Seattle Genetics and its collaborator, Takeda Pharmaceutical, have completed patient enrollment in the open label, phase III ALCANZA (NCT01578499) clinical trial. This randomized trial is designed to evaluate brentuximab vedotin (Adcetris®) versus investigator’s choice of methotrexate or bexarotene in 132 patients with CD30-expressing cutaneous T-cell lymphoma (CTCL), including those with primary cutaneous anaplastic large cell lymphoma (pcALCL) or mycosis fungoides, who received prior systemic therapy.
Brentuximab vedotin is an antibody-drug conjugate or ADC directed to CD30, which is expressed on skin lesions in at least 50% of patients with CTCL. The drug comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.
The ALCANZA trial is being conducted under a Special Protocol Assessment (SPA) agreement from the U.S. Food and Drug Administration (FDA). In addition, Takeda received European Medicines Agency (EMA) scientific advice.
In 2012, the FDA granted brentuximab vedotin orphan drug designation for the treatment of mycosis fungoides (MF), the most common subtype of CTCL, a disease which is a clinically and immunologically defined neoplasm and includes epidermotropic and nonepidermotropic variants.  Brentuximab vedotin is, however, currently not approved for the treatment of CTCL.
Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). Cutaneous lymphomas are a category of non-Hodgkin lymphomas that primarily involve the skin. According to the Cutaneous Lymphoma Foundation, CTCL is the most common type of cutaneous lymphoma and typically presents with red, scaly patches or thickened plaques of skin that often mimic eczema or chronic dermatitis. Progression from limited skin involvement is variable and may be accompanied by tumor formation, ulceration and exfoliation, complicated by itching and infections. Advanced stages are defined by involvement of lymph nodes, peripheral blood and internal organs. According to published literature, CD30 is expressed on skin lesions in at least 50% of CTCL patients.
The standard treatment for systemically pretreated CTCL includes skin-directed therapies, radiation and systemic therapies. The systemic therapies currently approved for treatment have demonstrated 30 to 45 percent objective response rates, with low complete response rates.
Mycosis Fungoides and Sézary syndrome
Patients with early stage mycosis fungoides have, in general, an excellent prognosis. Survival in patients with advanced disease is, however, compromised, especially when adverse prognostic factors such as folliculotropic, large-cell transformed, or extracutaneous disease, are present.
Mycosis fungoides, which affects man twice as often as women, occurs in about 1 in 100,000 to 350,000 individuals and accounts for approximately 70% of all cases of CTCL. In the United States, there are an estimated 3.6 cases per million people each year.
Both mycosis fungoides and Sézary syndrome, the second most common form of CTCL accounting for approximately 3 to 5% of all cases of cutaneous T-cell lymphoma occurring mostly in adults over 60 years of age, have unique characteristics that distinguish them from other types of non-Hodgkin’s lymphomas.
Published trial results
Data from two investigator-sponsored phase II clinical trials evaluating brentuximab vedotin in relapsed CTCL were recently published in the Journal of Clinical Oncology (JCO) by physicians at Stanford University and the University of Texas MD Anderson Cancer Center.
In these trials, the primary endpoint was overall response rate lasting at least 4 months in patients with CD30-expressing mycosis fungoides or pcALCL. Key secondary endpoints in both studies included complete response, progression-free survival and burden of symptoms during treatment.
The first phase II investigator-sponsored trial enrolled 32 CTCL patients with mycosis fungoides or Sézary syndrome. Of these patients, 30 were evaluable for efficacy and more than half had received three or more prior systemic therapies. The primary endpoint of the trial was objective clinical response rate. The study was led by principle investigator Youn H. Kim, MD, professor of dermatology, from Stanford University School of Medicine in Stanford, CA. 
A total of twenty-one of 30 patients (70%) achieved an objective response across all stages of disease, including Stage IB, Stage IIB and Stage IV/SS. Overall, one patient had a complete response, 20 patients had a partial response, four patients had stable disease and five patients had progressive disease. Two patients were not evaluable for response. Of the patients who had partial responses, seven had near complete responses with over 90% skin improvement as measured by modified Severity-Weighted Assessment Tool or mSWAT scores and eight were still responding to therapy.
Responses appeared to be durable; six- and 12-month Kaplan-Meier estimates indicated continuing responses in 90% and 79% of patients, respectively. The most common related adverse events of any grade were peripheral neuropathy (66%), fatigue (47%), nausea (28%), hair loss (22%) and neutropenia (19%). The most common Grade 3 or 4 related adverse events were neutropenia (in four patients), rash (in three patients) and peripheral neuropathy (in one patient).
Data from another trial, a phase II investigator-sponsored trial evaluating the use of brentuximab vedotin in CD30-positive CTCL patients, including lymphomatoid papulosis (LyP), primary cutaneous anaplastic large cell lymphoma (pcALCL) or mycosis fungoides, conducted Madeleine Duvic, MD and her team from the University of Texas MD Anderson Cancer Center in Houston, TX, enrolled 54 patients of which 48 patients were evaluable at the time of analysis. The primary endpoint of the trial was to evaluate the safety and efficacy of brentuximab vedotin in CD30-positive CTCL. 
Thirty-five of 48 patients (73%) achieved an objective response, including 20 of 20 (100%) with LyP and/or pcALCL and 15 of 28 (54%) with mycosis fungoides. Seventeen patients (35%) achieved a complete response.
The most common adverse events were peripheral neuropathy (67%), fatigue (35%), skin rash (24%), diarrhea (15%), muscle pain (17%), localized skin infection (15%), neutropenia (15%) and hair loss (11%). In the trial, the most common Grade 3 or 4 adverse events were neutropenia (three patients), nausea (two patients), unstable angina or myocardial infarction (two patients), infection (two patients), joint pain (two patients), fatigue (one patient), deep vein thrombosis (one patient), pulmonary embolism (one patient), aminotransferase elevation (one patient) and dehydration (one patient).
The results of these two clinical trials demonstrated objective response rates of 70 and 73%, respectively, in relapsed CTCL patients having variable levels of CD30 expression treated with brentuximab vedotin. This compares to objective response rates of 30 to 45% from published trials utilizing standard of care treatments in this disease setting. The most common adverse events in these trials were peripheral neuropathy, fatigue, nausea, skin rash, hair loss, diarrhea, muscle pain and neutropenia.
“We are pleased to announce the completion of patient enrollment in the phase III ALCANZA clinical trial evaluating [brentuximab vedotin] as a potential treatment for CD30-expressing CTCL,” noted Clay Siegall, PhD., President and Chief Executive Officer of Seattle Genetics. “We look forward to reporting results from the ALCANZA trial in the second half of 2016 to potentially support an [brentuximab vedotin] supplemental Biologics License Application seeking a label expansion for use in this setting.”