Anti-PD 1 Brain Collaboration + Radiotherapy Extension: The ABC-X Study
- Conditions
- melanoma brain metastases
- Interventions
- Registration Number
- 2024-518545-13-00
- Lead Sponsor
- Melanoma Institute Australia
- Brief Summary
Neurological-specific death rate at 1 year
- Detailed Description
1. BACKGROUND The ABC study (NCT02374242) is a phase II clinical trial recruiting 3 cohorts of patients with melanoma brain metastases. 76 patients received immunotherapy with either nivolumab alone or nivolumab combined with ipilimumab. Nivolumab together with ipilimumab was shown to be more effective than nivolumab alone in melanoma brain metastases. The combination will therefore be used in this trial.
Findings from pre-clinical and clinical research provides evidence supporting the ability of radiotherapy to induce anti-tumour immune responses and augment the efficacy of anti-PD1 checkpoint blockade in melanoma and provide mechanistic rationale for combined therapy.
2. STUDY DESIGN This current protocol builds on the ABC study and will assess clinical, functional, toxicities and quality of life outcomes with the combined modalities of immunotherapy with radiotherapy to the brain in melanoma patients.
The main aim of this study will be to assess the effect of immunotherapy +/- concurrent stereotactic radiotherapy (SRS) on the intracranial death rate at 12 months from the commencement of treatment. Secondary aims include the RECIST response in the brain, extracranially and overall, progression free survival, overall survival, neurocognitive function, adverse event rates and quality of life.
The study will recruit 218 patients with asymptomatic, untreated melanoma brain metastases. All patients will be treated with combination ipilimumab and nivolumab at the doses and duration approved by worldwide regulatory authorities for advanced melanoma. All patients will undergo the the SRS treatment planning MRI of the brain PRIOR to randomisation to ensure that the timing of the baseline intracranial measurements are made within a similar timeframe and so that the delineation of tumour volume is accurately recorded in the same way for both cohorts. Patents will be randomised to receive concurrent intracranial SRS (within 7 days of the baseline / planning MRI scan) or immunotherapy alone. At intracranial disease progression, any form of salvage local therapy (radiotherapy or surgery) may be administered to either cohort.
Randomisation is 1:1, using a permuted, random block design with stratification by participating centre, LDH (normal / elevated), BRAF (mutant / wild type), 1-2 brain metastases versus \> 2 brain metastases.
3. PRIMARY OUTCOME The neurological specific death rate at 12 months - defined as a proximate cause of death which is a sign, symptom, or diagnosis related to metastatic brain disease.
4. OBJECTIVE RESPONSES A modified version of RECIST will be used to assess response to treatment. The modification allows for up to 5 brain metastastes to be selected as target lesions and a further 5 extracranial lesions. The immune related response criteria (irRC) will also be applied and concordance evaluated with RECIST. The irRC measures the volume of tumour lesions by calculating bi-dimensional measurements of target lesions.
5. NEUROCOGNITIVE ASSESSMENT, FUNCTION AND QUALITY OF LIFE Neurocognitive impairment is a concern in the setting of radiotherapy delivered for brain metastases. The addition of immunotherapy for enhanced local disease control and survival may augment the risks. Quality of life (QoL) assessment is therefore an important objective in clinical trials studying the effects of new interventions, where side effects and tolerability are as important as clinical benefit.
Neurocognitive function will be assessed at baseline and every 6 to 12 weeks using the Montreal Cognitive Assessment (MoCA) and a neurological assessment of the patient. A member of the study team will be nominated to conduct the MoCA to allow for consistency of delivery of the examination. The MoCA measures six cognitive domains: visuospatial/executive function; naming; memory; language; abstraction; and attention. To decrease the learning effect from multiple administrations of the MoCA over a short period of time, alternate versions have been made available.
The Functional Assessment of Cancer Therapy (FACT) questionnaires are commonly used to assess cancer-related QoL issues. The FACT-Brain (FACT-Br) module provides an additional set of disease-specific questions pertaining to brain neoplasms and is completed by the patient.
Neurological assessments wil be made using the structured NANO scale at each physical examination - each neurological domain is subdivided into 3 or 4 levels of function with scores based on discrete quantifiable measures. Thus, levels of function for each domain range from 0 to 2 or 0 to 3. A score of 0 indicates normal function, while the highest score indicates the most severe level of deficit for that domain. Levels of function are distinguished by significant and measurable differences in order to avoid misinterpretation of subtle or nonspecific changes.
The EORTC QLQ-C30, an internationally validated cancer-specific QOL-instrument, assesses various facets of functioning, symptoms common in cancer patients and global QOL. The Brain Cancer Module (EORTC QLQ-BN20 is a 20-item supplement for the QLQ-C30 to assess neurological related quality of life and neurological symptoms and is being utilised in the main ABC study. Among the symptoms captured by neurocognitive tests are communication deficits and memory problems. In these cases, a patient-rated QoL tool may not capture the true effects of the disease or the intervention to treat it. Both C30 and BN20 modules have been validated for assessing health-related quality of life and symptoms in patients with brain cancer.
General health status will also be measured using the EQ-5D. The EQ-5D is a standardized instrument for use as a measure of self-reported health status. The EQ-5D comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety) and a visual analogue rating scale (VAS). The utility data generated from the EQ-5D is commonly used in cost effectiveness analyses.
6. TOXICITY AND TOLERABILITY Adverse events will be reported using the CTCAE version 5.0 in addition to causality, duration, treatment required and the need for treatment delays or discontinuation. Radionecrosis is an event of clinical interest and will be captured separately.
7. CORRELATIVE BLOOD AND TISSUE BIOMARKER STUDIES Some patients may not benefit from radiation therapy and immunotherapy combinations. Therefore, biomarkers predictive of response. or the lack of it are needed. Extensive correlative analyses of tumoural and peripheral blood immunologic changes will be essential to a better understanding of the mechanistic interactions between these 2 treatment modalities. The differential composition of the gut microbiome has been shown to affect antitumor immunity and immunotherapy efficacy and will also be correlated with response and toxicity.
To address this, blood, tissue, stool and urine samples will be obtained. Blood will be collected at baseline, at 1 week of treatment and then 6 to 12 weekly to examine serum chemokines, cytokines, inflammatory markers, lymphocyte and T cell subsets and myeloid derived suppressor cells and to assess correlation with disease response or progression. All Cohorts will be included in this study.
In patients with sufficient archival melanoma tissue from metastatic sites, a baseline tumour PD-L1 level, immune markers and genetics of response and resistance will also be measured. If available, tumour tissue following progression of accessible extracranial disease and / or craniotomy will also be tested for immune and genetic markers.
Stool samples will be obtained at baseline, at weeks 6 and 12 and at the end of immunotherapy to investigate the gut microbiome composition, diversity and abundance and correlation with the response to immunotherapy and immune-related gastrointestinal toxicity. A baseline evaluation of participants' dietary habits will also be included in these analyses.
A reduction in intestinal barrier function is currently believed to play an important role in pathogenesis of many diseases, response to immunotherapy and immune related toxicity. Urinary excretion of two orally-administered non-metabolizable sugars, lactulose and mannitol, is a valuable marker for evaluating intestinal permeability. Patients will collect a urine specimen at baseline to assess this biomarker.
8. CONTINUED SYSTEMIC TREATMENT IN CASES OF PROGRESSIVE DISEASE
The application of traditional RECIST criteria (Response Evaluation Criteria In Solid Tumors) in patients treated with immunotherapy may lead to premature discontinuation of treatment in a patient who will eventually respond to treatment or have prolonged disease stabilization. Disease progression may occur in extracranial lesions whilst patients may continue to have disease stabilisation or response of their intracranial melanoma disease, and vice versa. The patterns of response to treatment with these immunotherapy agents differ from those with molecularly targeted agents or cytotoxic chemotherapy in several important respects:
* Patients may have a transient worsening of disease, manifested either by progression of known lesions or the appearance of new lesions, before disease stabilizes or tumour regresses. Therefore caution should be taken in abandoning therapy early. In general these delayed responses are not observed in patients with rapidly progressive, symptomatic disease.
* Responses can take appreciably longer to become apparent compared with cytotoxic therapy. Continued disease regression is frequently observed well after completion of the initial induction period.
* Some patients who do not meet traditional criteria for objective response can have prolonged periods of stable disease that are clinically significant.
An evaluation of data from ipilimumab phase II clinical trials in advanced melanoma found patients characterized as PD at week 12 (by WHO criteria), either by an increase in tumour burden and/or the appearance of new lesions, subsequently experienced an objective response or SD (relative to baseline) without the addition of non-ipilimumab anticancer therapy. Examination of biopsies taken from patients receiving ipilimumab demonstrated that in some small unmeasurable lesions noted at baseline, an increase in size may be interpreted as PD, when instead, this may be due to inflammation due to T cell infiltration.
9. CONTINUED TREATMENT WITH NIVOLUMAB Patients who are found to have RECIST defined intracranial or extracranial progression (or both) from 6 weeks onwards, and who do not have clinical signs or symptoms of progression, may continue on nivolumab and must have a confirmatory scan within 4 to 6 weeks. The date of the original assessment of progression will be used to record progression, and not the date of the confirmatory imaging. Continued immunotherapy treatment is permitted if the treating clinician determines that the patient is still clinically benefiting from immunotherapy and the patient is willing to continue drug treatment. Consideration may be given to stable or good response extra- or intra- cranially with concurrent progression in the other as a scenario that may warrant further treatment.
There is growing evidence that patients may not need to be treated with immunotherapies indefinitely, or even for as long as the two years commonly studied in clinical trials. Rather, shorter courses of treatment may be just as effective and provide an option for retreatment should a patient progress after coming off a defined period of therapy. Patients who receive 2 years of immunotherapy have the option to cease treatment at this stage, with an option for a rechallenge of immunotherapy at the time of disease progression, if this occurs with 2 years of initial cessation.
Recruitment & Eligibility
- Status
- Authorised, recruitment pending
- Sex
- Not specified
- Target Recruitment
- 20
≥18 years of age
Life expectancy of > 30 days
Able to undergo MRI with Gadolinium contrast agent
Adequate haematological, hepatic and renal organ function
Women of childbearing potential with a negative pregnancy test, effective contraception
Men with female partner of childbearing potential use effective contraception and refrain from donating sperm during the study and for 31 weeks from end of treatment
Written informed consent
AJCC Stage IV (any T, any N, M1d) histologically confirmed cutaneous, acral or mucosal melanoma, or unknown primary melanoma, with metastases to the brain that are considered unresectable. Patients must have a minimum of one radiological definitive brain metastasis that is ≥ 5mm and ≤40mm, measurable per bm RECIST guidelines. There is no upper limit restriction to the number of brain metastases
Known BRAF mutation status prior to randomisation
The treating clinician(s) should consider all intracranial lesions (target and non-target) amenable to stereotactic radiotherapy over whole brain radiotherapy. This includes brain metastases ≤5mm diameter
No prior radiotherapy for brain metastases (previous surgery for melanoma brain metastases is permitted). Prior radiotherapy for extracranial disease is permitted
No prior systemic drug therapy for melanoma, unless given in the neoadjuvant or adjuvant setting and for the treatment of extracranial disease only. Radiological confirmation of the absence of brain metastases throughout prior systemic treatment should be documented. The presenting diagnosis of brain metastases must have occurred ≥ 6 months after stopping systemic therapy (prior anti PD1, anti PD-L1, anti CTLA-4, BRAF/MEK inhibitors or clinical trial agents are acceptable in the setting of neoadjuvant or adjuvant treatment)
Asymptomatic from brain metastases at the time of study enrolment without corticosteroids, analgesia or any other treatment for the management of active neurological symptoms. Resolved neurological symptoms are permitted if complete resolution has been sustained for a minimum of 7 days prior to randomisation. Antiepileptics are permitted regardless of the indication, provided the patient is asymptomatic at the time of randomisation
ECOG performance status of 0-2
Patients whose intracranial disease changes between the eligibility MRI scan and the SRS planning MRI rendering the patient unsuitable for randomised treatment on trial, or requires a specific alternative treatment
Active infection requiring therapy
History of interstitial lung disease
Any concurrent malignancy (excluding successful resection or curative treatment of in situ disease, superficial bladder cancer or non-melanoma skin cancer) requiring any treatment or a history of another malignancy, unless the patient has been disease-free for 1 year
Serious or unstable pre-existing medical conditions or other conditions that could interfere with the patient’s safety, consent, or compliance
Pregnant or breastfeeding females
Administration of any form of live vaccine within 30 days of starting the trial and during trial. Other vaccine use is cautionary within 30 days of starting trial and during treatment phase of trial
Hypersensitivity to study treatment or to any of the excipients listed in the corresponding Investigator's Brochure
Any melanoma brain metastasis >40mm
Evidence of leptomeningeal disease, with the exception of pathological findings seen at previous resection of brain disease, but no evidence of leptomeningeal disease elsewhere at the time of resection or at study entry
Ocular (both uveal and conjunctival) melanoma (mucosal and acral melanoma are eligible)
Current neurological symptoms from brain metastases or a requirement for corticosteroids, analgesia or other treatment for the management of symptoms
Prior radiotherapy to the brain (prior surgery for melanoma brain metastases permitted)
Prior systemic drug therapy for melanoma, unless given in the neoadjuvant or adjuvant setting, prior to the development of any brain metastases and completed ≥ 6 months before enrolment in this study
Patients with significant active, known or suspected autoimmune disease requiring past or current immunosuppression
Current systemic treatment with corticosteroids, or within 7 days of randomisation, except prednisone at non-immunosuppressive doses of ≤ 10 mg/day (or equivalent)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Nivolumab + ipilimumab Salvage therapy Nivolumab 1mg/kg and ipilimumab 3mg/kg Q3W x 4 doses, then nivolumab 480 mg every 4 weeks. Any form of salvage therapy (surgery or radiotherapy) may be administered to either cohort for the treatment of intracranial disease progression. Nivolumab + ipilimumab,concurrent SRS Nivolumab Nivolumab 1mg/kg and ipilimumab 3mg/kg Q3W x 4 doses, then nivolumab 480 mg every 4 weeks. Stereotactic radiotherapy 16 to 22 Gy in 1 fraction or 24 to 30 Gy, hypofractionated for larger lesions. Stereotactic radiotherapy to commence within 7 days of of the baseline / planning MRI brain. Hypofractionated stereotactic radiotherapy should be completed within 14 day of the first fraction. Any form of salvage therapy (surgery or radiotherapy) may be administered to either cohort for the treatment of intracranial disease progression. Nivolumab + ipilimumab,concurrent SRS Ipilimumab Nivolumab 1mg/kg and ipilimumab 3mg/kg Q3W x 4 doses, then nivolumab 480 mg every 4 weeks. Stereotactic radiotherapy 16 to 22 Gy in 1 fraction or 24 to 30 Gy, hypofractionated for larger lesions. Stereotactic radiotherapy to commence within 7 days of of the baseline / planning MRI brain. Hypofractionated stereotactic radiotherapy should be completed within 14 day of the first fraction. Any form of salvage therapy (surgery or radiotherapy) may be administered to either cohort for the treatment of intracranial disease progression. Nivolumab + ipilimumab,concurrent SRS Stereotactic Radiotherapy Nivolumab 1mg/kg and ipilimumab 3mg/kg Q3W x 4 doses, then nivolumab 480 mg every 4 weeks. Stereotactic radiotherapy 16 to 22 Gy in 1 fraction or 24 to 30 Gy, hypofractionated for larger lesions. Stereotactic radiotherapy to commence within 7 days of of the baseline / planning MRI brain. Hypofractionated stereotactic radiotherapy should be completed within 14 day of the first fraction. Any form of salvage therapy (surgery or radiotherapy) may be administered to either cohort for the treatment of intracranial disease progression. Nivolumab + ipilimumab,concurrent SRS Salvage therapy Nivolumab 1mg/kg and ipilimumab 3mg/kg Q3W x 4 doses, then nivolumab 480 mg every 4 weeks. Stereotactic radiotherapy 16 to 22 Gy in 1 fraction or 24 to 30 Gy, hypofractionated for larger lesions. Stereotactic radiotherapy to commence within 7 days of of the baseline / planning MRI brain. Hypofractionated stereotactic radiotherapy should be completed within 14 day of the first fraction. Any form of salvage therapy (surgery or radiotherapy) may be administered to either cohort for the treatment of intracranial disease progression. Nivolumab + ipilimumab Ipilimumab Nivolumab 1mg/kg and ipilimumab 3mg/kg Q3W x 4 doses, then nivolumab 480 mg every 4 weeks. Any form of salvage therapy (surgery or radiotherapy) may be administered to either cohort for the treatment of intracranial disease progression. Nivolumab + ipilimumab Nivolumab Nivolumab 1mg/kg and ipilimumab 3mg/kg Q3W x 4 doses, then nivolumab 480 mg every 4 weeks. Any form of salvage therapy (surgery or radiotherapy) may be administered to either cohort for the treatment of intracranial disease progression.
- Primary Outcome Measures
Name Time Method The incidence of neurological-specific death in the whole patient population at 1 year, from start of nivolumab and ipilimumab, where the immediate cause of death is due to brain metastases The incidence of neurological-specific death in the whole patient population at 1 year, from start of nivolumab and ipilimumab, where the immediate cause of death is due to brain metastases
- Secondary Outcome Measures
Name Time Method The best response in intracranial metastases as measured using brain modified (bm) RECIST, following at least ONE dose of nivolumab and ipilimumab and based on imaging from week 12 onwards and confirmed a minimum of 4 weeks later The best response in intracranial metastases as measured using brain modified (bm) RECIST, following at least ONE dose of nivolumab and ipilimumab and based on imaging from week 12 onwards and confirmed a minimum of 4 weeks later
The best response in extracranial disease for each patient measured using bm RECIST, following at least ONE dose of nivolumab and ipilimumab and based on imaging from week 12 onwards and confirmed a minimum of 4 weeks later The best response in extracranial disease for each patient measured using bm RECIST, following at least ONE dose of nivolumab and ipilimumab and based on imaging from week 12 onwards and confirmed a minimum of 4 weeks later
Proportion of patients with an overall complete or partial response as measured using bm RECIST following at least ONE dose of nivolumab and ipilimumab and based on imaging from week 12 onwards and confirmed a minimum of 4 weeks later Proportion of patients with an overall complete or partial response as measured using bm RECIST following at least ONE dose of nivolumab and ipilimumab and based on imaging from week 12 onwards and confirmed a minimum of 4 weeks later
a. Time from the start of nivolumab and ipilimumab to the date of any progression of disease as measured using bm RECIST with confirmation of response a minimum of 4 weeks later. b. Patients dying from causes other than melanoma or treatment related toxicity will be censored at the date of death. c. Patients alive without progression will be censored at the date of their last assessment. d. A diagnosis of a second primary melanoma is not considered a progression event. a. Time from the start of nivolumab and ipilimumab to the date of any progression of disease as measured using bm RECIST with confirmation of response a minimum of 4 weeks later. b. Patients dying from causes other than melanoma or treatment related toxicity will be censored at the date of death. c. Patients alive without progression will be censored at the date of their last assessment. d. A diagnosis of a second primary melanoma is not considered a progression event.
The incidence of non-neurological death in the whole patient population at 1 year from the start of nivolumab and ipilimumab where the immediate cause of death is due to melanoma but from causes other than brain metastases The incidence of non-neurological death in the whole patient population at 1 year from the start of nivolumab and ipilimumab where the immediate cause of death is due to melanoma but from causes other than brain metastases
a. Time from the start of nivolumab and ipilimumab to the date of death from any cause. b. Patients still alive at the end of the study will be censored at the date of their last assessment. a. Time from the start of nivolumab and ipilimumab to the date of death from any cause. b. Patients still alive at the end of the study will be censored at the date of their last assessment.
a. The incidence of radionecrosis, diagnosed by imaging and / or histopathology assessment, occurring within 5 years from the start of the first course of radiotherapy in either treatment arm (i.e. the start of concurrent SRS with immunotherapy and / or the start of any form of salvage radiotherapy). b. The number of repeat radionecrosis events per patient. a. The incidence of radionecrosis, diagnosed by imaging and / or histopathology assessment, occurring within 5 years from the start of the first course of radiotherapy in either treatment arm (i.e. the start of concurrent SRS with immunotherapy and / or the start of any form of salvage radiotherapy). b. The number of repeat radionecrosis events per patient.
Incidence of salvage radiotherapy to intracranial brain metastases in each cohort Incidence of salvage radiotherapy to intracranial brain metastases in each cohort
Incidence of craniotomy for intracranial brain metastases in each cohort Incidence of craniotomy for intracranial brain metastases in each cohort
a. The mean change from baseline assessment [CTCAE neurocognitive adverse events, Montreal Cognitive Assessment [MoCA] and FACT-cog) to the time of best response and progression of disease. b. The duration of each neurocognitive deficit. c. Proportion of patients in each Cohort recording decreased neurocognitive function. d. The proportion of patients requiring an intervention to treat neurocognitive dysfunction. a. The mean change from baseline assessment [CTCAE neurocognitive adverse events, Montreal Cognitive Assessment [MoCA] and FACT-cog) to the time of best response and progression of disease. b. The duration of each neurocognitive deficit. c. Proportion of patients in each Cohort recording decreased neurocognitive function. d. The proportion of patients requiring an intervention to treat neurocognitive dysfunction.
e. The correlation of neurocognitive function with neurological-specific death and overall survival. f. The correlation of patient-perceived cognitive impairment and researcher-rated neurocognitive function. e. The correlation of neurocognitive function with neurological-specific death and overall survival. f. The correlation of patient-perceived cognitive impairment and researcher-rated neurocognitive function.
a. The mean change from baseline quality of life scores [ED 5Q, QLQ-C30 + BN20, FACT-Br] to the time of response, stable disease or progression. b. Time from the start of nivolumab and ipilimumab to the time of deterioration of quality life scores and the duration of deterioration. a. The mean change from baseline quality of life scores [ED 5Q, QLQ-C30 + BN20, FACT-Br] to the time of response, stable disease or progression. b. Time from the start of nivolumab and ipilimumab to the time of deterioration of quality life scores and the duration of deterioration.
The incidence of reduced functional performance by 1, 2 or 3 grades of the Eastern Cooperative Oncology Group (ECOG) performance status scale compared to baseline following at least ONE dose of nivolumab and ipilimumab The incidence of reduced functional performance by 1, 2 or 3 grades of the Eastern Cooperative Oncology Group (ECOG) performance status scale compared to baseline following at least ONE dose of nivolumab and ipilimumab
a. Number of adverse events by type, frequency, duration, relatedness to any treatment, relatedness to disease progression and severity of the event using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v5) b. Number of patients who discontinue any study treatment due to intolerable or serious adverse events. c. Number and nature of serious adverse events and events of clinical interest using CTCAE criteria. a. Number of adverse events by type, frequency, duration, relatedness to any treatment, relatedness to disease progression and severity of the event using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v5) b. Number of patients who discontinue any study treatment due to intolerable or serious adverse events. c. Number and nature of serious adverse events and events of clinical interest using CTCAE criteria.
a. Correlation of the PD-L1 status, immune markers, genomics and other biomarkers of response and resistance in tumour tissue (extracranial and intracranial sites if possible, available and applicable) at baseline and at subsequent disease progression. a. Correlation of the PD-L1 status, immune markers, genomics and other biomarkers of response and resistance in tumour tissue (extracranial and intracranial sites if possible, available and applicable) at baseline and at subsequent disease progression.
b. Correlation of lymphocyte, T cell subsets, myeloid derived suppressor cells, genomic and other biomarkers in blood at baseline, at the commencement of radiotherapy (and conclusion of radiotherapy if fractionated), at complete or partial response and at subsequent disease progression. c. Investigation of histological features and biomarkers in brain tissue, if removed at biopsy or surgery. b. Correlation of lymphocyte, T cell subsets, myeloid derived suppressor cells, genomic and other biomarkers in blood at baseline, at the commencement of radiotherapy (and conclusion of radiotherapy if fractionated), at complete or partial response and at subsequent disease progression. c. Investigation of histological features and biomarkers in brain tissue, if removed at biopsy or surgery.
d. Investigation of the gut microbiome composition, diversity and abundance and correlation with baseline self-reported dietary habits, the response to immunotherapy and immune-related gastrointestinal toxicity. e. Correlation of gastrointestinal mucosal integrity with bacterial composition in stool samples, RECIST response and immune related adverse events. d. Investigation of the gut microbiome composition, diversity and abundance and correlation with baseline self-reported dietary habits, the response to immunotherapy and immune-related gastrointestinal toxicity. e. Correlation of gastrointestinal mucosal integrity with bacterial composition in stool samples, RECIST response and immune related adverse events.
Trial Locations
- Locations (1)
IRCCS Istituto Nazionale Tumori Fondazione Pascale
🇮🇹Naples, Italy
IRCCS Istituto Nazionale Tumori Fondazione Pascale🇮🇹Naples, ItalyPaolo Antonio AsciertoSite contact00398117770168p.ascierto@istitutotumori.na.it