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Inhaled Sirolimus in Lung Transplant Recipients With Bronchiolitis Obliterans Syndrome. (INSPO-BOS)

Primary Purpose

Bronchiolitis Obliterans Syndrome Due to and After Lung Transplantation (Disorder), Chronic Lung Allograft Dysfunction

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Sirolimus
Placebo
Sponsored by
Steven Hays, MD
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Bronchiolitis Obliterans Syndrome Due to and After Lung Transplantation (Disorder) focused on measuring Bronchiolitis Obliterans Syndrome, Chronic Lung Allograft Dysfunction, Lung Transplant Rejection, Sirolimus, mTOR inhibitor, CLAD

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Age > 18 years old Recipient of a double pulmonary allograft at least 12 months before study entry Subjects with clinically diagnosed CLAD-BOS phenotype (all 3 required) BOS defined as screening FEV1 between 85-51% of the baseline as defined by the 2 highest FEV1 measures at least 3 weeks apart. Diagnosis within 12 months of screening visit. FEV1 decline is persistent as defined by decline sustained for > 30 days. Currently receiving Standard Immunosuppression. This is defined as a combination of 3 medications including Prednisone, Mycophenolate or Azathioprine, and Tacrolimus or Cyclosporine. The dosing should be stable for 4 weeks prior to screening. Absence of oral sirolimus or everolimus treatment for at least 4 weeks prior to screening based on the half-life and resolution of the tissue effects Stable enough to enable routine post-transplant bronchoscopy with BAL and biopsy when indicated Capable of understanding the purposes and risks of the study Written informed consent (and assent when applicable) obtained from subject or subject's legal representative and ability for subject to comply with the requirements of the study. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to study entry Women of childbearing potential if sexually active must agree to using highly effective contraception during study and for 90 days after discontinuation of study treatment Women of childbearing potential must refrain from breast feeding or donating eggs for the duration of the study and for 90 days after the last dose of study treatment Male participants must agree to use a condom during sexual contact with a female of childbearing potential while participating in the study and for 90 days following discontinuation of investigational product use Male participants must refrain from donating sperm for the duration of the study and for 90 days after the last dose of study treatment Exclusion Criteria: Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study. Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data. Patients with re-transplantation or currently listed for re-transplantation Patients with confirmed other causes for loss of lung function, such as acute infection, acute rejection, restrictive allograft syndrome (CLAD - RAS phenotype, see Protocol Specific Definition), etc. Patients with acute antibody-mediated rejection at Screening. In this context, clinically stable patients (as judged by the Investigator) with detectable donor-specific antibodies (DSA) levels at the Screening Visit are eligible for the study Active acute bacterial, viral, or fungal infection that has not successfully resolved in at least 4 weeks prior to the Screening Visit. Patients with chronic infection or colonization who are clinically stable as per judgement of the investigator are eligible. Mechanical ventilation within 12 weeks prior to the randomization Patient has baseline resting oxygen saturation of < 89% on room air or use of supplemental oxygen at rest at screening Evidence of functional airway stenosis (i.e., bronchomalacia/ tracheomalacia, airway stents, or airways requiring balloon dilatations to maintain patency) with onset after the initial diagnosis of BOS and ongoing at Screening and/or Baseline Visit Known hypersensitivity to sirolimus or everolimus Currently enrolled in another investigational trial for obstructive chronic lung allograft dysfunction (BOS) Patients with chronic renal failure, defined as serum creatinine > 2.5 mg/dL at screening, or requiring chronic dialysis Patients with liver disease and serum bilirubin > 3-fold upper limit of normal range or transaminases > 2.5 upper limit of normal range Patients with active malignancy within the previous 2 years, including post-transplant lymphoproliferative disorder, except for treated, localized basal and squamous cell carcinomas Any history of malignancy likely to result in significant disability or likely to require significant medical or surgical intervention within the next 6 months. This does not include minor surgical procedures for localized skin cancer. History of severe allergic reaction to lactose (patients with lactose intolerance are eligible) Patients with uncontrolled hypertension

Sites / Locations

  • University of California, San FranciscoRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Sirolimus

Placebo

Arm Description

100 ug sirolimus capsule to be inhaled daily for 48 weeks via Plastiape RS01 dry powder inhaler Model 7.

Lactose capsule to be inhaled daily for 48 weeks via Plastiape RS01 dry powder inhaler Model 7.

Outcomes

Primary Outcome Measures

Time to Progression Free Survival (PFS), Level 1
Time to Progression Free Survival (PFS) Level 1, defined as the earliest of the following: Absolute decrease in FEV1 from baseline of > 10% Death from respiratory failure

Secondary Outcome Measures

Change in FEV1
Change in FEV1 from baseline
Change in forced expiratory volume in one second/forced vital capacity (FEV1/FVC)
Change in FEV1/FVC from baseline

Full Information

First Posted
June 1, 2023
Last Updated
August 28, 2023
Sponsor
Steven Hays, MD
Collaborators
OrphAI Therapeutics
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1. Study Identification

Unique Protocol Identification Number
NCT06018766
Brief Title
Inhaled Sirolimus in Lung Transplant Recipients With Bronchiolitis Obliterans Syndrome.
Acronym
INSPO-BOS
Official Title
A Randomized, Placebo-controlled Phase 2 Study to Demonstrate the Safety and Efficacy of the Addition of Inhaled Sirolimus to Standard Immunosuppression Therapy for Chronic Lung Allograft Dysfunction (BOS).
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
August 17, 2023 (Actual)
Primary Completion Date
December 2025 (Anticipated)
Study Completion Date
December 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Steven Hays, MD
Collaborators
OrphAI Therapeutics

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The goal of this clinical trial is to learn about the safety and effectiveness of inhaled sirolimus in patients who have developed bronchiolitis obliterans syndrome (BOS), a form of chronic rejection, after lung transplantation. The main questions it aims to answer are: Is inhaled sirolimus safe in these patients? Is inhaled sirolimus effective in slowing BOS progression? Participants will: Be randomly assigned to inhale either sirolimus or placebo (a look-alike substance that contains no active drug) daily for 48 weeks Attend 10 study visits (mixture of in-person and telehealth) over the 48 week period Undergo pulmonary function testing, bronchoscopy, lab testing, and physical examination Submit weekly home spirometry monitoring Researchers will compare participants assigned to inhaled sirolimus versus placebo to see if sirolimus is safely tolerated and to assess the effectiveness of inhaled sirolimus on slowing BOS progression.
Detailed Description
Chronic rejection, commonly denoted as bronchiolitis obliterans (BO), obliterative bronchiolitis (OB), or bronchiolitis obliterans syndrome (BOS), is the leading cause of death beyond the first year after lung transplantation. Whereas the development of BOS is rare within the first year after lung transplantation, annual increments of approximately 10% are recorded in subsequent years, resulting in a cumulative incidence range of 40-50% within the first five years and 70-80% within 10 years of transplantation. No current effective treatment for BOS exists. BOS represents the leading cause of morbidity and mortality after lung transplantation, limiting 5-year survival to well below other solid organ transplants. BOS is characterized by an inexorable lung function decline despite currently available immunomodulatory treatments. Sirolimus has been shown to block T-cell proliferative effects induced by cytokines, alloantigens, and mitogens in a dose-dependent manner(4, 5). Oral sirolimus has been shown in small studies to have a beneficial impact on rapidly progressive BOS; however, administration in this patient population has been challenged by a high degree of intolerance with the side effects. The development of inhaled sirolimus for lung transplant related BOS, conceptually a T-cell driven process against transplanted alloantigen, is based on the principal hypothesis that administration of a sirolimus dose to the rejecting lung allograft(s) by inhalation will result in improved efficacy by depositing higher drug concentrations directly within the allograft by inhalation than would be achieved by oral administration due to systemic toxicities associated with systemic sirolimus. Because of known reduced systemic bioavailability of inhaled sirolimus compared to oral sirolimus dosing, amelioration of the substantial adverse event profile compared to systemic drug is expected. Inhaled sirolimus is also expected to reduce serious complication risks by obviating requirements for maintenance and augmented immune drugs used to treat BOS. The primary objective is to assess the clinical efficacy of inhaled sirolimus in lung transplant recipients with bronchiolitis obliterans syndrome as measured by progression free survival and change in forced expiratory volume in one second (FEV1) over a 48-week period. Another primary objective is to assess the safety and tolerability of inhaled sirolimus in lung transplant recipients with bronchiolitis obliterans syndrome. Secondary objectives are: To determine the impact of inhaled sirolimus on genetic markers of bronchiolitis obliterans syndrome and activation of the mammalian target of rapamycin (mTOR) pathway by measuring chronic lung allograft dysfunction signature gene profiling and mTOR pathway activation in bronchoalveolar lavage fluid To determine whether donor-derived cell-free DNA (%ddcfDNA) will predict ongoing injury (versus cessation of BOS progression) by measuring %ddcfDNA in randomized subjects. % ddcfDNA will be correlated with clinical outcome measures of FEV1 change, death, and re-transplantation for both randomized groups. To determine the levels of sirolimus in the blood and bronchoalveolar lavage (BAL) fluid, the BAL as a surrogate for levels in the lung.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Bronchiolitis Obliterans Syndrome Due to and After Lung Transplantation (Disorder), Chronic Lung Allograft Dysfunction
Keywords
Bronchiolitis Obliterans Syndrome, Chronic Lung Allograft Dysfunction, Lung Transplant Rejection, Sirolimus, mTOR inhibitor, CLAD

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Sirolimus
Arm Type
Experimental
Arm Description
100 ug sirolimus capsule to be inhaled daily for 48 weeks via Plastiape RS01 dry powder inhaler Model 7.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Lactose capsule to be inhaled daily for 48 weeks via Plastiape RS01 dry powder inhaler Model 7.
Intervention Type
Drug
Intervention Name(s)
Sirolimus
Other Intervention Name(s)
LAM-001
Intervention Description
Inhaled sirolimus administered via dry powder inhaler
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Inhaled lactose administered via dry powder inhaler
Primary Outcome Measure Information:
Title
Time to Progression Free Survival (PFS), Level 1
Description
Time to Progression Free Survival (PFS) Level 1, defined as the earliest of the following: Absolute decrease in FEV1 from baseline of > 10% Death from respiratory failure
Time Frame
52 weeks
Secondary Outcome Measure Information:
Title
Change in FEV1
Description
Change in FEV1 from baseline
Time Frame
48 weeks
Title
Change in forced expiratory volume in one second/forced vital capacity (FEV1/FVC)
Description
Change in FEV1/FVC from baseline
Time Frame
48 weeks
Other Pre-specified Outcome Measures:
Title
Time to Progression Free Survival (PFS), Level 2
Description
Time to Progression Free Survival (PFS) Level 2, defined as the earliest of the following: Absolute decrease in the FEV1 from baseline of >20% Death from respiratory failure
Time Frame
52 weeks
Title
Change in Quality of Life
Description
Change in Quality of Life as measured by St. George's Respiratory Questionnaire -COPD (SGRQ-C). The range of scores is 0-100, with the higher scores representing more limitation in quality of life.
Time Frame
48 weeks
Title
Change in six-minute walk distance (6MWD)
Description
Change in 6MWD from baseline
Time Frame
48 weeks
Title
Donor-derived cell-free DNA: Ongoing lung injury
Description
Determine whether donor-derived cell-free DNA (%ddcfDNA) will predict ongoing injury (versus cessation of BOS progression) by measuring %ddcfDNA in randomized subjects. %ddcfDNA will be correlated with clinical outcome measures of FEV1 change, death, and re-transplantation for both randomized groups.
Time Frame
52 weeks
Title
% Reduced donor-derived cell-free DNA
Description
Determine whether the inhaled sirolimus group will have a salutary effect on allograft injury in terms of reduced %ddcfDNA compared to standard therapy by measuring %ddcfDNA values at determined time points and comparing values between the inhaled sirolimus and placebo groups.
Time Frame
48 weeks
Title
CLAD signature gene profiling
Description
Utilizing the endobronchial brush, we will quantify a metagene, or normalized sum of gene expression, from our previously published airway inflammation gene set, as described in our publication (PMID: 32885581). The metagene expression will be compared between randomized groups.
Time Frame
3 months post randomization
Title
mTOR pathway activation
Description
Utilizing the bronchioalveolar lavage fluid, we will quantify pS6S235/235 in lymphocytes using flow cytometry, to quantify mTORC1 activity, as previously published (PMID: 36066491). We will compare pS6S235/235 between randomized groups.
Time Frame
3 months post randomization
Title
Serum sirolimus levels
Description
Measured serum sirolimus levels
Time Frame
Assessed pre-inhalation at in-person study visits over 48 weeks and post-inhalation at 3 months post randomization
Title
Tolerability of inhaled therapy
Description
Measurement of FEV1 pre-inhalation and 4 hours following study drug inhalation.
Time Frame
Baseline Study Visit (Week 0)
Title
Adverse events
Description
Incidence and severity of treatment emergent adverse events (AE) and serious adverse events (SAE).
Time Frame
52 weeks
Title
Adverse events of special interest
Description
Incidence of local and systemic adverse events of special interest (AESI) including oral or dental lesions, pharyngeal soreness, cough, and dyspnea associated with inhalation will be recorded using a specific case report form and standard examination
Time Frame
52 weeks
Title
White blood cell (WBC) count
Description
WBC will be monitored and compared between randomized groups
Time Frame
52 weeks
Title
Hemoglobin
Description
Hemoglobin will be monitored and compared between randomized groups
Time Frame
52 weeks
Title
Platelet count
Description
Platelet count will be monitored and compared between randomized groups
Time Frame
52 weeks
Title
Aspartate Aminotransferase (AST)
Description
AST will be monitored and compared between randomized groups
Time Frame
52 weeks
Title
Alanine Aminotransferase (ALT)
Description
ALT will be monitored and compared between randomized groups
Time Frame
52 weeks
Title
Alkaline Phosphatase
Description
Alkaline Phosphatase will be monitored and compared between randomized groups
Time Frame
52 weeks
Title
Total Bilirubin
Description
Total Bilirubin will be monitored and compared between randomized groups
Time Frame
52 weeks
Title
Triglycerides
Description
Triglycerides will be monitored and compared between randomized groups
Time Frame
52 weeks
Title
Creatinine
Description
Creatinine will be monitored and compared between randomized groups
Time Frame
52 weeks
Title
Urine protein/creatinine ratio
Description
Urine protein/creatinine ratio will be monitored and compared between randomized groups
Time Frame
52 weeks
Title
Mortality
Description
Overall mortality in each group will be compared
Time Frame
52 weeks
Title
Infections
Description
Incidence of infections including pneumonia, bronchitis, viral infections (including COVID-19) in each group will be compared
Time Frame
52 weeks
Title
Malignancies
Description
Incidence of malignancies in each group will be compared
Time Frame
52 weeks
Title
Wound healing complications
Description
Wound healing complications in each group will be compared
Time Frame
52 weeks
Title
Hospitalization rates
Description
Hospitalization rates in each group will be compared
Time Frame
52 weeks
Title
Interstitial pneumonitis
Description
Incidence of interstitial pneumonitis in each group will be compared
Time Frame
52 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age > 18 years old Recipient of a double pulmonary allograft at least 12 months before study entry Subjects with clinically diagnosed CLAD-BOS phenotype (all 3 required) BOS defined as screening FEV1 between 85-51% of the baseline as defined by the 2 highest FEV1 measures at least 3 weeks apart. Diagnosis within 12 months of screening visit. FEV1 decline is persistent as defined by decline sustained for > 30 days. Currently receiving Standard Immunosuppression. This is defined as a combination of 3 medications including Prednisone, Mycophenolate or Azathioprine, and Tacrolimus or Cyclosporine. The dosing should be stable for 4 weeks prior to screening. Absence of oral sirolimus or everolimus treatment for at least 4 weeks prior to screening based on the half-life and resolution of the tissue effects Stable enough to enable routine post-transplant bronchoscopy with BAL and biopsy when indicated Capable of understanding the purposes and risks of the study Written informed consent (and assent when applicable) obtained from subject or subject's legal representative and ability for subject to comply with the requirements of the study. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to study entry Women of childbearing potential if sexually active must agree to using highly effective contraception during study and for 90 days after discontinuation of study treatment Women of childbearing potential must refrain from breast feeding or donating eggs for the duration of the study and for 90 days after the last dose of study treatment Male participants must agree to use a condom during sexual contact with a female of childbearing potential while participating in the study and for 90 days following discontinuation of investigational product use Male participants must refrain from donating sperm for the duration of the study and for 90 days after the last dose of study treatment Exclusion Criteria: Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study. Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data. Patients with re-transplantation or currently listed for re-transplantation Patients with confirmed other causes for loss of lung function, such as acute infection, acute rejection, restrictive allograft syndrome (CLAD - RAS phenotype, see Protocol Specific Definition), etc. Patients with acute antibody-mediated rejection at Screening. In this context, clinically stable patients (as judged by the Investigator) with detectable donor-specific antibodies (DSA) levels at the Screening Visit are eligible for the study Active acute bacterial, viral, or fungal infection that has not successfully resolved in at least 4 weeks prior to the Screening Visit. Patients with chronic infection or colonization who are clinically stable as per judgement of the investigator are eligible. Mechanical ventilation within 12 weeks prior to the randomization Patient has baseline resting oxygen saturation of < 89% on room air or use of supplemental oxygen at rest at screening Evidence of functional airway stenosis (i.e., bronchomalacia/ tracheomalacia, airway stents, or airways requiring balloon dilatations to maintain patency) with onset after the initial diagnosis of BOS and ongoing at Screening and/or Baseline Visit Known hypersensitivity to sirolimus or everolimus Currently enrolled in another investigational trial for obstructive chronic lung allograft dysfunction (BOS) Patients with chronic renal failure, defined as serum creatinine > 2.5 mg/dL at screening, or requiring chronic dialysis Patients with liver disease and serum bilirubin > 3-fold upper limit of normal range or transaminases > 2.5 upper limit of normal range Patients with active malignancy within the previous 2 years, including post-transplant lymphoproliferative disorder, except for treated, localized basal and squamous cell carcinomas Any history of malignancy likely to result in significant disability or likely to require significant medical or surgical intervention within the next 6 months. This does not include minor surgical procedures for localized skin cancer. History of severe allergic reaction to lactose (patients with lactose intolerance are eligible) Patients with uncontrolled hypertension
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Steven Hays, MD
Phone
415-336-4141
Email
steven.hays@ucsf.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Steven Hays, MD
Organizational Affiliation
University of California, San Francisco
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California, San Francisco
City
San Francisco
State/Province
California
ZIP/Postal Code
94143
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Steven Hays, MD
Phone
415-353-4141
Email
steven.hays@ucsf.edu
First Name & Middle Initial & Last Name & Degree
Steven Hays, MD
First Name & Middle Initial & Last Name & Degree
Julia Maheshwari, MD

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
23806229
Citation
Gillen JR, Zhao Y, Harris DA, LaPar DJ, Kron IL, Lau CL. Short-course rapamycin treatment preserves airway epithelium and protects against bronchiolitis obliterans. Ann Thorac Surg. 2013 Aug;96(2):464-72. doi: 10.1016/j.athoracsur.2013.04.068. Epub 2013 Jun 24.
Results Reference
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PubMed Identifier
23561805
Citation
Gillen JR, Zhao Y, Harris DA, Lapar DJ, Stone ML, Fernandez LG, Kron IL, Lau CL. Rapamycin blocks fibrocyte migration and attenuates bronchiolitis obliterans in a murine model. Ann Thorac Surg. 2013 May;95(5):1768-75. doi: 10.1016/j.athoracsur.2013.02.021. Epub 2013 Apr 2.
Results Reference
background
PubMed Identifier
26481278
Citation
Zhao Y, Gillen JR, Meher AK, Burns JA, Kron IL, Lau CL. Rapamycin prevents bronchiolitis obliterans through increasing infiltration of regulatory B cells in a murine tracheal transplantation model. J Thorac Cardiovasc Surg. 2016 Feb;151(2):487-96.e3. doi: 10.1016/j.jtcvs.2015.08.116. Epub 2015 Sep 7.
Results Reference
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PubMed Identifier
9721431
Citation
Sehgal SN. Rapamune (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression. Clin Biochem. 1998 Jul;31(5):335-40. doi: 10.1016/s0009-9120(98)00045-9.
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PubMed Identifier
30619313
Citation
Bak S, Tischer S, Dragon A, Ravens S, Pape L, Koenecke C, Oelke M, Blasczyk R, Maecker-Kolhoff B, Eiz-Vesper B. Selective Effects of mTOR Inhibitor Sirolimus on Naive and CMV-Specific T Cells Extending Its Applicable Range Beyond Immunosuppression. Front Immunol. 2018 Dec 17;9:2953. doi: 10.3389/fimmu.2018.02953. eCollection 2018.
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PubMed Identifier
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Sonis S, Treister N, Chawla S, Demetri G, Haluska F. Preliminary characterization of oral lesions associated with inhibitors of mammalian target of rapamycin in cancer patients. Cancer. 2010 Jan 1;116(1):210-5. doi: 10.1002/cncr.24696.
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Boers-Doets CB, Raber-Durlacher JE, Treister NS, Epstein JB, Arends AB, Wiersma DR, Lalla RV, Logan RM, van Erp NP, Gelderblom H. Mammalian target of rapamycin inhibitor-associated stomatitis. Future Oncol. 2013 Dec;9(12):1883-92. doi: 10.2217/fon.13.141.
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Vigarios E, Epstein JB, Sibaud V. Oral mucosal changes induced by anticancer targeted therapies and immune checkpoint inhibitors. Support Care Cancer. 2017 May;25(5):1713-1739. doi: 10.1007/s00520-017-3629-4. Epub 2017 Feb 22.
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Pilotte AP, Hohos MB, Polson KM, Huftalen TM, Treister N. Managing stomatitis in patients treated with Mammalian target of rapamycin inhibitors. Clin J Oncol Nurs. 2011 Oct;15(5):E83-9. doi: 10.1188/11.CJON.E83-E89.
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Inhaled Sirolimus in Lung Transplant Recipients With Bronchiolitis Obliterans Syndrome.

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