Clinical trial NCT01492088: Study of Brentuximab Vedotin (SGN-35) in Pediatric Participants With Relapsed or Refractory (r/r) Systemic Anaplastic Large-Cell Lymphoma or Hodgkin Lymphoma
Official title: A Phase 1/2 Study of Brentuximab Vedotin (SGN-35) in Pediatric Patients With Relapsed or Refractory Systemic Anaplastic Large-Cell Lymphoma or Hodgkin Lymphoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Relapsed or Refractory Hodgkin Lymphoma
Relapsed or Refractory Anaplastic Large-cell Lymphoma
Keywords: Pediatric
Lymphoma
Hodgkin
Anaplastic Large-cell
Relapsed
Refractory
Drug therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2011-12-14
Enrollment: 36
Sex: ALL
Minimum age (years): 2
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to assess the safety and pharmacokinetics, and determine the pediatric maximum tolerated dose and/or or recommended phase 2 dose of brentuximab vedotin.

Detailed description: The drug being tested in this study is called brentuximab vedotin. Brentuximab vedotin is being tested to treat children who have relapsed or refractory (r/r) anaplastic large-cell lymphoma (sALCL) or Hodgkin lymphoma (HL). This study will look at the maximum tolerated dose and/or recommended phase 2 dose, safety and pharmacokinetics of brentuximab vedotin along with overall response of people who took brentuximab vedotin.

The study enrolled 36 patients. In the phase 1 portion of the study, 12 participants were enrolled to receive brentuximab vedotin 1.4-1.8 mg/kg, 30-minute IV infusion, Day 1 of every 21-day cycle, until there was evidence of disease progression or unacceptable toxicity.

Once the maximum tolerated dose and/or recommended phase 2 dose and pharmacokinetics of brentuximab vedotin was reached, participants were enrolled by diagnosis into two phase 2 study arms: relapsed or refractory sALCL or relapsed or refractory HL and received brentuximab vedotin 1.8 mg/kg as 30-minute IV on Day 1 of every 21-day cycle for up to 16 cycles. One participant received a maximum of 20 cycles at the joint discretion of the sponsor and the investigator for continued clinical benefit.

This multicenter trial is being conducted worldwide. The overall time to participate in this study is approximately 5 years. Participants made multiple visits to the clinic, and were contacted by telephone every 12 weeks for 12 months after the end of treatment (EOT) for progression free survival and then every 6 months until death, study closure, or 2 years after enrollment of the last participant for overall survival.

Eligibility criteria: Inclusion Criteria:

* Male or female participants aged 2 to \<18 years (5 to \<18 years for Hodgkin lymphoma \[HL\])
* Diagnosis of systemic anaplastic large-cell lymphoma (sALCL), or HL for which standard, curative, life-prolonging, or palliative treatment does not exist or is no longer effective
* Participants with sALCL must have documented anaplastic lymphoma kinase (ALK) status and must be beyond first remission or refractory to front-line chemotherapy
* Participants diagnosed with any relapsed or refractory CD30+ hematologic malignancy (e.g., primary mediastinal B-cell lymphoma) may be included in phase 1 of the study
* Participants with HL must be in their second of later relapse, have failed systemic chemotherapy either as induction therapy for advanced stage disease or salvage therapy, and were ineligible for, refused, or previously received a stem cell transplant
* Performance score ≥ 60 from Lansky Play Performance Scale if ≤16 years
* Negative pregnancy test
* Fertile Participants must use 2 effective methods of contraception prior to and through 6 months after the last dose of the study drug

Exclusion Criteria:

* Current diagnosis of primary cutaneous ALCL (those with systemic ALCL are eligible)
* Received an allogeneic stem cell transplant \<3 months prior to the first dose of study medication, or presence of polymerase chain reaction (PCR)-detectable cytomegalovirus (CMV) in any post-allogeneic transplant participant
* Receiving immunosuppressive therapy
* Receiving systemic therapy for chronic graft-versus-host disease (topical therapy is allowed)
* Previous treatment with any anti-CD30 antibody
* Therapeutic monoclonal antibody use within the longer of 6 weeks or 5 plasma half-lives
* Systemic cardiac disease that would, in the opinion of the investigator or medical monitor, interfere with assessment of efficacy or safety of the drug
* History of another primary malignancy not in remission for at least 3 years (the following are exempt from the 3-year limit: nonmelanoma skin cancer and cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on Pap smear)
* Known active cerebral/meningeal disease, including signs or symptoms of progressive multifocal leukoencephalopathy (PML) or any history of PML
* History of cirrhosis
* Active systemic viral, bacterial, or fungal infection requiring antimicrobial, antiviral therapy or antifungal therapy within 2 weeks prior to the first dose of study drug (routine antimicrobial prophylaxis is acceptable)
* Concurrent therapy with other anti-neoplastic or experimental agents
* Systemic corticosteroid therapy \<7 days prior to first dose of the study medication
* Any serious underlying medical condition that, in the opinion of the investigator or medical monitor, would impair their ability to receive or tolerate the planned treatment
* Known hypersensitivity to recombinant proteins, murine proteins, or any excipient contained in the drug formulation
* Received nitrogen mustard agents, melphalan, or BCNU therapy within 6 weeks prior to the first study dose
* Prior autologous hematopoietic stem cell infusion \<4 weeks prior to first study dose
* Grade 2 or greater unresolved toxicity from prior antineoplastic therapy
* Grade 2 or greater peripheral neuropathy
* Female participants who are both lactating and breastfeeding, or have a positive serum pregnancy test during the screening period or a positive urine pregnancy test on Day 1 before the first dose of study drug
* Received local palliative radiation therapy \<14 days prior to the first dose of study medication
* Received radiation therapy to more than 25% of the bone marrow-containing spaces \< 84 days prior to first dose of study medication
* Received a strong or listed moderate inhibitor of CYP3A4 \<2 weeks prior to first study dose
* Participants must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study

Primary outcomes:
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) (Phase 1)
timeFrame: From the first dose through 30 days after the last dose of study medication (Up to 15 months)
measure: Number of Participants With Abnormal Clinical Laboratory Values Reported as AEs (Phase 1)
timeFrame: From the first dose through 30 days after the last dose of study medication (Up to 15 months)
measure: Number of Participants With Clinically Significant Vital Signs Values Reported as AEs (Phase 1)
timeFrame: From the first dose through 30 days after the last dose of study medication (Up to 15 months)
measure: Antibody-drug Conjugate (ADC) Serum Concentrations (Phase 1)
timeFrame: Cycle 1 and 8 pre-dose and 5 minutes, 24, 48, 96 and 312 hours post-dose; Cycle 2 pre-dose, 5 minutes and 24, 48 and 96 hours post-dose; Cycle 3 to 16 pre-dose and 5 minutes post-dose
measure: Serum Concentration of Total Antibodies (Conjugated and Unconjugated) (Phase 1)
timeFrame: Cycle 1 and 8 pre-dose and 5 minutes, 24, 48, 96 and 312 hours post-dose; Cycle 2 pre-dose, 5 minutes and 24, 48 and 96 hours post-dose; Cycle 3 to 16 pre-dose and 5 minutes post-dose
measure: Monomethyl Auristatin E (MMAE) Plasma Concentrations (Phase 1)
timeFrame: Cycle 1 and 8 pre-dose and 5 minutes, 24, 48, 96 and 312 hours post-dose; Cycle 2 pre-dose, 5 minutes and 24, 48 and 96 hours post-dose; Cycle 3 to 16 pre-dose and 5 minutes post-dose
measure: Overall Response Rate (ORR) (Phase 1 and 2)
timeFrame: Cycles 2, 4, 7, 10, 13 and 16 (21-day cycles) until disease progression, death or end of treatment (EOT) (Up to 15 months)
Secondary outcomes:
measure: Number of Participants With Antitherapeutic Antibodies (ATA) and Neutralizing ATA (nATA) (Phase 1 and 2)
timeFrame: Baseline up to EOT (Up to 15 months)
measure: Overall Response Rate (ORR) (Phase 1)
timeFrame: Cycles 2, 4, 7, 10, 13 and 16 (21-day cycles) until disease progression, death or EOT (Up to 15 months)
measure: Time to Progression (TTP) (Phase 1 and 2)
timeFrame: Cycles 2, 4, 7, 10, 13 and 16 (21-day cycles) until disease progression, death or EOT and then every 12 weeks for 12 months after EOT, until disease progression, or death (Up to 27 months)
measure: Time to Response (Phase 1 and 2)
timeFrame: Cycles 2, 4, 7, 10, 13 and 16 (21-day cycles) until disease progression, death or EOT (Up to 15 months)
measure: Duration of Response (DOR) (Phase 1 and 2)
timeFrame: Cycles 2, 4, 7, 10, 13 and 16 (21-day cycles) until disease progression, death or EOT and then every 12 weeks for 12 months after EOT, until disease progression, or death or end of study (Up to 72 months)
measure: Event Free Survival (EFS) (Phase 1 and 2)
timeFrame: Cycles 2, 4, 7, 10, 13 and 16 (21-day cycles) until disease progression, death or EOT and then every 12 weeks for 12 months after EOT, until disease progression, or death (Up to 27 months)
measure: Progression Free Survival (PFS) (Phase 1 and 2)
timeFrame: Cycles 2, 4, 7, 10, 13 and 16 (21-day cycles) until disease progression, death or EOT and then every 12 weeks for 12 months after EOT, until disease progression, or death or end of study (Up to 72 months)
measure: Overall Survival (OS) (Phase 1 and 2)
timeFrame: Every 6 months after EOT, until the sooner of death, study closure, or 2 years after enrolment of the last participant (Up to 72 months)
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) (Phase 1 and 2)
timeFrame: From the first dose through 30 days after the last dose of study medication (up to 15 months)
measure: Number of Participants With Abnormal Clinical Laboratory Values Reported as AEs (Phase 1 and 2)
timeFrame: From the first dose through 30 days after the last dose of study medication (Up to 15 months)
measure: Number of Participants With Clinically Significant Vital Signs Reported as AEs (Phase 1 and 2)
timeFrame: From the first dose through 30 days after the last dose of study medication (Up to 15 months)
measure: Antibody-drug Conjugate (ADC) Serum Concentrations (Phase 1 and 2)
timeFrame: Cycle 1 and 8 pre-dose and 5 minutes, 24, 48, 96 and 312 hours post-dose; Cycle 2 pre-dose, 5 minutes and 24, 48 and 96 hours post-dose; Cycle 3 to 16 pre-dose and 5 minutes post-dose
measure: Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
timeFrame: Cycle 1 and 8 pre-dose and 5 minutes, 24, 48, 96 and 312 hours post-dose; Cycle 2 pre-dose, 5 minutes and 24, 48 and 96 hours post-dose; Cycle 3 to 16 pre-dose and 5 minutes post-dose
measure: Monomethyl Auristatin E (MMAE) Plasma Concentrations (Phase 1 and 2)
timeFrame: Cycle 1 and 8 pre-dose and 5 minutes, 24, 48, 96 and 312 hours post-dose; Cycle 2 pre-dose, 5 minutes and 24, 48 and 96 hours post-dose; Cycle 3 to 16 pre-dose and 5 minutes post-dose
Other outcomes:
Locations:
city: Aurora
country: United States
state: Colorado
city: Kansas City
country: United States
state: Missouri
city: New York
country: United States
state: New York
city: Houston
country: United States
state: Texas
city: Bordeaux Cedex
country: France
city: Lyon
country: France
city: Paris Cedex 12
country: France
city: Berlin
country: Germany
city: Frankfurt
country: Germany
city: Giessen
country: Germany
city: Halle
country: Germany
city: Munster
country: Germany
city: Padova
country: Italy
city: Roma
country: Italy
city: Mexico Df
country: Mexico
city: Rotterdam
country: Netherlands
city: Barcelona
country: Spain
city: London
country: United Kingdom
Study officials:
affiliation: Millennium Pharmaceuticals, Inc.
name: Medical Monitor
role: STUDY_DIRECTOR
References:
citation: Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, Coiffier B, Fisher RI, Hagenbeek A, Zucca E, Rosen ST, Stroobants S, Lister TA, Hoppe RT, Dreyling M, Tobinai K, Vose JM, Connors JM, Federico M, Diehl V; International Harmonization Project on Lymphoma. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007 Feb 10;25(5):579-86. doi: 10.1200/JCO.2006.09.2403. Epub 2007 Jan 22.
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.
citation: Locatelli F, Mauz-Koerholz C, Neville K, Llort A, Beishuizen A, Daw S, Pillon M, Aladjidi N, Klingebiel T, Landman-Parker J, Medina-Sanson A, August K, Sachs J, Hoffman K, Kinley J, Song S, Song G, Zhang S, Suri A, Gore L. Brentuximab vedotin for paediatric relapsed or refractory Hodgkin's lymphoma and anaplastic large-cell lymphoma: a multicentre, open-label, phase 1/2 study. Lancet Haematol. 2018 Oct;5(10):e450-e461. doi: 10.1016/S2352-3026(18)30153-4.