Study of Brentuximab Vedotin Combined With Bendamustine in Patients With Hodgkin Lymphoma

• Sponsor: Seagen Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01874054
• Collaborator: (none)
• Enrollment: 55
• Locations: 13
• Arm: 1
• Duration (Months): 56.7
• Patients Per Site: 4.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to assess safety and efficacy of brentuximab vedotin in combination with bendamustine in patients with relapsed or refractory Hodgkin lymphoma. It is an open-label, 2-stage study designed to determine the recommended dose level of bendamustine in combination with brentuximab vedotin. The study will assess the safety profile of the combination treatment and determine what proportion of patients achieve a complete remission.

Condition or Disease	Intervention/Treatment	Phase
Hodgkin Disease	Drug: brentuximab vedotin; Drug: bendamustine	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 55 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1/2 Single-arm, Open-label Study to Evaluate the Safety and Efficacy of Brentuximab Vedotin in Combination With Bendamustine in Patients With Relapsed or Refractory Hodgkin Lymphoma (HL)
• Study Start Date: Jun 1, 2013
• Actual Primary Completion Date: Dec 1, 2015
• Actual Study Completion Date: Feb 20, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Brentuximab Vedotin + Bendamustine Brentuximab vedotin 1.8 mg/kg every 3 weeks for up to 16 cycles by IV infusion and bendamustine 90 mg/m2 on Days 1 and 2 every 3 weeks by IV infusion for up to 6 cycles	Drug: brentuximab vedotin; 1.8 mg/kg every 3 weeks by intravenous (IV) infusion; Other Names: Adcetris; SGN-35 ; Drug: bendamustine; 90 mg/m2 on Days 1 and 2 of 3-week cycles

Outcome Measures

Primary Outcome Measures

1. Complete Remission Rate [Up to 4.6 months]

   Complete remission rate among all subjects (Phase 1 and 2 combined) treated at the dose level selected for Phase 2. Complete remission (CR) per Cheson 2007 Revised Response Criteria for Malignant Lymphoma is a disappearance of all evidence of disease.

2. Incidence of Adverse Events (AEs) [Up to 13.8 months]

   All AEs reported after initiation of treatment and pre-existing conditions that worsen after initiation of treatment will be considered treatment-emergent AEs (TEAEs). All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE V4.03. All recorded AEs will be included in the data listings.

Secondary Outcome Measures

1. Incidence of Dose-limiting Toxicities [Up to 3 weeks; first cycle of therapy through the first day of Cycle 2]

   Incidence of dose-limiting toxicity (DLT) was evaluated in an initial safety cohort of 10 patients who were followed for protocol-defined DLT events until Cycle 2 Day 1.

2. Overall Best Response Rate [Up to 4.6 months]

   Percentage of participants who achieved a best response of complete remission (CR, disappearance of all evidence of disease), partial remission (PR, regression of greater than or equal to 50% of measurable disease and no new sites), stable disease (SD, failure to obtain a complete or partial response or progressive disease), or progressive disease (PD, any new lesion or increase by 50% or more of previously involved sites from nadir) per Cheson 2007 Revised Response Criteria for Malignant Lymphoma

3. Duration of Response [Up to 47.8 months]

   The time from first observation of remission to disease progression/relapse or death from any cause, whichever occurs first.

4. Progression-free Survival [Up to 49 months]

   The time from first dose of study medication to first documentation of disease progression/relapse, or to death due to any cause, whichever occurs first.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histopathological diagnosis of classical Hodgkin lymphoma

• Failed standard front-line therapy

• Measurable disease of at least 1.5 cm as documented by radiographic technique

• Eastern Cooperative Oncology Group performance status less than or equal to 2

Exclusion Criteria:

• Received prior salvage therapy, including radiotherapy

• Chemotherapy, radiotherapy, biologics, and/or other treatment with immunotherapy not completed 4 weeks prior to first dose of study drug

• Concurrent use of other investigational agents

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294
2	Pacific Hematology Oncology Associates	San Francisco	California	United States	94115
3	Stanford Cancer Center	Stanford	California	United States	94305
4	Oncology Institute of Hope & Innovation, The	Whittier	California	United States	90603
5	Colorado Blood Cancer Institute	Denver	Colorado	United States	80218
6	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
7	Mayo Clinic Minnesota	Rochester	Minnesota	United States	55905
8	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198-7680
9	Columbia University Medical Center	New York	New York	United States	10022
10	Jewish Hospital, The	Cincinnati	Ohio	United States	45236
11	Case Western Reserve University / University Hospitals Case Medical Center	Cleveland	Ohio	United States	44106
12	Saint Francis Hospital / Bon Secours	Greenville	South Carolina	United States	29601
13	Charles A. Sammons Cancer Center / Baylor University Medical Center	Dallas	Texas	United States	75246

Sponsors and Collaborators

• Seagen Inc.

Investigators

• Study Director: Neil Josephson, MD, Seagen Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Seagen Inc.
• ClinicalTrials.gov Identifier: NCT01874054
• Other Study ID Numbers: SGN35-016
• First Posted: Jun 10, 2013
• Last Update Posted: Feb 12, 2019
• Last Verified: Jan 1, 2019

• Keywords provided by Seagen Inc.: Antibody-Drug Conjugate; Antibodies, Monoclonal; Hodgkin Disease; Hematologic Diseases; Drug Therapy; Immunotherapy; Antigens, CD30; Lymphoma; monomethylauristatin E
• Additional relevant MeSH terms: Lymphoma; Hodgkin Disease; Bendamustine Hydrochloride; Brentuximab Vedotin

Study Results

Participant Flow

Recruitment Details	June 2013 - July 2016

Arm/Group Title	Brentuximab Vedotin + Bendamustine
Arm/Group Description	brentuximab vedotin (BV): 1.8 mg/kg on Day 1 of 3-week cycles by intravenous (IV) infusion bendamustine: 90 mg/m^2 on Days 1 and 2 of 3-week cycles by intravenous (IV) infusion
Period Title: Overall Study
STARTED	55
Completed ≥2 Cycles of Combo Treatment	53
Completed 16 Cycles of BV Treatment	17
COMPLETED	0
NOT COMPLETED	55

Baseline Characteristics

Arm/Group Title	Brentuximab Vedotin + Bendamustine
Arm/Group Description	brentuximab vedotin: 1.8 mg/kg on Day 1 of 3-week cycles by intravenous (IV) infusion bendamustine: 90 mg/m^2 on Days 1 and 2 of 3-week cycles by intravenous (IV) infusion
Overall Participants	55
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	50 90.9%
>=65 years	5 9.1%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	36
Sex: Female, Male (Count of Participants)
Female	31 56.4%
Male	24 43.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 5.5%
Not Hispanic or Latino	51 92.7%
Unknown or Not Reported	1 1.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	6 10.9%
White	46 83.6%
More than one race	0 0%
Unknown or Not Reported	3 5.5%
Region of Enrollment (participants) [Number]
United States	55 100%
Eastern Cooperative Group Oncology Performance Status (Count of Participants)
0	31 56.4%
1	23 41.8%
2	1 1.8%

Outcome Measures

1. Primary Outcome

Title	Complete Remission Rate
Description	Complete remission rate among all subjects (Phase 1 and 2 combined) treated at the dose level selected for Phase 2. Complete remission (CR) per Cheson 2007 Revised Response Criteria for Malignant Lymphoma is a disappearance of all evidence of disease.
Time Frame	Up to 4.6 months

Outcome Measure Data

Analysis Population Description

All patients who received at least 2 cycles of combination treatment at the recommended dose level and had a baseline tumor assessment and at least 1 postbaseline tumor assessment, or who had documented disease progression (including clinical disease progression) at any time after the first dose of combination therapy at the recommended dose level.

Arm/Group Title	Brentuximab Vedotin + Bendamustine
Arm/Group Description	brentuximab vedotin: 1.8 mg/kg on Day 1 of 3-week cycles by intravenous (IV) infusion bendamustine: 90 mg/m^2 on Days 1 and 2 of 3-week cycles by intravenous (IV) infusion
Measure Participants	53
Number (95% Confidence Interval) [percentage of participants]	73.6 133.8%

2. Primary Outcome

Title	Incidence of Adverse Events (AEs)
Description	All AEs reported after initiation of treatment and pre-existing conditions that worsen after initiation of treatment will be considered treatment-emergent AEs (TEAEs). All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE V4.03. All recorded AEs will be included in the data listings.
Time Frame	Up to 13.8 months

Outcome Measure Data

Analysis Population Description

All subjects who were enrolled and received at least 1 dose of brentuximab vedotin.

Arm/Group Title	Brentuximab Vedotin + Bendamustine
Arm/Group Description	brentuximab vedotin: 1.8 mg/kg on Day 1 of 3-week cycles by intravenous (IV) infusion bendamustine: 90 mg/m^2 on Days 1 and 2 of 3-week cycles by intravenous (IV) infusion
Measure Participants	55
Any Treatment-Emergent Adverse Event (TEAE)	55 100%
Any TEAE with Severity >= Grade 3	31 56.4%
Any Treatment-Related Adverse Event	54 98.2%
Any Serious Adverse Event	18 32.7%
Any Treatment-Related Serious Adverse Event	15 27.3%
Treatment Discontinuation Due to Adverse Event	20 36.4%

3. Secondary Outcome

Title	Incidence of Dose-limiting Toxicities
Description	Incidence of dose-limiting toxicity (DLT) was evaluated in an initial safety cohort of 10 patients who were followed for protocol-defined DLT events until Cycle 2 Day 1.
Time Frame	Up to 3 weeks; first cycle of therapy through the first day of Cycle 2

Outcome Measure Data

Analysis Population Description

An initial safety cohort of 10 patients who enrolled and received at least 1 dose of brentuximab vedotin were evaluated for this outcome.

Arm/Group Title	Brentuximab Vedotin + Bendamustine
Arm/Group Description	brentuximab vedotin: 1.8 mg/kg on Day 1 of 3-week cycles by intravenous (IV) infusion bendamustine: 90 mg/m^2 on Days 1 and 2 of 3-week cycles by intravenous (IV) infusion
Measure Participants	10
Count of Participants [Participants]	0 0%

4. Secondary Outcome

Title	Overall Best Response Rate
Description	Percentage of participants who achieved a best response of complete remission (CR, disappearance of all evidence of disease), partial remission (PR, regression of greater than or equal to 50% of measurable disease and no new sites), stable disease (SD, failure to obtain a complete or partial response or progressive disease), or progressive disease (PD, any new lesion or increase by 50% or more of previously involved sites from nadir) per Cheson 2007 Revised Response Criteria for Malignant Lymphoma
Time Frame	Up to 4.6 months

Outcome Measure Data

Analysis Population Description

All patients who received at least 2 cycles of combination treatment, had a baseline tumor assessment, and at least 1 post-baseline tumor assessment, or who had documented disease progression (including clinical disease progression) any time after the first dose of combination therapy.

Arm/Group Title	Brentuximab Vedotin + Bendamustine
Arm/Group Description	brentuximab vedotin: 1.8 mg/kg on Day 1 of 3-week cycles by intravenous (IV) infusion bendamustine: 90 mg/m^2 on Days 1 and 2 of 3-week cycles by intravenous (IV) infusion
Measure Participants	53
Complete Remission	39 70.9%
Partial Remission	10 18.2%
Stable Disease	3 5.5%
Progressive Disease	1 1.8%

5. Secondary Outcome

Title	Duration of Response
Description	The time from first observation of remission to disease progression/relapse or death from any cause, whichever occurs first.
Time Frame	Up to 47.8 months

Outcome Measure Data

Analysis Population Description

Patients with a complete or partial response who received at least 2 cycles of combination treatment and had a baseline tumor assessment and at least 2 post-baseline tumor assessment, or who had documented disease progression (including clinical disease progression) at any time after the first dose of combination therapy.

Arm/Group Title	Brentuximab Vedotin + Bendamustine
Arm/Group Description	brentuximab vedotin: 1.8 mg/kg on Day 1 of 3-week cycles by intravenous (IV) infusion bendamustine: 90 mg/m^2 on Days 1 and 2 of 3-week cycles by intravenous (IV) infusion
Measure Participants	49
Median (95% Confidence Interval) [months]	43.0

6. Secondary Outcome

Title	Progression-free Survival
Description	The time from first dose of study medication to first documentation of disease progression/relapse, or to death due to any cause, whichever occurs first.
Time Frame	Up to 49 months

Outcome Measure Data

Analysis Population Description

All patients who received at least 2 cycles of combination treatment and had a baseline tumor assessment and at least 1 post-baseline tumor assessment, or who had documented disease progression (including clinical disease progression) at any time after the first dose of combination therapy.

Arm/Group Title	Brentuximab Vedotin + Bendamustine
Arm/Group Description	brentuximab vedotin: 1.8 mg/kg on Day 1 of 3-week cycles by intravenous (IV) infusion bendamustine: 90 mg/m^2 on Days 1 and 2 of 3-week cycles by intravenous (IV) infusion
Measure Participants	53
Median (95% Confidence Interval) [months]	44.2

Adverse Events

Time Frame	Up to 13.8 months
Adverse Event Reporting Description	Treatment-emergent adverse events: a newly occurring or worsening adverse event after the first dose of study drug.
Arm/Group Title	Brentuximab Vedotin + Bendamustine
Arm/Group Description	brentuximab vedotin: 1.8 mg/kg on Day 1 of 3-week cycles by intravenous (IV) infusion bendamustine: 90 mg/m^2 on Days 1 and 2 of 3-week cycles by intravenous (IV) infusion
All Cause Mortality
	Brentuximab Vedotin + Bendamustine
	Affected / at Risk (%)	# Events
Total	5/55 (9.1%)
Serious Adverse Events
	Brentuximab Vedotin + Bendamustine
	Affected / at Risk (%)	# Events
Total	18/55 (32.7%)
Blood and lymphatic system disorders
Febrile neutropenia	2/55 (3.6%)
Gastrointestinal disorders
Diarrhoea	2/55 (3.6%)
Nausea	2/55 (3.6%)
Vomiting	2/55 (3.6%)
Colitis	1/55 (1.8%)
General disorders
Pyrexia	8/55 (14.5%)
Chills	3/55 (5.5%)
Malaise	2/55 (3.6%)
Pain	1/55 (1.8%)
Infections and infestations
Phlebitis infective	1/55 (1.8%)
Pneumonia	1/55 (1.8%)
Metabolism and nutrition disorders
Decreased appetite	2/55 (3.6%)
Dehydration	2/55 (3.6%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/55 (1.8%)
Myalgia	1/55 (1.8%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Myelodysplastic syndrome	1/55 (1.8%)
Nervous system disorders
Syncope	1/55 (1.8%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/55 (1.8%)
Hypoxia	1/55 (1.8%)
Pneumonitis	1/55 (1.8%)
Pulmonary embolism	1/55 (1.8%)
Throat tightness	1/55 (1.8%)
Wheezing	1/55 (1.8%)
Skin and subcutaneous tissue disorders
Rash maculo-papular	2/55 (3.6%)
Urticaria	2/55 (3.6%)
Erythema	1/55 (1.8%)
Rash papular	1/55 (1.8%)
Vascular disorders
Hypotension	5/55 (9.1%)
Deep vein thrombosis	1/55 (1.8%)
Other (Not Including Serious) Adverse Events
	Brentuximab Vedotin + Bendamustine
	Affected / at Risk (%)	# Events
Total	55/55 (100%)
Blood and lymphatic system disorders
Lymphopenia	7/55 (12.7%)
Neutropenia	4/55 (7.3%)
Cardiac disorders
Tachycardia	3/55 (5.5%)
Ear and labyrinth disorders
Ear pain	3/55 (5.5%)
Gastrointestinal disorders
Nausea	40/55 (72.7%)
Diarrhoea	20/55 (36.4%)
Vomiting	20/55 (36.4%)
Constipation	17/55 (30.9%)
Abdominal pain	5/55 (9.1%)
Dry mouth	4/55 (7.3%)
Dyspepsia	4/55 (7.3%)
Dysphagia	4/55 (7.3%)
Gastrooesophageal reflux disease	3/55 (5.5%)
General disorders
Fatigue	30/55 (54.5%)
Chills	15/55 (27.3%)
Pyrexia	15/55 (27.3%)
Oedemia peripheral	7/55 (12.7%)
Pain	7/55 (12.7%)
Malaise	4/55 (7.3%)
Non-cardiac chest pain	4/55 (7.3%)
Asthenia	3/55 (5.5%)
Chest discomfort	3/55 (5.5%)
Infections and infestations
Upper respiratory tract infection	8/55 (14.5%)
Urinary tract infection	5/55 (9.1%)
Herpes zoster	3/55 (5.5%)
Investigations
Weight decreased	5/55 (9.1%)
Metabolism and nutrition disorders
Decreased appetite	10/55 (18.2%)
Dehydration	5/55 (9.1%)
Hypokalaemia	5/55 (9.1%)
Hyperglycaemia	4/55 (7.3%)
Hyperuricaemia	3/55 (5.5%)
Musculoskeletal and connective tissue disorders
Back pain	10/55 (18.2%)
Bone pain	9/55 (16.4%)
Arthralgia	8/55 (14.5%)
Muscular weakness	7/55 (12.7%)
Pain in extremity	4/55 (7.3%)
Musculoskeletal pain	3/55 (5.5%)
Neck pain	3/55 (5.5%)
Nervous system disorders
Peripheral sensory neuropathy	14/55 (25.5%)
Headache	11/55 (20%)
Neuropathy peripheral	10/55 (18.2%)
Dizziness	8/55 (14.5%)
Paraesthesia	8/55 (14.5%)
Hypoaesthesia	4/55 (7.3%)
Dysgeusia	3/55 (5.5%)
Psychiatric disorders
Insomnia	11/55 (20%)
Anxiety	5/55 (9.1%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	14/55 (25.5%)
Cough	13/55 (23.6%)
Nasal congestion	7/55 (12.7%)
Oropharyngeal pain	6/55 (10.9%)
Dyspnoea exertional	5/55 (9.1%)
Productive cough	4/55 (7.3%)
Pulmonary embolism	3/55 (5.5%)
Throat tightness	3/55 (5.5%)
Wheezing	3/55 (5.5%)
Skin and subcutaneous tissue disorders
Alopecia	14/55 (25.5%)
Rash	14/55 (25.5%)
Pruritus	13/55 (23.6%)
Rash generalised	7/55 (12.7%)
Rash maculo-papular	7/55 (12.7%)
Rash pruritic	6/55 (10.9%)
Night sweats	5/55 (9.1%)
Erythema	3/55 (5.5%)
Pruritus generalised	3/55 (5.5%)
Rash erythematous	3/55 (5.5%)
Swelling face	3/55 (5.5%)
Vascular disorders
Flushing	10/55 (18.2%)
Hot flush	6/55 (10.9%)
Hypotension	3/55 (5.5%)

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 18 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 the 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.