MedPath

A Study of Brentuximab Vedotin + Adriamycin, Vinblastine, and Dacarbazine in Pediatric Participants With Advanced Stage Newly Diagnosed Hodgkin Lymphoma

Phase 1
Active, not recruiting
Conditions
Hodgkin Disease
Interventions
Registration Number
NCT02979522
Lead Sponsor
Takeda
Brief Summary

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).

Detailed Description

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.

Recruitment & Eligibility

Status
ACTIVE_NOT_RECRUITING
Sex
All
Target Recruitment
59
Inclusion Criteria

Each participant must meet all the following inclusion criteria to be enrolled in the study:

  1. Histologically confirmed CD30+ classical HL.
  2. Advanced stage, newly diagnosed HL (Stage III and Stage IV disease).
  3. Treatment-naive HL.
  4. Have performance scores of greater than or equal to (>=) 50 for Lansky Play-performance or Karnofsky Performance Status.
  5. Have bidimensional measurable disease as documented by radiographic technique per International Working Group (IWG) criteria.
  6. Have adequate blood counts, renal and liver function as defined in the protocol.
Exclusion Criteria

  1. Nodular lymphocyte predominant HL.

  2. Known active cerebral/meningeal disease, including signs or symptoms of progressive multifocal leukoencephalopathy (PML) or any history of PML.

  3. Any sensory or motor peripheral neuropathy.

  4. Symptomatic neurologic disease compromising normal activities of daily living or requiring medications.

  5. Any active systemic viral, bacterial, or fungal infection requiring systemic antibiotics within 2 weeks before the first study protocol therapy.

  6. Known hypersensitivity to recombinant proteins, murine proteins, or to any excipient contained in the drug formulation of brentuximab vedotin or any component of AVD.

  7. Known human immunodeficiency virus positive.

  8. 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.

  9. 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.

  10. 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).

  11. 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.

Study & Design

Study Type
INTERVENTIONAL
Study Design
SEQUENTIAL
Arm && Interventions
GroupInterventionDescription
Phase 1: Brentuximab Vedotin 48 mg/m^2 + AVDBrentuximab vedotinBrentuximab 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.
Phase 1: Brentuximab Vedotin 48 mg/m^2 + AVDDoxorubicinBrentuximab 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.
Phase 2: Brentuximab Vedotin 48 mg/m^2 + AVDDoxorubicinBrentuximab 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.
Phase 2: Brentuximab Vedotin 48 mg/m^2 + AVDDacarbazineBrentuximab 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.
Phase 1: Brentuximab Vedotin 48 mg/m^2 + AVDDacarbazineBrentuximab 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.
Phase 1: Brentuximab Vedotin 48 mg/m^2 + AVDVinblastineBrentuximab 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.
Phase 2: Brentuximab Vedotin 48 mg/m^2 + AVDBrentuximab vedotinBrentuximab 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.
Phase 2: Brentuximab Vedotin 48 mg/m^2 + AVDVinblastineBrentuximab 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.
Primary Outcome Measures
NameTimeMethod
Phase 2: Percentage of Participants Whose Disease Was Positron Emission Tomography (PET) Negative After 2 Cycles of Protocol Therapy Per IRF AssessmentFrom 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 VisitAt 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 VisitAt 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 DoseFrom 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 PopulationFrom 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 TherapyFrom 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 TherapyFrom 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) VisitAt 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.

Secondary Outcome Measures
NameTimeMethod
Phase 1: Mean Area Under the Serum Concentration-Time Curve From Day 0 to Day 15 (AUC0-15) of Brentuximab Vedotin and TAbDays 1 and 15 of Cycles 1 and 3 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days)

This outcome measure is planned to be assessed only for participants treated in Phase 1 arm.

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)

This outcome measure is planned to be assessed only for participants treated in Phase 1 arm.

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)

This outcome measure is planned to be assessed only for participants treated in Phase 1 arm.

Phase 1: Mean Area Under the Plasma Concentration-Time Curve From Day 0 to Day 15 (AUC0-15) of MMAEDays 1 and 15 of Cycles 1 and 3 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days)

This outcome measure is planned to be assessed only for participants treated in Phase 1 arm.

Phase 1: Median Time to Reach Cmax (Tmax) of Brentuximab Vedotin and TAb in SerumCycle 1-6: Days 1 and 15 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days)

This outcome measure is planned to be assessed only for participants treated in Phase 1 arm.

Phase 1: Median Time to Reach Cmax (Tmax) of MMAE in PlasmaDays 1 and 15 of Cycles 1 and 3 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days)

This outcome measure is planned to be assessed only for participants treated in Phase 1 arm.

Phase 1: Percentage of Participants Who Achieved a CR Per IRF Assessment Per IWG Criteria at EOT VisitAt 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 only for participants treated in Phase 1 arm.

Phase 1: Percentage of Participants Who Achieved a PR Per IRF Assessment Per IWG Criteria at EOT VisitAt 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 diseases as per IWG Criteria based on IRF. The confidence interval was based on exact binomial distribution (Clopper-Pearson method). This outcome measure was planned to be assessed only for participants treated in Phase 1 arm.

Phase 1: Percentage of Participants Who Achieved an ORR Per IRF Assessment Per IWG Criteria at EOT VisitAt 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 an IRF using IWG Revised Response Criteria. CR was defined as the disappearance of all evidence of disease and PR was defined as regression of measurable disease and no new sites. The confidence interval was based on exact binomial distribution (Clopper-Pearson method). This outcome measure was planned to be assessed only for participants treated in Phase 1 arm.

Phase 1: Percentage of Participants Whose Disease Was PET Negative After 2 Cycles of Protocol Therapy Per IRF AssessmentFrom first dose of study drug up to Cycle 2 (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 only for participants treated in Phase 1 arm.

Phase 1: Percentage of Participants Whose Disease Was PET Positive After 6 Cycles of Protocol Therapy Per IRF AssessmentFrom first dose of study drug up to Cycle 6 (Each Cycle length=28 days)

The Deauville score according to IRF assessment of response was used to evaluate the results of PET scans. PET positive after Cycle 6 defined as an IRF Deauville score of (4 or 5). This outcome measure was planned to be assessed only for participants treated in Phase 1 arm.

Phase 1: Percentage of Participants Who Were Antitherapeutic Antibody (ATA) Positive, Persistently Positive or Transiently Positive, and Neutralizing Antitherapeutic Antibody (nATA) PositiveUp to 7 months

ATA positive was defined as participants who have a positive ATA in any postbaseline sample. Transiently ATA positive was defined as participants who have positive ATA in 1 or 2 postbaseline samples. Persistently ATA positive was defined as participants who have positive ATA in more than 2 postbaseline timepoints. Transiently ATA positive was defined as participants who have positive ATA in 1 or 2 postbaseline samples. nATA positive was defined as participants who have at least one positive nATA in any postbaseline ATA positive sample. Here, percentage of participants who were transiently or persistently ATA positive are considered as ATA positive. This outcome measure is planned to be assessed only for participants treated in Phase 1 arm.

Phase 2: Duration of Response (DOR)Up to 24 months

DOR per IRF in participants with a response (CR or PR per IRF) was defined as the time from start of the first objective tumor response (CR or PR per IRF) to the first subsequent PD or death due to any cause, whichever occurred first. For patients who did not have an objective PD, did not die and are either still on a study follow-up at the time of the analysis, or were removed from the study prior to documentation of PD, DOR has been censored on the date of last adequate disease assessment. This outcome measure was planned to be assessed only 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 Receiving Irradiation for HL Following Study TreatmentUp to 24 months

This outcome measure was planned to be assessed only 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 Experienced AEs From the First Dose of Protocol Therapy Through 30 Days After Administration of the Last Dose of Protocol TherapyFrom 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)

This outcome measure was planned to be assessed only 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 Experienced SAEs From the First Dose of Protocol Therapy Through 30 Days After Administration of the Last Dose of Protocol TherapyFrom 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)

This outcome measure was planned to be assessed only 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 ATA Positive, Persistently Positive, or Transiently Positive, and nATA PositiveFrom first dose until 30 days after the last dose of study drug (up to 7 months)

ATA positive was defined as participants who have a positive ATA in any postbaseline sample. Transiently ATA positive was defined as participants who have positive ATA in 1 or 2 postbaseline samples. Persistently ATA positive was defined as participants who have positive ATA in more than 2 postbaseline timepoints. Transiently ATA positive was defined as participants who have positive ATA in 1 or 2 postbaseline samples. nATA positive was defined as participants who have at least one positive nATA in any postbaseline ATA positive sample. Here, percentage of participants who were transiently or persistently ATA positive are considered as ATA positive. This outcome measure was planned to be assessed only 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: Mean Serum Cmax of Brentuximab Vedotin and TAbDays 1 and 15 of Cycles 1 and 3 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days)

This outcome measure was planned to be assessed only 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: Mean Plasma Cmax of MMAEDays 1 and 15 of Cycles 1 and 3 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days)

This outcome measure was planned to be assessed only 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: Mean Serum AUC0-15d of Brentuximab Vedotin and TAbDays 1 and 15 of Cycles 1 and 3 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days)

This outcome measure was planned to be assessed only 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: Mean Plasma AUC0-15 of MMAEDays 1 and 15 of Cycles 1 and 3 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days)

This outcome measure was planned to be assessed only 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: Progression-free Survival (PFS)Up to 24 months

PFS per IRF:time from first dose until disease progression per IRF/death due to any cause,whichever occurred first.Participants with no objective progressive disease (PD),did not die,were still on study follow-up at time of analysis were removed from study prior to documentation of PD,PFS was censored on date of last adequate disease assessment before initiation of any non-protocol,alternative therapy.Participants who were on antitumor treatment,other than SCT/radiotherapy,censoring was at last adequate disease assessment before initiation of such alternative treatment.If participant experienced disease progression per IRF/died after initiation of antitumor treatment,other than SCT/radiotherapy,such participant was censored and not considered having PFS.Outcome measure was planned to be assessed for all participant treated at recommended dose in Phase 2.As per SAP,Phase 2 data was summarized and reported in two arms:Phase 2 and Phase 1 + Phase 2.

Phase 2: Event-free Survival (EFS)Up to 24 months

EFS:Time from first dose until any treatment failure:PD per IRF including progression events during follow-up period,failing to complete 6 cycles of treatment due to any reason or death due to any cause,whichever occurred first.EFS per IRF were censored on last adequate disease assessment date per IRF if none of above events occur during study.Participants with antitumor treatment,other than SCT/radiotherapy as part of frontline treatment were censored at last adequate disease assessment before initiation of such alternative treatment.If a participant experienced disease progression per IRF/died after initiation of antitumor treatment,other than SCT/radiotherapy,such participant was censored,and not be considered having EFS.This outcome measure was planned to be assessed for all patients treated at 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: Overall Survival (OS)Up to 24 months

Overall survival was defined as time from first dose until death. In the absence of confirmation of death, survival time was censored at the last date the participant was known to be alive, including study closure. This outcome measure was planned to be assessed only 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: Mean Cmax of Brentuximab Vedotin in ATA Positive and ATA Negative ParticipantsCycle 1 and 3: Days 1 and 15 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days)

This outcome measure is planned to be assessed only for participants treated in Phase 1 arm.

Phase 2: Median Tmax of Brentuximab Vedotin and TAb in SerumDays 1 and 15 of Cycles 1 and 3 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days)

This outcome measure was planned to be assessed only 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: Median Tmax of MMAE in PlasmaDays 1 and 15 of Cycles 1 and 3 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days)

This outcome measure was planned to be assessed only 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 Experienced Peripheral Neuropathy, Regardless of Seriousness, From the First Dose of Protocol TherapyUp to 24 months

Peripheral Neuropathy (PN) was defined by the peripheral neuropathy standardized MedDRA query (SMQ) broad search. This outcome measure was planned to be assessed only 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: Time to Onset and Resolution for All Peripheral Neuropathy EventsUp to 24 months

Time to onset of first event was defined as time from first dose of study drug to onset of first treatment-emergent PN event. Time to resolution was calculated as the time from onset date to the date of resolution PN (SMQ) event. Participants with multiple resolved events were counted once at the longest time to resolution. Resolution was defined as an event outcome of resolved or resolved with sequelae. This outcome measure was planned to be assessed only 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: Immune Reconstitution-Change From Baseline Immunoglobulin G Levels at End of Treatment (EOT)Baseline and End of Treatment (Month 7)

This outcome measure was planned to be assessed only 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: Percentage of Participants With Low and High ATA Titer ValuesUp to 6 months

High ATA titer was defined as participants who have at least one postbaseline ATA titer less than (\>) 25. Low ATA titer was defined as participants whose postbaseline ATA titer are all less than or equal to (\<=) 25. This outcome measure is planned to be assessed only for participants treated in Phase 1 arm.

Phase 2: Percentage of Participants With Low and High ATA Titer ValuesUp to 6 months

High ATA titer was defined as participants who have at least one postbaseline ATA titer \>25. Low ATA titer was defined as participants whose postbaseline ATA titer are all \<=25. This outcome measure was planned to be assessed only 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: Mean AUC 0-15d of Brentuximab Vedotin in ATA Positive and ATA Negative ParticipantsCycle 1 and 3: Days 1 and 15 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days)

This outcome measure is planned to be assessed only for participants treated in Phase 1 arm.

Phase 1: Percentage of Participants Achieving CR Per IRF Assessment Per IWG Criteria in ATA Positive and ATA Negative ParticipantsUp to 24 months

CR was defined as the disappearance of all evidence of disease as assessed by IRF as per IWG Criteria. The data is reported per ATA status as categories. This outcome measure is planned to be assessed only for participants treated in Phase 1 arm.

Phase 1: Number of ATA Positive and ATA Negative Participants With AEs and SAEsUp to 24 months

This outcome measure is planned to be assessed only for participants treated in Phase 1 arm.

Phase 2: Mean Cmax of Brentuximab Vedotin in ATA Positive and ATA Negative ParticipantsCycle 1-3: Days 1 and 15 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days)

This outcome measure was planned to be assessed only 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: Mean AUC 0-15 of Brentuximab Vedotin in ATA Positive and ATA Negative ParticipantsCycle 1-3: Days 1 and 15 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days)

This outcome measure was planned to be assessed only 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 Achieving CR Per IRF Assessment Per IWG Criteria in ATA Positive and ATA Negative ParticipantsUp to 24 months

CR is defined as the disappearance of all evidence of disease as assessed by IRF as per IWG Criteria. This outcome measure was planned to be assessed only 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: Number of ATA Positive and ATA Negative Participants With AEs and SAEsUp to 24 months

This outcome measure was planned to be assessed only 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: Immune Reconstitution-Change From Baseline in Immunoglobulin M at the End of Treatment (EOT)Baseline, EOT [Month 7]

This outcome measure was planned to be assessed only 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: Immune Reconstitution-Change From Baseline in Immunoglobulin A at EOTBaseline, EOT [Month 7]

This outcome measure was planned to be assessed only 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: Immune Reconstitution-Change From Baseline in Tetanus at EOTBaseline, EOT [Month 7]

This outcome measure was planned to be assessed only 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: Immune Reconstitution-Change From Baseline in Haemophilus Influenzae B Antibody, IgG at EOTBaseline, EOT [Month 7]

This outcome measure was planned to be assessed only 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: Immune Reconstitution-Change From Baseline Poliovirus Antibodies Ratio at EOTBaseline, EOT [Month 7]

This outcome measure was planned to be assessed only 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: Immune Reconstitution-Change From Baseline Total Immunoglobulin at EOTBaseline, EOT [Month 7]

This outcome measure was planned to be assessed only 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: Immune Reconstitution-Change From Baseline in Peripheral Blood CD34+A at EOTBaseline, EOT [Month 7]

This outcome measure was planned to be assessed only 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: Immune Reconstitution-Change From Baseline in Total Lymphocyte Count at EOTBaseline, EOT [Month 7]

This outcome measure was planned to be assessed only 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: Immune Reconstitution-Change From Baseline in the Percentage of CD4+ (CD4+CD45RA-CD197- and CD4+CD45RA+CD197+) Subset of Cells at EOTBaseline, EOT [Month 7]

This outcome measure was planned to be assessed only 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: Immune Reconstitution-Change From Baseline in the Percentage of CD8+ (CD8+CD45RA-CD197- and CD8+CD45RA-CD197+) Subset of Cells at EOTBaseline, EOT [Month 7]

This outcome measure was planned to be assessed only 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.

Trial Locations

Locations (14)

ICr - Instituto da Crianca - HCFMUSP

🇧🇷

Sao Paulo, Brazil

Ospedale Pediatrico Bambino Gesu,UOC Onco-ematologia

🇮🇹

Roma, Italy

Hospital Santa Marcelina

🇧🇷

Sao Paulo, Brazil

Azienda Ospedaliera Citta della Salute e della Scienza di Torino

🇮🇹

Torino, Italy

Jardim das Americas

🇧🇷

Parana, Brazil

Azienda Ospedaliero Universitaria Ospedale Pediatrico Meyer

🇮🇹

Firenze, Italy

GRAACC - Grupo de Apoio ao Adolescente e a Crianca com Cancer

🇧🇷

Sao Paulo, Brazil

Fondazione IRCCS Policlinico San Matteo

🇮🇹

Pavia, Italy

Hospital Sao Rafael S/A

🇧🇷

Salvador, Bahia, Brazil

Children's Hospital Colorado

🇺🇸

Aurora, Colorado, United States

Cincinnati Children's Hospital Medical Center

🇺🇸

Cincinnati, Ohio, United States

INCA - Instituto Nacional de Cancer

🇧🇷

Rio de Janeiro, Brazil

St. Marianna University School of Medicine Hospital

🇯🇵

Kawasaki-shi, Kanagawa-Ken, Japan

NHO Nagoya Medical Center

🇯🇵

Nagoya-shi, Aichi-Ken, Japan

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