Clinical Trials

Date: 2017-12-09

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at the 59th American Society of Hematology (ASH) Annual Meeting

Company: Millenium Pharmaceuticals (USA - MA) Seattle Genetics (USA - WA), wholly owned subsidiaries of Takeda Pharmaceutical (Japan)

Product: Adcetris® (brentuximab vedotin)

Action mechanism:

• monoclonal antibody/antibody drug conjugate (ADC). Adcetris® (brentuximab vedotin) is an antibody-drug conjugate (ADC) comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE). The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalisation into CD30-expressing tumor cells. The CD30 antibody part of the product acts as a carrier for the cytotoxic substance. When the antibody attached by the linker to the cytotoxin attaches to the CTCL cells, it is taken up by the cells. Once inside the cancer cells, the linker is cut and the cytotoxic molecule, monomethyl auristatin E, gets released and stops cell division. The cancer cells are then expected to undergo programmed cell death.
• In 2012, the FDA granted Adcetris® orphan drug designation for the treatment of mycosis fungoides (MF), which is the most common type of CTCL.
• Based on the ALCANZA study results, the FDA granted Breakthrough Therapy Designation to Adcetris® for the treatment of the most common subtypes of CTCL, mycosis fungoides (MF) and primary cutaneous anaplastic large cell lymphoma (pcALCL).

Disease: CD30-expressing cutaneous T-cell lymphoma (CTCL)

Therapeutic area: Cancer - Oncology

Country: Australia, Austria, Belgium, Brazil, France, Germany, Italy, Poland, Spain, Switzerland, UK, USA

Trial details:

• ALCANZA is a randomized, open-label, phase 3 trial of single agent Adcetris® versus investigator’s choice of methotrexate or bexarotene in patients with CD30-expressing cutaneous T-cell lymphoma, including those with pcALCL or MF. The primary endpoint of the study is overall response rate lasting at least 4 months in patients with CD30-expressing MF or pcALCL. Key secondary endpoints are complete response, progression-free survival and burden of symptoms during treatment.  A total of 131 patients were randomized with 128 patients in the intent-to-treat population. Sixty-four patients were assigned to the Adcetris® arm and 64 patients were assigned to the control arm. Patients received Adcetris® every three weeks versus investigator’s choice of bexarotene or methotrexate for up to approximately one year. This international multi-center trial was conducted across 52 sites in North and South America, Europe and Australia under operational responsibility of Takeda Pharmaceuticals. The ALCANZA trial received a Special Protocol Assessment (SPA) agreement from the FDA and scientific advice from the European Medicines Agency (EMA) (NCT01578499)

Latest news:

• • On December 9, 2017, Seattle Genetics presented updated results from the phase 3 ALCANZA clinical trial evaluating Adcetris® (brentuximab vedotin) in CD30-expressing cutaneous T-cell lymphoma (CTCL) at the 59th American Society of Hematology (ASH) Annual Meeting and Exposition. The presentation highlighted longer-term durability data from the phase 3 ALCANZA clinical trial of single-agent Adcetris® for the treatment of patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF). Together, these comprise approximately 70 percent of CTCL diagnoses and the majority of patients who require systemic therapy. A total of 131 patients were randomized with 128 patients in the intent-to-treat population. Sixty-four patients were assigned to the Adcetris® arm and 64 patients were assigned to the control arm. Patients received Adcetris® or investigator’s choice of methotrexate or bexarotene for up to approximately one year.
• Data from longer-term patient follow-up per investigator assessment in the phase 3 ALCANZA trial after a median observation time of 33.9 months from the first dose of Adcetris® versus physician’s choice include: The trial achieved its primary endpoint of demonstrating a highly statistically significant improvement in the rate of objective response lasting at least four months (ORR4) in the Adcetris® arm versus the control arm. The ORR4 per investigator assessment was 60.9 percent in the Adcetris® arm compared to 7.8 percent in the control arm (p-value <0.001). The key secondary endpoints per investigator, including complete response (CR) rate, progression-free survival (PFS) and reduction in the burden of symptoms during treatment (per Skindex-29 questionnaire), continued to be all highly statistically significant in favor of the Adcetris® arm. The median PFS per investigator in the ADCETRIS arm was 15.8 months compared to 3.6 months in the control arm (HR 0.373; 95% CI, 0.245-0.569; p-value <0.001). The CR rate in the Adcetris® arm was 18.8 percent compared to zero percent in the control arm (p-value <0.001). Patient-reported quality of life assessed by the Skindex-29 questionnaire showed significantly greater symptom reduction for patients in the Adcetris® arm versus the control arm (mean maximum change of -28.08 vs -8.62; p-value <0.001). At time of the analyses, 47 patients (73 percent) in the Adcetris® arm and 48 patients (75 percent) in the physician’s choice arm had received one or more subsequent skin-directed or systemic therapy. The median time to next treatment in the Adcetris® arm was significantly longer at 14.2 months compared with the physician’s choice arm at 6.1 months (p-value <0.001). In the Adcetris®versus physician’s choice arms, the probability of patients not requiring subsequent skin-directed or systemic therapy was greater at one year (65.5 percent vs. 15.3 percent) and two years (24.6 percent vs. 4.4 percent).
• Peripheral neuropathy events were observed in 44 of 66 patients (67 percent) in the Adcetris® arm and four of 62 patients (six percent) in the physician’s choice arm. In the Adcetris® arm, 86 percent of patients reported resolution or improvement in peripheral neuropathy events, with 59 percent reporting resolution of all events after a median of 30 weeks and 27 percent reporting some improvement after a median of 13 weeks. Eighteen patients had ongoing peripheral neuropathy events, including 15 patients with Grade 1 and three patients with Grade 2.
• • On June 7, 2017, Takeda Pharmaceutical and Seattle Genetics, announced that data from the randomized Phase 3 ALCANZA clinical trial evaluating ADCETRIS (brentuximab vedotin) in patients with cutaneous T-cell lymphoma (CTCL) were published in the journal Lancet. Data were previously presented in an oral session at the 58th American Society of Hematology (ASH) annual meeting in December 2016. (See below) Based on the study results, Takeda plans to begin to submit data from the ALCANZA trial to regulatory agencies in its territories in 2017.
• • On December 3, 2016, Takeda Pharmaceutical  and Seattle Genetics announced that data from the Phase 3 ALCANZA clinical trial evaluating Adcetris® (brentuximab vedotin) in patients with cutaneous T-cell lymphoma (CTCL) will be presented in an oral session at the 58th American Society of Hematology (ASH) annual meeting (Brentuximab Vedotin Demonstrates Significantly Superior Clinical Outcomes in Patients with CD30-Expressing Cutaneous T Cell Lymphoma Versus Physician's Choice (Methotrexate or Bexarotene): The Phase 3 ALCANZA Study - Abstract #182).  Topline data were reported in August 2016 demonstrating the ALCANZA trial met its primary endpoint of achieving a highly statistically significant improvement in the rate of objective response lasting at least four months (ORR4) (See below).   The trial achieved its primary endpoint and the Adcetris® treatment arm demonstrated a highly statistically significant improvement in the ORR4 versus the control arm as assessed by an independent review facility. The ORR4 was 56.3 percent in the Adcetris® arm compared to 12.5 percent in the control arm (p-value <0.0001).
• The key secondary endpoints specified in the protocol, including complete response (CR) rate, progression-free survival (PFS) and reduction in the burden of symptoms during treatment (per Skindex-29), were all highly statistically significant in favor of the Adcetris® arm. The median PFS in the Adcetris® arm was 16.7 months compared to 3.5 months in the control arm (HR 0.270; 95% CI, 0.169, 0.430; p-value <0.0001). The CR rate in the Adcetris® arm was 15.6 percent compared to 1.6 percent in the control arm (p-value = 0.0046). The Skindex-29 symptom domain showed a mean max reduction of -27.96 in the Adcetris® arm compared to -8.62 in the control arm (p-value <0.0001). There was a difference in mean maximum reduction of -18.9 (95% CI, -26.6, -11.2). Patients received a median of 12 cycles (36 weeks) of Adcetris® versus 17 weeks of bexarotene or nine weeks of methotrexate.
• The safety profile associated with Adcetris® from the ALCANZA trial was generally consistent with the existing prescribing information. The most common adverse events of any grade occurring in 15 percent or more of patients in the Adcetris® and control arms were: peripheral neuropathy (67 and six percent, respectively), nausea (36 and 13 percent, respectively), diarrhea (29 and six percent, respectively), fatigue (29 and 27 percent, respectively), vomiting (17 and five percent, respectively), alopecia (15 and three percent, respectively), pruritis (17 and 13 percent respectively), pyrexia (17 and 18 percent, respectively), decreased appetite (15 and five percent, respectively) and hypertriglyceridemia (two and 18 percent, respectively). In the Adcetris® arm, the most common grade 3 or 4 events were peripheral sensory neuropathy (no grade 4 events), fatigue, diarrhea, nausea, vomiting and pruritis. In the control arm, the most common grade 3 or 4 events were hypertriglyceridemia, pruritis, fatigue and pyrexia.
• The majority of the peripheral neuropathy events were grade 1 or 2 (26 percent and 32 percent, respectively). Peripheral neuropathy events were observed in nine percent at grade 3 and no grade 4 events were reported. Eighty-two percent of patients reported resolution or improvement in peripheral neuropathy events in the Adcetris® arm at a median of 22.9 months of follow-up.
• Discontinuation due to adverse events occurred in 24 percent of patients in the ADCETRIS arm compared to eight percent in the control arm. Serious adverse events were comparable between the ADCETRIS arm and the control arm (29 percent in each). Four deaths in the Adcetris® arm (three unrelated to study drug) occurred within 30 days of the last dose.
• • On August 1, 2016, Takeda Pharmaceutical and Seattle Genetics announced that the Phase 3 ALCANZA clinical trial evaluating Adcetris® (brentuximab vedotin) in patients with cutaneous T-cell lymphoma (CTCL) met its primary endpoint, demonstrating a highly statistically significant improvement in the rate of objective response lasting at least four months (ORR4). The results of the ALCANZA trial demonstrated that treatment with Adcetris® 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 Adcetris® arm compared to 12.5 percent 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 Adcetris® arm. The safety profile associated with Adcetris® from the ALCANZA trial was generally consistent with the existing prescribing information.
• • On September 9, 2015, Seattle Genetics announced that Takeda Pharmaceutical completed patient enrollment in the phase 3 ALCANZA clinical trial. Data from two investigator-sponsored phase 2 clinical trials evaluating Adcetris® (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. The results of these two clinical trials demonstrated objective response rates of 70 and 73 percent, respectively, in relapsed CTCL patients having variable levels of CD30 expression treated with Adcetris®. This compares to objective response rates of 30 to 45 percent from published trials utilizing standard of care treatments in this disease setting. Phase II Investigator-Initiated Study of Brentuximab Vedotin in Mycosis Fungoides and Sézary syndrome With Variable CD30 Expression Level: A Multi-Institution Collaborative Project ( Abstract). The phase 2 investigator-sponsored trial enrolled CTCL patients with mycosis fungoides or Sézary syndrome, which are types of CTCL. Of the 32 patients enrolled in the study, 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 Dr. Youn H. Kim from Stanford University School of Medicine in Stanford, CA. Key findings include: Twenty-one of 30 patients (70 percent) 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 percent skin improvement as measured by modified Severity-Weighted Assessment Tool (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 percent and 79 percent of patients, respectively. The most common related adverse events of any grade were peripheral neuropathy (66 percent), fatigue (47 percent), nausea (28 percent), hair loss (22 percent) and neutropenia (19 percent). The most common Grade 3 or 4 related adverse events were neutropenia (four patients), rash (three patients) and peripheral neuropathy (one patient).
• Results of a Phase II Trial of Brentuximab Vedotin (SGN-35) for CD30+ Cutaneous T-Cell Lymphomas and Lymphoproliferative Disorders (Abstract): Data were published from a phase 2 investigator-sponsored trial evaluating the use of Adcetris® in CD30-positive CTCL patients, including lymphomatoid papulosis (LyP), primary cutaneous anaplastic large cell lymphoma (pcALCL) or MF. The study was conducted by Dr. Madeleine Duvic from the University of Texas MD Anderson Cancer Center in Houston, TX. Among 54 patients enrolled, 48 patients were evaluable at the time of analysis. The primary endpoint of the trial was to evaluate the safety and efficacy of Adcetris® in CD30-positive CTCL. The key findings include: Thirty-five of 48 patients (73 percent) achieved an objective response, including 20 of 20 (100 percent) with LyP and/or pcALCL and 15 of 28 (54 percent) with MF. Seventeen patients (35 percent) achieved a complete response. The most common adverse events were peripheral neuropathy (67 percent), fatigue (35 percent), skin rash (24 percent), diarrhea (15 percent), muscle pain (17 percent), localized skin infection (15 percent), neutropenia (15 percent) and hair loss (11 percent). 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).

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