A Phase 1 Study in Patients With Relapsed or Refractory Hodgkin Lymphoma or Systemic Anaplastic Large Cell Lymphoma

A Phase 1 Study to Estimate MMAE Metabolites in Human Plasma and Urine in Patients With Relapsed or Refractory Classical Hodgkin Lymphoma or Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma Receiving Brentuximab Vedotin

This is an open-label trial to estimate the concentrations of brentuximab vedotin in relapsed/refractory Hodgkin lymphoma (HL) or relapsed/refractory systemic anaplastic large cell lymphoma (sALCL) participants treated with either brentuximab vedotin or brentuximab vedotin + rifampicin.

Study Overview

• Status: Completed
• Conditions: Hodgkin Lymphoma; Anaplastic Large-cell Lymphoma
• Intervention / Treatment: Drug: brentuximab vedotin; Drug: Brentuximab vedotin and rifampicin

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium
  • Gent, Belgium
• Lithuania
  • Vilnius, Lithuania
• Spain
  • Barcelona, Spain
  • Madrid, Spain
  • Salamanca, Spain

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female participants between 18 years and 75 years old, with relapsed or refractory HL or relapsed or refractory sALCL who have previously received at least 1 multiagent chemotherapy
• Measurable disease
• An Eastern Cooperative Oncology Group (ECOG) performance of 0 or 1
• 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, from the time of signing the informed consent form through 30 days after the last dose of study drug, or agree to practice true abstinence
• 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
• Clinical laboratory values as specified in the study protocol

Exclusion Criteria:

• Participants for whom rifampicin is contraindicated
• Previously received an allogeneic transplant.
• Participants with current diagnosis of primary cutaneous anaplastic large cell lymphoma (ALCL) (participants whose ALCL has transformed to sALCL are eligible).
• Known cerebral/meningeal disease including signs or symptoms of progressive multifocal leukoencephalopathy (PML)
• Female participants who are lactating and breastfeeding or pregnant
• Known human immunodeficiency virus (HIV) positive,
• Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Arm A: Brentuximab vedotin; Brentuximab vedotin will be administered every 3 weeks at a dose of 1.8 mg/kg.	Drug: brentuximab vedotin; Brentuximab vedotin will be administered every 3 weeks at a dose of 1.8 mg/kg.; Other Names: SGN-35
EXPERIMENTAL: Arm B: Brentuximab vedotin and rifampicin; Brentuximab vedotin will be administered every 3 weeks at a dose of 1.8 mg/kg beginning on Cycle 1, Day 1; daily rifampicin (600 mg PO) will be administered during Cycles 0 through 3 only, beginning on Cycle 0, Day 1 (7 days before the Cycle 1, Day 1 dose of brentuximab vedotin) and continuing through Cycle 3, Day 21.	Drug: Brentuximab vedotin and rifampicin; Brentuximab vedotin will be administered every 3 weeks at a dose of 1.8 mg/kg beginning on Cycle 1, Day 1; daily rifampicin (600 mg PO) will be administered during Cycles 0 through 3 only, beginning on Cycle 0, Day 1 (7 days before the Cycle 1, Day 1 dose of brentuximab vedotin) and continuing through Cycle 3, Day 21.; Other Names: SGN-35

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma Concentration of Monomethylauristatin E (MMAE) and Its Metabolites at Cycle 1, Predose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. The lower limit of Quantification (LLQ) for all the observations was 0.01 nanogram/milliliter (ng/mL).	Cycle 1: Predose
Plasma Concentration of Monomethylauristatin E (MMAE) and Its Metabolites at Cycle 2, Predose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. The LLQ for all the observations was 0.01 ng/mL.	Cycle 2: Predose
Plasma Concentration of Monomethylauristatin E (MMAE) and Its Metabolites at Cycle 3, Predose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. The LLQ for all the observations was 0.01 ng/mL.	Cycle 3: Predose
Plasma Concentration of Monomethylauristatin E (MMAE) and Its Metabolites at Cycle 1, 0.5 Hour Postdose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. The LLQ for all the observations was 0.01 ng/mL.	Cycle 1: 0.5 hour postdose
Plasma Concentration of Monomethylauristatin E (MMAE) and Its Metabolites at Cycle 2, 0.5 Hour Postdose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. The LLQ for all the observations was 0.01 ng/mL.	Cycle 2: 0.5 hour postdose
Plasma Concentration of Monomethylauristatin E (MMAE) and Its Metabolites at Cycle 3, 0.5 Hour Postdose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. The LLQ for all the observations was 0.01 ng/mL.	Cycle 3: 0.5 hour postdose
Plasma Concentration of Monomethylauristatin E (MMAE) and Its Metabolites at Cycle 1, 4 Hour Postdose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. The LLQ for all the observations was 0.01 ng/mL.	Cycle 1: 4 hour postdose
Plasma Concentration of Monomethylauristatin E (MMAE) and Its Metabolites at Cycle 3, 4 Hour Postdose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. The LLQ for all the observations was 0.01 ng/mL.	Cycle 3: 4 hour postdose
Plasma Concentration of Monomethylauristatin E (MMAE) and Its Metabolites at Cycle 1, 24 Hour Postdose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. The LLQ for all the observations was 0.01 ng/mL.	Cycle 1: 24 hour postdose
Plasma Concentration of Monomethylauristatin E (MMAE) and Its Metabolites at Cycle 3, 24 Hour Postdose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. The LLQ for all the observations was 0.01 ng/mL.	Cycle 3: 24 hour postdose
Plasma Concentration of Monomethylauristatin E (MMAE) and Its Metabolites at Cycle 1, 48 Hour Postdose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. The LLQ for all the observations was 0.01 ng/mL.	Cycle 1: 48 hour postdose
Plasma Concentration of Monomethylauristatin E (MMAE) and Its Metabolites at Cycle 3, 48 Hour Postdose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. The LLQ for all the observations was 0.01 ng/mL.	Cycle 3: 48 hour postdose
Plasma Concentration of Monomethylauristatin E (MMAE) and Its Metabolites at Cycle 1, 72 Hour Postdose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. The LLQ for all the observations was 0.01 ng/mL.	Cycle 1: 72 hour postdose
Plasma Concentration of Monomethylauristatin E (MMAE) and Its Metabolites at Cycle 3, 72 Hour Postdose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. The LLQ for all the observations was 0.01 ng/mL.	Cycle 3: 72 hour postdose
Plasma Concentration of Monomethylauristatin E (MMAE) and Its Metabolites at Cycle 1, 96 Hour Postdose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. The LLQ for all the observations was 0.01 ng/mL.	Cycle 1: 96 hour postdose
Plasma Concentration of Monomethylauristatin E (MMAE) and Its Metabolites at Cycle 3, 96 Hour Postdose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. The LLQ for all the observations was 0.01 ng/mL.	Cycle 3: 96 hour postdose
Plasma Concentration of Monomethylauristatin E (MMAE) and Its Metabolites at Cycle 1, 144 Hour Postdose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. The LLQ for all the observations was 0.01 ng/mL.	Cycle 1: 144 hour postdose
Plasma Concentration of Monomethylauristatin E (MMAE) and Its Metabolites at Cycle 3, 144 Hour Postdose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. The LLQ for all the observations was 0.01 ng/mL.	Cycle 3: 144 hour postdose
Plasma Concentration of Monomethylauristatin E (MMAE) and Its Metabolites at Cycle 1, 336 Hour Postdose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. The LLQ for all the observations was 0.01 ng/mL.	Cycle 1: 336 hour postdose
Plasma Concentration of Monomethylauristatin E (MMAE) and Its Metabolites at Cycle 3, 336 Hour Postdose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. The LLQ for all the observations was 0.01 ng/mL.	Cycle 3: 336 hour postdose
Plasma Concentration of Monomethylauristatin E (MMAE) and Its Metabolites at Cycle 3, 480 Hour Postdose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. The LLQ for all the observations was 0.01 ng/mL.	Cycle 3: 480 hour postdose
Amount of Monomethylauristatin E (MMAE) and Its Metabolites Excreted in Urine at Cycle 1, Predose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. Amount of MMAE and its metabolites in urine were determined by multiplying the volume of urine obtained and the concentration of MMAE and its metabolites present in it, respectively. The LLQ for determining the concentration was 0.01 ng/mL.	Cycle 1: Predose
Amount of Monomethylauristatin E (MMAE) and Its Metabolites Excreted in Urine at Cycle 1, 0-24 Hours Postdose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. Amount of MMAE and its metabolites in urine were determined by multiplying the volume of urine obtained and the concentration of MMAE and its metabolites present in it, respectively. The LLQ for determining the concentration was 0.01 ng/mL.	Cycle 1: 0-24 hours postdose
Amount of Monomethylauristatin E (MMAE) and Its Metabolites Excreted in Urine at Cycle 1, 24-48 Hours Postdose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. Amount of MMAE and its metabolites in urine were determined by multiplying the volume of urine obtained and the concentration of MMAE and its metabolites present in it, respectively. The LLQ for determining the concentration was 0.01 ng/mL.	Cycle 1: 24-48 hours postdose
Amount of Monomethylauristatin E (MMAE) and Its Metabolites Excreted in Urine at Cycle 1, 48-72 Hours Postdose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. Amount of MMAE and its metabolites in urine were determined by multiplying the volume of urine obtained and the concentration of MMAE and its metabolites present in it, respectively. The LLQ for determining the concentration was 0.01 ng/mL.	Cycle 1: 48-72 hours postdose
Amount of Monomethylauristatin E (MMAE) and Its Metabolites Excreted in Urine at Cycle 1, 72-96 Hours Postdose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. Amount of MMAE and its metabolites in urine were determined by multiplying the volume of urine obtained and the concentration of MMAE and its metabolites present in it, respectively. The LLQ for determining the concentration was 0.01 ng/mL.	Cycle 1: 72-96 hours postdose
Amount of Monomethylauristatin E (MMAE) and Its Metabolites Excreted in Urine at Cycle 1, 96-120 Hours Postdose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. Amount of MMAE and its metabolites in urine were determined by multiplying the volume of urine obtained and the concentration of MMAE and its metabolites present in it, respectively. The LLQ for determining the concentration was 0.01 ng/mL.	Cycle 1: 96-120 hours postdose
Amount of Monomethylauristatin E (MMAE) and Its Metabolites Excreted in Urine at Cycle 1, 120-144 Hours Postdose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. Amount of MMAE and its metabolites in urine were determined by multiplying the volume of urine obtained and the concentration of MMAE and its metabolites present in it, respectively. The LLQ for determining the concentration was 0.01 ng/mL.	Cycle 1: 120-144 hours postdose
Amount of Monomethylauristatin E (MMAE) and Its Metabolites Excreted in Urine at Cycle 1, 144-168 Hours Postdose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. Amount of MMAE and its metabolites in urine were determined by multiplying the volume of urine obtained and the concentration of MMAE and its metabolites present in it, respectively. The LLQ for determining the concentration was 0.01 ng/mL.	Cycle 1: 144-168 hours postdose
Amount of Monomethylauristatin E (MMAE) and Its Metabolites Excreted in Urine at Cycle 1, 336-360 Hours Postdose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. Amount of MMAE and its metabolites in urine were determined by multiplying the volume of urine obtained and the concentration of MMAE and its metabolites present in it, respectively. The LLQ for determining the concentration was 0.01 ng/mL.	Cycle 1: 336-360 hours postdose
Amount of Monomethylauristatin E (MMAE) and Its Metabolites Excreted in Urine at Cycle 1, 480-504 Hours Postdose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. Amount of MMAE and its metabolites in urine were determined by multiplying the volume of urine obtained and the concentration of MMAE and its metabolites present in it, respectively. The LLQ for determining the concentration was 0.01 ng/mL.	Cycle 1: 480-504 hours postdose
Amount of Monomethylauristatin E (MMAE) and Its Metabolites Excreted in Urine at Cycle 3, Predose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. Amount of MMAE and its metabolites in urine were determined by multiplying the volume of urine obtained and the concentration of MMAE and its metabolites present in it, respectively. The LLQ for determining the concentration was 0.01 ng/mL.	Cycle 3: Predose
Amount of Monomethylauristatin E (MMAE) and Its Metabolites Excreted in Urine at Cycle 3, 0-24 Hours Postdose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. Amount of MMAE and its metabolites in urine were determined by multiplying the volume of urine obtained and the concentration of MMAE and its metabolites present in it, respectively. The LLQ for determining the concentration was 0.01 ng/mL.	Cycle 3: 0-24 hours postdose
Amount of Monomethylauristatin E (MMAE) and Its Metabolites Excreted in Urine at Cycle 3, 24-48 Hours Postdose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. Amount of MMAE and its metabolites in urine were determined by multiplying the volume of urine obtained and the concentration of MMAE and its metabolites present in it, respectively. The LLQ for determining the concentration was 0.01 ng/mL.	Cycle 3: 24-48 hours postdose
Amount of Monomethylauristatin E (MMAE) and Its Metabolites Excreted in Urine at Cycle 3, 48-72 Hours Postdose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. Amount of MMAE and its metabolites in urine were determined by multiplying the volume of urine obtained and the concentration of MMAE and its metabolites present in it, respectively. The LLQ for determining the concentration was 0.01 ng/mL.	Cycle 3: 48-72 hours postdose
Amount of Monomethylauristatin E (MMAE) and Its Metabolites Excreted in Urine at Cycle 3, 72-96 Hours Postdose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. Amount of MMAE and its metabolites in urine were determined by multiplying the volume of urine obtained and the concentration of MMAE and its metabolites present in it, respectively. The LLQ for determining the concentration was 0.01 ng/mL.	Cycle 3: 72-96 hours postdose
Amount of Monomethylauristatin E (MMAE) and Its Metabolites Excreted in Urine at Cycle 3, 96-120 Hours Postdose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. Amount of MMAE and its metabolites in urine were determined by multiplying the volume of urine obtained and the concentration of MMAE and its metabolites present in it, respectively. The LLQ for determining the concentration was 0.01 ng/mL.	Cycle 3: 96-120 hours postdose
Amount of Monomethylauristatin E (MMAE) and Its Metabolites Excreted in Urine at Cycle 3, 120-144 Hours Postdose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. Amount of MMAE and its metabolites in urine were determined by multiplying the volume of urine obtained and the concentration of MMAE and its metabolites present in it, respectively. The LLQ for determining the concentration was 0.01 ng/mL.	Cycle 3: 120-144 hours postdose
Amount of Monomethylauristatin E (MMAE) and Its Metabolites Excreted in Urine at Cycle 3, 144-168 Hours Postdose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. Amount of MMAE and its metabolites in urine were determined by multiplying the volume of urine obtained and the concentration of MMAE and its metabolites present in it, respectively. The LLQ for determining the concentration was 0.01 ng/mL.	Cycle 3: 144-168 hours postdose
Amount of Monomethylauristatin E (MMAE) and Its Metabolites Excreted in Urine at Cycle 3, 336-360 Hours Postdose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. Amount of MMAE and its metabolites in urine were determined by multiplying the volume of urine obtained and the concentration of MMAE and its metabolites present in it, respectively. The LLQ for determining the concentration was 0.01 ng/mL.	Cycle 3: 336-360 hours postdose
Amount of Monomethylauristatin E (MMAE) and Its Metabolites Excreted in Urine at Cycle 3, 480-504 Hours Postdose	Metabolites of MMAE includes C4, C5, C7, C8 and C13. Amount of MMAE and its metabolites in urine were determined by multiplying the volume of urine obtained and the concentration of MMAE and its metabolites present in it, respectively. The LLQ for determining the concentration was 0.01 ng/mL.	Cycle 3: 480-504 hours postdose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum Concentrations of Antibody-drug Conjugate (ADC)	The LLQ for all the observations was 12.5 ng/mL.	Cycle 1 and 3: Predose, 0.5, 4, 72, 336 hours post-dose; Cycle 2: Predose, 0.5 hours post-dose; Cycle 3: 480 hours post-dose
Serum Concentration of Total Antibody (TAb)	The LLQ for all the observations was 12.5 ng/mL.	Cycle 1 and 3: Predose, 0.5, 4, 72, 336 hours post-dose; Cycle 2: Predose, 0.5 hours post-dose; Cycle 3: 480 hours post-dose
Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; or congenital anomaly; or a medically important event. AEs included both SAE and non-SAE.	Baseline up to 30 days after last dose of study drug (30 days after Cycle 16)
Number of Participants With Anti-therapeutic Antibodies (ATA) to Brentuximab Vedotin	Participants with positive ATA at both Cycle 1 and 3, negative ATA at both Cycle 1 and 3, and transient positive (positive at one time point, but negative at the other) ATA for brentuximab vedotin were reported.	Day 1 of Cycle 1 and 3
Number of Participants With Markedly Abnormal Laboratory Values	The number of participants with any markedly abnormal standard safety laboratory values collected throughout study.	Baseline up to 30 days after last dose of study drug (30 Days after Cycle 16)
Number of Participants With Clinically Significant Change From Baseline in Vital Signs	Vital signs included body temperature, body weight, blood pressure and heart rate.	Baseline up to 30 days after last dose of study drug (30 Days after Cycle 16)

Collaborators and Investigators

• Sponsor: Millennium Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start: November 1, 2013
• Primary Completion (ACTUAL): October 1, 2014
• Study Completion (ACTUAL): June 1, 2015

Study Registration Dates

• First Submitted: September 23, 2013
• First Submitted That Met QC Criteria: September 24, 2013
• First Posted (ESTIMATE): September 25, 2013

Study Record Updates

• Last Update Posted (ESTIMATE): May 11, 2016
• Last Update Submitted That Met QC Criteria: March 30, 2016
• Last Verified: March 1, 2016

More Information

Terms related to this study

• Keywords: Drug Therapy; Immunotherapy; Lymphoma; Relapsed; Refractory; Lymphoma, Non-Hodgkin; Hematologic Diseases; Antibody-Drug Conjugate; Antibodies, Monoclonal; Lymphoma, Large-Cell, Anaplastic; Antigens, CD30; Hodgkin; Monomethyl auristatin E; Anaplastic Large-cell
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, T-Cell; Lymphoma; Hodgkin Disease; Lymphoma, Non-Hodgkin; Lymphoma, Large-Cell, Anaplastic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Anti-Bacterial Agents; Leprostatic Agents; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Antibodies, Monoclonal; Rifampin; Brentuximab Vedotin
• Other Study ID Numbers: C25005; 2013-000193-29 (EUDRACT_NUMBER); U1111-1174-1958 (REGISTRY: WHO)