NCT03677596已完成4 期
A PHASE 4, OPEN-LABEL, RANDOMIZED STUDY OF TWO INOTUZUMAB OZOGAMICIN DOSE LEVELS IN ADULT PATIENTS WITH RELAPSED OR REFRACTORY B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA ELIGIBLE FOR HEMATOPOIETIC STEM CELL TRANSPLANTATION AND WHO HAVE RISK FACTOR(S) FOR VENO-OCCLUSIVE DISEASE
适应症
干预措施
相关药物
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 发起方
- Pfizer
- 入组人数
- 102
- 试验地点
- 44
- 主要终点
- Percentage of Participants With Veno-occlusive Disease (VOD)
研究概览
简要总结
This study will explore 2 different doses of inotuzumab ozogamicin including the dose that is approved and a lower dose. The main purpose of this study is to evaluate whether a dose of inotuzumab ozogamicin, lower than the approved dose, could be recommended for adult patient with relapsed or refractory ALL who may be at higher risk for severe liver problems after inotuzumab ozogamicin treatment and stem cell transplant (a potentially curative therapy that can replace cancer cells with healthy cells). Efficacy and safety of the 2 doses will be evaluated.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Relapsed or refractory precursor CD22 positive B cell ALL with M2 or M3 marrow (≥5% blasts) and who are eligible for HSCT;
- •Have 1 or more of the following risk factors for developing VOD:
- •Due to receive Salvage 2 or greater;
- •Prior HSCT;
- •Age ≥55 years.
- •Ongoing or prior hepatic disease which may include a prior history of hepatitis or drug induced liver injury, as well as hepatic steatosis, nonalcoholic steatohepatitis, baseline elevations of bilirubin > upper limit of normal (ULN) and ≤1.5 x ULN.
- •Ph+ ALL patients must have failed treatment with at least 1 second or third generation tyrosine kinase inhibitor and standard multi agent induction chemotherapy;
- •Patients in Salvage 1 with late relapse should be deemed poor candidates for reinduction with initial therapy;
- •Patients with lymphoblastic lymphoma and bone marrow involvement 5% lymphoblasts by morphologic assessment;
- •Age 18 years to 75 years;
- •Eastern Cooperative Oncology Group (ECOG) performance status 0 2;
- •Adequate liver function, including total serum bilirubin ≤1.5 x ULN unless the patient has documented Gilbert syndrome, and aspartate and alanine aminotransferase (AST and ALT) ≤2.5 x ULN;
- •Serum creatinine ≤1.5 x ULN or any serum creatinine level associated with a measured or calculated creatinine clearance of >=40 mL/min;
- •Male and female patients of childbearing potential and at risk for pregnancy must agree to use a highly effective method of contraception throughout the study and for a minimum of 8 months (females) and 5 months (males) after the last dose of assigned treatment. A patient is of childbearing potential if, in the opinion of the Investigator, he/she is biologically capable of having children and is sexually active. Female subjects of nonchildbearing potential must meet at least 1 of the following criteria:
- •Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; and have a serum follicle stimulating hormone (FSH) level confirming the postmenopausal state;
- •Have undergone a documented hysterectomy and/or bilateral oophorectomy;
- •Have medically confirmed ovarian failure. All other female subjects (including female subjects with tubal ligations) are considered to be of childbearing potential.
- •Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study; patients with mental capacity which requires the presence of a legally authorized representative will be excluded from the study;
- •Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
排除标准
- •Isolated extramedullary relapse (ie, testicular or central nervous system);
- •Burkitt's or mixed phenotype acute leukemia based on the WHO 2008 criteria;
- •Active central nervous system (CNS) leukemia, as defined by unequivocal morphologic evidence of lymphoblasts in the cerebrospinal fluid (CSF), use of CNS directed local treatment for active disease within the prior 28 days, symptomatic CNS leukemia (ie, cranial nerve palsies or other significant neurologic dysfunction) within 28 days. Prophylactic intrathecal medication is not a reason for exclusion;
- •Prior chemotherapy within 2 weeks before randomization with the following exceptions:
- •To reduce the circulating lymphoblast count or palliation: ie, steroids, hydroxyurea or vincristine;
- •For ALL maintenance: mercaptopurine, methotrexate, vincristine, thioguanine, and/or tyrosine kinase inhibitors.
- •Patients must have recovered from acute non hematologic toxicity (to Grade 1 or less) of all previous therapy prior to enrollment.
- •Prior monoclonal antibodies within 6 weeks of randomization, with the exception of rituximab which must be discontinued at least 2 weeks prior to randomization;
- •Prior inotuzumab ozogamicin treatment or other anti CD22 immunotherapy within 6 months before randomization;
- •Prior allogeneic hematopoietic stem cell transplant (HSCT) within 90 days before randomization. Patients must have completed immunosuppression therapy for treatment of graft versus host disease (GvHD) prior to enrollment. At randomization, patients must not have Grade 2 or higher acute GvHD, or extensive chronic GvHD;
- •Peripheral absolute lymphoblast count >=10,000 /L (treatment with hydroxyurea and/or steroids/vincristine is permitted within 2 weeks of randomization to reduce the white blood cell [WBC] count);
- •Known systemic vasculitides (eg, Wegener's granulomatosis, polyarteritis nodosa, systemic lupus erythematosus), primary or secondary immunodeficiency (such as human immunodeficiency virus [HIV] infection or severe inflammatory disease);
- •Active hepatitis B infection as evidenced by hepatitis B surface antigen, active hepatitis C infection (must be anti-hepatitis C antibody negative or hepatitis C ribonucleic acid negative), or known seropositivity for HIV. HIV testing may need to be performed in accordance with local regulations or local practice;
- •Major surgery within 4 weeks before randomization;
- •Unstable or severe uncontrolled medical condition (eg, unstable cardiac function or unstable pulmonary condition);
- •Concurrent active malignancy other than non-melanoma skin cancer, carcinoma in situ of the cervix, or localized prostate cancer that has been definitely treated with radiation or surgery. Patients with previous malignancies are eligible provided that they have been disease free for >=2 years;
- •Patients with active heart disease or the presence of New York Heart Association (NYHA) stage III or IV congestive heart failure;
- •QTcF >470 msec (based on the average of 3 consecutive electrocardiogram [ECGs]);
- •Myocardial infarction within 6 months before randomization;
- •History of clinically significant ventricular arrhythmia, or unexplained syncope not believed to be vasovagal in nature, or chronic bradycardic states such as sinoatrial block or higher degrees of atrioventricular (AV) block unless a permanent pacemaker has been implanted;
- •Uncontrolled electrolyte disorders that can compound the effects of a QTc prolonging drug (eg, hypokalemia, hypocalcemia, hypomagnesemia);
- •Prior confirmed or ongoing hepatic veno occlusive disease (VOD) or sinusoidal obstruction syndrome (SOS), or other serious or current ongoing liver disease such as cirrhosis or nodular regenerative hyperplasia;
- •Administration of live vaccine within 6 weeks before randomization;
- •Evidence of uncontrolled current serious active infection (including sepsis, bacteremia, fungemia) or patients with a recent history (within 4 months) of deep tissue infections such as fascitis or osteomyelitis;
- •Patients who have had a severe allergic reaction or anaphylactic reaction to any humanized monoclonal antibodies;
- •Pregnant female subjects; breastfeeding female subjects; fertile male subjects and female subjects of childbearing potential who are unwilling or unable to use highly effective contraception as outlined in this protocol for the duration of the study and for a minimum of 8 months (females) and 5 months (males) after the last dose of investigational product;
- •Investigative site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the Investigator, or subjects who are Pfizer employees, including their family members, directly involved in the conduct of the study;
- •Participation in other studies involving investigational drug(s) within 2 weeks prior to study entry and/or during study participation (up through the end of treatment visit);
- •Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the subject inappropriate for entry into this study.
研究组 & 干预措施
Dose Level 2
Experimental
Inotuzumab ozogamicin at starting dose 1.2 mg/m2/cycle (administered in 3 divided doses). Most patients expected to receive 2 or 3 cycles (cycle length 21 to 28 days)
干预措施: inotuzumab ozogamicin-dose level 2 (Drug)
Dose Level 1
Active Comparator
Inotuzumab ozogamicin at starting dose 1.8 mg/m2/cycle (administered in 3 divided doses). Most patients expected to receive 2 or 3 cycles (cycle length 21 to 28 days)
干预措施: Inotuzumab ozogamicin-dose level 1 (Drug)
结局指标
主要结局
Percentage of Participants With Veno-occlusive Disease (VOD)
时间窗: 2 years from randomization
VOD happened when the small blood vessels that lead into the liver and were inside the liver become blocked. VOD is defined as: a. Classical VOD (first 21 days after HSCT): Bilirubin\>=2 mg/dL and 2 (or more) of the following criteria must also be present: 1. Painful hepatomegaly; 2. Weight gain \>5%; 3. Ascites. b. Late onset VOD (\>21 days after HSCT): Classical VOD beyond Day 21; or Histologically proven VOD; or Two or more of the following criteria must be present: 1. Bilirubin \>2 mg/dL; 2. Painful hepatomegaly; 3. Weight gain \>5%; 4. Ascites. and hemodynamical and/or ultrasound evidence of VOD.
Rate of Hematologic Remission (Complete Response [CR] / Complete Response With Incomplete Hematologic Recovery[CRi])
时间窗: From first dose of study treatment of 6 cycles till follow-up up to 2 years, in total approximately 2.5 years
CR is defined as a disappearance of leukemia as indicated by\<5% marrow blasts and the absence of peripheral blood leukemic blasts, with recovery of hematopoiesis defined by absolute neutrophil count (ANC)\>=1000/µL and platelets\>=100000/µL. C1 extramedullary disease status is required. CRi is defined as CR except with ANC \<1000/µL and/or platelets \<100000/µL. C1 defined as complete disappearance of all measurable and non-measurable extramedullary disease with the exception of lesions with following must be true: For participants with\>= 1 measurable lesion, all nodal masses\>1.5cm in greatest transverse diameter (GTD) at baseline (last assessment before 1st dose of study treatment) must must have regressed to\>=1.5cm in GTD and all nodal masses\>=1cm \& \<=1.5cm in GTD at baseline have regressed to \<1cm GTD or must have reduced by 75% in sum of products of greatest diameters. No new lesions. Spleen and other previously enlarged organs must have regressed in size and must not be palpable.
次要结局
- Number of Participants With Treatment-Emergent Adverse Events (All Causalities)(From first dose of study treatment drug through 63 days after last dose (approximately 52 weeks))
- Shift Summary of Chemistry Laboratory Test Results From Grade <=2 at Baseline to Grade 3 or 4 Post-Baseline(From first dose of study treatment drug through 63 days after last dose (approximately 52 weeks))
- Number of Participants With Treatment-Emergent Adverse Events (Treatment-related)(From first dose of study treatment drug through 63 days after last dose (approximately 52 weeks))
- Number of Participants With Treatment-Emergent Serious Adverse Events (Post-HSCT)(Starting from the first transplant after inotuzumab ozogamicin treatment and including the entire duration of subsequent follow up (approximately 52 weeks)))
- Shift Summary of Hematology Laboratory Test Results From Grade <=2 at Baseline to Grade 3 or 4 Post-Baseline(From first dose of study treatment drug through 63 days after last dose (approximately 52 weeks))
- Number of Participants Achieving a CR/CRi With Minimal Residual Disease (MRD) Negativity(At screening, once at Day 16-28 of Cycles 1 and 2, or until CR/CRi and MRD negativity were achieved, then after every 1-2 cycles as clinically indicated, and at EOT visit (maximum of 2.5 years))
- Duration of Remission (DoR) in Participants Achieving CR/CRi(From first dose of study treatment of 6 cycles till follow-up up to 2 years, in total approximately 2.5 years)
- Progression-Free Survival(From first dose of study treatment of 6 cycles till follow-up up to 2 years, in total approximately 2.5 years)
- Overall Survival(From first dose of study treatment of 6 cycles till follow-up up to 2 years, in total approximately 2.5 years)
- Number of Participant Received HSCT Post Inotuzumab Ozogamicin Treatment(From first dose of study treatment of 6 cycles till follow-up up to 2 years, in total approximately 2.5 years)
- The Cumulative Incidence Rate of Post-HSCT Relapse at Month 12(From first dose of study treatment to Month 12)
- Number of Participants With Post-HSCT Mortality(From first dose of study treatment of 6 cycles till follow-up up to 2 years, in total approximately 2.5 years)
- Number of Participants With Post HSCT Non-Relapse Mortality(From first dose of study treatment of 6 cycles till follow-up up to 2 years, in total approximately 2.5 years)
- Number of Participants With Post HSCT Relapse-Related Mortality(From first dose of study treatment of 6 cycles till follow-up up to 2 years, in total approximately 2.5 years)
- Mean Predose Concentrations (Ctrough) of Inotuzumab Ozogamicin(Pre-dose on Cycle 1 Day 1, 8 and 15, and on Day1 and 8 of Cycle 2, 3 and 4.)
- Number of Participants With Positive Anti-Drug Antibody (ADA)(At Day 1 of every cycle prior to the beginning of inotuzumab ozogamicin infusion and at the EOT visit, up to approximately 52 weeks.)
- Number of Participants With Positive Neutralizing Antibody (NAb)(At Day 1 of every cycle prior to the beginning of inotuzumab ozogamicin infusion and at the EOT visit, up to approximately 52 weeks.)
研究者
研究点 (44)
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