Lonza 2024

Results of the phase III Alcanza trial evaluating brentuximab vedotin (Adcetris®; Takeda Pharmaceutical and Seattle Genetics)  in patients with cutaneous T-cell lymphoma (CTCL) shows that the trial met its primary endpoint, demonstrating a highly statistically significant improvement in the rate of objective response lasting at least four months (ORR4).

Brentuximab vedotin is an antibody-drug conjugate which is based on Seattle Genetics’ proprietary technology, includes an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to the microtubule disrupting agent monomethyl auristatin E (MMAE). The linker-system employs is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.


These remarkable, clinically meaningful results…  represent an important milestone for the [brentuximab vedotin] program….  and may offer a novel treatment option for patients with Cutaneous T-cell lymphoma…


Lymphoma
Lymphoma is a general term for a group of cancers that originate in the lymphatic system and includes two major categories: Hodgkin lymphoma and non-Hodgkin lymphoma.

Although lymphomas can develop at any age, most cases of non-Hodgkin lymphoma occur in adults in their early- to mid-60s.  And most people being diagnosed have no known risk factors.  According to the American Cancer Society, an estimated 72,580 new cases of NHL (40,170 in men and 32,410 in women) will be diagnosed in 2016, leading to approximately 20,150 deaths from NHL (11,520 in men and 8,630 in women).[1]

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Cutaneous T-cell lymphoma
Cutaneous lymphomas, a distinct subset of non-Hodgkin lymphoma that primarily involve the skin, are uncommon and account for only about 5% of all non-Hodgkin lymphomas. However, over the last few decades the rate of these skin lymphomas has, for unknown reasons, been rising.

According to the Cutaneous Lymphoma Foundation, an independent, nonprofit patient advocacy organization, cutaneous T-cell lymphoma or CTCL, affecting white blood cells called T-lymphocytes or T-cells, is the most common type of cutaneous lymphoma. There are about 3,000 new cases of mycosis fungoides each year in the U.S. and approximately 15% of patients with mycosis fungoides are diagnosed with the more advanced Sézary syndrome which usually occurs in adults ages 50+ and over and is slightly

Signs & Symptoms
Cutaneous T-cell lymphoma typically presents with red, scaly patches or thickened plaques of skin that often mimic eczema or chronic dermatitis. In many cases, progression from limited skin involvement may be accompanied by tumor formation, ulceration and exfoliation, complicated by itching and infections.

Cutaneous_T-cell_lymphoma_-_intermed_mag
Photo 1.0: Intermediate magnification micrograph of cutaneous T-cell lymphoma or CTCL. (Hematoxylin and eosin stain/H&E stain). Features include: Nests of lymphocytes in the epidermis (Pautrier microabscesses); Single lymphocytes in epidermis (lymphocyte exocytosis) and short linear arrays of lymphocytes along the basal layer of the epidermis (epidermotropism). Courtesy: © Michael Bonert/Nephron.

More than one disease
But cutaneous T-cell lymphoma or CTCL is not just one singe disease but describes various different disorders with different signs and symptoms, outcomes and treatment options. The two most common types of CTCL are mycosis fungoides (MF), which, in most cases, is indolent and can progress over many years.[2]

Advanced of mycosis fungoides called Sézary syndrome are defined by involvement of lymph nodes, peripheral blood and internal organs.[2]

Sézary syndrome is distinguished from mycosis fungoides by the presence of malignant lymphocytes in the blood and is characterized by extensive thin red, itchy rashes covering over 80% of the body. In some cases, thicker, red patches (or plaques) and tumors may also appear. In addition, these symptoms may be accompanied by changes in the nails, hair or eyelids or the presence of enlarged lymph nodes.[3]

According to published literature, CD30 is expressed on skin lesions in approximately 50% of all patients with cutaneous T-cell lymphoma.

Standard treatment
The standard treatment for systemically pre-treated CTCL includes skin-directed therapies, radiation and systemic therapies. The systemic therapies currently approved for treatment have demonstrated 30 to 45% objective response rates, with low complete response rates.

Most cutaneous T-cell lymphomas typically fall into the category of indolent (i.e. chronic) lymphomas – treatable, but not curable and usually not life-threatening.

Alcanza trial
Figure 1.0: The Alcanza trials is a randomized , open label, Phase III study of Brentuximab Vedotin  vs. Physician’s Choice (Methotrexate or Bexarotene) in patients with CD30+ Cutaneous T-Cell Lymphoma. (Study: NCT01578499).

Trial design
The Alcanza trial is a randomized, open-label Phase III study designed to evaluate single-agent brentuximab vedotin versus a control arm of investigator’s choice of standard therapies, methotrexate or bexarotene (Targetin®; Valeant Pharmaceuticals), in patients with CD30-expressing CTCL, including those with primary cutaneous anaplastic large cell lymphoma (pcALCL) or mycosis fungoides (MF). The primary endpoint is ORR4 as assessed by

Global Response Score in the brentuximab vedotin arm compared to the control arm. Key secondary endpoints are complete response rate, progression-free survival and reduction in the burden of symptoms during treatment. The clinical trial enrolled 131 patients at 50 sites globally.

Tot participate in the trial, patients with mycosis fungodies received at least one prior systemic therapy.  As part of the trial, patients received brentuximab vedotin every three weeks versus investigator’s choice for up to approximately one year.

Special protocol Assessment
The Alcanza trial, which received a Special Protocol Assessment (SPA) from the U.S. Food and Drug Administration (FDA) and scientific advice from the European Medicines Agency (EMA), compared the use of single-agent brentuximab vedotin to a control arm of investigator’s choice of standard therapies, methotrexate or bexarotene, in 131 patients with CD30-expressing CTCL who received prior systemic or radiation therapy.

Trial results
In earlier phase II trial of brentuximab vedotin for the treatment of CD30+ Cutaneous T cell lymphomas and lymphoproliferative disorders, presented by Madeleine Duvic, MD (University of Texas/MD Anderson Cancer Center, Houston, TX) during the 55th annual meeting of the American Society of Hematology (ASH) held in New Orleans, LA, in December 2013, the agent produced an unexpectedly high response rate in patients with mycosis fungodies, irrespective of degree of CD30 expression and including mycosis fungoides with large cell transformation or folliculotropic morphology. [4]

This single-center, open-label phase II trial enrolled 48 patients (22 women and 26 men with a median age of 59.5 years [range, 31–86]) who were, within the past 3 years, diagnosed with established CD30+ cutaneous T-cell lymphoma.  The trial participants received infusion of brentuximab vedotin over 30 minutes every 21 days for eight cycles. Patients who achieved partial remission (PR) received up to 16 doses. Treatment was continued for two doses past complete remission (CR). The overall response rate  (ORR) was 73%. Median time to response for all patients in this trial was 12 weeks while the median duration of response for mycosis fungoides patients was 39 weeks.

Based on these phase II results, the Alcanza trial was to determine whether FDA approval will be granted for the disease.

Alcanza results
The results of the Alcanza trial demonstrated that treatment with brentuximab vedotin resulted in a highly statistically significant improvement in the ORR4 versus the control arm as assessed by an independent review committee (p-value <0.0001). The ORR4 was 56.3 percent in the brentuximab vedotin arm compared to 12.5% in the control arm. The key secondary endpoints specified in the protocol, including complete response rate, progression-free survival and reduction in the burden of symptoms during treatment, were all highly statistically significant in favor of the brentuximab vedotin arm. The safety profile associated with brentuximab vedotin from the Alcanza trial was generally consistent with the existing prescribing information.

Milestone
“These remarkable, clinically meaningful results from the completed Alcanza trial represent an important milestone for the [brentuximab vedotin] program. If this new indication is approved by regulatory authorities, [brentuximab vedotin] may offer a novel treatment option for CTCL patients,” noted Dirk Huebner, M.D., Executive Medical Director, Oncology Therapeutic Area Unit, Takeda Pharmaceutical Company.

“We are excited by the data, which showed a significant improvement in the primary endpoint of ORR4 and all key secondary endpoints, along with a manageable safety profile. This outcome further establishes our commitment to patients living with CD30-expressing disease, and we look forward to sharing these data with regulatory authorities globally,” Huebner added.

Adding to Huebner’s comments Clay Siegall, PhD, President and Chief Executive Officer of Seattle Genetics said: “Cutaneous T-cell lymphoma is a debilitating, disfiguring and painful disease, and there is a significant need for additional effective treatment options with meaningful durable responses.”

“This is the first Phase III randomized trial in CTCL versus an active control to read out, and we are thrilled to have successfully demonstrated the positive impact of using [brentuximab vedotin] for patients enrolled in this study,” Siegall said.

ASH 2016
An abstract will be submitted for data presentation at the American Society of Hematology (ASH) annual meeting, December 3-6, 2016, in San Diego, California.

“We anticipate reporting more complete Alcanza data at the ASH annual meeting in December and intend to submit a supplemental Biologics License Application to the FDA in the first half of 2017 for approval in this setting,” Siegall concluded.

Regulatory approval
Brentuximab vedotin has received orphan drug designation from the FDA for the treatment of mycosis fungoides. The agent has also received orphan drug designation from the European Commission for CTCL, including mycosis fungoides.

Other trials
Brentuximab vedotin is being evaluated broadly in more than 70 ongoing clinical trials, including two Phase III studies, ECHELON-1 in frontline classical Hodgkin lymphoma and ECHELON-2 in frontline mature T-cell lymphomas, as well as trials in many additional types of CD30-expressing malignancies, including B-cell lymphomas.


Last Editorial Review: August 1, 2016

Featured Image: Oncology nurse talking to a patient. Courtesy: © Fotolia. Used with permission. Photo 1.0: Intermediate magnification micrograph of cutaneous T-cell lymphoma or CTCL. Courtesy: © Michael Bonert/Nephron. This file is licensed under the Creative Commons Attribution-Share Alike 3.0 Unported licenses. Figure 1.o: Schematic Alcanza trial.

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