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Brentuximab vedotin 1.8 mg/kg, intravenous over approximately 30 minutes, once on Day 1 of each 21-day cycle and may continue as monotherapy for up to a total of 16 cycles (48 weeks).

Methotrexate 5 to 50 mg, tablets, orally, once weekly (dose adjustment is guided by patient response and toxicity) or Bexarotene 300 mg/m\^2, tablets, orally, once daily with meals for up to 48 weeks.

Brentuximab vedotin intravenous injection.

Medical Monitor

The purpose of this study is to determine objective response rate (ORR), lasting at least 4 months (ORR4), with brentuximab vedotin in participants with cluster of differentiation antigen 30 positive (CD30+) cutaneous T-cell lymphoma \[mycosis fungoides (MF) and primary cutaneous anaplastic large cell lymphoma (pcALCL) \]compared to that achieved with therapy in the control arm.

The drug being tested in this study is called brentuximab vedotin. Brentuximab vedotin is being tested to treat people who have CD30+ cutaneous T-cell lymphoma (mycosis fungoides and primary cutaneous anaplastic large cell lymphoma). This study will look at the overall response of people who took brentuximab vedotin compared to people who took methotrexate or bexarotene as standard care.

The study enrolled 131 patients. Participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups-which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need):

* Methotrexate 5 to 50 mg or Bexarotene 300 mg/m\^2 (as per physician's choice)
* Brentuximab vedotin 1.8 mg/kg

This multicenter trial is being conducted worldwide. The overall time to participate in this study is approximately 6 years. Participants will make multiple visits to the clinic every 12 weeks for a minimum of 24 months after the end of treatment (EOT) visit, and then every 6 months until death, study closure, or 6 years after enrollment of the last participant.

A Phase 3 Trial of Brentuximab Vedotin(SGN-35) Versus Physician's Choice (Methotrexate or Bexarotene) in Participants With CD30-Positive Cutaneous T-Cell Lymphoma (ALCANZA Study)

A Randomized, Open-Label, Phase 3 Trial of Brentuximab Vedotin(SGN-35) Versus Physician's Choice (Methotrexate or Bexarotene) in Patients With CD30-Positive Cutaneous T-Cell Lymphoma

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.

ORR4 was determined by an Independent Review Facility (IRF) based on Global Response Score (GRS) which consisted of a skin assessment by the investigator using the modified severity-weighted assessment tool (mSWAT), nodal and visceral radiographic assessment by an IRF and for the participants with mycosis fungoides (MF) only, detection of circulation Sezary cells. Participants whose first response occurred after the start of subsequent anticancer therapy were excluded. Response Criteria was based on International Society for Cutaneous Lymphomas (ISCL), United States Cutaneous Lymphoma Consortium (USCLC) and Cutaneous Lymphoma Task Force (CLTF) of the European Organisation for Research and Treatment of Cancer (EORTC) Consensus guidelines (Olsen, 2011).

Complete Response (CR) was determined by the IRF based on Global Response Score (GRS) which consisted of a skin assessment by the investigator using the modified severity-weighted assessment tool (mSWAT), nodal and visceral radiographic and for the participants with mycosis fungoides (MF) only, detection of circulation Sezary cells. Response Criteria was based on ISCL, USCLC and CLTF of the EORTC Consensus guidelines (Olsen, 2011).

PFS was assessed by the IRF and is defined as the time from randomization until disease progression or death due to any cause, whichever occurs first. Disease progression was based on ISCL, USCLC and CLTF of the EORTC Consensus guidelines (Olsen, 2011).

Skindex-29 is a 29-item dermatology-specific health-related quality of life (HRQoL). The Skindex-29 incorporates a 28-day recall period and consists of 3 domains: symptoms, emotions, and functioning. The domain scores and an overall score are expressed on a 100-point scale, from 0 to 100 with higher scores indicating lower levels of health- HRQoL. A negative change (reduction) from Baseline indicates improvement.

Duration of response was assessed by the IRF in participants with confirmed response \[CR or Partial Response (PR)\] and is defined as the time between first documentation of response and disease progression. Response Criteria was based on ISCL, USCLC and CLTF of the EORTC Consensus guidelines (Olsen, 2011).

Duration of skin response (CR and PR) was assessed by the investigator and is defined as the time between the first skin response to progressive disease in skin. Per mSWAT, CR is defined as 100% clearance of skin lesions. PR is defined as 50%-99% clearance of skin disease from Baseline; No new tumors in participants without tumors at Baseline -MF; No new tumors-primary cutaneous anaplastic large cell lymphoma (pcALCL).Progressive disease is defined as ≥ 25% increase in skin disease from baseline, or loss of response: in those with CR or PR, increase of skin score of greater than the sum of nadir plus 50% baseline score, or new tumors in participants without tumors at baseline (MF).

EFS was assessed by the IRF and is defined as the time from randomization until any cause of treatment failure: disease progression, discontinuation of treatment for any reason, or death due to any cause, whichever occurs first. Disease progression was based on ISCL, USCLC and CLTF of the EORTC Consensus guidelines (Olsen, 2011).

Blood was collected and evaluated for ATA and neutralizing ATA in all participants who received brentuximab vedotin to assess immunogenicity.

Skindex-29 is a 29-item dermatology-specific health-related quality of life (HRQoL). The Skindex-29 incorporates a 28-day recall period and consists of 3 domains: symptoms, emotions, and functioning. The domain scores and an overall score are expressed on a 100-point scale, 0 to 100 with higher scores indicating lower levels of health- HRQoL. A negative change (reduction) from Baseline indicates improvement.

FACT-G is a 27-item general cancer QOL instrument completed by participants receiving cancer treatment. FACT-G incorporates a 7-day recall period and contains 4 primary subscales: Physical Well-Being (PWB; sum of 7 items, point range 0-28); Social/Family Well-Being (SWB, sum of 7-items, point range 0-28); Emotional Well-Being (EWB; sum of 6-items, point range 0-24); Functional Well-Being (FWB; sum of 7-items, point range 0-28); Fact-G total score=sum of PWB, SWB, EWB, FWB, point range 0-108. Higher scores for the total scales and subscales indicate better quality of life. A negative change (reduction) from Baseline indicates improvement.

AEs and SAEs were assessed according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. 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. A SAE is any AE that results in death, is life-threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event.

Seagen Inc.

Millennium Pharmaceuticals, Inc.

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.

Methotrexate or Bexarotene

Total

Safety population included participants who received at least 1 dose of study drug, analyzed according to the actual treatment received.

Age, Continuous

Sex: Female, Male

White

Black or African American

Asian

Not reported

Other

ITT population included all participants who were identified as CD30+ by the Ventana anti-CD30 (Ber-H2) assay and were randomized to treatment.

Race/Ethnicity, Customized

Hispanic or Latino

Not Hispanic or Latino

Australia

Belgium

France

Germany

Italy

Poland

Spain

Switzerland

United Kingdom

United States

Brazil

Region of Enrollment

Safety population included participants who received at least 1 dose of study drug, analyzed according to the actual treatment received (n=66,62). Intent-to-treat population (ITT) population included all participants who were identified as CD30+ by the Ventana anti-CD30 (Ber-H2) assay and were randomized to treatment (n=64,64).

Medical Director

Based on a two-sided Χ² test with a significance level of 0.05, and a 10% dropout rate, a sample size of approximately 124 participants was calculated to provide 90% power to detect a 30% improvement in ORR4 in the brentuximab vedotin group.

The ITT population included all participants who were identified as CD30+ by the Ventana anti-CD30 (Ber-H2) assay and were randomized to treatment.

Percentage of Participants Achieving an Objective Response That Lasts at Least 4 Months (ORR4)

Percentage of Participants Achieving a CR

Hazard ratio brentuximab vedotin/ comparator (methotrexate or bexarotene) with the 95% CI from a stratified Cox regression model with treatment as the explanatory variable and baseline disease diagnosis (MF or pcALCL) as stratification factor.

Progression-Free Survival (PFS)

P-value is calculated using the analysis of covariance (ANCOVA) model controlling for baseline symptom domain score, eastern cooperative oncology group (ECOG) performance status score (=0 and ≥1), and disease diagnosis (pcALCL and MF) between the brentuximab vedotin and comparator (methotrexate or bexarotene) arms.

The ITT population included all participants who were identified as CD30+ by the Ventana anti-CD30 (Ber-H2) assay and were randomized to treatment. Here number of participants analyzed are participants evaluable for this outcome measure.

Maximum Change From Baseline in Symptom Domain Score of the Skindex-29 Questionnaire

The ITT population included all participants who were identified as CD30+ by the Ventana anti-CD30 (Ber-H2) assay and were randomized to treatment. Responders in ITT population were analyzed in this outcome measure.

Duration of Response (DOR)

The ITT population included all participants who were identified as CD30+ by the Ventana anti-CD30 (Ber-H2) assay and were randomized to treatment. Skin responders in ITT population were analyzed in this outcome measure.

DOR of Skin Response

Event-Free Survival (EFS)

Cycle 1 Day 1

Cycle 3 Day 1

Participants with primary cutaneous anaplastic large cell lymphoma (pcALCL) received brentuximab vedotin 1.8 mg/kg, intravenous over approximately 30 minutes, once on Day 1 of each 21-day cycle and may continue as monotherapy for up to a total of 16 cycles (48 weeks).

pcALCL: Brentuximab Vedotin

Participants with mycosis fungoides (MF) received brentuximab vedotin 1.8 mg/kg, intravenous over approximately 30 minutes, once on Day 1 of each 21-day cycle and may continue as monotherapy for up to a total of 16 cycles (48 weeks).

MF: Brentuximab Vedotin 1.8 mg/kg

The pharmacokinetic (PK) population included participants with sufficient dose and PK data to reliably estimate PK parameters as determined by a clinical pharmacologist. Here 'Number analyzed' is the number of participants with evaluable data at the specified time-point.

Cmax: Maximum Observed Concentration for Brentuximab Vedotin

Cycle 2 Day 1

Cycle 4 Day 1

Participants with pcALCL received brentuximab vedotin 1.8 mg/kg, intravenous over approximately 30 minutes, once on Day 1 of each 21-day cycle and may continue as monotherapy for up to a total of 16 cycles (48 weeks).

Participants with MF received brentuximab vedotin 1.8 mg/kg, intravenous over approximately 30 minutes, once on Day 1 of each 21-day cycle and may continue as monotherapy for up to a total of 16 cycles (48 weeks).

The PK population included participants with sufficient dose and PK data to reliably estimate PK parameters as determined by a clinical pharmacologist. Here 'Number analyzed' is the number of participants with evaluable data at the specified time-point.

Ctrough: Observed Concentration at the End of a Dosing Interval for Brentuximab Vedotin

Cmax: Maximum Observed Concentration for Monomethyl Auristatin (MMAE) for Brentuximab Vedotin

Ctrough: Observed Concentration at the End of a Dosing Interval for MMAE for Brentuximab Vedotin

Immunogenicity-evaluable participants

Baseline Negative: ATA negative

Baseline Negative: ATA positive

Baseline Negative: Transiently Positive

Baseline Negative: Persistently Positive

Baseline Negative: Neutralizing ATA Positive

Baseline Positive: ATA Negative

Baseline Positive: ATA Positive

Baseline Positive: Transiently Positive

Baseline Positive: Persistently Positive

Baseline Positive: Neutralizing ATA Positive

The Safety population included participants who received at least one dose of study drug.

Number of Participants With Antitherapeutic Antibodies (ATA) to Brentuximab Vedotin

Change at Cycle 2

Change at Cycle 4

Change at Cycle 6

Change at Cycle 8

Change at Cycle 10

Change at Cycle 12

Change at Cycle 14

Change at Cycle 16

Change at End of Treatment

Change at 3-6 months LTFU

Change at 6-9 months LTFU

Change at 9-12 months LTFU

Change at 12-15 months LTFU

Change at 15-18 months LTFU

Change at 18-21 months LTFU

Change at 21-24 months LTFU

Change at 24-27 months LTFU

Change at 27-30 months LTFU

Change at >30 months LTFU

The ITT population included all participants who were identified as CD30+ by the Ventana anti-CD30 (Ber-H2) assay and were randomized to treatment. Here 'Number analyzed' is the number of participants with evaluable data at the specified time-point.

Change From Baseline in the Skindex-29 Questionnaire Total Score

Change From Baseline in Functional Assessment of Cancer Therapy General Questionnaire (FACT-G) Score

SAEs

Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

Overall Study

Recurrence

Lymphomatoid Papulosis

Disease Attributes

Antibodies

Antibodies, Monoclonal

Lenalidomide

Immunoglobulins

Immunoglobulins, Intravenous

Angiogenesis Inhibitors

Growth Inhibitors

Patients receive brentuximab vedotin IV over 30 minutes on day 1 and lenalidomide PO QD on day 1-21. Treatment repeats every 21 days for up to 16 courses in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis

John Reneau, MD

This phase II trial studies how well brentuximab vedotin and lenalidomide work in treating patients with stage IB-IVB T-cell lymphoma that have come back or do not respond to treatment. Monoclonal antibodies, such as brentuximab vedotin, may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as lenalidomide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving brentuximab vedotin and lenalidomide may work better in treating patients with T-cell lymphoma.

PRIMARY OBJECTIVES:

I. To determine the overall response rate (ORR) of the combination of brentuximab vedotin (BV) and lenalidomide in patients with relapsed or refractory cutaneous T-cell lymphoma (CTCL)/peripheral T-cell lymphoma (PTCL).

SECONDARY OBJECTIVES:

I. To estimate the duration of response and 2 year progression-free survival (PFS) and overall survival (OS) associated with the combination of brentuximab vedotin (BV) and lenalidomide in patients with relapsed or refractory CTCL/PTCL.

II. To define the qualitative and quantitative toxicities of the combination of brentuximab vedotin (BV) and lenalidomide in patients with relapsed or refractory CTCL/PTCL.

TERTIARY OBJECTIVES:

I. To correlate between the expression of CD30 in neoplastic cells by immunohistochemistry (IHC) and overall response rate (ORR) of the combination of brentuximab vedotin (BV) and lenalidomide in patients with relapsed or refractory CTCL/PTCL.

II. To determine T-cell and natural killer (NK) cell subset numbers, phenotype, and functional status in relapsed or refractory (rel/ref) CTCL/PTCL patients, and whether the combination of brentuximab vedotin and lenalidomide alters these parameters during therapy.

III. To determine changes in plasma cytokine levels and other biomarkers in this patient population during therapy with the combination of brentuximab vedotin and lenalidomide.

OUTLINE:

Patients receive brentuximab vedotin intravenously (IV) over 30 minutes on day 1 and lenalidomide orally (PO) once daily (QD) on day 1-21. Treatment repeats every 21 days for up to 16 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years.

Brentuximab Vedotin and Lenalidomide in Treating Patients With Stage IB-IVB Relapsed or Refractory T-Cell Lymphoma

A Phase II Study of Brentuximab Vedotin and Lenalidomide in Relapsed and Refractory T-Cell Lymphomas

the overall response rate (ORR) of the combination of brentuximab vedotin (BV) and lenalidomide in patients with relapsed or refractory CTCL/PTCL

Toxicity will be graded by the NCI Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0

Kaplan-Meier method will be used to estimate OS.

Kaplan-Meier method will be used to estimate PFS.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Phase 3 Trial of Brentuximab Vedotin(SGN-35) Versus Physician's Choice (Methotrexate or Bexarotene) in Participants With CD30-Positive Cutaneous T-Cell Lymphoma (ALCANZA Study)	NCT01578499	Primary Cutaneo... Mycosis Fungoid... Cutaneous T-Cel...	Brentuximab Ved... Methotrexate Bexarotene	18 Years -	Takeda
Brentuximab Vedotin and Lenalidomide in Treating Patients With Stage IB-IVB Relapsed or Refractory T-Cell Lymphoma	NCT03409432	Lymphomatoid Pa... Primary Cutaneo... Recurrent Prima... Recurrent T-Cel... Refractory Prim... Stage I Cutaneo... Stage II Cutane... Stage III Cutan... Stage IV Cutane...	Brentuximab Ved... Laboratory Biom... Lenalidomide	18 Years -	Ohio State University Comprehensive Cancer Center
A Phase 3 Trial of Brentuximab Vedotin(SGN-35) Versus Physician's Choice (Methotrexate or Bexarotene) in Participants With CD30-Positive Cutaneous T-Cell Lymphoma (ALCANZA Study)	NCT01578499	Primary Cutaneo... Mycosis Fungoid... Cutaneous T-Cel...	Brentuximab Ved... Methotrexate Bexarotene	18 Years -	Takeda

Spots Global Cancer Trial Database for primary cutaneous anaplastic large cell lymphoma