OncoTrials - мониторинг клинических исследований

Описание

Graft-versus-host disease is a complication of allogeneic hematopoietic cell transplantation with high morbidity and mortality. The standard treatment is corticosteroids, and based on the response within 3 to 7 days, a second-line therapy is added, which is expensive and not easily accessible. The administration of human chorionic gonadotropin has shown therapeutic effectiveness in 50% of patients in reported clinical cases.

Критерии включения

• * Aged 18 years or older.
• * Any gender.
• * Post-allogeneic transplantation status (haploidentical or identical) of hematopoietic cells.
• * Presenting recently onset aGVHD, grades 2 to 4, and requiring systemic steroid use as determined by the treating physician.
• * Have not received steroids (Prednisone ≥1 mg/kg/day or equivalent dose of another steroid) for more than 3 days in the last week.
• * Willing to participate in the study by signing informed consent.
• * If the subject is female and has the potential to procreate (a woman is considered fertile from menarche to postmenopausal stage or after undergoing a permanent contraceptive method), she agrees to use one of the following contraceptive methods from the start of the study and for 30 days after the protocol: oral hormonal contraception, intrauterine device, barrier methods (diaphragm, male or female condom, and foam, sponge, or spermicide film), or agrees to remain abstinent. Women who have been postmenopausal for more than a year, undergone hysterectomy, bilateral oophorectomy, or bilateral salpingectomy are not considered to have reproductive potential.
• * If the subject is male, he agrees to use one of the following contraceptive methods from the start of the study and for 30 days after the protocol: male condom, or remain abstinent.

Критерии исключения

• * Arterial or venous thrombosis in the past 3 months.
• * History of thromboembolic disease requiring full-dose anticoagulation.
• * Diagnosis of active malignant disease.
• * Uncontrolled infection.
• * Chronic use of supplemental therapy with sex hormones (estrogen, progesterone, and/or testosterone).
• * Women with a positive pregnancy test at the time of the initial evaluation.
• * Women or men of reproductive age who are unwilling to take appropriate precautions to avoid an unwanted pregnancy from the start of the protocol until 30 days after the protocol.

Описание

A Double-Masked, Randomized, Placebo-Controlled Study of the Safety and Tolerability and Efficacy of d-Mapps™ Opthalmic Solution in the Treatment of Chronic Oscular Graft-Versus-Host Disease (oGHVD)

Критерии включения

• * Age ≥ 18 years.
• * Willing and able to provide written informed consent.
• * Willing and able to comply with study assessments for the full duration of the study.
• * Patients may be using bilateral scleral lenses and/or bilateral punctal plugs at the time of accrual.
• * Minimum Oxford Schema grad of ≥ 1 in at least one eye.
• * OSDI scored of ≥ 22.
• * UNC DEMS score of ≥ 3.
• * In good stable overall health.

Критерии исключения

• * History of Rheumatoid Arthritis, Lupus, Scleroderma.
• * Ocular or periocular malignancy.
• * Significant change, as judged by the principal investigator, in systemic immunosuppressive regimen within 2 weeks of study entry.
• * Any history of topical tacrolimus use.
• * Any change in dosage of tetracycline compounds (tetracycline, doxycycline, and minocycline) within the last month.
• * Any change in frequency of preserved anti-glaucoma medications within 2 weeks of study entry.
• * Current use of topical steroids more than twice a day.
• * Corneal epithelial defect /> 1mm2.
• * Any history of herpetic keratitis.
• * Participation in another simultaneous medical research study.
• * Signs of current infection, including fever and current treatment with antibiotics.
• * All vaccination including COVID are prohibited during this study.
• * Signs of current infection, including fever and current treatment with antibiotics.
• * All vaccinations including COVID are prohibited during this study.
• * Intra-ocular surgery or ocular laser surgery within 3 months.
• * Women who are pregnant, breastfeeding, or plan to become pregnant while participating in the study. If of childbearing potential, unwillingness to use effective birth control while participating in the study.
• * Any condition (including language barrier) that precludes patient`s ability to comply with study requirements including completion of study.

Описание

The purpose of this study is to assess Tacrolimus/Methotrexate/Ruxolitinib versus Post-Transplant Cyclophosphamide/Tacrolimus/Mycophenolate Mofetil in Non-Myeloablative/Reduced Intensity Conditioning Allogeneic Peripheral Blood Stem Cell Transplantation

Критерии включения

• * Age 18.0 years or older at the time of enrollment.
• * Participants undergoing allogeneic HCT for one of the following indications:
• * Acute leukemia or chronic myelogenous leukemia with no circulating blasts and with less than 5% blasts in the bone marrow. Therapy related myeloid neoplasms are allowed.
• * Myelodysplasia/chronic myelomonocytic leukemia with no circulating blasts and with less than 10% blasts in the bone marrow (higher blast percentage allowed in MDS due to lack of differences in outcomes with /< 5% versus 5-10% blasts in this disease). Therapy related myeloid neoplasms are allowed.
• * Lymphoma /[follicular lymphoma, Hodgkin lymphoma, diffuse large B cell lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma and anaplastic large cell lymphoma/].
• * Planned NMA/reduced intensity conditioning regimen.
• * Participants must have a related or unrelated PBSC donor as follows:
• * Sibling donor must be a 6/6 match for HLA-A and -B at intermediate (or higher) resolution, and -DRB1 at high resolution using DNA-based typing and must be willing to donate peripheral blood stem cells and meet institutional criteria for donation. HLA-matched parents and children may be used as donors.
• * Unrelated donor must be a 7/8 or 8/8 match at HLA-A, -B, -C and -DRB1 at high resolution using DNA-based typing. Unrelated donor must be willing to donate peripheral blood stem cells and meet NMDP criteria for donation.
• * Donor selection must comply with 21 CFR 1271.
• * Cardiac function: Left ventricular ejection fraction at least 45%.
• * Estimated creatinine clearance greater than 60 ml/min using the 2021 CKD-EPI formula or 24-hour urine creatinine clearance.
• * Pulmonary function: DLCO corrected for hemoglobin at least 40% and FEV1 predicted at least 50%.
• * Liver function: AST/ALT /< 3x ULN; Total bilirubin /< 2 mg/dL excluding Gilbert`s syndrome or hemolysis.
• * Karnofsky Performance Score of at least 60%.
• * Female participants (unless postmenopausal for at least one year before the screening visit, or surgically sterilized), agree to practice two effective methods of contraception at the same time, or agree to completely abstain from heterosexual intercourse, from the time of signing the informed consent through 15 months post-transplant. Fertility preservation methods will be left to institutional standards.
• * Male participants (even if surgically sterilized), of partners of women of childbearing potential must agree to one of the following: practice effective barrier contraception or abstain from heterosexual intercourse from the time of signing the informed consent through 15 months post-transplant.
• * Plans for the use of targeted small molecule inhibitor post-transplant maintenance therapy must be disclosed upon enrollment and must be used irrespective of the outcome of the randomization. Planned use of investigational maintenance agents is not permitted. Planned hypomethylating agents as maintenance therapy is not permitted.
• * Voluntary written consent obtained prior to the performance of any study-related procedure that is not a part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care.

Критерии исключения

• * Prior allogeneic transplant.
• * Active CNS involvement by malignant cells.
• * Participants with secondary AML arising from myeloproliferative neoplasms or overlap syndromes, including CMML and MDS/MPN syndromes; participants with secondary AML arising from myelodysplastic neoplasm are eligible.
• * Participants with primary myelofibrosis.
• * Participants with uncontrolled bacterial, viral, or fungal infections (currently taking medication and with progression or no clinical improvement) at time of enrollment.
• * Active or inadequately treated latent infection with Mycobacterium tuberculosis (i.e., TB).
• * Presence of clinically significant fluid collection (ascites, pleural or pericardial effusion) that interferes with methotrexate clearance or makes methotrexate use contraindicated.
• * Participants seropositive for human immunodeficiency virus (HIV) with detectable viral load. HIV+ participants with an undetectable viral load on antiviral therapy are eligible.
• * Evidence of uncontrolled hepatitis B virus (HBV) or hepatitis C virus (HCV). The study allows:
• * Positive HBV serology with undetectable viral load and ongoing antiviral prophylaxis to prevent potential HBV reactivation.
• * Positive HCV serology with quantitative PCR for plasma HCV RNA below the lower limit of detection, with or without concurrent antiviral HCV treatment.
• * Arterial or venous thrombosis including DVT, PE, stroke, and myocardial infarction within six (6) months prior to enrollment or New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia. Catheter-associated DVT is not exclusionary.
• * Female participants who are pregnant (as per institutional practice) or lactating.
• * Participants with a serious medical or psychiatric illness likely to interfere with participation in this clinical study.
• * Participants with prior malignancies except resected non-melanoma skin cancer or treated cervical carcinoma in situ. Cancer treated with curative intent ≥ 5 years previously will be allowed. Cancer treated with curative intent /< 5 years previously must be reviewed and approved by the Protocol Officer or Chairs.
• * Planned use of ATG or alemtuzumab in conditioning regimen.
• * Planned use of prophylactic donor leukocyte infusions.
• * Prior use of ruxolitinib.
• * Prior use of immune checkpoint inhibitors (i.e., PD1, PDL1, CTLA4 modulators) within six (6) months prior to conditioning.
• * For participants with 7/8 HLA-matched donors:
• * Donor specific antibodies (DSAs) directed at the mismatched donor allele.
• * Any use of desensitization protocols.
• * Treatment with any other Investigational Medicinal Product (IMP) is not allowed while on study treatment. An IMP is defined as medications without any known FDA or EMA approved indications.

Описание

Chronic graft-versus-host disease (cGVHD) is a complication that occurs in 30-40% of recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is a major cause of late non-relapse mortality. In cases where the initial treatment response is inadequate, irreversible tissue damage often persists, making it a fatal complication that significantly reduces quality of life even for long-term survivors.

Therefore, the success of first-line treatment is crucial, but to date, there are no approved drugs specifically for the first-line treatment of chronic graft-versus-host disease. Besides corticosteroids, which have been used palliatively for over 50 years, there are no proven effective treatments available.

Against this background, this study was designed to explore the potential of new treatments as first-line therapy for chronic graft-versus-host disease, where effective treatment options are currently lacking.

Initially, the objective response rate will be analyzed at the 48-week mark based on the NIH Consensus Criteria (Lee 2015). Additionally, the study will evaluate the proportion of patients with steroid-resistant or steroid-dependent conditions, the objective response rate(ORR), failure-free survival(FFS), duration of response(DOR), and the proportion of patients who have reduced corticosteroids. Furthermore, the differences in treatment effects between the two groups of patients will be analyzed based on safety endpoints, including adverse events, laboratory tests, physical examinations, and vital signs.

Критерии включения

• /[Inclusion Data/]
• 1. Adult men and women aged 19 or older based on the date of signing on the informed consent form
• 2. On the screening visit, those who are diagnosed of a moderate to severe chronic graft-versus-host disease according to 2014 NIH consensus criteria
• -Moderate: At least one of the following conditions: />1 point for at least three organs />2 points for at least one organ except the lungs />1 point for the lungs
• -Severe: At least one of the following conditions: />3 points for at least one organ
• * At least 2 points for the lungs
• 3. Those who have no history of systemic treatment for chronic graft-versus-host disease and now need systemic corticosteroid treatment
• 4. Those whose ECOG (Eastern Cooperative Oncology Group) performance status is 0 to 2.
• 5. Regardless of the donor (matched sibling-family donor, matched unrelated donor, or partially matched family donor), those who have successfully taken same-type stem cell transplantation (alloSCT) from the marrow, peripheral blood stem cell, or cord blood
• 6. Those who voluntarily agree on participation in this clinical trial
• /[Exclusion Data/]
• 1. Those who meet the following criteria in laboratory tests during the screening and randomization visits
• * Those whose platelet count is less than or equal to 25,000/mm3 without blood transfusion
• * Those whose absolute neutrophil count is less than or equal to 1,000/mm3
• * Those whose total bilirubin /> 3 x ULN for any reason other than chronic graft-versus-host disease
• 2. Those with gastrointestinal troubles that hinder the intake and absorption of IMPs and concomitant medicines (systemic corticosteroid) (e.g.: signs such as ulcerative disease, unregulated nausea, vomiting, diarrhea, malabsorption, etc. or small intestine removal)
• 3. Those with a history of graft-versus-host disease treatment
• * Corticosteroid administration is permitted for chronic graft-versus-host disease treatment within 72 hours before the randomization visit
• * Except those who had therapeutic or preventive use of systemic corticosteroids and/or systemic immunosuppressants (CNI, MMF) for acute graft-versus-host disease (In case of prednisone administration for maintenance, only 0.5 mg/kg/day or less is permitted)
• 4. Those to whom the treatment for chronic graft-versus-host disease cannot begin as prednisone ≥ 0.5 mg/kg/day
• 5. Those whose same-type stem cell transplantation (alloSCT) has been confirmed as engraft-failed within 6 months before the screening visit
• 6. Those with an experience of ruxolitinib administration for acute graft-versus-host disease treatment (however, the patient may participate on the assumption that the response to the acute graft-versus-host disease treatment reaches the level of complete or partial response and that there is no ruxolitinib administration history within 4 weeks before the randomization visit. In addition, if ruxolitinib administration was for another disease, the patient may participate unless there is no history of ruxolitinib administration within 4 weeks before the randomization visit.)
• 7. Those who suffer chronic graft-versus-host disease after an unscheduled donor lymphocyte infusion for proactive treatment to prevent the recurrence of a malignant tumor (Participation is allowed if the scheduled lymphocyte infusion is performed as part of the transplantation procedure, not for the prevention of the recurrence of a malignant tumor.)
• 8. Those found to have the following history in the screening visit:
• * Relapsed primary malignancy
• * Those found to involve an unregulated sinusoidal obstruction syndrome
• * Those with a history of progressive multifocal leukoencephalopathy (PML)
• * Nephropathy whose creatinine clearance rate is lower than 30 mL/min (Cockroft Gault equation)
• * Infections that are clinically active and uncontrolled, requiring treatment, including significant bacteria, fungi, viruses, or parasitic infections. (However, if there are no signs of progression at the time of screening due to appropriate treatment, the infection is considered controlled. The progression of infection is defined by hemodynamic instability due to sepsis, new symptoms caused by the infection, worsening physical signs, or radiological findings. A persistent fever without other signs or symptoms is not interpreted as progressive infection.)
• * Active tuberculosis
• * HIV-infected individual
• * Active infection of hepatitis B virus (HBV) or hepatitis C virus (HCV) that the investigator views as significant
• * Cardiovascular disease that the investigator considers as clinically significant (acute cardiac infarction (within 6 months before randomization), NYHA class III or IV congestive heart failure, unstable angina (within 6 months before randomization), clinically significant symptomatic cardiac arrhythmia (e.g.: continued ventricular tachycardia, clinically significant level 2 or 3 AV blockage with no pacemaker used), unregulated hypertension)
• 9. Those allergic or sensitive to additives of IMPs and concomitant medicines (systemic corticosteroid) or similar compounds
• 10. Patients with genetic problems such as galactose intolerance, lapp lactase deficiency, glucose - galactose malabsorption, etc.
• 11. Those who are administrated with more than 200 mg of Fluconazole per day
• 12. Those being treated with systemic medicines that may hinder blood coagulation or platelet functions such as aspirin, heparin, and warfarin (However, those whose aspirin administration does not exceed 150 mg/day may participate.)
• 13. Pregnant or breast-feeding women
• 14. Those who do not agree on utilizing proper methods of contraception(e.g. a copper intrauterine device (copper loop), an intrauterine device containing hormones, condoms, a vasectomy, tubal surgery, a spermicide, a vagina-inserted contraceptive, a subdermal implant, an injectable contraceptive, a female condom, oral contraceptive, etc.) during the period of this clinical trial(the period of IP administration and at least 30 days after IP administration ends)
• 15. Those who have participated in another clinical trial within 30 days before the screening visit and have a history of IMP administration/medical equipment application (However, if the investigator views such a previous trial as not affecting this clinical trial`s efficacy and safety assessment such as observational study or retrospective study, the subject may participate.)
• 16. Those whose participation in this clinical trial is viewed as inappropriate in the investigator`s opinion.

Критерии исключения

Описание

Allogeneic transplant is potentially curative for hematological malignancies but its use is limited by the development of GVHD. Ruxolitinib now has FDA approval for treatment of chronic GVHD that has failed 1-2 prior lines of therapy based on a prior large, randomized phase III study. Given this evidence of safety and efficacy in the early refractory setting (after prednisone failure), Ruxolitinib represents an ideal agent to test in the primary therapy setting. Here investigators propose a phase 2 randomized study to compare Ruxolitinib to prednisone as a first-line therapy in the treatment of chronic GVHD.

Критерии включения

• * Age ≥ 18 years.
• * Karnofsky performance status ≥60%.
• * Patients with a diagnosis of chronic GVHD per NIH diagnostic criteria5 who are in need for first systemic therapy as per treating physician`s discretion, Overlap chronic GVHD will be allowed.
• * No new immune suppressive therapy added within preceding 2 weeks prior to study enrolment.
• * Able to take oral medications.
• * Participants must have adequate organ and marrow function as defined below:
• 1. absolute neutrophil count ≥1,000/mcL
• 2. platelets ≥30,000/mcL
• 3. Hemoglobin ≥ 7 g/dL
• 4. Bilirubin ≤ 3 times institutional upper limit of normal (ULN) unless attributable to GVH
• d. AST(SGOT)/ALT(SGPT) ≤5 × institutional ULN unless attributable to GVH e. creatinine clearance ≥30 ml/min
• * Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of study drug administration.
• * Ability to understand and the willingness to sign a written informed consent document.

Критерии исключения

• * Previously treated with systemic immune suppressive therapy for chronic GVHD (where the indication for start of that systemic immune suppressive therapy was chronic GVHD).
• * Patients with clinically significant or uncontrolled cardiovascular disease, including unstable angina, acute myocardial infarction, or stroke within 6 months, New York Heart Association class III or IV heart failure will be excluded.
• * Relapse malignancy post- transplant.
• * Active hepatitis B, hepatitis C and HIV will be excluded.
• * Any uncontrolled infection at the time if enrollment will be excluded.
• * History of allergic reactions attributed to compounds of similar chemical or biologic composition to Ruxolitinib.
• * Participants with psychiatric illness/social situations that would limit compliance with study requirements.
• * Pregnant women and lactating women are excluded from this study because of the potential for teratogenic or abortifacient effects and an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with Ruxolitinib, breastfeeding should be discontinued if the mother is treated with Ruxolitinib.
• * Current or history of active Tuberculosis.

Описание

This is a single arm, open-label, multi-center, pilot studies (Investigator Initiated Trial, IIT) to evaluate the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of universal T-cells engineered with chimeric natural killer receptor (CNK-UT) to treat the patients with steroid-refractory/resistant or steroid-dependent aGVHD.

Критерии включения

• 1. Aged 14-70 years, male or female;
• 2. Participants diagnosed with grade II/~IV steroid-refractory/resistant or steroid-dependent aGVHD after allogeneic hematopoietic stem cell transplantation.
• 3. ECOG physical status score 0/~3;
• 4. Estimated life expectancy /> 12 weeks;
• 5. Female participants of childbearing age must undergo a serum or urine pregnancy test before enrollment, and the results must be negative, and agree to take acceptable measures to minimize the possibility of pregnancy during the trial; For female participants of childbearing age or male participants whose sexual partners are women of childbearing age, effective contraceptive measures should be taken during the study and for at least 6 months following the last dose of the study cells infusion.
• 6. Participants voluntarily participate in clinical trial; Understand and know this study, sign an informed consent form, and be willing to follow all experimental procedures.

Критерии исключения

• 1. Suffering from malignant tumors or diagnosed within 5 years before enrollment, excluding radical skin basal cell carcinoma, skin squamous cell carcinoma, thyroid cancer, breast cancer (ductal carcinoma in situ) and / or radical resection of carcinoma in situ.
• 2. Participants with a history of organ transplantation;
• 3. Participants who have previously undergone more than one allogeneic hematopoietic stem cell transplantation.
• 4. Uncontrolled hypertension as determined by principal investigator, a history of hypertensive crisis or hypertensive encephalopathy; symptomatic congestive heart failure (New York Heart Association classification III-IV); symptomatic or poorly controlled arrhythmias; a history of congenital long QT syndrome or a corrected QT interval (QTc) /> 500 ms at screening (calculated using the Fridericia method)..
• 5. Systemic diseases deemed unstable by principal investigator include, but are not limited to, severe pulmonary, hepatic, renal, or metabolic disorders that require pharmacological intervention (excluding complications related to allogeneic hematopoietic stem cell transplantation).
• 6. Active pulmonary tuberculosis (TB), who is receiving anti-tuberculosis treatment or has received anti-tuberculosis treatment within 1 year before enrollment; human immunodeficiency virus (HIV) infection, known syphilis infection.
• 7. Severe infections that are active or poorly controlled clinically.
• 8. Participants who have received treatment from other clinical trials within 12 weeks prior to the initiation of the study.
• 9. Participants who have previously used any gene therapy products prior to the initiation of the study.
• 10. Allergic to components of CNK-UT injection.
• 11. Participants suffer from known mental or substance abuse disorders, which may interfere with their ability to comply with research requirements.
• 12. Women who are pregnant or breastfeeding, as well as male or female participants who have planned for birth within 1 year after receiving medication.
• 13. Uncontrolled/uncorrectable metabolic disorders or other non-malignant organ diseases or systemic diseases or secondary reactions to cancer, which can lead to higher medical risk and/or uncertainty in survival assessments.
• 14. Other situations that the participant is identified by the investigator as unsuitable to participate in the study.

Описание

The goal of this interventional study is to learn if the Horizons mobile application is feasible for survivors of allogeneic hematopoietic stem cell transplant who have chronic graft-versus-host disease. Participants will be asked to complete surveys and use the Horizons mobile application.

Критерии включения

• * Underwent allogeneic hematopoietic stem cell transplant
• * Have moderate to severe chronic graft-versus-host disease
• * Currently receiving care at the Sylvester Comprehensive Cancer Center Bone Marrow Transplant Program
• * Able to use an Ipad to participate in the Horizons app intervention
• * Able to participate in study procedures in English

Критерии исключения

• * comorbid conditions or cognitive impairment that the treating clinician believes prohibits informed consent or participation in the intervention
• * Vulnerable patients, defined here as prisoners and pregnant women

Описание

This phase II trial tests how well ibrutinib works in preventing chronic graft-versus-host disease (GVHD) in patients undergoing donor (allogeneic) hematopoietic cell transplantation (HCT). An allogeneic hematopoietic cell transplantation (allo-HCT) is a treatment in which a person receives blood-forming stem cells (cells from which all blood cells develop) from a genetically similar, but not identical donor. When healthy stem cells from a donor are infused into a patient, they may help the patient`s bone marrow make more healthy cells and platelets. However, sometimes the transplanted cells from a donor can attack the body`s normal cells (called GVHD). Giving ibrutinib after the transplant may stop that from happening. Ibrutinib is in a class of medications called kinase inhibitors. It works by blocking a protein in the blood called Bruton`s tyrosine kinase (BTK). By blocking BTK, ibrutinib inhibits certain immune cells that play a role in cGVHD. Giving ibrutinib after an allo-HCT may prevent the development of chronic GVHD.

Критерии включения

• * 50 to 110 days post-transplant prior to registration
• * Age ≥ 18 years
• * HLA matched-related, matched unrelated donors (defined as 8/8 /[class I: HLA A, B, C, and class II: DRB1/]), or HLA-mismatched-unrelated donors (defined as 7/8 /[with single mismatch at class I: HLA A, B, C, or class II: DRB1/])
• * Karnofsky performance status (PS) ≥ 70
• * Hemoglobin ≥ 8.0 g/dL (untransfused) (obtained ≤ 7 days prior to registration)
• * Absolute neutrophil count (ANC) ≥ 1000/mm/^3 (without growth factor support) (obtained ≤ 7 days prior to registration)
• * Platelet count ≥ 50,000/mm/^3 (untransfused) (obtained ≤ 7 days prior to registration)
• * Prothrombin time (PT)/international normalized ratio (INR)/activated partial thromboplastin time (aPTT) ≤ 1.5 x upper limit of normal (ULN) (obtained ≤ 7 days prior to registration)
• * Total bilirubin ≤ 1.5 x ULN (unless it is due to Gilbert`s syndrome or causes other than liver) OR alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤ 2 x ULN (unless it is due to Gilbert`s syndrome or causes other than liver) (obtained ≤ 7 days prior to registration)
• * Calculated creatinine clearance ≥ 40 ml/min using the Cockcroft-Gault formula (obtained ≤ 7 days prior to registration)
• * Adequate cardiac and pulmonary function at baseline (may be based on pre-transplant vital organ work up):
• * Cardiac evaluation to determine left ventricular ejection fraction (LV-EF) if there is any clinical reason (for example an ischemic event or hypovolemic shock) to suspect that the LV-EF was affected from the time of the prior measurement of baseline (required ≥ 45%)
• * Pulmonary evaluation to determine adequate pulmonary function with a diffusion capacity of the lung for carbon monoxide (DLCO) ≥ 50% predicted value, forced expiratory volume in 1 second (FEV1) ≥ 50% predicted value and forced vital capacity (FVC) ≥ 50% predicted value
• * Persons of childbearing potential must have negative serum pregnancy test ≤ 7 days prior to registration. Persons of non-reproductive potential are defined as follows: post-menopausal by history - no menses for ≥ 1 year; or status post (s/p) hysterectomy; or s/p bilateral tubal ligation; or history of bilateral oophorectomy
• * All subjects agreeable to using both a highly effective method of birth control /[for example, implants, injectables, combined oral contraceptives, intrauterine devices (IUDs), or sterilized partner/] and a barrier method (e.g., condoms, vaginal ring, sponge, etc.) during the period of therapy and for 90 days after the last dose of study drug
• * Provide written informed consent
• * Willingness to return to enrolling institution for follow-up (during the active monitoring phase of the study). Note: During the active monitoring phase of a study (i.e., active treatment and clinical follow-up), participants must be willing to return to the consenting institution for follow-up

Критерии исключения

• * Uncontrolled acute GVHD at time of registration. Note: Uncontrolled is defined as unable to tolerate tapering down of steroids or other therapies or requiring additional therapies or increase in doses of prescribed therapies
• * Evidence of NIH chronic GVHD preceding registration or at time of registration
• * Relapsed/progressive disease compared to prior to transplant and prior to registration. In this case, baseline represents the baseline disease staging (if no other disease staging has been performed prior to enrollment); or a post-transplant disease staging if that represents the most immediate staging prior to enrollment. In the event that both had been performed, the latest one performed (i.e. the one closest in time to the enrollment to this trial) will be considered the baseline for comparison. Note: Relapse and progression definitions for each hematologic malignancy/ disorder will follow standard definition
• * Uncontrolled active systemic fungal, viral, bacterial, or other infection Note: Infections are considered controlled if appropriate therapy has been instituted and at the time of registration have no signs of progression are present. Progression of infection is defined as hemodynamic instability attributable to sepsis, new symptoms, worsening physical signs or radiographic findings attributable to infection
• * Unable to swallow capsules or impairment/disease significantly affecting gastrointestinal function that may significantly alter the absorption of the drugs (e.g., gastric bypass surgeries, Celiac or Whipple disease)
• * Any of the following because this study involves) an agent that has known genotoxic, mutagenic and teratogenic effects:
• * Pregnant persons
• * Nursing persons
• * Persons of childbearing potential who are unwilling to employ adequate contraception
• * History of stroke or intracranial hemorrhage ≤ 6 months prior to registration
• * Active involvement of the central nervous system with malignancy. Note: Previous central nervous system (CNS) involvement is allowed if clearance of CNS disease has been documented prior to registration
• * Require anticoagulation with warfarin or other Vitamin K antagonists
• * Any of the following prior therapies:
• * Administration of anti-thymocyte globulin (or equivalent), alemtuzumab, or post transplant cyclophosphamide as part of the conditioning regimen or ≤ 1 month of allograft. Patients must not have received T-cell depletion or CD-34 selection
• * Administration of a strong cytochrome P450 (CYP) 3A inhibitor ≤ 7 days prior to the first dose or subjects who require continuous treatment with a strong CYP3A inhibitor
• * Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
• * Patients known to have tested positive on HIV antibody test
• * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• * Chronic liver disease with hepatic impairment Child Pugh class B or C
• * Active hepatitis B or C infection. Note: A detailed assessment of hepatitis B/C medical history and risk factors must be done at screening for all patients. hepatitis B immunoglobulin M antibody (HBcIgM Ab), hepatitis B surface antigen (HBsAg) and hepatitis C virus antibody (HCV Ab) screen (scrn) w/reflex testing are required at screening for all patients with a positive medical history based on risk factors and/or confirmation of prior hepatitis B virus (HBV) infection
• * Receiving any chemotherapy, anticancer immunotherapy, experimental therapy, or radiotherapy is prohibited while the subject is receiving study treatment with ibrutinib. The sponsor-investigator must be notified in advance (or as soon as possible thereafter) of any instances in which prohibited therapies are administered. EXCEPTIONS: Patients will be allowed to receive antimicrobial prophylaxis appropriate for allogeneic HCT recipients, according to institutional standards of practice (SOP) or common clinical practice
• * Other active malignancy ≤ 5 years prior to registration. EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix. NOTE: If there is a history of prior malignancy, they must not be receiving other treatment for their cancer
• * History of myocardial infarction ≤ 6 months, or uncontrolled cardiac arrhythmias

Описание

This is a single group, Phase 4, single-arm post-marketing study for treatment.

The purpose of this study is to verify the pharmacokinetics, efficacy, and safety of belumosudil mesylate tablets in Chinese adolescent participants (aged from 12 to less than 18) with cGVHD who have had an inadequate response to glucocorticoids or other systemic therapies.

Participants will receive treatment with belumosudil tablets 200 mg once daily in 28-day cycles during the study.

Критерии включения

• * Participant must be 12 to less than 18 years of age at the time of signing the informed consent.
• * Participant has undergone allogeneic hematopoietic stem cell transplantation (allo-HSCT).
• * Has active moderate to severe cGVHD.
• * Has received at least one line of prior systemic therapy for cGVHD.
• * Participant must receive a corticosteroid therapy for cGVHD with a stable dose for at least 2 weeks prior to the first dose of the IMP.
• * Has a Lansky-Play performance score of ≥60.
• * Participants should have an expected survival of longer than 6 months.
• * Body weight of 30 kg and above.
• * Contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• * The participant or their legally authorized representative (LAR) must be capable of giving signed informed consent.

Критерии исключения

• Participants are excluded from the study if any of the following criteria apply:
• * Recurrence of hematologic neoplasms (according to the corresponding criteria for recurrence of primary hematologic neoplasms) or post-transplant lymphoproliferative disease at screening.
• * Received investigational systemic therapy for cGVHD within 28 days prior to enrollment, unless the prior treatment had been washed out for at least 28 days or 5 half-lives prior to enrollment, whichever is shorter.
• * Absolute neutrophil count (ANC) /<1.0 × 10/^9/L.
• * Platelet count /<50 × 10/^9/L.
• * Alanine aminotransferase (ALT) />3× the upper limit of normal (ULN), aspartate aminotransferase (AST) />3 × ULN.
• * Total bilirubin (TBIL) />1.5 × ULN (/>3 ULN if Gilbert`s syndrome).
• * Estimated Glomerular Filtration Rate (eGFR) /<30 mL/min/1.73 m/^2 using the revised Bedside Schwartz formula . Revised Schwartz equation: CrCl (mL/min/1.73 m/^2) = 0.413 × (height /[in cm/])/Creatinine (in mg/dL) at screening visit.
• * Participant not suitable for participation, whatever the reason, as judged by the Investigator, including medical or clinical conditions, or participants potentially at risk of noncompliance to study procedures.

Описание

This study will be conducted to compare the efficacy of axatilimab versus placebo in combination with corticosteroids as initial treatment for moderate or severe chronic graft-versus-host disease (cGVHD).

Критерии включения

• * ≥ 12 years of age at the time of informed consent.
• * New-onset moderate or severe cGVHD, as defined by the 2014 NIH Consensus Development Project Criteria for Clinical Trials in cGVHD, requiring systemic therapy.
• * History of allo-HCT from any donor HLA type (related or unrelated donor with any degree of HLA matching) using any graft source (bone marrow, peripheral blood stem cells, or cord blood). Recipients of myeloablative, nonmyeloablative, or reduced-intensity conditioning are eligible.
• * Adequate hematologic function with ANC ≥ 0.5 × 109/L independent of growth factors for at least 7 days prior to study entry.
• * Willingness to avoid pregnancy or fathering children.

Критерии исключения

• * Received more than 1 prior allo-HCT. Prior autologous HCT is allowed.
• * Has overlap cGVHD, defined as simultaneous presence of features or characteristics of aGVHD in a patient with cGVHD.
• * Received more than 7 days of systemic corticosteroid treatment for cGVHD or unable to begin a prednisone dose ≥ 1.0 mg/kg per day (or methylprednisolone equivalent) for cGVHD.
• * Received previous systemic treatment for cGVHD, including extracorporeal photopheresis.
• * Systemic treatment with CNIs or mTOR inhibitors started within 2 weeks prior to C1D1.
• * Prior treatment with CSF-1R targeted therapies.
• * Active, uncontrolled bacterial, fungal, parasitic, or viral infection.
• * Evidence of relapse of the primary hematologic disease or treatment for relapse after the allo-HCT was performed, including DLIs for the treatment of molecular relapse.
• * History of acute or chronic pancreatitis.
• * Active symptomatic myositis.
• * History or current diagnosis of cardiac disease indicating significant risk of safety for participation in the study, such as uncontrolled or significant cardiac disease.
• * Severe renal impairment, that is, estimated CrCl /< 30 mL/min measured or calculated by Cockcroft-Gault equation in adults and Schwartz formula in pediatric participants, or endstage renal disease on dialysis.
• * Impaired liver function, defined as total bilirubin /> 1.5 × ULN and/or ALT and AST /> 3 × ULN in participants with no evidence of liver cGVHD.
• * Pregnant or breastfeeding.
• Other protocol-defined Inclusion/Exclusion Criteria may apply.

Описание

This is a prospective study investigating the role of tissue-resident immune cell subsets in the occurrence and progression of graft-versus-host disease following hematopoietic stem cell transplantation. Approximately 40 subjects(including 20 grade 3-4 aGVHD patients and 20 grade 1-2 aGVHD patients ).

Критерии включения

• 1. Voluntarily sign the informed consent form;
• 2. Age 16-65 years old
• 3. Clinically diagnosed with GVHD for the first time/receiving GVHD treatment.

Критерии исключения

• 1. Have a history of other tumors
• 2. With poor compliance or mental disorders
• 3. Infected with HIV and HCV
• 4. With uncontrolled HBV infection
• 5. With other autoimmune diseases
• 6. Those who are judged by the researcher to be unsuitable to participate in this study

Описание

The aim of this study is to demonstrate that in subjects with moderate to severe chronic graft-versus-host disease in the third line and beyond, the use of rosuvastatin compared to the protocol chosen by the researchers can significantly improve the objective response rate of subjects at week 24.

Критерии включения

• * Age: 18 to 70 years old; Karnofsky (KPS) ≥ 60 points; Expected survival period exceeding 6 months;
• * Previously received allogeneic hematopoietic stem cell transplantation;
• * According to NIH standards, the clinical diagnosis is moderate to severe cGVHD；
• * Previously received systematic treatment for cGVHD with 2-5 lines;
• * Stable dosage of corticosteroids and other immunosuppressants received within 2 weeks prior to screening;
• * The main organ functions well;
• * Starting from Day 1 after enrollment in the control group of this study, participants must receive one of the drugs specified in the study protocol;
• * Female participants of childbearing age should agree to use contraceptive measures (such as intrauterine devices, birth control pills, or condoms) during the study period and for 6 months after the end of the study; Serum pregnancy test negative within 7 days prior to enrollment in the study, and must be a non lactating subject; Male participants should agree to use contraceptive measures during the study period and within 6 months after the end of the study period;
• * Subjects voluntarily joined this study, signed informed consent, and had good compliance.

Критерии исключения

• * Has experienced or currently suffers from other malignant tumors within the past 3 years;
• * Known or suspected active aGVHD；
• * Individuals with interstitial pneumonia, non infectious pneumonia, uncontrolled active infections, or infections requiring systematic treatment within the first 7 days of randomization, except for those deemed suitable for inclusion by the researchers;
• * The occurrence and progression of other underlying diseases include post transplant lymphoid tissue proliferative diseases and recurrence of primary malignant hematological diseases;
• * Random failure of allogeneic hematopoietic stem cell transplantation within the first 6 months or having received 2 allogeneic hematopoietic stem cell transplants in the past;
• * Used JAK inhibitors, Bruton`s tyrosine kinase (BTK) inhibitors, etc. within the first 2 weeks of randomization;
• * There are multiple factors that can affect oral medication, such as inability to swallow, intestinal obstruction, etc;
• * Individuals with a history of abuse of psychotropic drugs who are unable to quit or have mental disorders;
• * Subjects with any severe and/or uncontrolled illnesses;
• * Individuals who are allergic to research drugs or their components;
• * Participated in other clinical trials within the first 4 weeks of randomization;
• * According to the researcher`s judgment, there are accompanying diseases that seriously endanger the safety of the subjects or affect the completion of the study, or subjects who are deemed unsuitable for inclusion due to other reasons.

Описание

The goal of this observational study is to investigate the development of vulvovaginal graft-versus-host- disease (GVHD), an under-reported and under-recognized manifestation of chronic GVHD. This study aims to characterize the vaginal microbiome in participants undergoing allogeneic hematopoietic cell transplantation (HCT). The main questions it aims to answer are:

* Is the vaginal microbiome altered during allogeneic HCT?
* What changes may help researchers understand the development of vulvovaginal GVHD?

Participants will be asked to undergo an assessment of vulvovaginal symptoms through a vulvovaginal symptom questionnaire once pre-transplant, 6 months post-transplant, and twelve12 months post- transplant. Participants will also be asked to undergo a vaginal microbiome (collection of bacteria, fungi, and viruses that live on our bodies) evaluation through a vaginal exam performed by a gynecologist with collection of vaginal samples once pre-transplant and again six months post-treatment and twelve months post-transplant. If a participant develops symptoms of vulvovaginal GVHD at any point in time during the post-transplant follow up, the participant may partake in additional vaginal exams to diagnose GVHD at the time of symptom onset.

Критерии включения

• * Female participants planning to undergo allogeneic HCT for any disease indication, OR, female participants who have already received HCT and have developed vulvovaginal GVHD during their post-transplant follow-up period
• * All conditioning regimens (myeloablative or reduced intensity) will be included.
• * All donor sources (HLA matched/mismatched related, unrelated, umbilical cord, haploidentical) will be included.
• * All graft sources (bone marrow or peripheral blood stem cells) will be included.
• * All GVHD prophylaxis regimens will be included.
• * Aged 18-70.
• * English speaking and able to sign written informed consent.
• * Participants agree to a vaginal gynecologic exam.
• * Co-enrollment on other clinical trials will be allowed.

Критерии исключения

• * Participants who decline or unable to undergo vaginal gynecologic exam due to any discomfort or pain.
• * Any concurrent medical, psychiatric or other illness in which the provider believes the participants may not be able to comply with study assessments.
• * Participants with a current diagnosis of a sexually transmitted infection (STI) (Herpes Simplex Virus, Gonorrhea, Chlamydia, Trichomonas,) or a history of previously untreated STI which may incite inflammation that will impact the microbiome.
• * Participants with a history of lichen sclerosis, lichen planus, pre-transplant.
• * Participants with a history or current diagnosis of vaginal or vulvar malignancy.

Описание

While hematopoietic stem cell transplant (HSCT) is an effective therapy, graft versus host disease (GVHD) is the most significant complication after HSCT. Corticosteroids (or steroids) have been the mainstay of treatment for chronic GVHD for many decades now. Increasingly, newer immunosuppressive and immunomodulating agents are being studied in adults and children affected by cGVHD. Ruxolitinib is one of these promising newer agents, which has been shown to be effective in the treatment of cGVHD in both children and adults. Currently, ruxolitinib is generally added to a patient`s treatment regimen after (or with) a course of high dose steroids.

The purpose of this study is to examine the effectiveness of upfront single agent ruxolitinib for cGVHD.

Критерии включения

• * Newly diagnosed moderate to severe chronic graft versus host disease (as defined by NIH cGVHD consensus criteria), requiring systemic treatment
• * Patient aged ≥12 year-old and ≤30 year-old
• * Patient able to take oral or enteral medication
• * No active, clinically significant uncontrolled infections
• * ALT ≤ 5x upper limit of normal (ULN) and total bilirubin ≤ 5xULN (unless presumed liver GVHD)
• * Platelet ≥ 20k and ANC ≥ 500. The use of transfusions or growth factors is permitted to maintain counts at these thresholds
• * No prior systemic treatment for chronic GVHD. Patients previously treated for acute GVHD are eligible, including those who received ruxolitinib for treatment of their aGVHD
• * Patients must be on ≤ physiologic dosing (i.e. hydrocortisone 8-12mg/m2/day) at enrollment
• * Patients with prior acute GVHD on /< 1 mg/kg steroids with new onset moderate-severe chronic GVHD may be considered for enrollment if they can taper steroids to reach physiological hydrocortisone in 1 month. If unable to do so these patients will come off study and be replaced

Критерии исключения

• * Mild cGVHD (as defined by NIH cGVHD consensus criteria11), that does not require systemic therapy
• * Acute or late acute GVHD without any evidence of chronic GVHD features
• * Patients who have received corticosteroids for ≥ 24 hours at 1 mg/kg/day of methylprednisolone or prednisone with the intent to treat cGVHD at time of enrollment
• * Corticosteroid dosing above physiologic dose hydrocortisone (i.e. /> 8-12mg/m2/day) at time of enrollment
• * Clinical evidence suggesting active malignancy (including PTLD and primary/secondary malignancy)
• * Clinical evidence of clinically significant active infection
• * Ongoing cytopenias which cannot be supported with routine supportive care (keeping hemoglobin over 7 g/dL and platelets />20,000 and absolute neutrophil count over 500/uL)
• * Active lower gastrointestinal bleeding
• * Thrombosis within 6 months (including myocardial infarction, stroke, deep venous thrombosis, pulmonary embolism). IV infiltration will not be included as an example of thrombosis
• * Pregnant or lactating females; patients of childbearing age who are not able to comply with contraceptive recommendations
• * Other condition that PI feels would preclude the patient from complying with study activities
• * ESRD /[CLcr /< 15 mL/min/] not on dialysis
• * Overlap syndrome

Описание

The purpose of this study is to determine if vimseltinib is safe, tolerable and works effectively to treat adults with active moderate to severe cGVHD. Participants will be treated with vimseltinib in 28-day treatment cycles for approximately 2 years.

Критерии включения

• 1. Must be allogeneic hematopoietic stem cell transplant (HSCT) recipients with moderate to severe cGVHD requiring systemic immune suppression.
• a. May have persistent active GVHD (aGVHD) and chronic GVHD (cGVHD) manifestations (overlap syndrome).
• 2. Participants with active cGVHD who have received and failed at least 2 prior lines of systemic therapy.
• 3. Stable dose of systemic corticosteroids is permitted but not required. If being taken, participants should be on a stable dose of corticosteroids for at least 2 weeks prior to starting study drug treatment.
• 4. Adequate organ and bone marrow functions.
• 5. Participants of reproductive potential agree to follow the contraception requirements.
• 6. Karnofsky Performance Scale (KPS) of ≥60.

Критерии исключения

• 1. Has aGVHD without manifestations of cGVHD.
• 2. Prior use of colony-stimulating factor 1 receptor (CSF1R) inhibitor for cGVHD.
• 3. History or other evidence of severe illness, uncontrolled infection, or any other conditions that would make the participant unsuitable for the study.
• 4. History of malignancy except for:
• 1. Underlying malignancy for which the transplant was performed
• 2. Malignancy treated with curative intent and with no evidence of active disease present for more than 3 years prior to enrollment and felt to be at low risk for recurrence.
• 5. Malabsorption syndrome or other illness that could affect oral absorption.

Описание

This phase I trial studies how well fecal microbiota transplant and dietary fiber supplementation work in treating patients with gut graft versus host disease. Fecal microbiota transplant entails inoculating donor stool into a recipient`s gastrointestinal tract. Changing the gut microbiome by fecal microbiota transplant and fiber supplementation may help treat gut graft versus host disease.

Критерии включения

• * 18 years of age or older
• * History of allogeneic hematopoietic stem cell transplant in the past 100 days
• * Post-engraftment, defined by time period following three consecutive days of sustained neutrophil engraftment with an absolute neutrophil count of at least 500 cells/mm/^1
• * Mild to severe acute GI GvHD stage 1 as measured by the modified Glucksberg criteria and averaged over 3 consecutive days in the last week. In patients who have already had GI biopsy, biopsy histology must be compatible with GVHD, although biopsy is not required

Критерии исключения

• * History of previous serious adverse events associated with FMT
• * History of bowel perforation
• * History of bowel resection
• * History of intestinal obstruction
• * History of gastric bypass
• * History of diverticulitis
• * History of inflammatory bowel disease (i.e. Crohn`s disease and ulcerative colitis)
• * History of celiac disease confirmed by serologic testing or small bowel biopsy
• * History of severe dietary allergy as designated by World Allergy Organization Subcutaneous Immunotherapy Systemic Reaction Grading System grade 2 or more
• * Current evidence of mechanical obstruction of the bowel
• * Subjects who are cytomegalovirus (CMV) seronegative at the time of enrollment as indicated by clinical testing unless the fecal microbiota transplant (FMT) donor is CMV seronegative with negative plasma polymerase chain reaction (PCR) assays for CMV.
• * Known allergies to loperamide, sodium chloride, glycerol, theobroma oil, hide bovine gelatin, sodium lauryl sulfate, colorants FD/&C, titanium dioxide, polyethylene glycol, sodium sulfate, sodium bicarbonate, sodium phosphate, benzalkonium chloride, disodium EDTA or potassium chloride.
• * Currently pregnant, planning to become pregnant or breastfeeding during the study period. Women of childbearing potential (those who are not post-menopausal or post-hysterectomy) must be negative for pregnancy per urine pregnancy test at enrollment
• * Individuals with the ability to conceive children who are not willing to abstain from sexual activity or use an effective form of birth control during the duration of the study
• * Unwilling or unable to participate in study procedures including oral intake of FMT, colonoscopy, fiber supplementation, collection of stool samples and completion study surveys
• * Cannot reasonably and safely participate in the study in the opinion of the investigators

Описание

This study will be conducted to determine the preliminary efficacy of axatilimab in combination with ruxolitinib and to assess the contribution of axatilimab to the combination treatment effect in participants with cGVHD.

Критерии включения

• * ≥ 12 years of age at the time of informed consent.
• * New-onset moderate or severe cGVHD, as defined by the 2014 NIH Consensus Development Project Criteria for Clinical Trials in cGVHD, requiring systemic therapy.
• * History of 1 allo-SCT (any type of stem cell donor, any conditioning regimen, and source of hematopoietic stem cells).
• * Adequate hematologic function independent of platelet transfusion and growth factors for at least 7 days prior to study entry: ANC ≥ 0.75 × 109/L and platelet count ≥ 20 × 109/L.
• * Willingness to avoid pregnancy or fathering children.

Критерии исключения

• * Received more than 1 prior allo-SCT. Prior autologous HCT is allowed.
• * Has overlap cGVHD, defined as simultaneous presence of features or characteristics of aGVHD in a patient with cGVHD.
• * Received previous systemic treatment for cGVHD, including systemic corticosteroids and extracorporeal photopheresis.
• * Received systemic corticosteroids within 2 weeks prior to C1D1, regardless of indication.
• * Initiated systemic treatment with CNIs or mTOR inhibitors within 2 weeks prior to C1D1.
• * Prior treatment with a JAK inhibitor within 8 weeks before randomization. Participants who received a JAK inhibitor for the treatment of aGVHD are eligible only if they achieved a response (CR or PR) to JAK inhibitor treatment and did not discontinue due to toxicity.
• * Evidence of relapse of the primary hematologic disease or treatment for relapse after the allo-SCT was performed, including DLIs for the treatment of molecular relapse.
• * History of acute or chronic pancreatitis.
• * History of thromboembolic events (such as deep vein thrombosis, pulmonary embolism, stroke, myocardial infarction) in the 6 months prior to study entry.
• * Active symptomatic myositis.
• * Severe renal impairment, that is, estimated CrCl /< 30 mL/min measured or calculated by Cockcroft-Gault equation in adults and Schwartz formula in pediatric participants, or end-stage renal disease on dialysis. Participants with CrCl of 30 to 59 mL/min on treatment with fluconazole are not eligible.
• * Impaired liver function, defined as total bilirubin /> 1.5 × ULN and/or ALT and AST /> 3 × ULN in participants with no evidence of liver cGVHD.
• * Currently active significant cardiac disease, such as uncontrolled arrhythmias, uncontrolled hypertension, or Class 3 or 4 congestive heart failure as defined by New York Heart Association, or a history of myocardial infarction or unstable angina within 6 months prior to randomization.
• * Pregnant or breastfeeding.
• Other protocol-defined Inclusion/Exclusion Criteria may apply.

Описание

The purpose of this study is to measure safety and efficacy of oral belumosudil in Black or African American, American Indian or Alaska Native, and Native Hawaiian or Other Pacific Islander male and female participants with cGVHD who have previously been treated with at least 2 prior lines of systemic therapy aged 12 years and above.

The duration of participants participation will be up to 4 weeks for screening, treatment until clinically significant progression of disease, and 4 weeks of safety follow-up, and then long-term follow-up every 12 weeks.1 Cycle = 28 days.

Критерии включения

• * Participants are included in the study if any of the following criteria apply:
• * Participant is Black or African American, or American Indian or Alaska Native, or Native Hawaiian or Other Pacific Islander by self-identification.
• * Previously received at least 2 and not more than 5 lines of systemic therapy for cGVHD.
• * Receiving glucocorticoid therapy with a stable dose over the 2 weeks prior to screening.
• * Have persistent cGVHD manifestations and systemic therapy is indicated.
• * Karnofsky (if aged ≥ 16 years) / Lansky (if aged /< 16 years) Performance Score of ≥ 60.
• * At least 12 years of age; weight ≥ 40 kilograms (kg).
• * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x upper limit of normal (ULN).
• * Total bilirubin ≤ 1.5 x ULN.
• * Contraception (with double contraception methods) for male and female participants; not pregnant or breastfeeding for female participants
• * Capable of giving signed informed consent.

Критерии исключения

• * Participants are excluded from the study if any of the following criteria apply:
• * Participant has not been on a stable dose/regimen of systemic cGVHD treatment(s) for at least 2 weeks prior to screening. (Note: Concomitant corticosteroids, calcineurin inhibitors, sirolimus, MMF, methotrexate, rituximab, and ECP are acceptable. Systemic investigational GVHD treatments are not permitted).
• * Histological relapse of the underlying cancer or post-transplant lymphoproliferative disease at the time of screening.
• * Current treatment with ibrutinib or ruxolitinib. Prior treatment with ibrutinib or ruxolitinib is allowed with a washout of at least 28 days prior to enrollment.
• * History or other evidence of severe illness or any other conditions that would make the participant, in the opinion of the Investigator, unsuitable for the study (such as malabsorption syndromes, poorly controlled psychiatric disease, or coronary artery disease).
• * Corrected QT interval using Fridericia`s formula (QTc/[F/]) /> 480 ms.
• * Forced expiratory volume (in the first second; FEV1) ≤ 39% The above information is not intended to contain all considerations relevant to the potential participation in a clinical trial.