An Open-Label Study of Brentuximab Vedotin + Adriamycin, Vinblastine, and Dacarbazine in Pediatric Patients With Advanced Stage Newly Diagnosed Hodgkin Lymphoma
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 59
- 试验地点
- 14
- 主要终点
- Phase 2: Percentage of Participants Whose Disease Was Positron Emission Tomography (PET) Negative After 2 Cycles of Protocol Therapy Per IRF Assessment
研究概览
简要总结
The purpose of this study is to assess the safety, tolerability, and anti-tumor activity, as well as confirm the recommended dose of brentuximab vedotin (ADCETRIS) in combination with a multiagent chemotherapy regimen, doxorubicin (Adriamycin), vinblastine, and dacarbazine, in pediatric participants with advanced stage newly diagnosed classical CD30+ Hodgkin Lymphoma (HL).
详细描述
The drug being tested in this study is called brentuximab vedotin. Brentuximab vedotin is being tested to treat pediatric participants who have advanced stage, newly diagnosed, classical CD30+ HL. This study will assess the safety, tolerability, and anti-tumor activity, as well as recommended dose of brentuximab vedotin in combination with a multiagent chemotherapy regimen that is based on a current standard of care (SOC) first-line treatment regimen for newly diagnosed HL.
The study will enroll approximately 55 evaluable participants. The study will be conducted in 2 phases, Phase 1 and Phase 2. Phase 1 study will enroll at least 6 participants to determine the recommended dose. Once the recommended dose is identified additional participants will be enrolled into phase 2 so that the total number of evaluable participants will be at least 55, including participants treated at recommended dose in Phase 1. Participants will be enrolled to the following initial dose cohort with an option to explore a reduced dose cohort at 36 mg/m^2 if needed:
• Brentuximab vedotin 48 mg/m^2 in combination with doxorubicin, vinblastine, and dacarbazine.
This multi-center trial will be conducted in the United States, Italy, Brazil and Japan. The overall time to participate in this study is approximately 55 months, including the follow-up period. Participants will be followed for a maximum of 30 days following the last dose of protocol therapy for a follow-up assessment and will be followed for survival and disease status every 12 weeks for 12 months, and then every 24 weeks until death or study closure or for up to 2 years from the date of the last participant enrolled.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 5 Years 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Each participant must meet all the following inclusion criteria to be enrolled in the study:
- •Histologically confirmed CD30+ classical HL.
- •Advanced stage, newly diagnosed HL (Stage III and Stage IV disease).
- •Treatment-naive HL.
- •Have performance scores of greater than or equal to (>=) 50 for Lansky Play-performance or Karnofsky Performance Status.
- •Have bidimensional measurable disease as documented by radiographic technique per International Working Group (IWG) criteria.
- •Have adequate blood counts, renal and liver function as defined in the protocol.
排除标准
- •Nodular lymphocyte predominant HL.
- •Known active cerebral/meningeal disease, including signs or symptoms of progressive multifocal leukoencephalopathy (PML) or any history of PML.
- •Any sensory or motor peripheral neuropathy.
- •Symptomatic neurologic disease compromising normal activities of daily living or requiring medications.
- •Any active systemic viral, bacterial, or fungal infection requiring systemic antibiotics within 2 weeks before the first study protocol therapy.
- •Known hypersensitivity to recombinant proteins, murine proteins, or to any excipient contained in the drug formulation of brentuximab vedotin or any component of AVD.
- •Known human immunodeficiency virus positive.
- •Known hepatitis B surface antigen positive or known or suspected active hepatitis C infection, as determined by hepatitis B DNA or hepatitis C RNA, respectively, in blood.
- •Diagnosed or treated for another malignancy within 3 years before the first dose or previously diagnosed with another malignancy and have any evidence of residual disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
- •Use of any strong or listed moderate cytochrome P450 (CYP) 3A4 inhibitors less than (<) 2 weeks before the first dose of protocol therapy (please refer to the Study Manual for an example list of prohibited CYP3A4 inhibitors).
- •Any of the following cardiovascular conditions or values within 6 months before the first dose of protocol therapy:
- •Shortening fraction of <27 percent (%) by echocardiogram or, if echocardiogram not feasible, ejection fraction of <50% by radionuclide angiogram (RNA or MUGA [multiple-gated acquisition scan]).
- •New York Heart Association Class III or IV heart failure.
- •Evidence of current uncontrolled cardiovascular conditions, including cardiac arrhythmias, congestive heart failure, angina, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.
研究组 & 干预措施
Phase 1: Brentuximab Vedotin 48 mg/m^2 + AVD
Brentuximab vedotin 48 mg/m^2 (A), intravenous infusion, once on Days 1 and 15 of each 28-day cycle approximately 1 hour after administration of doxorubicin 25 mg/m^2, vinblastine 6 mg/m^2, and dacarbazine 375 mg/m^2 (AVD), intravenous infusion, once on Days 1 and 15 of each 28-day cycle for up to 6 cycles.
干预措施: Brentuximab vedotin (Drug)
Phase 1: Brentuximab Vedotin 48 mg/m^2 + AVD
Brentuximab vedotin 48 mg/m^2 (A), intravenous infusion, once on Days 1 and 15 of each 28-day cycle approximately 1 hour after administration of doxorubicin 25 mg/m^2, vinblastine 6 mg/m^2, and dacarbazine 375 mg/m^2 (AVD), intravenous infusion, once on Days 1 and 15 of each 28-day cycle for up to 6 cycles.
干预措施: Doxorubicin (Drug)
Phase 1: Brentuximab Vedotin 48 mg/m^2 + AVD
Brentuximab vedotin 48 mg/m^2 (A), intravenous infusion, once on Days 1 and 15 of each 28-day cycle approximately 1 hour after administration of doxorubicin 25 mg/m^2, vinblastine 6 mg/m^2, and dacarbazine 375 mg/m^2 (AVD), intravenous infusion, once on Days 1 and 15 of each 28-day cycle for up to 6 cycles.
干预措施: Vinblastine (Drug)
Phase 1: Brentuximab Vedotin 48 mg/m^2 + AVD
Brentuximab vedotin 48 mg/m^2 (A), intravenous infusion, once on Days 1 and 15 of each 28-day cycle approximately 1 hour after administration of doxorubicin 25 mg/m^2, vinblastine 6 mg/m^2, and dacarbazine 375 mg/m^2 (AVD), intravenous infusion, once on Days 1 and 15 of each 28-day cycle for up to 6 cycles.
干预措施: Dacarbazine (Drug)
Phase 2: Brentuximab Vedotin 48 mg/m^2 + AVD
Brentuximab vedotin 48 mg/m^2 (A), intravenous infusion, once on Days 1 and 15 of each 28-day cycle approximately 1 hour after administration of doxorubicin 25 mg/m^2, vinblastine 6 mg/m^2, and dacarbazine 375 mg/m^2 (AVD), intravenous infusion, once on Days 1 and 15 of each 28-day cycle for up to 6 cycles.
干预措施: Brentuximab vedotin (Drug)
Phase 2: Brentuximab Vedotin 48 mg/m^2 + AVD
Brentuximab vedotin 48 mg/m^2 (A), intravenous infusion, once on Days 1 and 15 of each 28-day cycle approximately 1 hour after administration of doxorubicin 25 mg/m^2, vinblastine 6 mg/m^2, and dacarbazine 375 mg/m^2 (AVD), intravenous infusion, once on Days 1 and 15 of each 28-day cycle for up to 6 cycles.
干预措施: Doxorubicin (Drug)
Phase 2: Brentuximab Vedotin 48 mg/m^2 + AVD
Brentuximab vedotin 48 mg/m^2 (A), intravenous infusion, once on Days 1 and 15 of each 28-day cycle approximately 1 hour after administration of doxorubicin 25 mg/m^2, vinblastine 6 mg/m^2, and dacarbazine 375 mg/m^2 (AVD), intravenous infusion, once on Days 1 and 15 of each 28-day cycle for up to 6 cycles.
干预措施: Vinblastine (Drug)
Phase 2: Brentuximab Vedotin 48 mg/m^2 + AVD
Brentuximab vedotin 48 mg/m^2 (A), intravenous infusion, once on Days 1 and 15 of each 28-day cycle approximately 1 hour after administration of doxorubicin 25 mg/m^2, vinblastine 6 mg/m^2, and dacarbazine 375 mg/m^2 (AVD), intravenous infusion, once on Days 1 and 15 of each 28-day cycle for up to 6 cycles.
干预措施: Dacarbazine (Drug)
结局指标
主要结局
Phase 2: Percentage of Participants Whose Disease Was Positron Emission Tomography (PET) Negative After 2 Cycles of Protocol Therapy Per IRF Assessment
时间窗: From first dose of study drug up to Cycle 2 Day 25 (Each Cycle length=28 days)
The Deauville score according to IRF assessment of response was used to evaluate the results of PET scans. PET negative after Cycle 2 was defined as an IRF Deauville score of (1 or 2 or 3). This outcome measure was planned to be assessed for all participants treated at the recommended dose in Phase 2. As prespecified in SAP, data for Phase 2 was summarized and reported in two arms: Phase 2 and Phase 1 + Phase 2.
Phase 2: Percentage of Participants Who Achieved a Partial Remission (PR) Per IRF Assessment Per IWG Criteria at EOT Visit
时间窗: At EOT visit 30 days after the last dose of study drug (at Month 7)
PR was defined as regression of measurable disease and no new sites as assessed by IRF as per IWG criteria. Percentage of participants in the response-evaluable population who achieved a partial response based on the IRF assessment at the EOT visit based on the IWG criteria are reported. The confidence interval was based on exact binomial distribution (Clopper-Pearson method). This outcome measure was planned to be assessed for all participants treated at the recommended dose in Phase 2. As prespecified in SAP, data for Phase 2 was summarized and reported in two arms: Phase 2 and Phase 1 + Phase 2.
Phase 2: Percentage of Participants Who Achieved an Overall Response Rate (ORR) Per IRF Assessment Per IWG Criteria at EOT Visit
时间窗: At EOT visit 30 days after the last dose of study drug (at Month 7)
Overall response rate was defined as the percentage of participants with CR or PR as assessed by IRF using IWG criteria. CR was defined as the disappearance of all evidence of disease and PR was defined as regression of measurable disease and no new diseases. The confidence interval was based on exact binomial distribution (Clopper-Pearson method). This outcome measure was planned to be assessed for all participants treated at the recommended dose in Phase 2. As prespecified in SAP, data for Phase 2 was summarized and reported in two arms: Phase 2 and Phase 1 + Phase 2.
Phase 2: Percentage of Participants Who Were Able to Complete 6 Cycles of Protocol Therapy at the Recommended Dose
时间窗: From first dose of study drug up to Cycle 6 (Each Cycle length=28 days)
This outcome measure was planned to be assessed for all participants treated at the recommended dose in Phase 2. As prespecified in SAP, data for Phase 2 was summarized and reported in two arms: Phase 2 and Phase 1 + Phase 2.
Phase 1: Recommended Dose of Brentuximab Vedotin in Combination With Doxorubicin, Vinblastine, and Dacarbazine in a Pediatric Population
时间窗: From the first dose (Cycle 1) up to Day 56 (Cycle length=28 days)
The recommended dose was determined after considering all safety data in phase 1 and assessing for dose limiting toxicities (DLTs) which are defined as the dose range at which less than or equal to (\<=) 1 of 6 evaluable participants experience DLT within the defined observation period (Cycle 1 + 28 days). This outcome measure is planned to be assessed only for participants treated in Phase 1 arm.
Phase 1: Percentage of Participants Who Experienced Adverse Events (AEs) From the First Dose of Protocol Therapy Through 30 Days After Administration of the Last Dose of Protocol Therapy
时间窗: From first dose in Cycle 1 Day 1 until 30 days after the last dose of study drug in Cycle 6 Day 15 (up to Cycle 7 Day 15) (Cycle length=28 days)
AE means any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not it is related to the medicinal product. This outcome measure is planned to be assessed only for participants treated in Phase 1 arm.
Phase 1: Percentage of Participants Who Experienced Serious Adverse Events (SAEs) From the First Dose of Protocol Therapy Through 30 Days After Administration of the Last Dose of Protocol Therapy
时间窗: From first dose in Cycle 1 Day 1 until 30 days after the last dose of study drug in Cycle 6 Day 15 (up to Cycle 7 Day 15) (Cycle length=28 days)
AE means any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not it is related to the medicinal product. SAE is defined as any untoward medical occurrence that at any dose results in death, Is life-threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, Is a congenital anomaly/birth defect, Is a medically important event.
Phase 2: Percentage of Participants Who Achieved a Complete Remission (CR) Per Independent Review Facility (IRF) Assessment Per International Working Group (IWG) Criteria at End of Treatment (EOT) Visit
时间窗: At end of treatment (EOT) visit 30 days after the last dose of study drug (at Month 7)
CR was defined as the disappearance of all evidence of disease as assessed by IRF as per IWG Criteria. The confidence interval was based on exact binomial distribution (Clopper-Pearson method). This outcome measure was planned to be assessed for all participants treated at the recommended dose in Phase 2. As prespecified in the statistical analysis plan (SAP) , data for Phase 2 was summarized and reported in two arms: Phase 2 and Phase 1 + Phase 2.
次要结局
- Phase 1: Mean Area Under the Serum Concentration-Time Curve From Day 0 to Day 15 (AUC0-15) of Brentuximab Vedotin and TAb(Days 1 and 15 of Cycles 1 and 3 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days))
- Phase 1: Mean Maximum Observed Serum Concentration (Cmax) of Brentuximab Vedotin Total Conjugated and Therapeutic Antibody (TAb)(Days 1 and 15 of Cycles 1 and 3 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days))
- Phase 1: Mean Maximum Observed Plasma Concentration (Cmax) of Monomethyl Auristatin E (MMAE)(Days 1 and 15 of Cycles 1 and 3 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days))
- Phase 1: Mean Area Under the Plasma Concentration-Time Curve From Day 0 to Day 15 (AUC0-15) of MMAE(Days 1 and 15 of Cycles 1 and 3 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days))
- Phase 1: Median Time to Reach Cmax (Tmax) of Brentuximab Vedotin and TAb in Serum(Cycle 1-6: Days 1 and 15 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days))
- Phase 1: Median Time to Reach Cmax (Tmax) of MMAE in Plasma(Days 1 and 15 of Cycles 1 and 3 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days))
- Phase 1: Percentage of Participants Who Achieved a CR Per IRF Assessment Per IWG Criteria at EOT Visit(At EOT visit 30 days after the last dose of study drug (at Month 7))
- Phase 1: Percentage of Participants Who Achieved a PR Per IRF Assessment Per IWG Criteria at EOT Visit(At EOT visit 30 days after the last dose of study drug (at Month 7))
- Phase 1: Percentage of Participants Who Achieved an ORR Per IRF Assessment Per IWG Criteria at EOT Visit(At EOT visit 30 days after the last dose of study drug (at Month 7))
- Phase 1: Percentage of Participants Whose Disease Was PET Negative After 2 Cycles of Protocol Therapy Per IRF Assessment(From first dose of study drug up to Cycle 2 (Each Cycle length=28 days))
- Phase 1: Percentage of Participants Whose Disease Was PET Positive After 6 Cycles of Protocol Therapy Per IRF Assessment(From first dose of study drug up to Cycle 6 (Each Cycle length=28 days))
- Phase 1: Percentage of Participants Who Were Antitherapeutic Antibody (ATA) Positive, Persistently Positive or Transiently Positive, and Neutralizing Antitherapeutic Antibody (nATA) Positive(Up to 7 months)
- Phase 2: Duration of Response (DOR)(Up to 24 months)
- Phase 2: Percentage of Participants Receiving Irradiation for HL Following Study Treatment(Up to 24 months)
- Phase 2: Percentage of Participants Who Experienced AEs From the First Dose of Protocol Therapy Through 30 Days After Administration of the Last Dose of Protocol Therapy(From first dose in Cycle 1 Day 1 until 30 days after the last dose of study drug in Cycle 6 Day 15 (up to Cycle 7 Day 15) (Cycle length=28 days))
- Phase 2: Percentage of Participants Who Experienced SAEs From the First Dose of Protocol Therapy Through 30 Days After Administration of the Last Dose of Protocol Therapy(From first dose in Cycle 1 Day 1 until 30 days after the last dose of study drug in Cycle 6 Day 15 (up to Cycle 7 Day 15) (Cycle length=28 days))
- Phase 2: Percentage of Participants Who Were ATA Positive, Persistently Positive, or Transiently Positive, and nATA Positive(From first dose until 30 days after the last dose of study drug (up to 7 months))
- Phase 2: Mean Serum Cmax of Brentuximab Vedotin and TAb(Days 1 and 15 of Cycles 1 and 3 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days))
- Phase 2: Mean Plasma Cmax of MMAE(Days 1 and 15 of Cycles 1 and 3 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days))
- Phase 2: Mean Serum AUC0-15d of Brentuximab Vedotin and TAb(Days 1 and 15 of Cycles 1 and 3 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days))
- Phase 2: Mean Plasma AUC0-15 of MMAE(Days 1 and 15 of Cycles 1 and 3 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days))
- Phase 2: Progression-free Survival (PFS)(Up to 24 months)
- Phase 2: Event-free Survival (EFS)(Up to 24 months)
- Phase 2: Overall Survival (OS)(Up to 24 months)
- Phase 2: Median Tmax of Brentuximab Vedotin and TAb in Serum(Days 1 and 15 of Cycles 1 and 3 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days))
- Phase 2: Median Tmax of MMAE in Plasma(Days 1 and 15 of Cycles 1 and 3 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days))
- Phase 2: Percentage of Participants Who Experienced Peripheral Neuropathy, Regardless of Seriousness, From the First Dose of Protocol Therapy(Up to 24 months)
- Phase 2: Time to Onset and Resolution for All Peripheral Neuropathy Events(Up to 24 months)
- Phase 2: Immune Reconstitution-Change From Baseline Immunoglobulin G Levels at End of Treatment (EOT)(Baseline and End of Treatment (Month 7))
- Phase 1: Percentage of Participants With Low and High ATA Titer Values(Up to 6 months)
- Phase 2: Percentage of Participants With Low and High ATA Titer Values(Up to 6 months)
- Phase 1: Mean Cmax of Brentuximab Vedotin in ATA Positive and ATA Negative Participants(Cycle 1 and 3: Days 1 and 15 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days))
- Phase 1: Mean AUC 0-15d of Brentuximab Vedotin in ATA Positive and ATA Negative Participants(Cycle 1 and 3: Days 1 and 15 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days))
- Phase 1: Percentage of Participants Achieving CR Per IRF Assessment Per IWG Criteria in ATA Positive and ATA Negative Participants(Up to 24 months)
- Phase 1: Number of ATA Positive and ATA Negative Participants With AEs and SAEs(Up to 24 months)
- Phase 2: Mean Cmax of Brentuximab Vedotin in ATA Positive and ATA Negative Participants(Cycle 1-3: Days 1 and 15 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days))
- Phase 2: Mean AUC 0-15 of Brentuximab Vedotin in ATA Positive and ATA Negative Participants(Cycle 1-3: Days 1 and 15 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days))
- Phase 2: Percentage of Participants Achieving CR Per IRF Assessment Per IWG Criteria in ATA Positive and ATA Negative Participants(Up to 24 months)
- Phase 2: Number of ATA Positive and ATA Negative Participants With AEs and SAEs(Up to 24 months)
- Phase 2: Immune Reconstitution-Change From Baseline in Immunoglobulin M at the End of Treatment (EOT)(Baseline, EOT [Month 7])
- Phase 2: Immune Reconstitution-Change From Baseline in Immunoglobulin A at EOT(Baseline, EOT [Month 7])
- Phase 2: Immune Reconstitution-Change From Baseline in Tetanus at EOT(Baseline, EOT [Month 7])
- Phase 2: Immune Reconstitution-Change From Baseline in Haemophilus Influenzae B Antibody, IgG at EOT(Baseline, EOT [Month 7])
- Phase 2: Immune Reconstitution-Change From Baseline Poliovirus Antibodies Ratio at EOT(Baseline, EOT [Month 7])
- Phase 2: Immune Reconstitution-Change From Baseline Total Immunoglobulin at EOT(Baseline, EOT [Month 7])
- Phase 2: Immune Reconstitution-Change From Baseline in Peripheral Blood CD34+A at EOT(Baseline, EOT [Month 7])
- Phase 2: Immune Reconstitution-Change From Baseline in Total Lymphocyte Count at EOT(Baseline, EOT [Month 7])
- Phase 2: Immune Reconstitution-Change From Baseline in the Percentage of CD4+ (CD4+CD45RA-CD197- and CD4+CD45RA+CD197+) Subset of Cells at EOT(Baseline, EOT [Month 7])
- Phase 2: Immune Reconstitution-Change From Baseline in the Percentage of CD8+ (CD8+CD45RA-CD197- and CD8+CD45RA-CD197+) Subset of Cells at EOT(Baseline, EOT [Month 7])