibody test are eligible for the study if a PCR assay is negative for HCV RNA.</li><li>History of other malignancies within the past 5 years except for treated skin basal cell carcinoma, squamous cell carcinoma, non-malignant melanoma &lt;= 1.0 mm without ulceration, localized thyroid cancer, or cervical carcinoma in-situ.</li><li>Administration of a live, attenuated vaccine within 4 weeks prior to initiation of study treatment or anticipation of need for such a vaccine during the study.</li><li>Cardiopulmonary dysfunction.</li><li>Other medical or psychiatric conditions that, in the opinion of the investigatory, may interfere with the participant&#x27;s participation in the study.</li><li>Inability or unwillingness to swallow pills or receive intramuscular (IM) injections.</li><li>History of malabsorption syndrome or other condition that would interfere with enteral absorption.</li><li>History of inflammatory bowel disease (e.g., Crohn&#x27;s disease or ulcerative colitis) or active bowel inflammation (e.g., diverticulitis).</li><li>Concurrent hormone replacement therapy.</li><li>Inability to comply with study and follow-up procedures.</li><li>History or active cardiopulmonary dysfunction.</li><li>Known hypersensitivity to any of the study medications (fulvestrant, venetoclax) or to any of the excipients.</li></ul>"
    }
  ],
  "provenance": {
    "from_snapshot_hash": "87eddce93c661b84cd67b7e9a57e14102844a052947e189b2f6b4a03de2b7288",
    "materiality_event_hash": "c2d2ef30c86db8b42568544788b7adc1ffa8115c5fc2c35610aab5538e526bc8",
    "patch_hash": "1a39a795ad2b5442dd8e9f98761ab287329ce64cc5187f99db00e9bafdf60c5c",
    "patch_raw_hash": "3aca7900a982d2f690bdbc294420d57c9d38796e32d3136c06f228e42fca4c82",
    "patch_source": "ctgov_internal_history",
    "patch_source_url": "https://clinicaltrials.gov/api/int/studies/NCT03584009/history/19?patchToVersion=20",
    "to_snapshot_hash": "44043ef17567fdbee62f948aa5a5168145de2848bb61c8ab9f08f1c9c25edd70"
  },
  "review_question": "What did the primary outcome field say before and after the amendment, and is there a public protocol, statistical analysis plan, or manuscript explaining the change?",
  "schema": "trialdiff.evidence_record",
  "trial": {
    "clinicaltrials_gov_url": "https://clinicaltrials.gov/study/NCT03584009",
    "nct_id": "NCT03584009"
  },
  "versions": {
    "from_version": 19,
    "submitted_date": "2020-11-09",
    "to_version": 20
  }
}