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Study of Brentuximab Vedotin (SGN-35) in Pediatric Participants With Relapsed or Refractory Systemic Anaplastic Large-Cell Lymphoma or Hodgkin Lymphoma

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Takeda ( Millennium Pharmaceuticals, Inc. )
ClinicalTrials.gov Identifier:
NCT01492088
First received: December 12, 2011
Last updated: March 10, 2017
Last verified: March 2017
  Purpose
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.

Condition Intervention Phase
Hodgkin Lymphoma
Anaplastic Large-cell Lymphoma
Drug: Brentuximab vedotin
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Takeda:

Primary Outcome Measures:
  • Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) (Phase 1) [ Time Frame: From the first dose through 30 days after the last dose of study medication (Up to 15 months) ]
    An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A Serious Adverse Event (SAE) is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. AE severity was graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.

  • Number of Participants with Abnormal Clinical Laboratory Values Reported as AEs (Phase 1) [ Time Frame: From the first dose through 30 days after the last dose of study medication (Up to 15 months) ]
    Abnormal clinical laboratory values (serum chemistry and hematology) were reported as AEs if they were considered by the investigator to be a clinically significant change from Baseline or led to premature discontinuation of study treatment, dose modification, or other therapeutic intervention.

  • Number of Participants with Clinically Significant Vital Signs Values Reported as AEs (Phase 1) [ Time Frame: From the first dose through 30 days after the last dose of study medication (Up to 15 months) ]
    Vital signs measurements included supine (after 3-5 minutes in this position) and standing (after 3-5 minutes in this position) measurements of diastolic and systolic blood pressure, heart rate, and oral temperature.

  • Antibody-drug Conjugate (ADC) Serum Concentrations (Phase 1) [ Time Frame: 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 ]
    Blood samples were collected and tested for serum concentrations of brentuximab vedotin antibody-drug conjugate.

  • Serum Concentration of Total Antibodies (Conjugated and Unconjugated) (Phase 1) [ Time Frame: 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 ]
    Blood samples were collected and tested for conjugated and unconjugated antibodies.

  • Monomethyl Auristatin E (MMAE) Serum Concentrations (Phase 1) [ Time Frame: 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 ]
    Blood samples were collected and tested for MMAE serum concentrations.

  • Overall Response Rate (ORR) (Phase 1 and 2) [ Time Frame: Cycles 2, 4, 7, 10, 13 and 16 (21-day cycles) until disease progression, death or end of treatment (EOT) (Up to 15 months) ]
    Overall response rate is defined as the percentage of participants with complete remission (CR) or partial remission (PR) as assessed by an independent review facility (IRF) using International Working Group (IWG) Revised Response Criteria for Malignant Lymphoma. CR is defined as the disappearance of all evidence of disease and PR is defined as regression of measurable disease and no new sites.


Secondary Outcome Measures:
  • Number of Participants with Antitherapeutic Antibodies (ATA) and Neutralizing ATA (nATA) (Phase 1 and 2) [ Time Frame: Baseline up to EOT (Up to 15 months) ]
    Blood samples were collected to assess the immunogenicity of brentuximab vedotin (ATA development) using a laboratory test. Confirmed ATA-positive response was categorized as transient (defined as 1 or 2 post-Baseline confirmed ATA-positive responses) and persistent (defined as more than 2 post-Baseline confirmed ATA positive responses) and neutralizing ATA (nATA) status.

  • Overall Response Rate (ORR) (Phase 1) [ Time Frame: Cycles 2, 4, 7, 10, 13 and 16 (21-day cycles) until disease progression, death or EOT (Up to 15 months) ]
    Overall response rate is defined as the percentage of participants with CR or PR as assessed by an IRF using IWG Revised Response Criteria for Malignant Lymphoma. CR is defined as the disappearance of all evidence of disease and PR is defined as regression of measurable disease and no new sites.

  • Time to Progression (TTP) (Phase 1 and 2) [ Time Frame: Cycles 2, 4, 7, 10, 13 and 16 (21-day cycles) until disease progression, death or EOT (Up to 15 months) ]
    TTP is defined as the time in months from first dose until the first subsequent documentation of objective tumor progression. Progressive disease (PD) is defined as any new lesion or increase by ≥50% of previously involved sites from nadir.

  • Time to response (Phase 1 and 2) [ Time Frame: Cycles 2, 4, 7, 10, 13 and 16 (21-day cycles) until disease progression, death or EOT (Up to 15 months) ]
    Time to response is defined as the time in months from the first dose of study treatment until the date of the first assessment of confirmed CR or PR. as assessed by an IRF using IWG revised response criteria for malignant lymphoma. CR is defined as the disappearance of all evidence of disease and PR is defined as regression of measurable disease and no new sites.

  • Duration of Response (DOR) (Phase 1 and 2) [ Time Frame: From first documented response until disease progression (Up to 15 months) ]
    DOR is defined as the time in months from the date of first documentation of a CR response to the date of first documentation of tumor progression or PD per IRF assessment according to IWG criteria. CR is defined as the disappearance of all evidence of disease and PD is defined as any new lesion or increase by >50% of previously involved sites from nadir.

  • Event Free Survival (EFS) (Phase 1 and 2) [ Time Frame: Cycles 2, 4, 7, 10, 13 and 16 (21-day cycles) until disease progression, death or EOT (Up to 15 months) ]
  • Progression Free Survival (PFS) (Phase 1 and 2) [ Time Frame: 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) ]
    PFS is defined as time in months from start of study treatment to first documentation of objective tumor progression per IRF assessment or up to death due to any cause, whichever occurs first. and PD is defined as any new lesion or increase by >50% of previously involved sites from nadir.

  • Overall Survival (OS) (Phase 1 and 2) [ Time Frame: Every 6 months after EOT, until the sooner of death, study closure, or 2 years after enrollment of the last participant (Up to 48 months) ]
    OS is the time in months from start of study treatment to date of death due to any cause.

  • Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) (Phase 1 and 2) [ Time Frame: From the first dose through 30 days after the last dose of study medication (up to 15 months) ]
    An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A SAE is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. AE severity was graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.

  • Number of Participants with Abnormal Clinical Laboratory Values Reported as AEs (Phase 1 and 2) [ Time Frame: From the first dose through 30 days after the last dose of study medication (Up to 15 months) ]
    Abnormal clinical laboratory values (serum chemistry and hematology) were reported as AEs if they were considered by the investigator to be a clinically significant change from Baseline or led to premature discontinuation of study treatment, dose modification, or other therapeutic intervention.

  • Number of Participants with Clinically Significant Vital Signs Reported as AEs (Phase 1 and 2) [ Time Frame: From the first dose through 30 days after the last dose of study medication (Up to 15 months) ]
    Vital signs measurements included supine (after 3-5 minutes in this position) and standing (after 3-5 minutes in this position) measurements of diastolic and systolic blood pressure, heart rate, and oral temperature.

  • Antibody-drug Conjugate (ADC) Serum Concentrations (Phase 1 and 2) [ Time Frame: 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 ]
    Blood samples were collected and tested for serum concentrations of brentuximab vedotin antibody-drug conjugate.

  • Serum Concentration of Total Antibodies (Conjugated and Unconjugated) [ Time Frame: 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 ]
    Blood samples were collected and tested for conjugated and unconjugated antibodies.

  • Monomethyl Auristatin E (MMAE) Serum Concentrations (Phase 1 and 2) [ Time Frame: 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 ]
    Blood samples were collected and tested for MMAE serum concentrations.


Enrollment: 36
Study Start Date: April 2012
Estimated Study Completion Date: March 2018
Primary Completion Date: October 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Brentuximab vedotin: Phase 1
Brentuximab vedotin 1.4 mg/kg, 30-minute IV infusion, Day 1 of every 21-day cycle, until there was evidence of disease progression or unacceptable toxicity for up to 7 cycles. Dose was escalated up to 1.8 mg/kg using a 3 + 3 dose escalation design to determine a maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) depending upon the dose limiting toxicity (DLT).
Drug: Brentuximab vedotin
Brentuximab vedotin IV infusion
Other Names:
  • SGN-35
  • ADCETRIS
Experimental: Brentuximab vedotin: Phase 2
Brentuximab vedotin 1.8 mg/kg, 30-minute IV infusion, Day 1 of every 21-day cycle (starting from Cycle 2), until there is evidence of disease progression or unacceptable toxicity (Up to 20 cycles).
Drug: Brentuximab vedotin
Brentuximab vedotin IV infusion
Other Names:
  • SGN-35
  • ADCETRIS

Detailed Description:

The drug being tested in this study is called brentuximab vedotin. Brentuximab vedotin is being tested to treat people who have relapsed or refractory anaplastic large-cell lymphoma (sALCL) or Hodgkin lymphoma (HL). This study will look at the maximum tolerated dose and/or recommended phase 2 dose 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 (up to 7 cycles).

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 20 cycles.

This multicenter trial is being conducted worldwide. The overall time to participate in this study is 4.5 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

Ages Eligible for Study:   2 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01492088

Locations
United States, Colorado
Aurora, Colorado, United States
United States, Missouri
Kansas City, Missouri, United States
United States, New York
New York, New York, United States
United States, Texas
Houston, Texas, United States
France
Bordeaux Cedex, France
Lyon, France
Paris Cedex 12, France
Germany
Berlin, Germany
Frankfurt, Germany
Giessen, Germany
Halle, Germany
Munster, Germany
Italy
Padova, Italy
Roma, Italy
Mexico
Mexico Df, Mexico
Netherlands
Rotterdam, Netherlands
Spain
Barcelona, Spain
United Kingdom
London, United Kingdom
Sponsors and Collaborators
Millennium Pharmaceuticals, Inc.
Investigators
Study Director: Medical Monitor Millennium Pharmaceuticals, Inc.
  More Information

Responsible Party: Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT01492088     History of Changes
Other Study ID Numbers: C25002
2011-001240-29 ( EudraCT Number )
U1111-1158-2613 ( Registry Identifier: WHO )
133300410A0384 ( Registry Identifier: RNEC )
NL38209.078.11 ( Registry Identifier: CCMO )
Study First Received: December 12, 2011
Last Updated: March 10, 2017

Keywords provided by Takeda:
Pediatric
Lymphoma
Hodgkin
Anaplastic Large-cell
Relapsed
Refractory
Drug therapy

Additional relevant MeSH terms:
Lymphoma
Lymphoma, Non-Hodgkin
Hodgkin Disease
Lymphoma, Large-Cell, Anaplastic
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, T-Cell
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on March 22, 2017