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A Frontline Therapy Trial in Participants With Advanced Classical Hodgkin Lymphoma

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ClinicalTrials.gov Identifier: NCT01712490
Recruitment Status : Active, not recruiting
First Posted : October 23, 2012
Results First Posted : November 27, 2018
Last Update Posted : November 27, 2018
Sponsor:
Collaborator:
Seattle Genetics, Inc.
Information provided by (Responsible Party):
Takeda ( Millennium Pharmaceuticals, Inc. )

Brief Summary:
This open-label, randomized, 2-arm, multicenter, phase 3 study has the primary objective of comparing the modified progression-free survival (mPFS) obtained with brentuximab vedotin (ADCETRIS®) plus AVD (doxorubicin [Adriamycin], vinblastine, and dacarbazine; abbreviated A+AVD) versus that obtained with ABVD (doxorubicin [Adriamycin],bleomycin, vinblastine, and dacarbazine) for the frontline treatment of advanced classical Hodgkin lymphoma(HL)

Condition or disease Intervention/treatment Phase
Hodgkin Lymphoma Drug: brentuximab vedotin Drug: doxorubicin Drug: bleomycin Drug: vinblastine Drug: dacarbazine Phase 3

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1334 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized, Open-label, Phase 3 Trial of A+AVD Versus ABVD as Frontline Therapy in Patients With Advanced Classical Hodgkin Lymphoma
Actual Study Start Date : November 9, 2012
Actual Primary Completion Date : April 20, 2017
Estimated Study Completion Date : March 1, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: A + AVD
A+AVD consists of brentuximab vedotin (ADCETRIS®) 1.2 milligram per kilogram (mg/kg) plus doxorubicin 25 milligram per square meter (mg/m^2), vinblastine 6 mg/m^2, and dacarbazine (DTIC) 375 mg/m^2.
Drug: brentuximab vedotin
Brentuximab vedotin (ADCETRIS®)1.2 mg/kg by IV infusion on Days 1 and 15 of each 28-day cycle.
Other Names:
  • ADCETRIS®
  • SGN-35

Drug: doxorubicin
Doxorubicin: 25 mg/m^2 by IV infusion on Days 1 and 15 of each 28-day cycle.
Other Name: Adriamycin

Drug: vinblastine
Vinblastine: 6 mg/m2 will be administered by IV infusion on Days 1 and 15 of each 28-day cycle

Drug: dacarbazine
Dacarbazine (DTIC): 375 mg/m^2 by IV infusion on Days 1 and 15 of each 28-day cycle.
Other Name: DTIC

Active Comparator: ABVD
ABVD consists of doxorubicin 25 mg/m^2, bleomycin 10 units per square meter (units/m^2), vinblastine 6 mg/m^2, and dacarbazine (DTIC) 375 mg/m^2.
Drug: doxorubicin
Doxorubicin: 25 mg/m^2 by IV infusion on Days 1 and 15 of each 28-day cycle.
Other Name: Adriamycin

Drug: bleomycin
Bleomycin: 10 units/m^2 by IV infusion on Days 1 and 15 of each 28-day cycle.

Drug: vinblastine
Vinblastine: 6 mg/m2 will be administered by IV infusion on Days 1 and 15 of each 28-day cycle

Drug: dacarbazine
Dacarbazine (DTIC): 375 mg/m^2 by IV infusion on Days 1 and 15 of each 28-day cycle.
Other Name: DTIC




Primary Outcome Measures :
  1. Modified Progression-free Survival (mPFS) Per Independent Review Facility (IRF) [ Time Frame: Baseline until PD or death or receipt of any subsequent anticancer therapy for HL after completion of frontline therapy (approximately up to 4 years) ]
    mPFS was defined as the time from the date of randomization to the date of the first of documentation of progressive disease (PD), death due to any cause, or for participants who were confirmed non complete responders per IRF, receipt of subsequent anticancer therapy for Hodgkin lymphoma (HL) after completion of frontline therapy. PD was defined as any new lesion or increase by greater than or equal to (>=) 50 percent (%) of previously involved sites from nadir. Frontline therapy is the part of standard set of treatments.


Secondary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: Baseline until death (approximately up to 4 years) ]
    OS was defined as the time from the date of randomization to the date of death. Participants without documented death at the time of analysis were censored at the date last known to be alive.

  2. Complete Remission (CR) Rate at the End of Randomized Regimen Per IRF [ Time Frame: Baseline up to end of randomized regimen (approximately 1 year) ]
    CR rate at the end of randomized regimen per investigator was defined as the percentage of participants who achieved CR at the end of treatment with randomized regimen (ABVD or A+AVD) as determined by IRF. CR was defined as disappearance of all evidence of disease.

  3. Number of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE) and Serious Adverse Event (SAE) [ Time Frame: Baseline up to 30 days after last dose of study drug (approximately 1 year) ]
  4. Number of Participants With Abnormal Clinical Laboratory Values [ Time Frame: Baseline up to 30 days after last dose of study drug (approximately 1 year) ]
  5. Event-free Survival (EFS) Per IRF [ Time Frame: Baseline until PD or discontinuation of treatment or death, whichever occurs first (approximately up to 4 years) ]
    EFS was defined as the time from randomization until any cause of treatment failure: PD, premature discontinuation of randomized treatment for any reason, or death due to any cause, whichever occurs first. PD was defined as any new lesion or increase by >=50% of previously involved sites from nadir per IRF.

  6. Disease-free Survival (DFS) Per IRF [ Time Frame: From CR until PD or death (approximately up to 4 years) ]
    DFS per IRF was defined as the time from CR to disease progression as determined by an IRF or to death from lymphoma or acute toxicity from treatment. CR was defined as disappearance of all evidence of disease.

  7. Overall Response Rate (ORR) Per IRF [ Time Frame: Baseline up to end of randomized regimen (approximately 1 year) ]
    ORR per IRF was defined as the percentage of participants who achieved CR or partial remission (PR) at the end of treatment with randomized regimen (ABVD or A+AVD) as determined by an IRF. CR was defined as disappearance of all evidence of disease. PR was defined as regression of measurable disease and no new sites.

  8. Duration of Response (DOR) Per IRF [ Time Frame: From first documented response until PD (approximately 4 years) ]
    DOR per IRF in participants with response was the time between first documentation of response (PR or CR) and PD as determined by an IRF. PD was defined as any new lesion or increase by >=50% of previously involved sites from nadir. CR was defined as disappearance of all evidence of disease. PR was defined as regression of measurable disease and no new sites.

  9. Duration of Complete Remission (DOCR) Per IRF [ Time Frame: From first documentation of CR until PD (approximately 4 years) ]
    DOCR per IRF in participants with CR was the time between first documentation of CR and PD as determined by an IRF. PD was defined as any new lesion or increase by >=50% of previously involved sites from nadir. CR was defined as disappearance of all evidence of disease.

  10. Percentage of Participants Not in CR Per IRF Who Received Subsequent Radiation After Completion of Frontline Therapy [ Time Frame: Baseline up to end of frontline therapy (approximately 4 years) ]
    CR was defined as disappearance of all evidence of disease as determined by an IRF.

  11. Complete Remission (CR) Per IRF Rate at the End of Frontline Therapy [ Time Frame: Baseline up to end of frontline therapy (approximately 4 years) ]
    CR rate at the end of frontline therapy per IRF was defined as the percentage of participants who achieved CR at the end of frontline therapy that is after completion of either randomized regimen or alternate frontline therapy as determined by an IRF. CR was defined as disappearance of all evidence of disease.

  12. Positron Emission Tomography (PET) Negativity Rate Per IRF at Cycle 2 [ Time Frame: Cycle 2 Day 25 ]
    PET negativity rate at Cycle 2 was defined as the percentage of participants with negative Cycle 2 PET results defined as Deauville score less than or equal to (<=) 3 at Cycle 2. The Deauville score according to IRF assessment of response was used to evaluate the results of PET scans.

  13. A+AVD: Cmax: Maximum Observed Serum Concentration for Brentuximab Vedotin Antibody-drug Conjugate (ADC) and Total Antibody (TAb) [ Time Frame: Cycle 1 Day 1 and Cycle 3 Day 1: pre-dose and at multiple timepoints (up to 48 hours) post-dose ]
  14. A+AVD: Cmax: Maximum Observed Plasma Concentration for Brentuximab Vedotin Monomethyl Auristatin E (MMAE) [ Time Frame: Cycle 1 Day 1 and Cycle 3 Day 1: pre-dose and at multiple timepoints (up to 48 hours) post-dose ]
  15. A+AVD: AUCinf: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Brentuximab Vedotin ADC and TAb [ Time Frame: Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 48 hours) post-dose ]
  16. A+AVD: AUCinf: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Brentuximab Vedotin MMAE [ Time Frame: Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 48 hours) post-dose ]
  17. A+AVD: Number of Participants With Antitherapeutic Antibody (ATA) and Neutralizing Antitherapeutic Antibody (nATA) Positive for Brentuximab Vedotin [ Time Frame: Baseline up to end of treatment (approximately 1 year) ]
    The nATA positive was defined as positive ATA with neutralizing activity at any postbaseline visit.

  18. Change From Baseline in Patient-Reported Outcome (PRO) Scores by mPFS Based on European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-C30 (EORTC QLQ-C30) at EOT [ Time Frame: Baseline up to end of treatment (approximately 1 year) ]
    EORTC QLQ-C30 included 30 items across 5 functional scales (physical, role, cognitive, emotional, and social), 9 symptom scales (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties) and global health status/QOL scale. It has 28 questions (4-point scale where 1=not at all [best] to 4=Very Much [worst]) and 2 questions (7-point scale where 1=very poor [worst] to 7= excellent [best]). Raw scores were converted into scale scores from 0 to 100. For functional scales and global health status/QOL scale, higher scores show better QOL; for symptom scales, lower scores show better QOL. mPFS was time from date of randomization to date of first of documentation of PD, death due to any cause, or for participants who were confirmed non complete responders per IRF, receipt of subsequent anticancer therapy for HL after completion of frontline therapy. PD is any new lesion or increase by >=50% of previously involved sites from nadir.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Treatment-naïve participants with Ann Arbor Stage III or IV HL.
  2. Histologically confirmed classical Hodgkin Lymphoma (HL) according to the current World Health Organization (WHO) classification.
  3. Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to (<=) 2.
  4. Bidimensional measurable disease as documented by radiographic technique per the International Working Group Revised Criteria for Response Assessment for Malignant Lymphoma.

Exclusion Criteria:

  1. Nodular lymphocyte predominant Hodgkin lymphoma.
  2. Cerebral/meningeal disease, including signs and symptoms of progressive multifocalleukoencephalopathy (PML).
  3. Sensory or motor peripheral neuropathy.
  4. Prior immunosuppressive chemotherapy, therapeutic radiation, or any immunotherapy within 12 weeks of first study drug dose.
  5. Known human immunodeficiency virus (HIV) positive.
  6. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection.

Please note that there are additional exclusion criteria. The study center will determine if you meet all of the criteria.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01712490


  Show 216 Study Locations
Sponsors and Collaborators
Millennium Pharmaceuticals, Inc.
Seattle Genetics, Inc.
Investigators
Study Director: Medical Director Millennium Pharmaceuticals, Inc.
  Study Documents (Full-Text)

Documents provided by Takeda ( Millennium Pharmaceuticals, Inc. ):
Study Protocol  [PDF] March 2, 2015
Statistical Analysis Plan  [PDF] March 10, 2015


Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT01712490     History of Changes
Other Study ID Numbers: C25003
2011-005450-60 ( EudraCT Number )
U1111-1161-4937 ( Registry Identifier: WHO )
12/LO/1950 ( Registry Identifier: NRES )
JapicCTI-142491 ( Registry Identifier: JapicCTI )
REec-2013-0114 ( Registry Identifier: REec )
1025002760 ( Registry Identifier: TCTIN )
C25003CTID ( Other Identifier: Israel )
First Posted: October 23, 2012    Key Record Dates
Results First Posted: November 27, 2018
Last Update Posted: November 27, 2018
Last Verified: October 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Takeda ( Millennium Pharmaceuticals, Inc. ):
Hodgkin Lymphoma
Hodgkins Lymphoma
Antibody, Monoclonal
Antibody-Drug Conjugate
Antigens, CD-30
Immunotherapy
Lymphoma
Lymphoma, Classical
ECHELON-1

Additional relevant MeSH terms:
Lymphoma
Hodgkin Disease
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Antibodies
Antibodies, Monoclonal
Doxorubicin
Liposomal doxorubicin
Bleomycin
Vinblastine
Immunologic Factors
Physiological Effects of Drugs
Antibiotics, Antineoplastic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Phytogenic
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators