Inotuzumab Ozogamicin Post-Transplant For Acute Lymphocytic Leukemia
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 44
- 试验地点
- 14
- 主要终点
- Phase II Median DFS
研究概览
简要总结
This study has two phases, Phase I and Phase II. The main goal of the Phase I portion of this research study is to see what doses post-transplant inotuzumab ozogamicin can safely be given to subjects without having too many side effects.
The Phase II portion of this study is to see what side effects are seen with medication after transplant.
Inotuzumab ozogamicin is a combination of an antibody and chemotherapy which has been shown to have significant activity against relapsed/refractory acute lymphocytic leukemia (ALL).
Inotuzumab ozogamicin is considered experimental in this study.
详细描述
Study Design This is a Phase I/II study of inotuzumab ozogamicin for the treatment of patients who underwent allogeneic transplantation for ALL and have a high risk of relapse. The Phase I portion of this study will be a 3+3 dose escalation trial. This is followed by a phase 2 cohort at the recommended Phase 2 dose (RP2D). Participants will receive study treatment up to 4 cycles until relapse of disease, unacceptable toxicity, or death, whichever occurs first
Phase I: Inotuzumab Ozogamicin Dosing Escalation Subjects will be assessed for safety and tolerability (including adverse events, serious adverse events, and clinical/laboratory assessments) using a continuous monitoring approach.
Phase II: Inotuzumab Ozogamicin Subjects will be assessed for safety and tolerability (including adverse events, serious adverse events, and clinical/laboratory assessments) using a continuous monitoring approach. In order to be included in the safety profile endpoint review, subjects must have received at least of 1 cycle of treatment.
Primary Objective
Phase I: To define a post hematopoietic stem cell transplantation maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of inotuzumab ozogamicin.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 16 Years 至 75 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Phase 1 Inclusion Criteria
- •Diagnosis of CD22-positive Acute Lymphoblastic Leukemia
- •Patients who underwent an allogeneic hematopoietic stem cell transplantation from any donor source for acute lymphocytic leukemia
- •Patients who are between T+40 and T+100 after allogeneic transplantation. Patients must receive their first dose of inotuzumab at or before T+
- •Patients who have/are either:
- •Transplanted in hematologic first complete remission with evidence of minimal residual disease within 45 days of allogeneic transplantation
- •--Pre- or Post-Transplant Minimal Residual Disease defined by:
- •---Any detectable ALL (by flow cytometry, cytogenetics, or PCR techniques) as per clinical indication.
- •In second or third complete remission at the time of allogeneic transplantation
- •Treated with reduced intensity regimens or non-myeloablative conditioning regimens
- •Lymphoid blast crisis of CML
- •Are relapsed or refractory to at least 1 line of chemotherapy
- •Philadelphia-like ALL
- •Patients who have evidence of donor chimerism after allogeneic transplantation.
- •ECOG Performance status < 2
- •Participants must have ANC > 1,000/µL for 3 days and platelet transfusion independence as defined as a platelet count > 50,000/µL for 7 days.
- •Able to adhere to the study visit schedule and other protocol requirements.
- •Participants must have the ability to understand and the willingness to sign a written informed consent document.
- •Phase 2 Inclusion Criteria
- •Diagnosis of CD22-positive Acute Lymphoblastic Leukemia
- •Patients who underwent an allogeneic hematopoietic stem cell transplantation from any donor source for acute lymphocytic leukemia
- •Patients who are between T+40 and T+100 after allogeneic transplantation
- •Patients who have/are either:
- •Transplanted in hematologic first complete remission with evidence of minimal residual disease within 45 days of allogeneic transplantation
- •--Post-Transplant Minimal Residual Disease defined by:
- •---Any detectable ALL (by flow cytometry, cytogenetics, or PCR techniques) as per clinical indication.
- •In second or third complete remission at the time of allogeneic transplantation
- •Treated with reduced intensity regimens as defined per institutional standard of practice
- •Lymphoid blast crisis of CML
- •Are relapsed or refractory to at least 1 line of chemotherapy
- •Philadelphia-like ALL
- •Patients who have > 80% donor chimerism after allogeneic transplantation.
- •Philadelphia chromosome positive ALL must have failed at least 1 TKI
- •ECOG Performance status < 1
- •pre-transplant evaluation, see 10.1.1
- •Participants must have ANC > 1,000/µL for 3 days and platelet transfusion independence as defined as a platelet count > 50,000/µL for 7 days.
- •Able to adhere to the study visit schedule and other protocol requirements.
- •Participants must have the ability to understand and the willingness to sign a written informed consent document.
- •Phase 1 and 2
排除标准
- •Patients with clinical evidence of disease progression prior to enrollment
- •Persistent prior treatment toxicities Grade 2 and above according to NCI CTCAE Version 4.03 (with the exception for alopecia, neuropathy, etc.)
- •Patients with inadequate organ function as defined by:
- •Creatinine clearance < 30ml/min
- •Bilirubin > 2X institutional upper limit of normal
- •AST (SGOT) > 2X institutional upper limit of normal
- •ALT (SGPT) > 2X institutional upper limit of normal
- •GVHD grade III or IV (for patients with a prior allogeneic transplant).
- •Active acute or chronic GVHD of the liver (for patients with a prior allogeneic transplant)
- •History of VOD
- •Use of concomitant TKI or sirolimus
- •Second active malignancy, other than non-melanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast)
- •Patients with uncontrolled inter-current 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.
- •Pregnant or breastfeeding women are excluded from this study because inotuzumab ozogamicin may be associated with the potential for teratogenic or abortifacient effects. Because there is an unknown, but potential risk for adverse events in nursing infants secondary to treatment of the mother with inotuzumab ozogamicin, breastfeeding should be discontinued if the mother is treated with inotuzumab ozogamicin. These potential risks may also apply to other agents used in this study.
- •Evidence of myelodysplasia or cytogenetic abnormality indicative of myelodysplasia on any bone marrow biopsy prior to initiation of therapy Serologic status reflecting active hepatitis B or C infection. Patients that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment. (PCR positive patients will be excluded.)
- •Serologic status reflecting active hepatitis B or C infection. Patients that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment. (PCR positive patients will be excluded.)
- •Participation in any other investigational drug study or had exposure to any other investigational agent, device, or procedure, within 21 days (or 5 half-lives, whichever is greater)
- •Any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration of study drug and attending required study visits; pose a significant risk to the participant; or interfere with interpretation of study data.
- •Known allergies, hypersensitivity, or intolerance to any of the study medications, excipients, or similar compounds
研究组 & 干预措施
Inotuzumab Ozogamicin
Phase I:
A maximum of 4 cycles will be allowed and doses will be adjusted in 0.1mg/m2 increments using a dose escalation scale depending on tolerability. Total range of dose levels for participants is 0.1-0.6mg/m^2.
Phase II:
Participants will be enrolled until all Phase I participants have been followed and assessed for toxicity for at least 4 weeks after the fourth treatment dose of inotuzumab ozogamicin or 4 weeks after the participant goes off treatment, whichever comes first. Doses to be administered will be determined in the phase I portion of the study. The recommended phase 2 dose is 0.3mg/m2. Repeat cycles every 28 days for up to 4 cycles
干预措施: Inotuzumab Ozogamicin (Drug)
结局指标
主要结局
Phase II Median DFS
时间窗: Post first dose of inotuzumab ozogamicin
Efficacy as measured by phase II DFS at one year, estimated using Kaplan-Meier, reported as median and 2-sided 80% and 95% Confidence Interval (CI) DFS is defined as "Time from date of first dose to the date of disease progression (ie,objective progression, relapse from CR/CRi), or death due to any cause, whichever occurs first (including post-study treatment follow-up disease assessments)". Difference in time-to-event endpoints will be tested using a 1-sided log-rank test at a significance level of 0.10 In Phase II, the null hypothesis of H0: DFS at 1-year ≤ 55% versus the alternative hypothesis of Ha: DFS at 1-year ≥ 75% using 1-sided alpha of 10% will be tested
Phase I DLTs
时间窗: Up to 112 days (16 weeks)
Frequency of DLTs during the first two cycles in ALL-participants
Phase I MTD
时间窗: Up to 112 days (16 weeks)
Defined post hematopoietic stem cell transplantation MTD
Phase II Median DFS
时间窗: At 3 months after initial treatment
Efficacy as measured by phase II DFS at one year, estimated using Kaplan-Meier, reported as median and 2-sided 80% and 95% Confidence Interval (CI) DFS is defined as "Time from date of first dose to the date of disease progression (ie,objective progression, relapse from CR/CRi), or death due to any cause, whichever occurs first (including post-study treatment follow-up disease assessments)". Difference in time-to-event endpoints will be tested using a 1-sided log-rank test at a significance level of 0.10 In Phase II, the null hypothesis of H0: DFS at 1-year ≤ 55% versus the alternative hypothesis of Ha: DFS at 1-year ≥ 75% using 1-sided alpha of 10% will be tested
Phase II Median DFS
时间窗: At 6 months after initial treatment
Efficacy as measured by phase II DFS at one year, estimated using Kaplan-Meier, reported as median and 2-sided 80% and 95% Confidence Interval (CI) DFS is defined as "Time from date of first dose to the date of disease progression (ie,objective progression, relapse from CR/CRi), or death due to any cause, whichever occurs first (including post-study treatment follow-up disease assessments)". Difference in time-to-event endpoints will be tested using a 1-sided log-rank test at a significance level of 0.10 In Phase II, the null hypothesis of H0: DFS at 1-year ≤ 55% versus the alternative hypothesis of Ha: DFS at 1-year ≥ 75% using 1-sided alpha of 10% will be tested
Phase II Median DFS
时间窗: At 9 months after initial treatment
Efficacy as measured by phase II DFS at one year, estimated using Kaplan-Meier, reported as median and 2-sided 80% and 95% Confidence Interval (CI) DFS is defined as "Time from date of first dose to the date of disease progression (ie,objective progression, relapse from CR/CRi), or death due to any cause, whichever occurs first (including post-study treatment follow-up disease assessments)". Difference in time-to-event endpoints will be tested using a 1-sided log-rank test at a significance level of 0.10 In Phase II, the null hypothesis of H0: DFS at 1-year ≤ 55% versus the alternative hypothesis of Ha: DFS at 1-year ≥ 75% using 1-sided alpha of 10% will be tested
Phase II Median DFS
时间窗: At 1 year after initial treatment
Efficacy as measured by phase II DFS at one year, estimated using Kaplan-Meier, reported as median and 2-sided 80% and 95% Confidence Interval (CI) DFS is defined as "Time from date of first dose to the date of disease progression (ie,objective progression, relapse from CR/CRi), or death due to any cause, whichever occurs first (including post-study treatment follow-up disease assessments)". Difference in time-to-event endpoints will be tested using a 1-sided log-rank test at a significance level of 0.10 In Phase II, the null hypothesis of H0: DFS at 1-year ≤ 55% versus the alternative hypothesis of Ha: DFS at 1-year ≥ 75% using 1-sided alpha of 10% will be tested
次要结局
- Phase I Median DFS(Post first dose of inotuzumab ozogamicin on Day 1, Cycle 1, where cycle length is 28 days)
- Phase I Relapse-related mortality(Post first dose of inotuzumab ozogamicin on Day 1, Cycle 1, where cycle length is 28 days)
- Phase I Median OS(Post first dose of inotuzumab ozogamicin on Day 1, Cycle 1, where cycle length is 28 days)
- Phase I NRM(Post first dose of inotuzumab ozogamicin on Day 1, Cycle 1, where cycle length is 28 days)
- Phase I rate of VOD/SOS - number of participants affected(At 1 year)
- Phase I - Percent of participants with grade 3 + AE/SAEs(At 1 year)
- Phase II Non-relapse mortality (NRM)(At 3 months after initial treatment)
- Phase II Relapse(At 9 months after initial treatment)
- Phase II Response Rate(Post first dose of inotuzumab ozogamicin on Day 1, Cycle 1, where cycle length is 28 days)
- Phase I Relapse(Post first dose of inotuzumab ozogamicin on Day 1, Cycle 1, where cycle length is 28 days)
- Phase I Incidence of myeloid toxicity(At 1 year)
- Phase I Incidence of secondary graft failure(At 1 year)
- Phase I incidence of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS)(At 1 year)
- Phase II Relapse-related mortality(Post first dose of inotuzumab ozogamicin on Day 1, Cycle 1, where cycle length is 28 days)
- Phase II Median OS(Post first dose of inotuzumab ozogamicin on Day 1, Cycle 1, where cycle length is 28 days)
- Phase II Incidence of myeloid toxicity(At 1 year)
- Phase II Incidence of secondary graft failure(At 1 year after initial treatment)
- Phase I incidence of VOD/SOS(At 1 year)
- Phase II rate of VOD/SOS - number of participants affected(At 1 year)
- Phase II pharmacokinetic (PK) parameters - Cmax(At Cycle 4 Day 1 (C4D1) after 1 hour (each cycle is 28 days))
- Phase II pharmacokinetic (PK) parameters - Ctrough(At Cycle 4 Day 1 (C4D1) after 1 hour (each cycle is 28 days))
- Phase I Median DFS(At 3 months after initial treatment)
- Phase I Median DFS(At 6 months after initial treatment)
- Phase I Median DFS(At 9 months after initial treatment)
- Phase I Median DFS(At 1 year after initial treatment)
- Phase I NRM(At 3 months after initial treatment)
- Phase I NRM(At 6 months after initial treatment)
- Phase I Relapse(At 1 year after initial treatment)
- Phase I NRM(At 9 months after initial treatment)
- Phase I NRM(At 1 year after initial treatment)
- Phase I Relapse(At 3 months after initial treatment)
- Phase I Relapse(At 6 months after initial treatment)
- Phase I Relapse(At 9 months after initial treatment)
- Phase I Relapse-related mortality(At 3 months after initial treatment)
- Phase I Relapse-related mortality(At 6 months after initial treatment)
- Phase I Relapse-related mortality(At 9 months after initial treatment)
- Phase I Relapse-related mortality(At 1 year after initial treatment)
- Phase I Median OS(At 3 months after initial treatment)
- Phase I Median OS(At 6 months after initial treatment)
- Phase I Median OS(At 9 months after initial treatment)
- Phase I Median OS(At 1 year after initial treatment)
- Phase II Relapse(At 6 months after initial treatment)
- Phase II Relapse-related mortality(At 1 year after initial treatment)
- Phase II Median OS(At 3 months after initial treatment)
- Phase II Median OS(At 6 months after initial treatment)
- Phase II Median OS(At 9 months after initial treatment)
- Phase II Median OS(At 1 year after initial treatment)
- Phase II Response Rate(At 3 months after initial treatment)
- Phase II Response Rate(At 6 months after initial treatment)
- Phase II Response Rate(At 9 months after initial treatment)
- Phase II Response Rate(At 1 year after initial treatment)
- Phase II pharmacokinetic (PK) parameters - Cmax(At Cycle 1 Day 1 (C1D1) after 0 hours (each cycle is 28 days))
- Phase II pharmacokinetic (PK) parameters - Cmax(At Cycle 1 Day 1 (C1D1) after 1 hour (each cycle is 28 days))
- Phase II pharmacokinetic (PK) parameters - Cmax(At Cycle 1 Day 1 (C1D1) after 4 hours (each cycle is 28 days))
- Phase II pharmacokinetic (PK) parameters - Cmax(At Cycle 1 Day 7 (C1D7) (each cycle is 28 days))
- Phase II pharmacokinetic (PK) parameters - Cmax(At Cycle 2 Day 1 (C2D1) after 0 hours (each cycle is 28 days))
- Phase II pharmacokinetic (PK) parameters - Cmax(At Cycle 2 Day 1 (C2D1) after 1 hour (each cycle is 28 days))
- Phase II pharmacokinetic (PK) parameters - Cmax(At Cycle 4 Day 1 (C4D1) after 0 hours (each cycle is 28 days))
- Phase II pharmacokinetic (PK) parameters - Ctrough(At Cycle 1 Day 1 (C1D1) after 0 hours (each cycle is 28 days))
- Phase II pharmacokinetic (PK) parameters - Ctrough(At Cycle1 Day 1 (C1D1) after 1 hour (each cycle is 28 days))
- Phase II pharmacokinetic (PK) parameters - Ctrough(At Cycle1 Day 1 (C1D1) after 4 hours (each cycle is 28 days))
- Phase II pharmacokinetic (PK) parameters - Ctrough(At Cycle 1 Day 7 (C1D7) (each cycle is 28 days))
- Phase II pharmacokinetic (PK) parameters - Ctrough(At Cycle 2 Day 1 (C2D1) after 0 hours (each cycle is 28 days))
- Phase II pharmacokinetic (PK) parameters - Ctrough(At Cycle 2 Day 1 (C2D1) after 1 hour (each cycle is 28 days))
- Phase II pharmacokinetic (PK) parameters - Ctrough(At Cycle 4 Day 1 (C4D1) after 0 hours (each cycle is 28 days))
研究者
Leland Metheny
Principal Investigator
Case Comprehensive Cancer Center