A Frontline Therapy Trial in Participants With Advanced Classical Hodgkin Lymphoma

• ClinicalTrials.gov Identifier: NCT01712490
• Recruitment Status: Active, not recruiting
• First Posted: October 23, 2012
• Results First Posted: November 27, 2018
• Last Update Posted: February 20, 2024
• Sponsor: Takeda
• Collaborator: Seagen Inc.
• Information provided by (Responsible Party): Takeda

Tracking Information

• First Submitted Date: October 19, 2012
• First Posted Date: October 23, 2012
• Results First Submitted Date: April 18, 2018
• Results First Posted Date: November 27, 2018
• Last Update Posted Date: February 20, 2024
• Actual Study Start Date: November 9, 2012
• Actual Primary Completion Date: April 20, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 29, 2018)

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.

• Original Primary Outcome Measures (submitted: October 19, 2012): Modified progression free survival (mPFS) per independent review facility (IRF) [ Time Frame: Date of randomization to mPFS event, for approximately 3 to 5 years ]

Current Secondary Outcome Measures (submitted: October 29, 2018)

• 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.
• 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.
• 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) ]
• Number of Participants With Abnormal Clinical Laboratory Values [ Time Frame: Baseline up to 30 days after last dose of study drug (approximately 1 year) ]
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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 ]
• 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 ]
• 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 ]
• 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 ]
• 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.
• 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.

Original Secondary Outcome Measures (submitted: October 19, 2012)

Overall survival rate [ Time Frame: Date of randomization to the date of death, for approximately 5 to 7 years ]

Date of randomization to the date of death

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Frontline Therapy Trial in Participants With Advanced Classical Hodgkin Lymphoma
• Official Title: A Randomized, Open-label, Phase 3 Trial of A+AVD Versus ABVD as Frontline Therapy in Patients With Advanced Classical Hodgkin Lymphoma
• 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)
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Hodgkin Lymphoma

Intervention

• 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: 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

Study Arms

• 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.
  Interventions:

  • Drug: brentuximab vedotin
  • Drug: doxorubicin
  • Drug: vinblastine
  • Drug: dacarbazine
• 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.
  Interventions:

  • Drug: doxorubicin
  • Drug: bleomycin
  • Drug: vinblastine
  • Drug: dacarbazine

Publications *

• Ansell SM, Radford J, Connors JM, Dlugosz-Danecka M, Kim WS, Gallamini A, Ramchandren R, Friedberg JW, Advani R, Hutchings M, Evens AM, Smolewski P, Savage KJ, Bartlett NL, Eom HS, Abramson JS, Dong C, Campana F, Fenton K, Puhlmann M, Straus DJ; ECHELON-1 Study Group. Overall Survival with Brentuximab Vedotin in Stage III or IV Hodgkin's Lymphoma. N Engl J Med. 2022 Jul 28;387(4):310-320. doi: 10.1056/NEJMoa2206125. Epub 2022 Jul 13.
• Evens AM, Connors JM, Younes A, Ansell SM, Kim WS, Radford J, Feldman T, Tuscano J, Savage KJ, Oki Y, Grigg A, Pocock C, Dlugosz-Danecka M, Fenton K, Forero-Torres A, Liu R, Jolin H, Gautam A, Gallamini A. Older patients (aged >/=60 years) with previously untreated advanced-stage classical Hodgkin lymphoma: a detailed analysis from the phase III ECHELON-1 study. Haematologica. 2022 May 1;107(5):1086-1094. doi: 10.3324/haematol.2021.278438.
• Straus DJ, Dlugosz-Danecka M, Connors JM, Alekseev S, Illes A, Picardi M, Lech-Maranda E, Feldman T, Smolewski P, Savage KJ, Bartlett NL, Walewski J, Ramchandren R, Zinzani PL, Hutchings M, Munoz J, Lee HJ, Kim WS, Advani R, Ansell SM, Younes A, Gallamini A, Liu R, Little M, Fenton K, Fanale M, Radford J. Brentuximab vedotin with chemotherapy for stage III or IV classical Hodgkin lymphoma (ECHELON-1): 5-year update of an international, open-label, randomised, phase 3 trial. Lancet Haematol. 2021 Jun;8(6):e410-e421. doi: 10.1016/S2352-3026(21)00102-2. Erratum In: Lancet Haematol. 2022 Feb;9(2):e91.
• Straus DJ, Dlugosz-Danecka M, Alekseev S, Illes A, Picardi M, Lech-Maranda E, Feldman T, Smolewski P, Savage KJ, Bartlett NL, Walewski J, Ramchandren R, Zinzani PL, Hutchings M, Connors JM, Radford J, Munoz J, Kim WS, Advani R, Ansell SM, Younes A, Miao H, Liu R, Fenton K, Forero-Torres A, Gallamini A. Brentuximab vedotin with chemotherapy for stage III/IV classical Hodgkin lymphoma: 3-year update of the ECHELON-1 study. Blood. 2020 Mar 5;135(10):735-742. doi: 10.1182/blood.2019003127.
• Ramchandren R, Advani RH, Ansell SM, Bartlett NL, Chen R, Connors JM, Feldman T, Forero-Torres A, Friedberg JW, Gopal AK, Gordon LI, Kuruvilla J, Savage KJ, Younes A, Engley G, Manley TJ, Fenton K, Straus DJ. Brentuximab Vedotin plus Chemotherapy in North American Subjects with Newly Diagnosed Stage III or IV Hodgkin Lymphoma. Clin Cancer Res. 2019 Mar 15;25(6):1718-1726. doi: 10.1158/1078-0432.CCR-18-2435. Epub 2019 Jan 7.
• Connors JM, Jurczak W, Straus DJ, Ansell SM, Kim WS, Gallamini A, Younes A, Alekseev S, Illes A, Picardi M, Lech-Maranda E, Oki Y, Feldman T, Smolewski P, Savage KJ, Bartlett NL, Walewski J, Chen R, Ramchandren R, Zinzani PL, Cunningham D, Rosta A, Josephson NC, Song E, Sachs J, Liu R, Jolin HA, Huebner D, Radford J; ECHELON-1 Study Group. Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin's Lymphoma. N Engl J Med. 2018 Jan 25;378(4):331-344. doi: 10.1056/NEJMoa1708984. Epub 2017 Dec 10. Erratum In: N Engl J Med. 2018 Mar 1;378(9):878.
• Younes A, Connors JM, Park SI, Fanale M, O'Meara MM, Hunder NN, Huebner D, Ansell SM. Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin's lymphoma: a phase 1, open-label, dose-escalation study. Lancet Oncol. 2013 Dec;14(13):1348-56. doi: 10.1016/S1470-2045(13)70501-1. Epub 2013 Nov 15.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: July 19, 2016): 1334
• Original Estimated Enrollment (submitted: October 19, 2012): 1040
• Estimated Study Completion Date: January 13, 2026
• Actual Primary Completion Date: April 20, 2017 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, Brazil, Canada, Czechia, Denmark, France, Hong Kong, Hungary, Italy, Japan, Korea, Republic of, Norway, Poland, Russian Federation, South Africa, Spain, Taiwan, Turkey, United Kingdom, United States
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT01712490
• 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 ); 2023-506419-16 ( Other Identifier: EU CTIS )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: Yes
• 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.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• 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.
• URL: https://vivli.org/ourmember/takeda/

• Current Responsible Party: Takeda
• Original Responsible Party: Millennium Pharmaceuticals, Inc.
• Current Study Sponsor: Takeda
• Original Study Sponsor: Millennium Pharmaceuticals, Inc.
• Collaborators: Seagen Inc.

Investigators

• Study Director: Study Director; Takeda

• PRS Account: Takeda
• Verification Date: February 2024