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

Primary Purpose

Hodgkin Disease

Status

Completed

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

Brentuximab vedotin

Doxorubicin

Vinblastine

Dacarbazine

About this trial

This is an interventional treatment trial for Hodgkin Disease focused on measuring Drug therapy, pediatric Hodgkin disease, frontline Hodgkin disease, advanced stage Hodgkin disease, pediatric lymphoma

Eligibility Criteria

5 Years - 17 Years (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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.

Exclusion Criteria:

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.

Sites / Locations

Children's Hospital Colorado
Cincinnati Children's Hospital Medical Center
Hospital Sao Rafael S/A
Jardim das Americas
INCA - Instituto Nacional de Cancer
GRAACC - Grupo de Apoio ao Adolescente e a Crianca com Cancer
ICr - Instituto da Crianca - HCFMUSP
Hospital Santa Marcelina
Azienda Ospedaliero Universitaria Ospedale Pediatrico Meyer
Fondazione IRCCS Policlinico San Matteo
Ospedale Pediatrico Bambino Gesu,UOC Onco-ematologia
Azienda Ospedaliera Citta della Salute e della Scienza di Torino
NHO Nagoya Medical Center
St. Marianna University School of Medicine Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Phase 1: Brentuximab Vedotin 48 mg/m^2 + AVD

Phase 2: Brentuximab Vedotin 48 mg/m^2 + AVD

Arm Description

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.

Outcomes

Primary Outcome Measures

Phase 1: Recommended Dose of Brentuximab Vedotin in Combination With Doxorubicin, Vinblastine, and Dacarbazine in a Pediatric Population

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

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

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

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.

Phase 2: Percentage of Participants Whose Disease Was Positron Emission Tomography (PET) Negative After 2 Cycles of Protocol Therapy Per IRF Assessment

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

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

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

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.

Secondary Outcome Measures

Phase 1: Mean Maximum Observed Serum Concentration (Cmax) of Brentuximab Vedotin Total Conjugated and Therapeutic Antibody (TAb)

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)

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

Phase 1: Mean Area Under the Serum Concentration-Time Curve From Day 0 to Day 15 (AUC0-15) of Brentuximab Vedotin and TAb

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 MMAE

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 Serum

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 Plasma

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 Visit

Phase 1: Percentage of Participants Who Achieved a PR Per IRF Assessment Per IWG Criteria at EOT Visit

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 Visit

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 Assessment

Phase 1: Percentage of Participants Whose Disease Was PET Positive After 6 Cycles of Protocol Therapy Per IRF Assessment

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) Positive

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: Progression-free Survival (PFS)

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)

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)

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 2: Duration of Response (DOR)

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 Treatment

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 Therapy

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

Phase 2: Percentage of Participants Who Were ATA Positive, Persistently Positive, or Transiently Positive, and nATA Positive

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 TAb

Phase 2: Mean Plasma Cmax of MMAE

Phase 2: Mean Serum AUC0-15d of Brentuximab Vedotin and TAb

Phase 2: Mean Plasma AUC0-15 of MMAE

Phase 2: Median Tmax of Brentuximab Vedotin and TAb in Serum

Phase 2: Median Tmax of MMAE in Plasma

Phase 2: Percentage of Participants Who Experienced Peripheral Neuropathy, Regardless of Seriousness, From the First Dose of Protocol Therapy

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 Events

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)

Phase 1: Percentage of Participants With Low and High ATA Titer Values

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 Values

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 Cmax of Brentuximab Vedotin in ATA Positive and ATA Negative Participants

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

Phase 1: Mean AUC 0-15d of Brentuximab Vedotin in ATA Positive and ATA Negative Participants

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 Participants

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 SAEs

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 Participants

Phase 2: Mean AUC 0-15 of Brentuximab Vedotin in ATA Positive and ATA Negative Participants

Phase 2: Percentage of Participants Achieving CR Per IRF Assessment Per IWG Criteria in ATA Positive and ATA Negative Participants

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 SAEs

Phase 2: Immune Reconstitution-Change From Baseline in Immunoglobulin M at the End of Treatment (EOT)

Phase 2: Immune Reconstitution-Change From Baseline in Immunoglobulin A at EOT

Phase 2: Immune Reconstitution-Change From Baseline in Tetanus at EOT

Phase 2: Immune Reconstitution-Change From Baseline in Haemophilus Influenzae B Antibody, IgG at EOT

Phase 2: Immune Reconstitution-Change From Baseline Poliovirus Antibodies Ratio at EOT

Phase 2: Immune Reconstitution-Change From Baseline Total Immunoglobulin at EOT

Phase 2: Immune Reconstitution-Change From Baseline in Peripheral Blood CD34+A at EOT

Phase 2: Immune Reconstitution-Change From Baseline in Total Lymphocyte Count at EOT

Phase 2: Immune Reconstitution-Change From Baseline in the Percentage of CD4+ (CD4+CD45RA-CD197- and CD4+CD45RA+CD197+) Subset of Cells at EOT

Phase 2: Immune Reconstitution-Change From Baseline in the Percentage of CD8+ (CD8+CD45RA-CD197- and CD8+CD45RA-CD197+) Subset of Cells at EOT

Full Information

NCT ID

NCT02979522

First Posted

November 11, 2016

Last Updated

June 17, 2022

Sponsor

Takeda

1. Study Identification

Unique Protocol Identification Number

NCT02979522

Brief Title

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

Official Title

An Open-Label Study of Brentuximab Vedotin + Adriamycin, Vinblastine, and Dacarbazine in Pediatric Patients With Advanced Stage Newly Diagnosed Hodgkin Lymphoma

Study Type

Interventional

2. Study Status

Record Verification Date

June 2022

Overall Recruitment Status

Completed

Study Start Date

September 6, 2017 (Actual)

Primary Completion Date

May 5, 2020 (Actual)

Study Completion Date

September 24, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Takeda

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hodgkin Disease

Keywords

Drug therapy, pediatric Hodgkin disease, frontline Hodgkin disease, advanced stage Hodgkin disease, pediatric lymphoma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Sequential Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

59 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Phase 1: Brentuximab Vedotin 48 mg/m^2 + AVD

Arm Type

Experimental

Arm Description

Arm Title

Phase 2: Brentuximab Vedotin 48 mg/m^2 + AVD

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Brentuximab vedotin

Other Intervention Name(s)

Adcetris

Intervention Description

Brentuximab vedotin infusion

Intervention Type

Drug

Intervention Name(s)

Doxorubicin

Other Intervention Name(s)

Adriamycin

Intervention Description

Doxorubicin infusion

Intervention Type

Drug

Intervention Name(s)

Vinblastine

Intervention Description

Vinblastine infusion

Intervention Type

Drug

Intervention Name(s)

Dacarbazine

Intervention Description

Dacarbazine infusion

Primary Outcome Measure Information:

Title

Phase 1: Recommended Dose of Brentuximab Vedotin in Combination With Doxorubicin, Vinblastine, and Dacarbazine in a Pediatric Population

Description

Time Frame

From the first dose (Cycle 1) up to Day 56 (Cycle length=28 days)

Title

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

Description

Time Frame

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)

Title

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

Description

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.

Time Frame

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)

Title

Description

Time Frame

At end of treatment (EOT) visit 30 days after the last dose of study drug (at Month 7)

Title

Phase 2: Percentage of Participants Whose Disease Was Positron Emission Tomography (PET) Negative After 2 Cycles of Protocol Therapy Per IRF Assessment

Description

Time Frame

From first dose of study drug up to Cycle 2 Day 25 (Each Cycle length=28 days)

Title

Phase 2: Percentage of Participants Who Achieved a Partial Remission (PR) Per IRF Assessment Per IWG Criteria at EOT Visit

Description

Time Frame

At EOT visit 30 days after the last dose of study drug (at Month 7)

Title

Phase 2: Percentage of Participants Who Achieved an Overall Response Rate (ORR) Per IRF Assessment Per IWG Criteria at EOT Visit

Description

Time Frame

At EOT visit 30 days after the last dose of study drug (at Month 7)

Title

Phase 2: Percentage of Participants Who Were Able to Complete 6 Cycles of Protocol Therapy at the Recommended Dose

Description

Time Frame

From first dose of study drug up to Cycle 6 (Each Cycle length=28 days)

Secondary Outcome Measure Information:

Title

Phase 1: Mean Maximum Observed Serum Concentration (Cmax) of Brentuximab Vedotin Total Conjugated and Therapeutic Antibody (TAb)

Description

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

Time Frame

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)

Title

Phase 1: Mean Maximum Observed Plasma Concentration (Cmax) of Monomethyl Auristatin E (MMAE)

Description

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

Time Frame

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)

Title

Phase 1: Mean Area Under the Serum Concentration-Time Curve From Day 0 to Day 15 (AUC0-15) of Brentuximab Vedotin and TAb

Description

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

Time Frame

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)

Title

Phase 1: Mean Area Under the Plasma Concentration-Time Curve From Day 0 to Day 15 (AUC0-15) of MMAE

Description

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

Time Frame

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)

Title

Phase 1: Median Time to Reach Cmax (Tmax) of Brentuximab Vedotin and TAb in Serum

Description

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

Time Frame

Cycle 1-6: Days 1 and 15 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days)

Title

Phase 1: Median Time to Reach Cmax (Tmax) of MMAE in Plasma

Description

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

Time Frame

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)

Title

Phase 1: Percentage of Participants Who Achieved a CR Per IRF Assessment Per IWG Criteria at EOT Visit

Description

Time Frame

At EOT visit 30 days after the last dose of study drug (at Month 7)

Title

Phase 1: Percentage of Participants Who Achieved a PR Per IRF Assessment Per IWG Criteria at EOT Visit

Description

Time Frame

At EOT visit 30 days after the last dose of study drug (at Month 7)

Title

Phase 1: Percentage of Participants Who Achieved an ORR Per IRF Assessment Per IWG Criteria at EOT Visit

Description

Time Frame

At EOT visit 30 days after the last dose of study drug (at Month 7)

Title

Phase 1: Percentage of Participants Whose Disease Was PET Negative After 2 Cycles of Protocol Therapy Per IRF Assessment

Description

Time Frame

From first dose of study drug up to Cycle 2 (Each Cycle length=28 days)

Title

Phase 1: Percentage of Participants Whose Disease Was PET Positive After 6 Cycles of Protocol Therapy Per IRF Assessment

Description

Time Frame

From first dose of study drug up to Cycle 6 (Each Cycle length=28 days)

Title

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

Description

Time Frame

Up to 7 months

Title

Phase 2: Progression-free Survival (PFS)

Description

Time Frame

Up to 24 months

Title

Phase 2: Event-free Survival (EFS)

Description

Time Frame

Up to 24 months

Title

Phase 2: Overall Survival (OS)

Description

Time Frame

Up to 24 months

Title

Phase 2: Duration of Response (DOR)

Description

Time Frame

Up to 24 months

Title

Phase 2: Percentage of Participants Receiving Irradiation for HL Following Study Treatment

Description

Time Frame

Up to 24 months

Title

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

Description

Time Frame

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)

Title

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

Description

Time Frame

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)

Title

Phase 2: Percentage of Participants Who Were ATA Positive, Persistently Positive, or Transiently Positive, and nATA Positive

Description

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.

Time Frame

From first dose until 30 days after the last dose of study drug (up to 7 months)

Title

Phase 2: Mean Serum Cmax of Brentuximab Vedotin and TAb

Description

Time Frame

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)

Title

Phase 2: Mean Plasma Cmax of MMAE

Description

Time Frame

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)

Title

Phase 2: Mean Serum AUC0-15d of Brentuximab Vedotin and TAb

Description

Time Frame

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)

Title

Phase 2: Mean Plasma AUC0-15 of MMAE

Description

Time Frame

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)

Title

Phase 2: Median Tmax of Brentuximab Vedotin and TAb in Serum

Description

Time Frame

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)

Title

Phase 2: Median Tmax of MMAE in Plasma

Description

Time Frame

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)

Title

Phase 2: Percentage of Participants Who Experienced Peripheral Neuropathy, Regardless of Seriousness, From the First Dose of Protocol Therapy

Description

Time Frame

Up to 24 months

Title

Phase 2: Time to Onset and Resolution for All Peripheral Neuropathy Events

Description

Time Frame

Up to 24 months

Title

Phase 2: Immune Reconstitution-Change From Baseline Immunoglobulin G Levels at End of Treatment (EOT)

Description

Time Frame

Baseline and End of Treatment (Month 7)

Title

Phase 1: Percentage of Participants With Low and High ATA Titer Values

Description

Time Frame

Up to 6 months

Title

Phase 2: Percentage of Participants With Low and High ATA Titer Values

Description

Time Frame

Up to 6 months

Title

Phase 1: Mean Cmax of Brentuximab Vedotin in ATA Positive and ATA Negative Participants

Description

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

Time Frame

Cycle 1 and 3: Days 1 and 15 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days)

Title

Phase 1: Mean AUC 0-15d of Brentuximab Vedotin in ATA Positive and ATA Negative Participants

Description

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

Time Frame

Cycle 1 and 3: Days 1 and 15 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days)

Title

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

Description

Time Frame

Up to 24 months

Title

Phase 1: Number of ATA Positive and ATA Negative Participants With AEs and SAEs

Description

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

Time Frame

Up to 24 months

Title

Phase 2: Mean Cmax of Brentuximab Vedotin in ATA Positive and ATA Negative Participants

Description

Time Frame

Cycle 1-3: Days 1 and 15 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days)

Title

Phase 2: Mean AUC 0-15 of Brentuximab Vedotin in ATA Positive and ATA Negative Participants

Description

Time Frame

Cycle 1-3: Days 1 and 15 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days)

Title

Phase 2: Percentage of Participants Achieving CR Per IRF Assessment Per IWG Criteria in ATA Positive and ATA Negative Participants

Description

Time Frame

Up to 24 months

Title

Phase 2: Number of ATA Positive and ATA Negative Participants With AEs and SAEs

Description

Time Frame

Up to 24 months

Title

Phase 2: Immune Reconstitution-Change From Baseline in Immunoglobulin M at the End of Treatment (EOT)

Description

Time Frame

Baseline, EOT [Month 7]

Title

Phase 2: Immune Reconstitution-Change From Baseline in Immunoglobulin A at EOT

Description

Time Frame

Baseline, EOT [Month 7]

Title

Phase 2: Immune Reconstitution-Change From Baseline in Tetanus at EOT

Description

Time Frame

Baseline, EOT [Month 7]

Title

Phase 2: Immune Reconstitution-Change From Baseline in Haemophilus Influenzae B Antibody, IgG at EOT

Description

Time Frame

Baseline, EOT [Month 7]

Title

Phase 2: Immune Reconstitution-Change From Baseline Poliovirus Antibodies Ratio at EOT

Description

Time Frame

Baseline, EOT [Month 7]

Title

Phase 2: Immune Reconstitution-Change From Baseline Total Immunoglobulin at EOT

Description

Time Frame

Baseline, EOT [Month 7]

Title

Phase 2: Immune Reconstitution-Change From Baseline in Peripheral Blood CD34+A at EOT

Description

Time Frame

Baseline, EOT [Month 7]

Title

Phase 2: Immune Reconstitution-Change From Baseline in Total Lymphocyte Count at EOT

Description

Time Frame

Baseline, EOT [Month 7]

Title

Phase 2: Immune Reconstitution-Change From Baseline in the Percentage of CD4+ (CD4+CD45RA-CD197- and CD4+CD45RA+CD197+) Subset of Cells at EOT

Description

Time Frame

Baseline, EOT [Month 7]

Title

Phase 2: Immune Reconstitution-Change From Baseline in the Percentage of CD8+ (CD8+CD45RA-CD197- and CD8+CD45RA-CD197+) Subset of Cells at EOT

Description

Time Frame

Baseline, EOT [Month 7]

10. Eligibility

Sex

All

Minimum Age & Unit of Time

5 Years

Maximum Age & Unit of Time

17 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 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. Exclusion Criteria: 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Study Director

Organizational Affiliation

Takeda

Official's Role

Study Director

Facility Information:

Facility Name

Children's Hospital Colorado

City

Aurora

State/Province

Colorado

ZIP/Postal Code

80045

Country

United States

Facility Name

Cincinnati Children's Hospital Medical Center

City

Cincinnati

State/Province

Ohio

ZIP/Postal Code

45229

Country

United States

Facility Name

Hospital Sao Rafael S/A

City

Salvador

State/Province

Bahia

ZIP/Postal Code

41253-190

Country

Brazil

Facility Name

Jardim das Americas

City

Parana

ZIP/Postal Code

81520-060

Country

Brazil

Facility Name

INCA - Instituto Nacional de Cancer

City

Rio de Janeiro

ZIP/Postal Code

20230-230

Country

Brazil

Facility Name

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

City

Sao Paulo

ZIP/Postal Code

04023-062

Country

Brazil

Facility Name

ICr - Instituto da Crianca - HCFMUSP

City

Sao Paulo

ZIP/Postal Code

05403-000

Country

Brazil

Facility Name

Hospital Santa Marcelina

City

Sao Paulo

ZIP/Postal Code

08270-070

Country

Brazil

Facility Name

Azienda Ospedaliero Universitaria Ospedale Pediatrico Meyer

City

Firenze

ZIP/Postal Code

50139

Country

Italy

Facility Name

Fondazione IRCCS Policlinico San Matteo

City

Pavia

ZIP/Postal Code

27100

Country

Italy

Facility Name

Ospedale Pediatrico Bambino Gesu,UOC Onco-ematologia

City

Roma

ZIP/Postal Code

165

Country

Italy

Facility Name

Azienda Ospedaliera Citta della Salute e della Scienza di Torino

City

Torino

ZIP/Postal Code

10126

Country

Italy

Facility Name

NHO Nagoya Medical Center

City

Nagoya-shi

State/Province

Aichi-Ken

ZIP/Postal Code

460-0001

Country

Japan

Facility Name

St. Marianna University School of Medicine Hospital

City

Kawasaki-shi

State/Province

Kanagawa-Ken

ZIP/Postal Code

216-8511

Country

Japan

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

IPD Sharing Access Criteria

IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.

IPD Sharing URL

https://vivli.org/ourmember/takeda/

Citations:

PubMed Identifier

32596842

Citation

Suri A, Mould DR, Song G, Kinley J, Venkatakrishnan K. Population Pharmacokinetics of Brentuximab Vedotin in Adult and Pediatric Patients With Relapsed/Refractory Hematologic Malignancies: Model-Informed Hypothesis Generation for Pediatric Dosing Regimens. J Clin Pharmacol. 2020 Dec;60(12):1585-1597. doi: 10.1002/jcph.1682. Epub 2020 Jun 28.

Results Reference

derived

Learn more about this trial

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

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