OncoTrials - мониторинг клинических исследований

Описание

This is an open label, phase 2 study investigating asciminib in patients previously treated with one line of TKI therapy.

Критерии включения

• 1. Age ≥ 18 years.
• 2. Diagnosis of Ph-positive (by cytogenetics or FISH) or BCR-ABL-positive (by PCR) CML in chronic phase and have received one prior line of therapy with a TKI.
• 3. History of treatment failure defined as either:
• * BCR::ABL1 />0.1% for patients with intolerance to first-line TKI
• * Less than complete hematologic response (CHR) at ≥3 months
• * No partial cytogenetic response at ≥3 months
• * BCR::ABL1 ≥ 10% at if 3-6 months
• * BCR::ABL1 ≥ 1% at ≥6 months
• * Loss of CCyR or development of mutations or other clonal chromosomal abnormalities at any time during TKI treatment
• 4. ECOG performance status ≤ 2.
• 5. Adequate end organ function within 12 days before the first dose of asciminib treatment. Patients with mild to moderate renal and hepatic impairment are eligible if:
• * Total bilirubin ≤ 3.0 x ULN without AST/ALT increase
• * Aspartate transaminase (AST) ≤ 5.0 x ULN
• * Alanine transaminase (ALT) ≤ 5.0 x ULN
• * Serum lipase ≤ 1.5 x ULN. For serum lipase /> ULN and ≤ 1.5 x ULN, value should be considered not clinically significant and not associated with risk factors for acute pancreatitis
• * Alkaline phosphatase ≤ 2.5 x ULN
• * Creatinine clearance ≥ 30 mL/min as calculated using Cockcroft-Gault formula
• 6. The effects of Asciminib on the developing human fetus are unknown. For this reason, 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. Women of child-bearing potential must agree to use highly effective methods of contraception during dosing and for 30 days after study treatment. 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. Allowable methods of birth control:
• * Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
• * Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before the start of study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
• * Male sterilization (at least 6 months prior to screening). The vasectomized male partner should be the sole partner for that subject.
• * Use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate /<1%), for example hormone vaginal ring or transdermal hormone contraception.
• * Sexually active males must use a condom during intercourse while taking the drug and for 30 days after stopping treatment and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid.

Критерии исключения

• 1. Patients with a history of T315I mutation.
• 2. Patients with New York Heart Association (NYHA) Class III or IV congestive heart failure or LVEF /< 40% by echocardiogram or multi-gated acquisition (MUGA) scan.
• 3. Patients with a history of myocardial infarction within the last 6 months or unstable/uncontrolled angina pectoris or history of severe and/or uncontrolled ventricular arrhythmias. Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third-degree AV block).
• 4. Corrected QT interval (QTc) of /> 450 milliseconds (ms) on baseline electrocardiogram (ECG or EKG) (using the Fridericia Formula)
• 5. Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:
• * Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia.
• * Concomitant medication(s) with a known risk to prolong the QT interval and/or known to cause Torsades de Pointes that cannot be discontinued or replaced 7 days prior to starting study drug by safe alternative medication.
• 6. Patients with known active infection with human immunodeficiency virus (HIV) or Hepatitis B or C.
• 7. Patients with known conditions that would significantly affect the ingestion or gastrointestinal absorption of drugs administered orally.
• 8. Nursing women, women of childbearing potential (WOCBP) with positive blood or urine pregnancy test, or women of childbearing potential who are not willing to maintain adequate contraception (see inclusion criteria 8)
• 9. History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis.
• 10. ANC /< 500/mm3, platelet count /< 50,000 mm3.
• 11. History of other active malignancy within 2 years prior to study entry except for previous or concomitant basal cell skin cancer and previous carcinoma in situ treated curatively.
• 12. Subject has any other significant medical or psychiatric history that in the opinion of the investigator would adversely affect participation in this study.
• Patients should have discontinued therapy with imatinib, bosutinib, dasatinib or nilotinib or other anti-leukemia therapy (except hydroxyurea), at least 48 hours prior to start of study therapy and recovered from any toxicity due to these therapies to at least grade 1. The use of hydroxyurea is allowed immediately prior to study entry.

Описание

The study is a Phase II clinical trial. Patients will receive intensity-modulated total marrow irradiation (TMI) at a dose of 9 Gray (Gy) with standard myeloablative fludarabine intravenous (IV) and targeted busulfan (FluBu4) conditioning prior to allogeneic hematopoietic stem cell transplant (HSCT). Graft-versus-host disease (GVHD) prophylaxis will include Cyclophosphamide on Day +3 and +4, tacrolimus, and mycophenolate mofetil.

Критерии включения

• * 1. Age 18-65 years.
• * 2. Patients with CML, AML, or MDS who meet one of the following criteria: 2a. Relapsed or refractory AML (including AML in CR2) 2b. Poor-risk AML in first remission, with remission defined as /<5% bone marrow blasts morphologically:
• * AML arising from MDS, a myeloproliferative disorder, or secondary AML
• * Poor risk molecular features according to Leukemia Net including ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, and/or ZRSR2
• * Poor-risk cytogenetics: Monosomal karyotype, complex karyotype (/> 3 abnormalities), inv (3), t(3;3), t(6;9), MLL rearrangement with the exception of t(9;11), or abnormalities of chromosome 5 or 7. 2c. Primary refractory disease 2d. MDS with at least one of the following poor-risk features:
• * Poor-risk cytogenetics including 3q abnormalities, 7/7q minus or complex cytogenetics (/>3 abnormalities).
• * Current or previous INT-2 or high IPSS score.
• * Treatment-related MDS.
• * MDS diagnosed before the age of 21 years.
• * Progression on or lack of response to standard DNA-methyltransferase inhibitor therapy.
• * Life-threatening cytopenias, including those requiring regular PRBC or platelet transfusions. 2e. CML with a history of accelerated or blast phase.

Критерии исключения

• * 1. Presence of significant co-morbidity as shown by:
• * 1a. Left ventricular ejection fraction /< 50%
• * 2b. Creatinine clearance /<30ml/min.
• * 3c. Bilirubin /> 2.0 mg/dL (unless due to Gilbert`s syndrome or hemolysis), and ALT and AST /> 5 x ULN.
• * 4d. FEV1 and FVC /< 50% of predicted or DLCO /<50% of predicted once corrected for anemia.
• * 5e. Karnofsky score /<70
• * 6f. Active viral hepatitis or HIV infection.
• * 7g. Cirrhosis.
• * 2. Pregnancy or breast feeding
• * 3. Patients unable to sign informed consent.
• * 4. Patients previously received radiation to />20% of bone marrow-containing areas.

Описание

The purpose of this study is to evaluate the safety, tolerability and determine the recommended dose for further clinical evaluation of ELVN-001 in Japanese patients with chronic phase chronic myeloid leukemia with and without T315I mutations in patients who has failed, or the patient is intolerant to, or not a candidate for, at least 2 prior TKIs.

Критерии включения

• * BCR::ABL1 positive CP-CML that has failed, or the patient is intolerant to, or not a candidate for, at least 2 prior TKIs.
• * ECOG performance status of 0 to 2.
• * The patient was born in Japan and both parents and grandparents are Japanese.
• * Adequate hematologic, hepatic and renal function.
• * Prior bone marrow transplant allowed if ≥ 6 months prior to the first dose of ELVN-001.

Критерии исключения

• * Treatment with anti-cancer or anti-CML therapy within 7 days or 5 half-lives, whichever is longer.
• * History of acute tyrosine kinase inhibitor (TKI)-related pancreatitis within 6 months of study entry. Active chronic pancreatitis, or pancreatic disease due to any cause.
• * QTc />470 ms.

Описание

The goal of this observational study is to learn about the efficacy and safety profile when Radotinib dose redution is performed in Ph+ CML subjects.

The main efficacy is checked by MMR rate by 12 months from IP treatment.

Критерии включения

• 1. Male or female patients aged 19 years old or older
• 2. Patients with confirmed diagnosis of chronic phase CML within last 8weeks(throung chromosome testing or bone marrow testing)
• * Chronic phase CML is defined as follows:
• * Blast in peripheral blood and bone marrow /<15%
• * The sum of blast and promyelocyte in peripheral blood and bone marrow /<30%
• * Basophil in peripheral blood /<20%
• * Platelets count ≥ 50 × 109/L (≥ 50,000/mm3) (But, transient prior therapy related thrombocytopenia /[/<50 × 109/L (/< 50,000/mm3)/] is acceptable)
• * No extramedullary involvement other than enlargements of liver and spleen
• 3. Patients with positive Philadelphia chromosome and confirmed expression of BCR:ABL1 transcript
• 4. ECOG scale 0, 1 or 2
• 5. Patients who have adequate organ functions as defined below:
• * Total bilirubin /< 1.5 × upper limit of normal (ULN)
• * SGOT and SGPT /< 2.5× ULN
• * Creatinine /< 1.5 × ULN
• * Serum amylase and lipase ≤ 1.5 × ULN
• * Alkaline Phosphatase ≤ 2.5 × ULN (only if not related to the tumor)
• 6. Women of childbearing potential should have a negative serum or urine pregnancy test
• 7. Women of childbearing potential must be using an adequate method of contraception to avoid pregnancy throughout the study and for a period of at least 1 month (4 weeks) after the last dose of investigational product in such a manner that the risk of pregnancy is minimized.
• 8. Patients providing written informed consent form before the study related screening procedures.

Критерии исключения

• 1. Patients with Philadelphia chromosome negative
• 2. Patients who used Radotinib for 8 days or longer before study entry
• 3. Patients who had been treated with other targeted anti-cancer therapy, except for Hydrea or Agrylin, which inhibits the growth of leukemic cells
• 4. Patients who have hypersensitivity to active ingredient or any of the excipients of this investigational product.
• 5. Patients with impaired cardiac function as defined below:
• * Patients who cannot have QT intervals measured according to ECG
• * Complete left bundle branch block
• * Patients with cardiac pacemakers
• * Patients with congenital long QT syndrome or the family history of known long QT syndrome
• * The mean QTcF />450msec ECG tests at baseline
• * Clinically significant resting bradycardia (/< 50 bpm) History of, or presence of symptomatic ventricular or atrial tachyarrhythmias
• * Clinically significant resting bradycardia (/< 50 bpm)
• * Medical history of clinically confirmed myocardial or infarctionof unstable angina (within last 12 months)
• * Other clinically significant cardiac disease (e.g. congestive heart failure, or uncontrolled hypertension)
• 6. Cytologically confirmed CNS involvement (if asymptomatic, spinal fluid examination is not necessary prior to first treatment)
• 7. Severe or uncontrolled chronic medical condition (e.g., uncontrolled diabetes, active or uncontrolled infection)
• 8. Other significant congenital or acquired bleeding disorders that are not related to underlying leukemia
• 9. Patients who previously received radiotherapy to at least 25% of the bone marrow
• 10. Patients who had a major surgery within 4 weeks prior to study entry or has not recovered from side effects of such surgery
• 11. Patients who diagosed with another clinically significant malignant tumor wihin 5years before study etnry, excluding basal cell carcinoma
• 12. Patients who are currently receiving treatment with a strong CYP3A4 inhibitor (e.g., erythromycin, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, mibefradil) or CYP3A4 inducer (e.g., dexamthasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbitol, St. John`s Wort). Treatment cannot be safely discontinued or switched to a different medication prior to initiation of study treatment
• 13. Patients who are currently receiving treatment with a medication that has the potential to prolong the QT interval. Treatment cannot be safely discontinued or switched to a different medication prior to initiation of study treatment
• 14. Impairment of GI function or GI disease that may significantly alter absorption of study drugs (e.g., ulcerative colitis, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, GI bypass surgery).
• 15. History of acute or chronic pancreatitis within last one year
• 16. Acute or chronic liver or pancreas disease or severe renal disease
• 17. Patients with HbsAg, HCV Ab positive
• * following subjects can be enrolled.
• * Inactive hepatitis B surface antigen (HBsAg) carriers(site specific local lab normal range lower limit assessed by investigator)
• * undergoding HCV Ab or HCV RNA testing judged by investigator to be eligible for enroll
• 18. History of HIV Ab positive or confirmed HIV Ab positvie.
• 19. Pregnant or the women with breast-feeding 2

Описание

This research is being done to investigate the safety and effectiveness of Darzalex Faspro (daratumumab and hyaluronidase-fihj) (a monoclonal antibody that targets plasma cells that make antibodies) and whether it can lower donor specific antibodies (DSA) levels to low enough levels to permit patients to proceed with allogeneic peripheral blood transplant (alloBMT). Those being asked to participate have high DSA levels that puts those being asked to participate at high risk of rejecting the available donor`s blood stem cells and making those being asked to participate ineligible to receive a stem cell transplant.

Критерии включения

• 1. Participates must meet all other institutional criteria for the planned reduced intensity conditioning allogeneic peripheral blood stem cell transplant (RIC alloHSCT) as defined in Johns Hopkins BMT Policy; all potential non-cord blood donor sources are included: matched related, haploidentical, matched unrelated, mismatched unrelated.
• 2. Participants must be ≥18 years of age.
• 3. Participants must have adequate organ function for undergoing RIC allogeneic peripheral blood stem cell transplant, and for undergoing a clinical trial.
• a. Hematologic. i. White blood cell (WBC). ANC ≥ 500/mm3 (growth factor support allowed). ii. Hemoglobin. No specific cut-off. (PRBC transfusion allowed). iii. Platelets. Platelets ≥ 10,000/mm3 (platelet transfusion allowed). b. Liver. Bilirubin ≤ 3.0 mg/dL (unless due to Gilbert`s syndrome or hemolysis), and Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) /< 5x Upper limit of normal (ULN) c. Renal. Serum creatinine ≤ 2.0 mg/dL. d. Cardiac. Left ventricular ejection fraction ≥ 35%. e. Pulmonary. FEV1 ≥ 50%.
• 4. Subjects are eligible if there are high levels of Donor Specific Antibody levels based on protocol specific scoring system regardless of prior attempts at standard desensitization.
• 5. Participants must have a no other readily available suitable alternative donor.
• 6. All potential Participants must be pre-approved by BMT faculty consensus.
• 7. Participants must have adequate willingness to participate in a clinical trial.

Критерии исключения

• 1. Previous exposure to Daratumumab-SC or other anti-CD38 therapy
• 1. Exposure to Daratumumab-SC or other anti-CD38 therapies (unless a re-treatment study)
• 2. Exposure to an investigational drug (including investigational vaccine) or invasive investigational medical device for any indication within 4 weeks or 5 pharmacokinetic half-lives, whichever is longer.
• 3. Focal radiation therapy within 14 days prior to beginning of planned RIC allogeneic peripheral blood stem cell transplant regimen with the exception of palliative radiotherapy for symptomatic management but not on measurable extramedullary plasmacytoma
• 2. Chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) /< 50% of predicted normal. Note that FEV1 testing is required for participants suspected of having COPD and participants must be excluded if FEV1 is /< 50% of predicted normal.
• 3. Moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification. Note that participants who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate.
• 4. Known hypersensitivity or intolerance to boron or mannitol, sorbitol, corticosteroids, monoclonal antibodies or human proteins, or the excipients
• 5. Diagnosis of multiple myeloma or Amyloid light-chain (AL) amyloidosis
• 6. A planned myeloablative alloBMT or the planned use of bone marrow or cord blood as a stem cell source
• 7. History of HIV infection at any time in past.
• 8. Seropositive for hepatitis B (HBV) (defined by a positive test for hepatitis B surface antigen /[HBsAg/] positive, or antibodies to hepatitis B surface and/or core antigens /[antiHBs or antiHBc, respectively/] with hepatitis B virus /[HBV/]- DNA quantitation positive). Patients who are positive for antiHBs and/or antiHBc must have a negative polymerase chain reaction (PCR) for HBV-DNA quantitation result during screening. Patients with serologic findings suggestive of HBV vaccination (antiHBs positivity as the only serologic marker) AND a known history of prior HBV vaccination do not need to be tested for HBV DNA by PCR. Those who are PCR positive will be excluded.
• 9. Seropositive for hepatitis C (except in the setting of a sustained virologic response (SVR), defined as aviremia at least 12 weeks after completion of antiviral therapy)
• 10. Clinically significant cardiac disease, including:
• 1. Myocardial infarction within 6 months before RIC alloHSCT or unstable or uncontrolled disease/condition related to or affection cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV)
• 2. Uncontrolled cardiac arrhythmia