A Study of Brentuximab Vedotin in Participants With Relapsed or Refractory Hodgkin Lymphoma

• Sponsor: Millennium Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01990534
• Collaborator: (none)
• Enrollment: 60
• Locations: 18
• Arm: 1
• Actual Duration (Months): 72
• Patients Per Site: 3.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This phase 4, single-arm, open-label, multicenter study is designed to evaluate the efficacy and safety of brentuximab vedotin as a single agent in adult participants with histologically confirmed CD30+ relapsed or refractory classical Hodgkin Lymphoma who have not received a prior stem cell transplantation (SCT) and are considered to be not suitable for SCT or multiagent chemotherapy at the time of study entry.

Condition or Disease	Intervention/Treatment	Phase
Hodgkin Lymphoma	Drug: Brentuximab Vedotin	Phase 4

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 Hodgkin Lymphoma. This study will look at the overall response of people who took brentuximab vedotin.

The study will enroll 60 patients. Participants received:

• Brentuximab vedotin 1.8 mg/kg

This multicenter trial is being conducted worldwide. The overall time to participate in this study is approximately 6 to 7 years. Participants will make multiple visits to the clinic, and will be contacted by telephone every 3 months for 18 months after the end of treatment (EOT) for follow-up assessment of overall survival and then every 6 months until death, study closure, or 5 years after enrollment of the last participant.

Study Design

• Study Type: Interventional
• Actual Enrollment: 60 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Single-arm Study of Brentuximab Vedotin in Patients With Relapsed or Refractory Hodgkin Lymphoma Who Are Not Suitable for Stem Cell Transplantation or Multiagent Chemotherapy
• Actual Study Start Date: Mar 14, 2014
• Actual Primary Completion Date: Mar 24, 2016
• Actual Study Completion Date: Mar 12, 2020

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Brentuximab Vedotin 1.8 mg/kg Brentuximab vedotin 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 in every 3-week cycle, until there is evidence of disease progression or unacceptable toxicity occurs (Up to 16 cycles). The dose could be decreased or delayed or discontinued in participants who develop treatment-associated non-hematologic, hematologic toxicity or peripheral neuropathy to brentuximab vedotin.

Drug: Brentuximab Vedotin; Brentuximab vedotin IV infusion; Other Names: SGN-35 ADCETRIS

Outcome Measures

Primary Outcome Measures

1. Objective Response Rate (ORR) [Baseline until disease progression, death or end of study (EOS) (Up to 24 months)]

   Objective 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

1. Duration of Response (DOR) [From first documented complete or partial remission until disease progression (Up to 24 months)]

   DOR is defined as the time in months from the date of first documentation of a CR or PR response to the date of first documentation of tumor progression or progressive disease (PD) per IRF assessment according to IWG criteria. CR is defined as the disappearance of all evidence of disease. PR is defined as regression of measurable disease and no new sites. PD is defined as any new lesion or increase by >50% of previously involved sites from nadir.

2. Progression Free Survival (PFS) [Baseline until disease progression, death or end of treatment (EOT), and then every 3 months up to approximately 6 years]

   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.

3. Complete Remission Rate [Baseline until disease progression, death or EOS (Up to approximately 6 years)]

   Complete remission rate is defined as percentage of participants with CR per IRF response assessment based on IWG criteria are reported. CR is defined as the disappearance of all evidence of disease.

4. Duration of Complete Remission [From first documented complete remission until disease progression (up to approximately 6 years)]

   Duration of CR is defined as the time from the date of first documentation of a CR or to the date of first documentation of tumor progression or progressive disease (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.

5. Overall Survival (OS) [Every 3 months for 18 months after EOT, thereafter, every 6 months until the sooner of death, study closure, or 5 years after enrollment of the last participant (up to approximately 6 years)]

   OS is the time in months from start of study treatment to date of death due to any cause.

6. Percentage of Participants Who Received Hematopoietic SCT [Baseline up to EOS (up to approximately 6 years)]

7. Number of Participants With Adverse Events (AEs), Drug-Related AEs, Grade 3 or Higher AEs, Serious Adverse Events (SAEs), Drug-Related SAEs and Grade 3 or Higher SAEs [From first dose through 30 days after the last dose of study medication (Up to 24 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 a serious 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. AEs Grade 3 and higher are severe.

8. Number of Participants With Abnormal Clinical Laboratory Values Reported as AEs [From the first dose through 30 days after the last dose of study medication (Up to 24 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.

9. Antibody-drug Conjugate (ADC) Serum Concentrations [Cycle 1 pre-dose and 10 minutes, 24 hours and 336 hours post-dose; Cycle 2 pre-dose and 10 minutes post-dose; Cycle 3 pre-dose and 10 minutes, 24 hours and 336 hours post-dose; Cycle 4 to 16 pre-dose and 10 minutes post-dose; EOT (Up to 24 months)]

   Blood samples were collected and tested for serum concentrations of brentuximab vedotin antibody-drug conjugate.

10. Serum Concentration of Total Antibodies (Conjugated and Unconjugated) [Cycle 1 pre-dose and 10 minutes, 24 hours and 336 hours post-dose; Cycle 2 pre-dose and 10 minutes post-dose; Cycle 3 pre-dose and 10 minutes, 24 hours and 336 hours post-dose; Cycle 4 to 16 pre-dose and 10 minutes post-dose; EOT (Up to 24 months)]

    Blood samples were collected and tested for conjugated and unconjugated antibodies.

11. Monomethyl Auristatin E (MMAE) Serum Concentrations [Cycle 1 pre-dose and 10 minutes, 24 hours and 336 hours post-dose; Cycle 2 pre-dose and 10 minutes post-dose; Cycle 3 pre-dose and 10 minutes, 24 hours and 336 hours post-dose; Cycle 4 to 16 pre-dose and 10 minutes post-dose; EOT (Up to 24 months)]

    Blood samples were collected and tested for MMAE serum concentrations.

12. Number of Participants With Antitherapeutic Antibodies (ATA) [Day 1 of every 3-week cycle up to 16 cycles and EOT (Up to 24 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. The confirmed ATA-positive samples were assessed for ATA titer and delineated into having high or low titers.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Each participant must meet all of the following inclusion criteria to be enrolled in the study:

1. Male or female participants 18 years or older, with relapsed or refractory classical Hodgkin lymphoma (HL), who have previously received at least 1 prior systemic chemotherapeutic regimen

2. Not suitable for stem cell transplantation (SCT) or multiagent chemotherapy, according to 1 of the following criteria:

• Disease progression within 90 days of the earliest date of complete remission (CR) or complete remission unconfirmed (CRu) after the end of treatment with multiagent chemotherapeutic regimens and/or radiotherapy

• Progressive disease during frontline multiagent chemotherapy

• Disease relapse after treatment with at least 2 chemotherapeutic regimens, including any salvage treatments

1. Bidimensional measurable disease

2. An Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1

3. Female participants who are postmenopausal for at least 1 year before the screening visit, surgically sterile, or agree to practice 2 effective methods of contraception at the same time, or agree to practice true abstinence.

4. Male participants who agree to practice effective barrier contraception during the entire study treatment period through 6 months after the last dose of study drug or agree to practice true abstinence.

5. Clinical laboratory values as specified in the study protocol.

Exclusion Criteria:

Participants who meet any of the following exclusion criteria are not to be enrolled in the study:

1. Previous treatment with brentuximab vedotin

2. Previously received an autologous stem cell transplantation (ASCT) or alloSCT

3. Known cerebral/meningeal disease, including signs or symptoms suggestive of progressive multifocal leukoencephalopathy (PML), or any history of PML.

4. Female participants who are lactating and breastfeeding or pregnant.

5. Known human immunodeficiency virus (HIV).

6. Known hepatitis B surface antigen positive, or known or suspected active hepatitis C infection.

7. Grade 2 or higher peripheral neuropathy.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Praha	Prague	Czechia
2		Brno		Czechia
3		Heidelberg	Baden Wuerttemberg	Germany
4		Koeln		Germany
5		Georgetown	Penang	Malaysia
6		Ampang	Selangor	Malaysia
7		Kuala Lumpur		Malaysia
8		Gdansk		Poland
9		Krakow		Poland
10		Warszawa		Poland
11		Pamplona	Navarra	Spain
12		Madrid		Spain
13		Bangkoknoi	Bangkok	Thailand
14		Patumwan	Bangkok	Thailand
15		Ratchathewi	Bangkok	Thailand
16		Izmir	Bornova	Turkey
17		Ankara		Turkey
18		Izmir		Turkey

Sponsors and Collaborators

• Millennium Pharmaceuticals, Inc.

Investigators

• Study Director: Medical Monitor, Millennium Pharmaceuticals, Inc.

Study Documents (Full-Text)

• Study Protocol - Jul 11, 2013
• Statistical Analysis Plan - Feb 22, 2016

More Information

Publications

None provided.

• Responsible Party: Millennium Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT01990534
• Other Study ID Numbers: C25007; 2013-000232-10; U1111-1154-2250; NMRR-13-1246-18099; REec-2014-0619
• First Posted: Nov 21, 2013
• Last Update Posted: Apr 9, 2021
• Last Verified: Mar 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Millennium Pharmaceuticals, Inc.: Lymphoma; Hodgkin; Relapsed; Refractory; Antigens, CD30; Antibody-Drug Conjugate; Antibodies, Monoclonal; Monomethyl auristatin E; Drug Therapy; Immunotherapy; Hematologic Diseases; Additional Relevant MeSH terms:; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Hodgkin; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Lymphoma, B-Cell; Lymphoma, T-Cell; Immunologic Factors; Physiological Effects of Drugs; Pharmacologic Actions
• Additional relevant MeSH terms: Lymphoma; Hodgkin Disease; Brentuximab Vedotin

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 18 investigative sites in Czech Republic, Germany, Malaysia, Poland, Spain, Thailand and Turkey, from 14 March 2014 to 12 March 2020.
Pre-assignment Detail	Participants with a diagnosis of relapsed or refractory Hodgkin Lymphoma were enrolled in 1 treatment group to receive brentuximab vedotin 1.8 mg/kg, 30-minute intravenous (IV) infusion on Day 1 of every 3-week cycle and were followed for progression free survival (PFS) and overall survival (OS) up to the End of study (approximately 6 years).

Arm/Group Title	Brentuximab Vedotin 1.8 mg/kg
Arm/Group Description	Brentuximab vedotin 1.8 mg/kg, 30-minute IV infusion, Day 1 of every 3-week cycle, until there is evidence of disease progression or unacceptable toxicity occurs (Up to 16 cycles). The dose could be decreased or delayed or discontinued in participants who develop treatment-associated non-hematologic toxicity, hematologic toxicity or peripheral neuropathy to brentuximab vedotin.
Period Title: Overall Study
STARTED	60
COMPLETED	25
NOT COMPLETED	35

Baseline Characteristics

Arm/Group Title	Brentuximab Vedotin 1.8 mg/kg
Arm/Group Description	Brentuximab vedotin 1.8 mg/kg, 30-minute IV infusion, Day 1 of every 3-week cycle, until there is evidence of disease progression or unacceptable toxicity occurs (Up to 16 cycles). The dose could be decreased or delayed or discontinued in participants who develop treatment-associated non-hematologic toxicity, hematologic toxicity or peripheral neuropathy to brentuximab vedotin.
Overall Participants	60
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	35.4 (13.83)
Sex: Female, Male (Count of Participants)
Female	24 40%
Male	36 60%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 3.3%
Not Hispanic or Latino	58 96.7%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	18 30%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	42 70%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
Czech Republic	3 5%
Germany	2 3.3%
Malaysia	8 13.3%
Poland	26 43.3%
Spain	2 3.3%
Thailand	10 16.7%
Turkey	9 15%
Baseline Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	171.0 (9.66)
Baseline Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	70.3 (19.41)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	23.864 (5.4085)

Outcome Measures

1. Primary Outcome

Title	Objective Response Rate (ORR)
Description	Objective 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.
Time Frame	Baseline until disease progression, death or end of study (EOS) (Up to 24 months)

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population included all participants who were enrolled in the study.

Arm/Group Title	Brentuximab Vedotin 1.8 mg/kg
Arm/Group Description	Brentuximab vedotin 1.8 mg/kg, 30-minute IV infusion, Day 1 of every 3-week cycle, until there is evidence of disease progression or unacceptable toxicity occurs (Up to 16 cycles). The dose could be decreased or delayed or discontinued in participants who develop treatment-associated non-hematologic toxicity, hematologic toxicity or peripheral neuropathy to brentuximab vedotin.
Measure Participants	60
Number (95% Confidence Interval) [percentage of participants]	50 83.3%

2. Secondary Outcome

Title	Duration of Response (DOR)
Description	DOR is defined as the time in months from the date of first documentation of a CR or PR response to the date of first documentation of tumor progression or progressive disease (PD) per IRF assessment according to IWG criteria. CR is defined as the disappearance of all evidence of disease. PR is defined as regression of measurable disease and no new sites. PD is defined as any new lesion or increase by >50% of previously involved sites from nadir.
Time Frame	From first documented complete or partial remission until disease progression (Up to 24 months)

Outcome Measure Data

Analysis Population Description

ITT Population included all participants who were enrolled in the study. DOR was censored on the date of last disease assessment documenting absence of PD for those that were lost to follow-up, withdrew consent, started a new anticancer therapy other than stem cell transplantation (SCT), or discontinued treatment due to undocumented PD after last disease assessment. All responders were evaluated in this outcome measure.

Arm/Group Title	Brentuximab Vedotin 1.8 mg/kg
Arm/Group Description	Brentuximab vedotin 1.8 mg/kg, 30-minute IV infusion, Day 1 of every 3-week cycle, until there is evidence of disease progression or unacceptable toxicity occurs (Up to 16 cycles). The dose could be decreased or delayed or discontinued in participants who develop treatment-associated non-hematologic toxicity, hematologic toxicity or peripheral neuropathy to brentuximab vedotin.
Measure Participants	30
Median (95% Confidence Interval) [months]	4.6

3. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	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.
Time Frame	Baseline until disease progression, death or end of treatment (EOT), and then every 3 months up to approximately 6 years

Outcome Measure Data

Analysis Population Description

ITT Population included all participants who were enrolled in the study. For a participant that has not progressed and has not died, PFS is censored at the last response assessment that is SD or better.

Arm/Group Title	Brentuximab Vedotin 1.8 mg/kg
Arm/Group Description	Brentuximab vedotin 1.8 mg/kg, 30-minute IV infusion, Day 1 of every 3-week cycle, until there is evidence of disease progression or unacceptable toxicity occurs (Up to 16 cycles). The dose could be decreased or delayed or discontinued in participants who develop treatment-associated non-hematologic toxicity, hematologic toxicity or peripheral neuropathy to brentuximab vedotin.
Measure Participants	60
Median (95% Confidence Interval) [months]	4.8

4. Secondary Outcome

Title	Complete Remission Rate
Description	Complete remission rate is defined as percentage of participants with CR per IRF response assessment based on IWG criteria are reported. CR is defined as the disappearance of all evidence of disease.
Time Frame	Baseline until disease progression, death or EOS (Up to approximately 6 years)

Outcome Measure Data

Analysis Population Description

ITT Population included all participants who were enrolled in the study. In the absence of confirmation of death, survival time is censored at the last date the participant is known to be alive, including study closure.

Arm/Group Title	Brentuximab Vedotin 1.8 mg/kg
Arm/Group Description	Brentuximab vedotin 1.8 mg/kg, 30-minute IV infusion, Day 1 of every 3-week cycle, until there is evidence of disease progression or unacceptable toxicity occurs (Up to 16 cycles). The dose could be decreased or delayed or discontinued in participants who develop treatment-associated non-hematologic toxicity, hematologic toxicity or peripheral neuropathy to brentuximab vedotin.
Measure Participants	60
Number (95% Confidence Interval) [percentage of participants]	13 21.7%

5. Secondary Outcome

Title	Duration of Complete Remission
Description	Duration of CR is defined as the time from the date of first documentation of a CR or to the date of first documentation of tumor progression or progressive disease (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.
Time Frame	From first documented complete remission until disease progression (up to approximately 6 years)

Outcome Measure Data

Analysis Population Description

ITT Population included all participants who were enrolled in the study. Duration of complete remission was censored on the date of last disease assessment documenting absence of PD for those that were lost to follow-up, withdrew consent, started a new anticancer therapy other than SCT, or discontinued treatment due to undocumented PD after last disease assessment. Only participants with CR were analyzed for this outcome measure.

Arm/Group Title	Brentuximab Vedotin 1.8 mg/kg
Arm/Group Description	Brentuximab vedotin 1.8 mg/kg, 30-minute IV infusion, Day 1 of every 3-week cycle, until there is evidence of disease progression or unacceptable toxicity occurs (Up to 16 cycles). The dose could be decreased or delayed or discontinued in participants who develop treatment-associated non-hematologic toxicity, hematologic toxicity or peripheral neuropathy to brentuximab vedotin.
Measure Participants	8
Median (95% Confidence Interval) [months]	6.1

6. Secondary Outcome

Title	Overall Survival (OS)
Description	OS is the time in months from start of study treatment to date of death due to any cause.
Time Frame	Every 3 months for 18 months after EOT, thereafter, every 6 months until the sooner of death, study closure, or 5 years after enrollment of the last participant (up to approximately 6 years)

Outcome Measure Data

Analysis Population Description

ITT Population included all participants who were enrolled in the study. In the absence of confirmation of death, survival time is censored at the last date the participant is known to be alive, including study closure.

Arm/Group Title	Brentuximab Vedotin 1.8 mg/kg
Arm/Group Description	Brentuximab vedotin 1.8 mg/kg, 30-minute IV infusion, Day 1 of every 3-week cycle, until there is evidence of disease progression or unacceptable toxicity occurs (Up to 16 cycles). The dose could be decreased or delayed or discontinued in participants who develop treatment-associated non-hematologic toxicity, hematologic toxicity or peripheral neuropathy to brentuximab vedotin.
Measure Participants	60
Median (95% Confidence Interval) [months]	NA

7. Secondary Outcome

Title	Percentage of Participants Who Received Hematopoietic SCT
Time Frame	Baseline up to EOS (up to approximately 6 years)

Outcome Measure Data

Analysis Population Description

ITT Population included all participants who were enrolled in the study.

Arm/Group Title	Brentuximab Vedotin 1.8 mg/kg
Arm/Group Description	Brentuximab vedotin 1.8 mg/kg, 30-minute IV infusion, Day 1 of every 3-week cycle, until there is evidence of disease progression or unacceptable toxicity occurs (Up to 16 cycles). The dose could be decreased or delayed or discontinued in participants who develop treatment-associated non-hematologic toxicity, hematologic toxicity or peripheral neuropathy to brentuximab vedotin.
Measure Participants	60
Number [percentage of participants]	53 88.3%

8. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs), Drug-Related AEs, Grade 3 or Higher AEs, Serious Adverse Events (SAEs), Drug-Related SAEs and Grade 3 or Higher SAEs
Description	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 a serious 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. AEs Grade 3 and higher are severe.
Time Frame	From first dose through 30 days after the last dose of study medication (Up to 24 months)

Outcome Measure Data

Analysis Population Description

Safety Population was defined as all enrolled participants who received at least one dose of brentuximab vedotin.

Arm/Group Title	Brentuximab Vedotin 1.8 mg/kg
Arm/Group Description	Brentuximab vedotin 1.8 mg/kg, 30-minute IV infusion, Day 1 of every 3-week cycle, until there is evidence of disease progression or unacceptable toxicity occurs (Up to 16 cycles). The dose could be decreased or delayed or discontinued in participants who develop treatment-associated non-hematologic toxicity, hematologic toxicity or peripheral neuropathy to brentuximab vedotin.
Measure Participants	60
Any AEs	52 86.7%
Grade 3 or higher AEs	21 35%
Drug-related AEs	41 68.3%
Drug-related Grade 3 or higher AEs	11 18.3%
SAEs	11 18.3%
Drug-related SAEs	3 5%

9. Secondary Outcome

Title	Number of Participants With Abnormal Clinical Laboratory Values Reported as AEs
Description	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.
Time Frame	From the first dose through 30 days after the last dose of study medication (Up to 24 months)

Outcome Measure Data

Analysis Population Description

Safety Population was defined as all enrolled participants who received at least one dose of brentuximab vedotin.

Arm/Group Title	Brentuximab Vedotin 1.8 mg/kg
Arm/Group Description	Brentuximab vedotin 1.8 mg/kg, 30-minute IV infusion, Day 1 of every 3-week cycle, until there is evidence of disease progression or unacceptable toxicity occurs (Up to 16 cycles). The dose could be decreased or delayed or discontinued in participants who develop treatment-associated non-hematologic toxicity, hematologic toxicity or peripheral neuropathy to brentuximab vedotin.
Measure Participants	60
Neutrophil count decreased	2 3.3%
Lymphocyte count decreased	1 1.7%
Alanine aminotransferase increased	2 3.3%
Aspartate aminotransferase increased	2 3.3%
Gamma-glutamyltransferase increased	1 1.7%
Blood thyroid stimulating hormone increased	1 1.7%
Platelet count decreased	1 1.7%
Haemoglobin decreased	1 1.7%
Blood alkaline phosphatase increased	1 1.7%
Blood lactate dehydrogenase increased	1 1.7%

10. Secondary Outcome

Title	Antibody-drug Conjugate (ADC) Serum Concentrations
Description	Blood samples were collected and tested for serum concentrations of brentuximab vedotin antibody-drug conjugate.
Time Frame	Cycle 1 pre-dose and 10 minutes, 24 hours and 336 hours post-dose; Cycle 2 pre-dose and 10 minutes post-dose; Cycle 3 pre-dose and 10 minutes, 24 hours and 336 hours post-dose; Cycle 4 to 16 pre-dose and 10 minutes post-dose; EOT (Up to 24 months)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-evaluable Population was defined as participants with sufficient dosing and PK data to reliably estimate PK parameters. Number analyzed is the number of participants with data available at the given time-point.

Arm/Group Title	Brentuximab Vedotin 1.8 mg/kg
Arm/Group Description	Brentuximab vedotin 1.8 mg/kg, 30-minute IV infusion, Day 1 of every 3-week cycle, until there is evidence of disease progression or unacceptable toxicity occurs (Up to 16 cycles). The dose could be decreased or delayed or discontinued in participants who develop treatment-associated non-hematologic toxicity, hematologic toxicity or peripheral neuropathy to brentuximab vedotin.
Measure Participants	60
Cycle 1 Day 1, Pre-Dose	0.00 (0.000)
Cycle 1 Day 1, 10 minutes Post-Dose	35504.65 (10226.104)
Cycle 1 Day 2, 24 hours Post-Dose	14517.67 (4481.312)
Cycle 1 Day 15, 336 hours Post-Dose	1410.43 (1946.525)
Cycle 2 Day 1, Pre-Dose	526.42 (350.467)
Cycle 2 Day 1, 10 minutes Post-Dose	37118.32 (11678.088)
Cycle 3 Day 1, Pre-Dose	2283.30 (7552.322)
Cycle 3 Day 1, 10 minutes Post-Dose	35878.77 (12724.898)
Cycle 3 Day 2, 24 hours Post-Dose	14737.82 (4512.358)
Cycle 3 Day 15, 336 hours Post-Dose	1586.45 (680.955)
Cycle 4 Day 1, Pre-Dose	1313.56 (2566.360)
Cycle 4 Day 1, 10 minutes Post-Dose	42915.34 (28221.764)
Cycle 5 Day 1, Pre-Dose	1117.01 (637.637)
Cycle 5 Day 1, 10 minutes Post-Dose	36418.77 (10041.935)
Cycle 6 Day 1, Pre-Dose	1231.45 (714.383)
Cycle 6 Day 1, 10 minutes Post-Dose	39000.95 (12484.458)
Cycle 7 Day 1, Pre-Dose	1285.91 (712.625)
Cycle 7 Day 1, 10 minutes Post-Dose	38814.82 (12471.299)
Cycle 8 Day 1, Pre-Dose	1413.98 (782.391)
Cycle 8 Day 1, 10 minutes Post-Dose	39027.22 (9919.251)
Cycle 9 Day 1, Pre-Dose	1277.18 (594.603)
Cycle 9 Day 1, 10 minutes Post-Dose	38359.15 (13421.064)
Cycle 10 Day 1, Pre-Dose	1498.44 (754.721)
Cycle 10 Day 1, 10 minutes Post-Dose	39890.12 (5376.038)
Cycle 11 Day 1, Pre-Dose	1511.35 (461.907)
Cycle 11 Day 1, 10 minutes Post-Dose	39132.17 (6316.541)
Cycle 12 Day 1, Pre-Dose	1479.38 (397.816)
Cycle 12 Day 1, 10 minutes Post-Dose	39955.13 (7821.656)
Cycle 13 Day 1, Pre-Dose	1423.56 (415.744)
Cycle 13 Day 1, 10 minutes Post-Dose	37609.69 (4563.601)
Cycle 14 Day 1, Pre-Dose	1185.62 (422.664)
Cycle 14 Day 1, 10 minutes Post-Dose	38282.29 (10324.023)
Cycle 15 Day 1, Pre-Dose	2279.42 (2919.545)
Cycle 15 Day 1, 10 minutes Post-Dose	39068.14 (7981.110)
Cycle 16 Day 1, Pre-Dose	1452.23 (429.731)
Cycle 16 Day 1, 10 minutes Post-Dose	38414.73 (9427.315)
End of Treatment	1515.30 (6413.367)

11. Secondary Outcome

Title	Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Description	Blood samples were collected and tested for conjugated and unconjugated antibodies.
Time Frame	Cycle 1 pre-dose and 10 minutes, 24 hours and 336 hours post-dose; Cycle 2 pre-dose and 10 minutes post-dose; Cycle 3 pre-dose and 10 minutes, 24 hours and 336 hours post-dose; Cycle 4 to 16 pre-dose and 10 minutes post-dose; EOT (Up to 24 months)

Outcome Measure Data

Analysis Population Description

PK-evaluable Population was defined as participants with sufficient dosing and PK data to reliably estimate PK parameters. Number analyzed is the number of participants with data available at the given time-point.

Arm/Group Title	Brentuximab Vedotin 1.8 mg/kg
Arm/Group Description	Brentuximab vedotin 1.8 mg/kg, 30-minute IV infusion, Day 1 of every 3-week cycle, until there is evidence of disease progression or unacceptable toxicity occurs (Up to 16 cycles). The dose could be decreased or delayed or discontinued in participants who develop treatment-associated non-hematologic toxicity, hematologic toxicity or peripheral neuropathy to brentuximab vedotin.
Measure Participants	60
Cycle 1 Day 1, Pre-Dose	0.00 (0.000)
Cycle 1 Day 1, 10 minutes Post-Dose	37329.59 (17724.247)
Cycle 1 Day 2, 24 hours Post-Dose	23248.90 (8228.938)
Cycle 1 Day 15, 336 hours Post-Dose	2791.49 (1413.452)
Cycle 2 Day 1, Pre-Dose	1254.86 (774.586)
Cycle 2 Day 1, 10 minutes Post-Dose	39801.87 (12914.837)
Cycle 3 Day 1, Pre-Dose	2645.22 (5685.914)
Cycle 3 Day 1, 10 minutes Post-Dose	36461.28 (11144.634)
Cycle 3 Day 2, 24 hours Post-Dose	27071.46 (8069.489)
Cycle 3 Day 15, 336 hours Post-Dose	4033.28 (1760.094)
Cycle 4 Day 1, Pre-Dose\	2600.73 (2275.881)
Cycle 4 Day 1, 10 minutes Post-Dose	41823.31 (11761.223)
Cycle 5 Day 1, Pre-Dose	2690.61 (1254.886)
Cycle 5 Day 1, 10 minutes Post-Dose	43786.57 (15470.979)
Cycle 6 Day 1, Pre-Dose	2806.17 (1021.877)
Cycle 6 Day 1, 10 minutes Post-Dose	44936.89 (13827.929)
Cycle 7 Day 1, Pre-Dose	3889.94 (6201.351)
Cycle 7 Day 1, 10 minutes Post-Dose	41840.20 (12552.597)
Cycle 8 Day 1, Pre-Dose	2932.19 (1089.138)
Cycle 8 Day 1, 10 minutes Post-Dose	42013.77 (12754.334)
Cycle 9 Day 1, Pre-Dose	2959.26 (970.811)
Cycle 9 Day 1, 10 minutes Post-Dose	37300.95 (13442.910)
Cycle 10 Day 1, Pre-Dose	3189.16 (1484.258)
Cycle 10 Day 1, 10 minutes Post-Dose	38910.05 (6169.552)
Cycle 11 Day 1, Pre-Dose	3393.07 (1160.604)
Cycle 11 Day 1, 10 minutes Post-Dose	41238.25 (8081.750)
Cycle 12 Day 1, Pre-Dose	3270.44 (965.895)
Cycle 12 Day 1, 10 minutes Post-Dose	37550.64 (12459.906)
Cycle 13 Day 1, Pre-Dose	3406.00 (1067.414)
Cycle 13 Day 1, 10 minutes Post-Dose	35694.80 (3720.378)
Cycle 14 Day 1, Pre-Dose	2723.01 (1286.457)
Cycle 14 Day 1, 10 minutes Post-Dose	40848.64 (8704.538)
Cycle 15 Day 1, Pre-Dose	3111.63 (941.200)
Cycle 15 Day 1, 10 minutes Post-Dose	37091.56 (6644.258)
Cycle 16 Day 1, Pre-Dose	3159.38 (1017.679)
Cycle 16 Day 1, 10 minutes Post-Dose	39266.07 (9358.163)
End of Treatment	2340.49 (6715.837)

12. Secondary Outcome

Title	Monomethyl Auristatin E (MMAE) Serum Concentrations
Description	Blood samples were collected and tested for MMAE serum concentrations.
Time Frame	Cycle 1 pre-dose and 10 minutes, 24 hours and 336 hours post-dose; Cycle 2 pre-dose and 10 minutes post-dose; Cycle 3 pre-dose and 10 minutes, 24 hours and 336 hours post-dose; Cycle 4 to 16 pre-dose and 10 minutes post-dose; EOT (Up to 24 months)

Outcome Measure Data

Analysis Population Description

PK-evaluable Population was defined as participants with sufficient dosing and PK data to reliably estimate PK parameters. Number analyzed is the number of participants with data available at the given time-point.

Arm/Group Title	Brentuximab Vedotin 1.8 mg/kg
Arm/Group Description	Brentuximab vedotin 1.8 mg/kg, 30-minute IV infusion, Day 1 of every 3-week cycle, until there is evidence of disease progression or unacceptable toxicity occurs (Up to 16 cycles). The dose could be decreased or delayed or discontinued in participants who develop treatment-associated non-hematologic toxicity, hematologic toxicity or peripheral neuropathy to brentuximab vedotin.
Measure Participants	60
Cycle 1 Day 1, Pre-Dose	0.78 (5.976)
Cycle 1 Day 1, 10 minutes Post-Dose	591.09 (662.608)
Cycle 1 Day 2, 24 hours Post-Dose	6056.44 (3850.457)
Cycle 1 Day 15, 336 hours Post-Dose	746.12 (1123.502)
Cycle 2 Day 1, Pre-Dose	140.11 (111.036)
Cycle 2 Day 1, 10 minutes Post-Dose	539.38 (593.150)
Cycle 3 Day 1, Pre-Dose	130.62 (84.152)
Cycle 3 Day 1, 10 minutes Post-Dose	484.88 (701.402)
Cycle 3 Day 2, 24 hours Post-Dose	3076.75 (2330.510)
Cycle 3 Day 15, 336 hours Post-Dose	442.63 (259.360)
Cycle 4 Day 1, Pre-Dose	150.95 (123.841)
Cycle 4 Day 1, 10 minutes Post-Dose	497.20 (520.110)
Cycle 5 Day 1, Pre-Dose	153.95 (123.337)
Cycle 5 Day 1, 10 minutes Post-Dose	392.50 (320.346)
Cycle 6 Day 1, Pre-Dose	158.89 (109.024)
Cycle 6 Day 1, 10 minutes Post-Dose	369.53 (260.871)
Cycle 7 Day 1, Pre-Dose	185.91 (147.311)
Cycle 7 Day 1, 10 minutes Post-Dose	363.83 (237.883)
Cycle 8 Day 1, Pre-Dose	136.37 (86.947)
Cycle 8 Day 1, 10 minutes Post-Dose	303.43 (202.351)
Cycle 9 Day 1, Pre-Dose	142.30 (114.794)
Cycle 9 Day 1, 10 minutes Post-Dose	224.52 (159.833)
Cycle 10 Day 1, Pre-Dose	100.78 (57.270)
Cycle 10 Day 1, 10 minutes Post-Dose	253.73 (113.311)
Cycle 11 Day 1, Pre-Dose	158.09 (169.963)
Cycle 11 Day 1, 10 minutes Post-Dose	302.60 (175.869)
Cycle 12 Day 1, Pre-Dose	175.02 (141.192)
Cycle 12 Day 1, 10 minutes Post-Dose	382.52 (428.255)
Cycle 13 Day 1, Pre-Dose	146.76 (61.758)
Cycle 13 Day 1, 10 minutes Post-Dose	258.78 (108.871)
Cycle 14 Day 1, Pre-Dose	82.13 (22.661)
Cycle 14 Day 1, 10 minutes Post-Dose	204.29 (121.162)
Cycle 15 Day 1, Pre-Dose	133.78 (59.213)
Cycle 15 Day 1, 10 minutes Post-Dose	246.63 (98.399)
Cycle 16 Day 1, Pre-Dose	163.39 (114.821)
Cycle 16 Day 1, 10 minutes Post-Dose	264.63 (103.269)
End of Treatment	139.72 (220.211)

13. Secondary Outcome

Title	Number of Participants With Antitherapeutic Antibodies (ATA)
Description	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. The confirmed ATA-positive samples were assessed for ATA titer and delineated into having high or low titers.
Time Frame	Day 1 of every 3-week cycle up to 16 cycles and EOT (Up to 24 months)

Outcome Measure Data

Analysis Population Description

Participants from the Safety Population, all enrolled participants who received at least one dose of brentuximab vedotin, with data available for analysis.

Arm/Group Title	Brentuximab Vedotin 1.8 mg/kg
Arm/Group Description	Brentuximab vedotin 1.8 mg/kg, 30-minute IV infusion, Day 1 of every 3-week cycle, until there is evidence of disease progression or unacceptable toxicity occurs (Up to 16 cycles). The dose could be decreased or delayed or discontinued in participants who develop treatment-associated non-hematologic toxicity, hematologic toxicity or peripheral neuropathy to brentuximab vedotin.
Measure Participants	56
ATA Positive	21 35%
Transient Positive	17 28.3%
Persistently Positive	4 6.7%
ATA Titer Low (≤25)	21 35%
ATA Titer High (>25)	0 0%

Adverse Events

Time Frame	First dose of study drug up to 30 days post last dose of study drug (Up to 24 months)
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Arm/Group Title	Brentuximab Vedotin 1.8 mg/kg
Arm/Group Description	Brentuximab vedotin 1.8 mg/kg, 30-minute IV infusion, Day 1 of every 3-week cycle, until there is evidence of disease progression or unacceptable toxicity occurs (Up to 16 cycles). The dose could be decreased or delayed or discontinued in participants who develop treatment-associated non-hematologic toxicity, hematologic toxicity or peripheral neuropathy to brentuximab vedotin.
All Cause Mortality
	Brentuximab Vedotin 1.8 mg/kg
	Affected / at Risk (%)	# Events
Total	22/60 (36.7%)
Serious Adverse Events
	Brentuximab Vedotin 1.8 mg/kg
	Affected / at Risk (%)	# Events
Total	11/60 (18.3%)
Cardiac disorders
Tachycardia	1/60 (1.7%)
Gastrointestinal disorders
Vomiting	1/60 (1.7%)
General disorders
General physical health deterioration	1/60 (1.7%)
Immune system disorders
Serum sickness-like reaction	1/60 (1.7%)
Anaphylactic reaction	1/60 (1.7%)
Infections and infestations
Bronchitis	1/60 (1.7%)
Pneumonia	1/60 (1.7%)
Device related sepsis	1/60 (1.7%)
Septic shock	1/60 (1.7%)
Dengue fever	1/60 (1.7%)
Urinary tract infection	1/60 (1.7%)
Viral infection	1/60 (1.7%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hodgkin's disease	1/60 (1.7%)
Nervous system disorders
Cerebrovascular accident	1/60 (1.7%)
Psychiatric disorders
Anxiety	1/60 (1.7%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion	1/60 (1.7%)
Vascular disorders
Vena cava thrombosis	1/60 (1.7%)
Other (Not Including Serious) Adverse Events
	Brentuximab Vedotin 1.8 mg/kg
	Affected / at Risk (%)	# Events
Total	51/60 (85%)
Blood and lymphatic system disorders
Anaemia	5/60 (8.3%)
Leukocytosis	1/60 (1.7%)
Leukopenia	1/60 (1.7%)
Neutropenia	6/60 (10%)
Thrombocytopenia	2/60 (3.3%)
Cardiac disorders
Tachycardia	2/60 (3.3%)
Ear and labyrinth disorders
Ear pain	1/60 (1.7%)
Endocrine disorders
Autoimmune thyroiditis	1/60 (1.7%)
Eye disorders
Diplopia	1/60 (1.7%)
Gastrointestinal disorders
Abdominal pain	2/60 (3.3%)
Constipation	2/60 (3.3%)
Diarrhoea	6/60 (10%)
Nausea	5/60 (8.3%)
Toothache	1/60 (1.7%)
Vomiting	4/60 (6.7%)
General disorders
Asthenia	3/60 (5%)
Catheter site inflammation	1/60 (1.7%)
Chest pain	1/60 (1.7%)
Chills	1/60 (1.7%)
Extravasation	1/60 (1.7%)
Fatigue	1/60 (1.7%)
Malaise	1/60 (1.7%)
Oedema	1/60 (1.7%)
Oedema peripheral	1/60 (1.7%)
Pyrexia	11/60 (18.3%)
Soft tissue inflammation	1/60 (1.7%)
Temperature regulation disorder	1/60 (1.7%)
Vaccination site pain	1/60 (1.7%)
Hepatobiliary disorders
Liver disorder	1/60 (1.7%)
Infections and infestations
Breast cellulitis	1/60 (1.7%)
Bronchitis	3/60 (5%)
Conjunctivitis	1/60 (1.7%)
Coxsackie viral infection	1/60 (1.7%)
Dengue fever	1/60 (1.7%)
Device related infection	1/60 (1.7%)
Herpes zoster	1/60 (1.7%)
Hordeolum	1/60 (1.7%)
Influenza	1/60 (1.7%)
Klebsiella infection	1/60 (1.7%)
Nasopharyngitis	2/60 (3.3%)
Oral herpes	2/60 (3.3%)
Pseudomonas infection	1/60 (1.7%)
Sinusitis	1/60 (1.7%)
Subcutaneous abscess	2/60 (3.3%)
Upper respiratory tract infection	5/60 (8.3%)
Viral infection	1/60 (1.7%)
Injury, poisoning and procedural complications
Contusion	1/60 (1.7%)
Ligament sprain	1/60 (1.7%)
Procedural pain	1/60 (1.7%)
Investigations
Alanine aminotransferase increased	2/60 (3.3%)
Aspartate aminotransferase increased	2/60 (3.3%)
Blood alkaline phosphatase increased	1/60 (1.7%)
Blood lactate dehydrogenase increased	1/60 (1.7%)
Blood thyroid stimulating hormone increased	1/60 (1.7%)
Gamma-glutamyltransferase increased	1/60 (1.7%)
Haemoglobin decreased	1/60 (1.7%)
Lymphocyte count decreased	1/60 (1.7%)
Neutrophil count decreased	2/60 (3.3%)
Platelet count decreased	1/60 (1.7%)
Weight decreased	1/60 (1.7%)
Metabolism and nutrition disorders
Decreased appetite	4/60 (6.7%)
Hyperglycaemia	1/60 (1.7%)
Hyperuricaemia	1/60 (1.7%)
Hypokalaemia	3/60 (5%)
Hypomagnesaemia	3/60 (5%)
Musculoskeletal and connective tissue disorders
Arthralgia	4/60 (6.7%)
Back pain	2/60 (3.3%)
Bone pain	2/60 (3.3%)
Pain in extremity	1/60 (1.7%)
Nervous system disorders
Autonomic neuropathy	1/60 (1.7%)
Dysgeusia	1/60 (1.7%)
Facial nerve disorder	1/60 (1.7%)
Headache	2/60 (3.3%)
Neuropathy peripheral	6/60 (10%)
Paraesthesia	3/60 (5%)
Peripheral sensory neuropathy	7/60 (11.7%)
Polyneuropathy	5/60 (8.3%)
Somnolence	1/60 (1.7%)
Psychiatric disorders
Depression	2/60 (3.3%)
Insomnia	1/60 (1.7%)
Renal and urinary disorders
Renal tubular disorder	1/60 (1.7%)
Reproductive system and breast disorders
Genital haemorrhage	1/60 (1.7%)
Respiratory, thoracic and mediastinal disorders
Cough	3/60 (5%)
Dyspnoea	1/60 (1.7%)
Dyspnoea exertional	1/60 (1.7%)
Nasal congestion	1/60 (1.7%)
Upper respiratory tract inflammation	1/60 (1.7%)
Skin and subcutaneous tissue disorders
Alopecia	3/60 (5%)
Dermatitis	1/60 (1.7%)
Dermatitis acneiform	1/60 (1.7%)
Dermatitis allergic	1/60 (1.7%)
Dermatitis contact	1/60 (1.7%)
Erythema	1/60 (1.7%)
Pruritus	2/60 (3.3%)
Pruritus generalised	1/60 (1.7%)
Rash	2/60 (3.3%)
Rash macular	1/60 (1.7%)
Rash maculo-papular	1/60 (1.7%)
Rash papular	1/60 (1.7%)
Rash pruritic	1/60 (1.7%)
Urticaria	1/60 (1.7%)
Vascular disorders
Haematoma	1/60 (1.7%)
Lymphoedema	1/60 (1.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.