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NCT02576431

A Study to Test the Effect of the Drug Larotrectinib in Adults and Children With NTRK-fusion Positive Solid Tumors

Version 69 to 70 · Bayer

Patch inspector

Version 69 to 70

70 operations 7 path groups ctgov_internal_history
ClinicalTrials.gov
Severity is deterministic uncalibrated triage metadata, not validated review priority. Operation-level severity is inferred from deterministic path rules. Rule matches shown per operation are approximate previews (they skip the pipeline's suppression passes); the authoritative classification is the stored event record.
Plain-language summary

Manual review pending.

Rules fired
arms_or_interventions_changeeligibility_criteria_changeprimary_outcome_any_changesecondary_outcome_any_change
Value signals

None recorded.

Provenance
Source
ctgov_internal_history
Fetched
2026-06-18 19:12:31+00
Raw hash
ec756864e2a89f86d3993a71b3cdc24c3ebe28ba071d31e6b193a6a9969778b0
Payload
Source URL
Primary outcomes Outcome measures that define the trial's primary evidence target. Triage: Critical 2 ops
replace /protocolSection/outcomesModule/primaryOutcomes/0/measure
Triage: Critical
Primary Outcome Change Operation 9
Matched rules
  • primary_outcome_any_change Any add/remove/replace under primary outcome measures is critical review priority.
Before
Best overall response rate by IRC
After
Best overall response of confirmed complete response (CR) or partial response (PR) as determined by an independent radiology review committee using RECIST v1.1 or RANO criteria, as appropriate to tumor type.
remove /protocolSection/outcomesModule/primaryOutcomes/0/description
Triage: Critical
Primary Outcome Change Operation 10
Matched rules
  • primary_outcome_any_change Any add/remove/replace under primary outcome measures is critical review priority.
Before
Proportion of subjects with either complete response or partial response as determined by an independent radiology committee (IRC) using RECIST or RANO criteria.
Design Trial model, phase, allocation, masking, arms, or interventions. Triage: High 3 ops
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Arm Intervention Change Operation 6
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  • arms_or_interventions_change Arms or interventions changes can alter treatment/comparator structure.
Before
Arm 10- Prospective cohort
After
Arm 10_Prospective cohort
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Arm Intervention Change Operation 7
Matched rules
  • arms_or_interventions_change Arms or interventions changes can alter treatment/comparator structure.
Before
Patients with melanoma, non secretory breast and colorectal cancer or other tumor types harboring NTRK fusions, except soft tissue sarcoma, salivary gland and thyroid cancer (closed)
After
Patients with melanoma, non secretory breast and colorectal cancer or other tumor types harboring NTRK fusions, except soft tissue sarcoma, salivary gland and thyroid cancer (arm closed)
replace /protocolSection/armsInterventionsModule/interventions/0/armGroupLabels/0
Triage: High
Arm Intervention Change Operation 8
Matched rules
  • arms_or_interventions_change Arms or interventions changes can alter treatment/comparator structure.
Before
Arm 10- Prospective cohort
After
Arm 10_Prospective cohort
Eligibility Criteria and population definition changes. Triage: High 1 ops
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Triage: High
Eligibility Change Operation 36
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  • eligibility_criteria_change Eligibility criteria changes can alter the studied population.
Before
<p>Inclusion Criteria:</p><ul><li>Locally-advanced or metastatic malignancy with an NTRK1, NTRK2, or NTRK3 gene fusion, identified through molecular assays as routinely performed at Clinical Laboratory Improvement Amendments (CLIA) or other similarly-certified laboratories.</li><li>Subjects who have received prior standard therapy appropriate for their tumor type and stage of disease, or who have no satisfactory alternative treatments and in the opinion of the Investigator, would be unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy.</li><li><p>Subjects must have at least one measurable lesion as defined by RECIST v1.1.
Subjects with solid tumors without RECIST v1.1 measurable disease (e.g., evaluable disease only) had been eligible for enrollment to Cohort 8 as per protocol versions 1.0 - 8.0, regardless of tumor type.
Subjects with primary CNS tumors should meet the following criteria</p><ol><li>Have received prior treatment including radiation and&#x2F;or chemotherapy, with radiation completed &gt; 12 weeks prior to C1D1 of therapy, as recommended or appropriate for that CNS tumor type.</li><li>Have ≥ 1 site of bi-dimensionally measurable disease (confirmed by magnetic resonance imaging [MRI] and evaluable by RANO criteria), with the size of at least one of the measurable lesions ≥ 1 cm in each dimension and noted on more than one imaging slice.</li><li>Imaging study performed within 28 days before enrollment.
If on steroid therapy, the dose must be stable for at least 7 days immediately before and during the imaging study.</li><li><p>Must be neurologically stable based on stable neurologic exam for 7 days prior to enrollment.</p><p>For subjects eligible for enrollment to bone health cohort, inclusion criterion 3 is modified as the following:</p></li><li>Subjects must have at least one lesion at baseline (measurable or non-measurable as defined by RECIST v1.1 or RANO criteria, as appropriate to tumor type).</li><li>Subjects with primary CNS tumors must be neurologically stable based on stable neurologic exam for 7 days prior to enrollment.</li></ol></li><li>Performance Status: Eastern Cooperative Oncology Group (ECOG) score ≤ 3 If enrolled with primary CNS tumor to be assessed by RANO, Karnofsky Performance Score (KPS) ≥50%</li><li>Tumor tissue before treatment (mandatory).
If neither fresh tissue can be obtained nor archival tissue is available patients might be enrolled after consultation with the sponsor.</li><li>Willingness of men and women of reproductive potential to use double effective birth control methods, defined as one used by the subject and another by his&#x2F;her partner, for the duration of treatment and for 1 month following study completion.</li><li>For subjects eligible for enrollment to bone health cohort only: life expectancy of at least 6 months, based on investigator assessment.</li></ul><p>Exclusion Criteria:</p><ul><li>Prior progression while receiving approved or investigational tyrosine kinase inhibitors targeting tropomyosin receptor kinase (TRK).
Subjects who received less than 28 days of treatment and discontinued because of intolerance or toxicity are eligible.</li><li>Symptomatic or unstable brain metastases.
(Note: Subjects with asymptomatic brain metastases are eligible to participate in the study.)
Subjects with primary central nervous system (CNS) tumors are eligible.</li><li>Pregnancy or lactation.</li><li>Active uncontrolled systemic bacterial, viral, or fungal infection Common Terminology Criteria for Adverse Events(CTCAE) grade ≥ 2; unstable cardiovascular disease, or other systemic disease that would limit compliance with study procedures.</li><li><p>Unstable cardiovascular disease is defined as:</p><ul><li>In adults, persistently uncontrolled hypertension defined as systolic blood pressure (BP) &gt; 150 mmHg and&#x2F;or diastolic BP &gt; 100 mmHg despite antihypertensive therapy.</li><li>Myocardial infarction within 3 months of screening.</li><li>Stroke within 3 months of screening.</li></ul></li></ul>
After
<p>Inclusion Criteria:</p><ul><li>Locally-advanced or metastatic malignancy with an NTRK1, NTRK2, or NTRK3 gene fusion, identified through molecular assays as routinely performed at CLIA or other similarly-certified laboratories.
Subjects who have an NTRK gene fusion identified in a lab where CLIA or equivalent certification cannot be confirmed by the Sponsor at the time of consent may have been enrolled in Cohort 9 as per protocol versions 1.0 - 8.0.
From protocol version 9.0: CLIA or similar certification of the lab performing the fusion assay is required.
However, patients may be included after discussion with the sponsor if the lab performing the fusion assay is not CLIA or similar certified.</li><li>Subjects who have received prior standard therapy appropriate for their tumor type and stage of disease, or who have no satisfactory alternative treatments and in the opinion of the Investigator, would be unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy.</li><li><p>Subjects must have at least one measurable lesion as defined by RECIST v1.1 (Eisenhauer et al. 2009).
Subjects with solid tumors without RECIST v1.1 measurable disease (e.g., evaluable disease only) had been eligible for enrollment to Cohort 8 as per protocol versions 1.0 - 8.0, regardless of tumor type.
Subjects with primary CNS tumors should meet the following criteria:</p><ol><li>Have received prior treatment including radiation and&#x2F;or chemotherapy, with radiation completed &gt; 12 weeks prior to C1D1 of therapy, as recommended or appropriate for that CNS tumor type.</li><li>Have ≥ 1 site of bi-dimensionally measurable disease (confirmed by magnetic resonance imaging [MRI] and evaluable by RANO criteria), with the size of at least one of the measurable lesions ≥ 1 cm in each dimension and noted on more than one imaging slice.</li><li>Imaging study performed within 28 days before enrollment.
If on steroid therapy, the dose must be stable for at least 7 days immediately before and during the imaging study.</li><li><p>Must be neurologically stable based on stable neurologic exam for 7 days prior to enrollment.</p><p>For subjects eligible for enrollment to bone health cohort, inclusion criterion 3 is modified as the following:</p></li><li>Subjects must have at least one lesion at baseline (measurable or non-measurable as defined by RECIST v1.1 or RANO criteria, as appropriate to tumor type).</li><li>Subjects with primary CNS tumors must be neurologically stable based on stable neurologic exam for 7 days prior to enrollment.</li></ol></li><li>At least 18 years of age</li><li>Performance Status: Eastern Cooperative Oncology Group (ECOG) score ≤ 3.
If enrolled with primary CNS tumor to be assessed by RANO, Karnofsky Performance Score (KPS) ≥ 50%.</li><li>Tumor tissue before treatment (mandatory).
If neither fresh tissue can be obtained nor archival tissue is available patients might be enrolled after consultation with the sponsor.</li><li><p>Adequate organ function as defined by the following criteria:</p><ol><li>Serum AST and serum ALT &lt; 2.5 x upper limit of normal (ULN), or AST and ALT &lt; 5 x ULN if liver function abnormalities are due to underlying malignancy</li><li>Total bilirubin &lt; 2.5 x ULN, except in the setting of biliary obstruction.
Subjects with a known history of Gilberts Disease and an isolated elevation of indirect bilirubin are eligible</li><li>Serum creatinine &lt; 2.0 x ULN OR an estimated glomerular filtration rate ≥ 30 mL&#x2F;minute using the Cockcroft-Gault formula: (140- age) x body weight (kg) x 0.85 (if female)&#x2F;serum creatinine (mg&#x2F;dL) x 72 with either result acceptable for enrollment.</li></ol></li><li>Ability to comply (or for guardian to ensure compliance) with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation.</li><li>Willingness of men and women of reproductive potential to use double effective birth control methods, defined as one used by the subject and another by his&#x2F;her partner, for the duration of treatment and for 1 month following study completion.</li><li>For subjects eligible for enrollment to bone health cohort only: life expectancy of at least 6 months, based on investigator assessment.</li></ul><p>Exclusion Criteria:</p><ul><li>Investigational agent or anticancer therapy within 2 weeks prior to the planned start of larotrectinib or 5 half-lives, whichever is shorter, and without recovery of acute and&#x2F;or clinically significant toxicities from that therapy.</li><li>Prior progression while receiving approved or investigational tyrosine kinase inhibitors targeting TRK.
Subjects who received less than 28 days of treatment and discontinued because of intolerance or toxicity are eligible.</li><li>Symptomatic or unstable brain metastases.
(Note: Subjects with asymptomatic brain metastases are eligible to participate in the study.)
Subjects with primary CNS tumors are eligible.</li><li>Uncontrolled concurrent malignancy that would limit assessment of efficacy of larotrectinib.
Allowed conditions may include, but are not limited to in situ cancers of cervix, breast, or skin, superficial bladder cancer, limited-stage prostate cancer, and basal or squamous cancers of the skin.</li><li><p>Active uncontrolled systemic bacterial, viral, or fungal infection CTCAE grade ≥ 2; unstable cardiovascular disease, or other systemic disease that would limit compliance with study procedures.
Unstable cardiovascular disease is defined as:</p><ol><li>In adults, persistently uncontrolled hypertension defined as systolic blood pressure (BP) &gt; 150 mmHg and&#x2F;or diastolic BP &gt; 100 mmHg despite antihypertensive therapy.</li><li>Myocardial infarction within 3 months of screening.</li><li>Stroke within 3 months of screening.</li></ol></li><li>Inability to discontinue treatment with a strong CYP3A4 inhibitor or inducer</li><li>Currently recovering from AEs&#x2F; ADRs due to previous treatments (excluding alopecia).
Inclusion is only advised once the AE&#x2F;ADR resolves or recovers to baseline or at least to CTCAE grade 1.</li><li>Known or suspected hypersensitivity against the active substance or any of the ingredients of the IMP.</li><li>Known history of HIV infection.
All patients must be screened for HIV up to 28 days prior to study drug start using a blood test for HIV according to local regulations.</li><li>HBV or HCV infection.
All patients must be screened for HBV and HCV up to 28 days prior to study drug start using the routine hepatitis virus laboratorial panel.
Patients positive for HBsAg or HBcAb will be eligible if they are negative for HBVDNA.
Patients positive for anti-HCV antibody will be eligible if they are negative for HCV-RNA.</li></ul>
Secondary outcomes Additional endpoints and outcome descriptions. Triage: High 25 ops
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Secondary Outcome Change Operation 11
Matched rules
  • secondary_outcome_any_change Any add/remove/replace under secondary outcome measures is high review priority.
Before
Best overall response rate by investigator
After
Best overall response of confirmed CR or PR as determined by the treating Investigator using RECIST v1.1 or RANO criteria, as appropriate to tumor type
remove /protocolSection/outcomesModule/secondaryOutcomes/0/description
Triage: High
Secondary Outcome Change Operation 12
Matched rules
  • secondary_outcome_any_change Any add/remove/replace under secondary outcome measures is high review priority.
Before
Proportion of subjects with either complete response or partial response as determined by the treating investigator using RECIST or RANO criteria.
replace /protocolSection/outcomesModule/secondaryOutcomes/1/measure
Triage: High
Secondary Outcome Change Operation 13
Matched rules
  • secondary_outcome_any_change Any add/remove/replace under secondary outcome measures is high review priority.
Before
Duration of response (DOR) by IRC
After
Duration of response (DOR): determined for subjects with best overall response of confirmed CR or PR by 1) an independent radiology review committee and 2) the treating Investigator
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Secondary Outcome Change Operation 14
Matched rules
  • secondary_outcome_any_change Any add/remove/replace under secondary outcome measures is high review priority.
Before
Duration of response (DOR) by investigator
After
Clinical benefit rate (CBR): best overall response of confirmed CR, PR, or stable disease lasting 16 or more weeks following the initiation of Larotrectinib
remove /protocolSection/outcomesModule/secondaryOutcomes/2/description
Triage: High
Secondary Outcome Change Operation 15
Matched rules
  • secondary_outcome_any_change Any add/remove/replace under secondary outcome measures is high review priority.
Before
<p>Duration of response is the number of months from the start of confirmed complete response or partial response to disease progression or death.</p><p>Complete response, partial response and disease progression are assessed by the treating investigator.</p>
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Triage: High
Secondary Outcome Change Operation 16
Matched rules
  • secondary_outcome_any_change Any add/remove/replace under secondary outcome measures is high review priority.
Before
Clinical benefit rate (CBR)
After
Rate of subjects that have any tumor regression as a best response, measured as shrinkage of target lesions
remove /protocolSection/outcomesModule/secondaryOutcomes/3/description
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Secondary Outcome Change Operation 17
Matched rules
  • secondary_outcome_any_change Any add/remove/replace under secondary outcome measures is high review priority.
Before
Proportion of subjects with best overall response of complete response, partial response or stable disease lasting 16 or more weeks following the initiation of larotrectinib.
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Triage: High
Secondary Outcome Change Operation 18
Matched rules
  • secondary_outcome_any_change Any add/remove/replace under secondary outcome measures is high review priority.
Before
Progression-free survival (PFS) after Larotrectinib
After
PFS: Number of months from initiation of larotrectinib to the earlier of disease progression or death due to any cause
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Secondary Outcome Change Operation 19
Matched rules
  • secondary_outcome_any_change Any add/remove/replace under secondary outcome measures is high review priority.
Before
Number of months from initiation of larotrectinib to either disease progression or death due to any cause.
replace /protocolSection/outcomesModule/secondaryOutcomes/5/measure
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Secondary Outcome Change Operation 20
Matched rules
  • secondary_outcome_any_change Any add/remove/replace under secondary outcome measures is high review priority.
Before
Overall survival time
After
Overall Survival (OS): Number of months from the initiation of larotrectinib to the date of death due to any cause.
remove /protocolSection/outcomesModule/secondaryOutcomes/5/description
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Secondary Outcome Change Operation 21
Matched rules
  • secondary_outcome_any_change Any add/remove/replace under secondary outcome measures is high review priority.
Before
Number of months from the initiation of larotrectinib to the date of death due to any cause.
replace /protocolSection/outcomesModule/secondaryOutcomes/6/measure
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Secondary Outcome Change Operation 22
Matched rules
  • secondary_outcome_any_change Any add/remove/replace under secondary outcome measures is high review priority.
Before
Progression-free survival (PFS) after past cancer therapy
After
Comparison of PFS following initiation of larotrectinib to that following the line of therapy immediately preceding larotrectinib in each subject who has received prior therapy
remove /protocolSection/outcomesModule/secondaryOutcomes/6/description
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Secondary Outcome Change Operation 23
Matched rules
  • secondary_outcome_any_change Any add/remove/replace under secondary outcome measures is high review priority.
Before
Number of months from initiation of the line of therapy preceding larotrectinib to either disease progression or death due to any cause.
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Secondary Outcome Change Operation 24
Matched rules
  • secondary_outcome_any_change Any add/remove/replace under secondary outcome measures is high review priority.
Before
Number of subjects with adverse events
After
Number of subjects with AEs categorized by severity. (including all, serious, and those considered treatment related.)
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Secondary Outcome Change Operation 25
Matched rules
  • secondary_outcome_any_change Any add/remove/replace under secondary outcome measures is high review priority.
Before
{
  "measure": "Number of subjects with serious adverse events",
  "timeFrame": "Up to 120 months"
}
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Secondary Outcome Change Operation 26
Matched rules
  • secondary_outcome_any_change Any add/remove/replace under secondary outcome measures is high review priority.
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{
  "measure": "Number of subjects with treatment-related adverse events",
  "timeFrame": "Up to 120 months"
}
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Secondary Outcome Change Operation 27
Matched rules
  • secondary_outcome_any_change Any add/remove/replace under secondary outcome measures is high review priority.
Before
{
  "measure": "Severity of adverse events",
  "timeFrame": "Up to 120 months"
}
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Secondary Outcome Change Operation 28
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  • secondary_outcome_any_change Any add/remove/replace under secondary outcome measures is high review priority.
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{
  "measure": "Severity of serious adverse events",
  "timeFrame": "Up to 120 months"
}
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Matched rules
  • secondary_outcome_any_change Any add/remove/replace under secondary outcome measures is high review priority.
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{
  "measure": "Severity of treatment-related adverse events",
  "timeFrame": "Up to 120 months"
}
remove /protocolSection/outcomesModule/secondaryOutcomes/8
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  • secondary_outcome_any_change Any add/remove/replace under secondary outcome measures is high review priority.
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{
  "measure": "Duration of adverse events",
  "timeFrame": "Up to 120 months"
}
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Secondary Outcome Change Operation 31
Matched rules
  • secondary_outcome_any_change Any add/remove/replace under secondary outcome measures is high review priority.
Before
{
  "measure": "Duration of serious adverse events",
  "timeFrame": "Up to 120 months"
}
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Secondary Outcome Change Operation 32
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  • secondary_outcome_any_change Any add/remove/replace under secondary outcome measures is high review priority.
Before
{
  "measure": "Duration of treatment-related adverse events",
  "timeFrame": "Up to 120 months"
}
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Secondary Outcome Change Operation 33
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  • secondary_outcome_any_change Any add/remove/replace under secondary outcome measures is high review priority.
Before
Proportion of patients with any tumor regression (i.e., measured as shrinkage of target lesions) as a best response
After
Concordance coefficient
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Secondary Outcome Change Operation 34
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  • secondary_outcome_any_change Any add/remove/replace under secondary outcome measures is high review priority.
After
Concordance of prior molecular profiling that detected an NTRK fusion within the subject&#x27;s tumor with the diagnostic test being evaluated by the Sponsor.
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Secondary Outcome Change Operation 35
Matched rules
  • secondary_outcome_any_change Any add/remove/replace under secondary outcome measures is high review priority.
Before
{
  "measure": "Concordance coefficient",
  "timeFrame": "Up to 120 months",
  "description": "Concordance of prior molecular profiling that detected an NTRK fusion within the subject&#x27;s tumor with the diagnostic test being evaluated by the Sponsor"
}
Contacts and locations Site, contact, and location updates that are usually operational. Triage: Uncategorized 34 ops
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{
  "lat": -20.55722,
  "lon": -48.56778
}
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  "lat": -23.5475,
  "lon": -46.63611
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Other registry fields Changes outside the current high-signal rule families. Triage: Uncategorized 3 ops
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Uncategorized Operation 5
Before
2023-04-24
After
2023-05-31
Sponsor and administrative fields Sponsor, collaborator, oversight, or registry maintenance changes. Triage: Uncategorized 2 ops
add /protocolSection/identificationModule/secondaryIdInfos/1
Triage: Uncategorized
Uncategorized Operation 1
After
{
  "id": "2022-502667-38-00",
  "type": "OTHER",
  "domain": "CTIS (EU)"
}
replace /protocolSection/identificationModule/officialTitle
Triage: Uncategorized
Uncategorized Operation 2
Before
A Phase 2 Basket Study of the Oral TRK Inhibitor Larotrectinib in Subjects With NTRK Fusion-positive Tumors
After
A Study to Learn How Well the Drug Larotrectinib Works in Adults With Different Solid Cancers With a Change in the Genes Called NTRK Fusion
Raw JSON Patch 
[
  {
    "op": "add",
    "path": "/protocolSection/identificationModule/secondaryIdInfos/1",
    "value": {
      "id": "2022-502667-38-00",
      "type": "OTHER",
      "domain": "CTIS (EU)"
    }
  },
  {
    "op": "replace",
    "path": "/protocolSection/identificationModule/officialTitle",
    "value": "A Study to Learn How Well the Drug Larotrectinib Works in Adults With Different Solid Cancers With a Change in the Genes Called NTRK Fusion"
  },
  {
    "op": "replace",
    "path": "/protocolSection/statusModule/statusVerifiedDate",
    "value": "2023-05"
  },
  {
    "op": "replace",
    "path": "/protocolSection/statusModule/lastUpdateSubmitDate",
    "value": "2023-05-26"
  },
  {
    "op": "replace",
    "path": "/protocolSection/statusModule/lastUpdatePostDateStruct/date",
    "value": "2023-05-31"
  },
  {
    "op": "replace",
    "path": "/protocolSection/armsInterventionsModule/armGroups/9/label",
    "value": "Arm 10_Prospective cohort"
  },
  {
    "op": "replace",
    "path": "/protocolSection/armsInterventionsModule/armGroups/9/description",
    "value": "Patients with melanoma, non secretory breast and colorectal cancer or other tumor types harboring NTRK fusions, except soft tissue sarcoma, salivary gland and thyroid cancer (arm closed)"
  },
  {
    "op": "replace",
    "path": "/protocolSection/armsInterventionsModule/interventions/0/armGroupLabels/0",
    "value": "Arm 10_Prospective cohort"
  },
  {
    "op": "replace",
    "path": "/protocolSection/outcomesModule/primaryOutcomes/0/measure",
    "value": "Best overall response of confirmed complete response (CR) or partial response (PR) as determined by an independent radiology review committee using RECIST v1.1 or RANO criteria, as appropriate to tumor type."
  },
  {
    "op": "remove",
    "path": "/protocolSection/outcomesModule/primaryOutcomes/0/description"
  },
  {
    "op": "replace",
    "path": "/protocolSection/outcomesModule/secondaryOutcomes/0/measure",
    "value": "Best overall response of confirmed CR or PR as determined by the treating Investigator using RECIST v1.1 or RANO criteria, as appropriate to tumor type"
  },
  {
    "op": "remove",
    "path": "/protocolSection/outcomesModule/secondaryOutcomes/0/description"
  },
  {
    "op": "replace",
    "path": "/protocolSection/outcomesModule/secondaryOutcomes/1/measure",
    "value": "Duration of response (DOR): determined for subjects with best overall response of confirmed CR or PR by 1) an independent radiology review committee and 2) the treating Investigator"
  },
  {
    "op": "replace",
    "path": "/protocolSection/outcomesModule/secondaryOutcomes/2/measure",
    "value": "Clinical benefit rate (CBR): best overall response of confirmed CR, PR, or stable disease lasting 16 or more weeks following the initiation of Larotrectinib"
  },
  {
    "op": "remove",
    "path": "/protocolSection/outcomesModule/secondaryOutcomes/2/description"
  },
  {
    "op": "replace",
    "path": "/protocolSection/outcomesModule/secondaryOutcomes/3/measure",
    "value": "Rate of subjects that have any tumor regression as a best response, measured as shrinkage of target lesions"
  },
  {
    "op": "remove",
    "path": "/protocolSection/outcomesModule/secondaryOutcomes/3/description"
  },
  {
    "op": "replace",
    "path": "/protocolSection/outcomesModule/secondaryOutcomes/4/measure",
    "value": "PFS: Number of months from initiation of larotrectinib to the earlier of disease progression or death due to any cause"
  },
  {
    "op": "remove",
    "path": "/protocolSection/outcomesModule/secondaryOutcomes/4/description"
  },
  {
    "op": "replace",
    "path": "/protocolSection/outcomesModule/secondaryOutcomes/5/measure",
    "value": "Overall Survival (OS): Number of months from the initiation of larotrectinib to the date of death due to any cause."
  },
  {
    "op": "remove",
    "path": "/protocolSection/outcomesModule/secondaryOutcomes/5/description"
  },
  {
    "op": "replace",
    "path": "/protocolSection/outcomesModule/secondaryOutcomes/6/measure",
    "value": "Comparison of PFS following initiation of larotrectinib to that following the line of therapy immediately preceding larotrectinib in each subject who has received prior therapy"
  },
  {
    "op": "remove",
    "path": "/protocolSection/outcomesModule/secondaryOutcomes/6/description"
  },
  {
    "op": "replace",
    "path": "/protocolSection/outcomesModule/secondaryOutcomes/7/measure",
    "value": "Number of subjects with AEs categorized by severity. (including all, serious, and those considered treatment related.)"
  },
  {
    "op": "remove",
    "path": "/protocolSection/outcomesModule/secondaryOutcomes/8"
  },
  {
    "op": "remove",
    "path": "/protocolSection/outcomesModule/secondaryOutcomes/8"
  },
  {
    "op": "remove",
    "path": "/protocolSection/outcomesModule/secondaryOutcomes/8"
  },
  {
    "op": "remove",
    "path": "/protocolSection/outcomesModule/secondaryOutcomes/8"
  },
  {
    "op": "remove",
    "path": "/protocolSection/outcomesModule/secondaryOutcomes/8"
  },
  {
    "op": "remove",
    "path": "/protocolSection/outcomesModule/secondaryOutcomes/8"
  },
  {
    "op": "remove",
    "path": "/protocolSection/outcomesModule/secondaryOutcomes/8"
  },
  {
    "op": "remove",
    "path": "/protocolSection/outcomesModule/secondaryOutcomes/8"
  },
  {
    "op": "replace",
    "path": "/protocolSection/outcomesModule/secondaryOutcomes/10/measure",
    "value": "Concordance coefficient"
  },
  {
    "op": "add",
    "path": "/protocolSection/outcomesModule/secondaryOutcomes/10/description",
    "value": "Concordance of prior molecular profiling that detected an NTRK fusion within the subject&#x27;s tumor with the diagnostic test being evaluated by the Sponsor."
  },
  {
    "op": "remove",
    "path": "/protocolSection/outcomesModule/secondaryOutcomes/11"
  },
  {
    "op": "replace",
    "path": "/protocolSection/eligibilityModule/eligibilityCriteria",
    "value": "<p>Inclusion Criteria:</p><ul><li>Locally-advanced or metastatic malignancy with an NTRK1, NTRK2, or NTRK3 gene fusion, identified through molecular assays as routinely performed at CLIA or other similarly-certified laboratories.\nSubjects who have an NTRK gene fusion identified in a lab where CLIA or equivalent certification cannot be confirmed by the Sponsor at the time of consent may have been enrolled in Cohort 9 as per protocol versions 1.0 - 8.0.\nFrom protocol version 9.0: CLIA or similar certification of the lab performing the fusion assay is required.\nHowever, patients may be included after discussion with the sponsor if the lab performing the fusion assay is not CLIA or similar certified.</li><li>Subjects who have received prior standard therapy appropriate for their tumor type and stage of disease, or who have no satisfactory alternative treatments and in the opinion of the Investigator, would be unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy.</li><li><p>Subjects must have at least one measurable lesion as defined by RECIST v1.1 (Eisenhauer et al. 2009).\nSubjects with solid tumors without RECIST v1.1 measurable disease (e.g., evaluable disease only) had been eligible for enrollment to Cohort 8 as per protocol versions 1.0 - 8.0, regardless of tumor type.\nSubjects with primary CNS tumors should meet the following criteria:</p><ol><li>Have received prior treatment including radiation and&#x2F;or chemotherapy, with radiation completed &gt; 12 weeks prior to C1D1 of therapy, as recommended or appropriate for that CNS tumor type.</li><li>Have ≥ 1 site of bi-dimensionally measurable disease (confirmed by magnetic resonance imaging [MRI] and evaluable by RANO criteria), with the size of at least one of the measurable lesions ≥ 1 cm in each dimension and noted on more than one imaging slice.</li><li>Imaging study performed within 28 days before enrollment.\nIf on steroid therapy, the dose must be stable for at least 7 days immediately before and during the imaging study.</li><li><p>Must be neurologically stable based on stable neurologic exam for 7 days prior to enrollment.</p><p>For subjects eligible for enrollment to bone health cohort, inclusion criterion 3 is modified as the following:</p></li><li>Subjects must have at least one lesion at baseline (measurable or non-measurable as defined by RECIST v1.1 or RANO criteria, as appropriate to tumor type).</li><li>Subjects with primary CNS tumors must be neurologically stable based on stable neurologic exam for 7 days prior to enrollment.</li></ol></li><li>At least 18 years of age</li><li>Performance Status: Eastern Cooperative Oncology Group (ECOG) score ≤ 3.\nIf enrolled with primary CNS tumor to be assessed by RANO, Karnofsky Performance Score (KPS) ≥ 50%.</li><li>Tumor tissue before treatment (mandatory).\nIf neither fresh tissue can be obtained nor archival tissue is available patients might be enrolled after consultation with the sponsor.</li><li><p>Adequate organ function as defined by the following criteria:</p><ol><li>Serum AST and serum ALT &lt; 2.5 x upper limit of normal (ULN), or AST and ALT &lt; 5 x ULN if liver function abnormalities are due to underlying malignancy</li><li>Total bilirubin &lt; 2.5 x ULN, except in the setting of biliary obstruction.\nSubjects with a known history of Gilberts Disease and an isolated elevation of indirect bilirubin are eligible</li><li>Serum creatinine &lt; 2.0 x ULN OR an estimated glomerular filtration rate ≥ 30 mL&#x2F;minute using the Cockcroft-Gault formula: (140- age) x body weight (kg) x 0.85 (if female)&#x2F;serum creatinine (mg&#x2F;dL) x 72 with either result acceptable for enrollment.</li></ol></li><li>Ability to comply (or for guardian to ensure compliance) with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation.</li><li>Willingness of men and women of reproductive potential to use double effective birth control methods, defined as one used by the subject and another by his&#x2F;her partner, for the duration of treatment and for 1 month following study completion.</li><li>For subjects eligible for enrollment to bone health cohort only: life expectancy of at least 6 months, based on investigator assessment.</li></ul><p>Exclusion Criteria:</p><ul><li>Investigational agent or anticancer therapy within 2 weeks prior to the planned start of larotrectinib or 5 half-lives, whichever is shorter, and without recovery of acute and&#x2F;or clinically significant toxicities from that therapy.</li><li>Prior progression while receiving approved or investigational tyrosine kinase inhibitors targeting TRK.\nSubjects who received less than 28 days of treatment and discontinued because of intolerance or toxicity are eligible.</li><li>Symptomatic or unstable brain metastases.\n(Note: Subjects with asymptomatic brain metastases are eligible to participate in the study.)\nSubjects with primary CNS tumors are eligible.</li><li>Uncontrolled concurrent malignancy that would limit assessment of efficacy of larotrectinib.\nAllowed conditions may include, but are not limited to in situ cancers of cervix, breast, or skin, superficial bladder cancer, limited-stage prostate cancer, and basal or squamous cancers of the skin.</li><li><p>Active uncontrolled systemic bacterial, viral, or fungal infection CTCAE grade ≥ 2; unstable cardiovascular disease, or other systemic disease that would limit compliance with study procedures.\nUnstable cardiovascular disease is defined as:</p><ol><li>In adults, persistently uncontrolled hypertension defined as systolic blood pressure (BP) &gt; 150 mmHg and&#x2F;or diastolic BP &gt; 100 mmHg despite antihypertensive therapy.</li><li>Myocardial infarction within 3 months of screening.</li><li>Stroke within 3 months of screening.</li></ol></li><li>Inability to discontinue treatment with a strong CYP3A4 inhibitor or inducer</li><li>Currently recovering from AEs&#x2F; ADRs due to previous treatments (excluding alopecia).\nInclusion is only advised once the AE&#x2F;ADR resolves or recovers to baseline or at least to CTCAE grade 1.</li><li>Known or suspected hypersensitivity against the active substance or any of the ingredients of the IMP.</li><li>Known history of HIV infection.\nAll patients must be screened for HIV up to 28 days prior to study drug start using a blood test for HIV according to local regulations.</li><li>HBV or HCV infection.\nAll patients must be screened for HBV and HCV up to 28 days prior to study drug start using the routine hepatitis virus laboratorial panel.\nPatients positive for HBsAg or HBcAb will be eligible if they are negative for HBVDNA.\nPatients positive for anti-HCV antibody will be eligible if they are negative for HCV-RNA.</li></ul>"
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    "op": "replace",
    "path": "/protocolSection/contactsLocationsModule/locations/1/status",
    "value": "COMPLETED"
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    "op": "replace",
    "path": "/protocolSection/contactsLocationsModule/locations/21/zip",
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    "op": "replace",
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    "op": "replace",
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    "op": "replace",
    "path": "/protocolSection/contactsLocationsModule/locations/36/city",
    "value": "Barretos/SP"
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    "op": "remove",
    "path": "/protocolSection/contactsLocationsModule/locations/36/geoPoint"
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    "op": "replace",
    "path": "/protocolSection/contactsLocationsModule/locations/41/city",
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