Clinical trial NCT02979522: 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
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Hodgkin Disease
Keywords: Drug therapy, pediatric Hodgkin disease, frontline Hodgkin disease, advanced stage Hodgkin disease, pediatric lymphoma
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2016-12-01
Enrollment: 59
Sex: ALL
Minimum age (years): 5
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Phase 1: Recommended Dose of Brentuximab Vedotin in Combination With Doxorubicin, Vinblastine, and Dacarbazine in a Pediatric Population
timeFrame: From the first dose (Cycle 1) up to Day 56 (Cycle length=28 days)
measure: 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
timeFrame: 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)
measure: 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
timeFrame: 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)
measure: 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
timeFrame: At end of treatment (EOT) visit 30 days after the last dose of study drug (at Month 7)
measure: Phase 2: Percentage of Participants Whose Disease Was Positron Emission Tomography (PET) Negative After 2 Cycles of Protocol Therapy Per IRF Assessment
timeFrame: From first dose of study drug up to Cycle 2 Day 25 (Each Cycle length=28 days)
measure: Phase 2: Percentage of Participants Who Achieved a Partial Remission (PR) Per IRF Assessment Per IWG Criteria at EOT Visit
timeFrame: At EOT visit 30 days after the last dose of study drug (at Month 7)
measure: Phase 2: Percentage of Participants Who Achieved an Overall Response Rate (ORR) Per IRF Assessment Per IWG Criteria at EOT Visit
timeFrame: At EOT visit 30 days after the last dose of study drug (at Month 7)
measure: Phase 2: Percentage of Participants Who Were Able to Complete 6 Cycles of Protocol Therapy at the Recommended Dose
timeFrame: From first dose of study drug up to Cycle 6 (Each Cycle length=28 days)
Secondary outcomes:
measure: Phase 1: Mean Maximum Observed Serum Concentration (Cmax) of Brentuximab Vedotin Total Conjugated and Therapeutic Antibody (TAb)
timeFrame: 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)
measure: Phase 1: Mean Maximum Observed Plasma Concentration (Cmax) of Monomethyl Auristatin E (MMAE)
timeFrame: 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)
measure: Phase 1: Mean Area Under the Serum Concentration-Time Curve From Day 0 to Day 15 (AUC0-15) of Brentuximab Vedotin and TAb
timeFrame: 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)
measure: Phase 1: Mean Area Under the Plasma Concentration-Time Curve From Day 0 to Day 15 (AUC0-15) of MMAE
timeFrame: 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)
measure: Phase 1: Median Time to Reach Cmax (Tmax) of Brentuximab Vedotin and TAb in Serum
timeFrame: Cycle 1-6: Days 1 and 15 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days)
measure: Phase 1: Median Time to Reach Cmax (Tmax) of MMAE in Plasma
timeFrame: 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)
measure: Phase 1: Percentage of Participants Who Achieved a CR Per IRF Assessment Per IWG Criteria at EOT Visit
timeFrame: At EOT visit 30 days after the last dose of study drug (at Month 7)
measure: Phase 1: Percentage of Participants Who Achieved a PR Per IRF Assessment Per IWG Criteria at EOT Visit
timeFrame: At EOT visit 30 days after the last dose of study drug (at Month 7)
measure: Phase 1: Percentage of Participants Who Achieved an ORR Per IRF Assessment Per IWG Criteria at EOT Visit
timeFrame: At EOT visit 30 days after the last dose of study drug (at Month 7)
measure: Phase 1: Percentage of Participants Whose Disease Was PET Negative After 2 Cycles of Protocol Therapy Per IRF Assessment
timeFrame: From first dose of study drug up to Cycle 2 (Each Cycle length=28 days)
measure: Phase 1: Percentage of Participants Whose Disease Was PET Positive After 6 Cycles of Protocol Therapy Per IRF Assessment
timeFrame: From first dose of study drug up to Cycle 6 (Each Cycle length=28 days)
measure: Phase 1: Percentage of Participants Who Were Antitherapeutic Antibody (ATA) Positive, Persistently Positive or Transiently Positive, and Neutralizing Antitherapeutic Antibody (nATA) Positive
timeFrame: Up to 7 months
measure: Phase 2: Progression-free Survival (PFS)
timeFrame: Up to 24 months
measure: Phase 2: Event-free Survival (EFS)
timeFrame: Up to 24 months
measure: Phase 2: Overall Survival (OS)
timeFrame: Up to 24 months
measure: Phase 2: Duration of Response (DOR)
timeFrame: Up to 24 months
measure: Phase 2: Percentage of Participants Receiving Irradiation for HL Following Study Treatment
timeFrame: Up to 24 months
measure: 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
timeFrame: 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)
measure: 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
timeFrame: 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)
measure: Phase 2: Percentage of Participants Who Were ATA Positive, Persistently Positive, or Transiently Positive, and nATA Positive
timeFrame: From first dose until 30 days after the last dose of study drug (up to 7 months)
measure: Phase 2: Mean Serum Cmax of Brentuximab Vedotin and TAb
timeFrame: 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)
measure: Phase 2: Mean Plasma Cmax of MMAE
timeFrame: 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)
measure: Phase 2: Mean Serum AUC0-15d of Brentuximab Vedotin and TAb
timeFrame: 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)
measure: Phase 2: Mean Plasma AUC0-15 of MMAE
timeFrame: 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)
measure: Phase 2: Median Tmax of Brentuximab Vedotin and TAb in Serum
timeFrame: 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)
measure: Phase 2: Median Tmax of MMAE in Plasma
timeFrame: 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)
measure: Phase 2: Percentage of Participants Who Experienced Peripheral Neuropathy, Regardless of Seriousness, From the First Dose of Protocol Therapy
timeFrame: Up to 24 months
measure: Phase 2: Time to Onset and Resolution for All Peripheral Neuropathy Events
timeFrame: Up to 24 months
measure: Phase 2: Immune Reconstitution-Change From Baseline Immunoglobulin G Levels at End of Treatment (EOT)
timeFrame: Baseline and End of Treatment (Month 7)
measure: Phase 1: Percentage of Participants With Low and High ATA Titer Values
timeFrame: Up to 6 months
measure: Phase 2: Percentage of Participants With Low and High ATA Titer Values
timeFrame: Up to 6 months
measure: Phase 1: Mean Cmax of Brentuximab Vedotin in ATA Positive and ATA Negative Participants
timeFrame: Cycle 1 and 3: Days 1 and 15 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days)
measure: Phase 1: Mean AUC 0-15d of Brentuximab Vedotin in ATA Positive and ATA Negative Participants
timeFrame: Cycle 1 and 3: Days 1 and 15 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days)
measure: Phase 1: Percentage of Participants Achieving CR Per IRF Assessment Per IWG Criteria in ATA Positive and ATA Negative Participants
timeFrame: Up to 24 months
measure: Phase 1: Number of ATA Positive and ATA Negative Participants With AEs and SAEs
timeFrame: Up to 24 months
measure: Phase 2: Mean Cmax of Brentuximab Vedotin in ATA Positive and ATA Negative Participants
timeFrame: Cycle 1-3: Days 1 and 15 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days)
measure: Phase 2: Mean AUC 0-15 of Brentuximab Vedotin in ATA Positive and ATA Negative Participants
timeFrame: Cycle 1-3: Days 1 and 15 pre-infusion and up to 30 minutes after the end of infusion (Cycle length=28 days)
measure: Phase 2: Percentage of Participants Achieving CR Per IRF Assessment Per IWG Criteria in ATA Positive and ATA Negative Participants
timeFrame: Up to 24 months
measure: Phase 2: Number of ATA Positive and ATA Negative Participants With AEs and SAEs
timeFrame: Up to 24 months
measure: Phase 2: Immune Reconstitution-Change From Baseline in Immunoglobulin M at the End of Treatment (EOT)
timeFrame: Baseline, EOT [Month 7]
measure: Phase 2: Immune Reconstitution-Change From Baseline in Immunoglobulin A at EOT
timeFrame: Baseline, EOT [Month 7]
measure: Phase 2: Immune Reconstitution-Change From Baseline in Tetanus at EOT
timeFrame: Baseline, EOT [Month 7]
measure: Phase 2: Immune Reconstitution-Change From Baseline in Haemophilus Influenzae B Antibody, IgG at EOT
timeFrame: Baseline, EOT [Month 7]
measure: Phase 2: Immune Reconstitution-Change From Baseline Poliovirus Antibodies Ratio at EOT
timeFrame: Baseline, EOT [Month 7]
measure: Phase 2: Immune Reconstitution-Change From Baseline Total Immunoglobulin at EOT
timeFrame: Baseline, EOT [Month 7]
measure: Phase 2: Immune Reconstitution-Change From Baseline in Peripheral Blood CD34+A at EOT
timeFrame: Baseline, EOT [Month 7]
measure: Phase 2: Immune Reconstitution-Change From Baseline in Total Lymphocyte Count at EOT
timeFrame: Baseline, EOT [Month 7]
measure: Phase 2: Immune Reconstitution-Change From Baseline in the Percentage of CD4+ (CD4+CD45RA-CD197- and CD4+CD45RA+CD197+) Subset of Cells at EOT
timeFrame: Baseline, EOT [Month 7]
measure: Phase 2: Immune Reconstitution-Change From Baseline in the Percentage of CD8+ (CD8+CD45RA-CD197- and CD8+CD45RA-CD197+) Subset of Cells at EOT
timeFrame: Baseline, EOT [Month 7]
Other outcomes:
Locations:
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Salvador
country: Brazil
facility: Hospital Sao Rafael S/A
state: Bahia
city: Parana
country: Brazil
facility: Jardim das Americas
city: Rio de Janeiro
country: Brazil
facility: INCA - Instituto Nacional de Cancer
city: Sao Paulo
country: Brazil
facility: GRAACC - Grupo de Apoio ao Adolescente e a Crianca com Cancer
city: Sao Paulo
country: Brazil
facility: ICr - Instituto da Crianca - HCFMUSP
city: Sao Paulo
country: Brazil
facility: Hospital Santa Marcelina
city: Firenze
country: Italy
facility: Azienda Ospedaliero Universitaria Ospedale Pediatrico Meyer
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo
city: Roma
country: Italy
facility: Ospedale Pediatrico Bambino Gesu,UOC Onco-ematologia
city: Torino
country: Italy
facility: Azienda Ospedaliera Citta della Salute e della Scienza di Torino
city: Nagoya-shi
country: Japan
facility: NHO Nagoya Medical Center
state: Aichi-Ken
city: Kawasaki-shi
country: Japan
facility: St. Marianna University School of Medicine Hospital
state: Kanagawa-Ken
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References:
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.