ASH Clinical News ACN_3.13_FULL_ISSUE_DIGITAL | Page 24

The U . S . Food and Drug Administration ( FDA ) placed partial clinical holds on five trials and a full clinical hold on one trial of the PD-L1 inhibitor durvalumab in combination with other immunomodulatory agents with or without chemotherapy in patients with multiple myeloma ( MM ), chronic lymphocytic leukemia ( CLL ), or lymphoma .

The decision was based on risks identified in trials evaluating another PD-1 inhibitor , pembrolizumab , also being studied in combination with immunomodulatory agents in patients with MM . Earlier this year , the FDA placed holds on three clinical trials of pembrolizumab after safety monitors reported more deaths in the treatment arms than in the control arms .

The following trials evaluating durvalumab were placed on partial clinical hold :

• MEDI4736-MM-001 : durvalumab either as monotherapy or in combination with pomalidomide with or without low-dose dexamethasone in patients with relapsed / refractory MM

• MEDI4736-MM-003 : durvalumab plus daratumumab in patients with relapsed / refractory MM

• MEDI4736-MM-005 : durvalumab plus daratumumab in patients with relapsed / refractory MM that progressed during a treatment regimen containing daratumumab

• MEDI4736-NHL-001 : only on the durvalumab , lenalidomide , and rituximab treatment arm in patients with lymphoma or CLL

• MEDI4736-DLBCL-001 : durvalumab in combination with R-CHOP ( rituximab , cyclophosphamide , doxorubicin , vincristine , prednisone ) or with lenalidomide plus R-CHOP in patients with previously untreated , highrisk , diffuse large B-cell lymphoma ( DLBCL )

The MEDI4736-MM-002 trial , which is investigating durvalumab in combination with lenalidomide with or without low-dose dexamethasone in patients with newly diagnosed MM , was placed on full clinical hold .

Patients enrolled in partially held trials and who are receiving clinical benefit may continue treatment , but treatment has been stopped for patients enrolled in the trial on

full clinical hold . The trials are not enrolling any new patients .

One week before issuing the clinical holds on the durvalumab trials , Janet Woodcock , MD , director of the FDA ’ s Center for Drug Evaluation and Research , released a statement reiterating the safety risks associated with PD-1 and PD-L1 inhibitors in patients with MM : “ Today ’ s alert underscores the importance of why new therapies are thoroughly studied to ensure the benefits of taking them outweigh the risks to patients , and we will continue to aggressively monitor clinical trials to ensure patients are protected when safety concerns arise . The FDA still believes the benefits of taking [ pembrolizumab and other PD-1 / PD-L1 inhibitors ] for their approved uses and as indicated in the labels continue to outweigh their risks .”

Sources : AstraZeneca press release , September 7 , 2017 ; U . S . Food and Drug Administration news release , August 31 , 2017 .

The FDA granted priority review to the anti-CD30 monoclonal antibody brentuximab vedotin ( BV ) for the treatment of cutaneous T-cell lymphoma ( CTCL ).

The decision was based on results from the international , open-label , phase III ALCANZA trial , which included 128 patients with CD30-expressing mycosis fungoides ( n = 97 ) or primary cutaneous anaplastic large-cell lymphoma ( ALCL ; n = 31 ), both common subtypes of CTCL . Patients were randomized 1:1 to receive BV 1.8 mg / kg once every three weeks for up to 48 weeks ( n = 64 ; median age = 62 years ; range not provided ) or physician ’ s choice of either methotrexate 5 to 50 mg onceweekly or bexarotene 300 mg / m 2 oncedaily ( control group ; n = 64 ; median age = 59 years ; range not provided ).

BV induced responses lasting four or more months ( primary endpoint ) in 56 percent of patients , compared with 12.5 percent of patients receiving physician ’ s choice of therapy ( p < 0.0001 ).

At a median follow-up of 22.9 months , the median progression-free survival ( PFS ) was 16.7 months for BV-treated patients versus 3.5 months for the control group ( hazard ratio [ HR ] = 0.270 ; 95 % CI 0.169-0.430 ; p < 0.0001 ). The overall response rate ( ORR ) was 67 percent ( n = 43 ) with BV and 20 percent ( n = 13 ) with the control therapies ( p < 0.0001 ); complete response ( CR ) rates were 16 percent and 2 percent , respectively ( p = 0.0046 ).

Grade ≥3 adverse events ( AEs ) were

observed in 41 percent of BV-treated patients and 47 percent of control patients ; serious AEs occurred in 29 percent of patients in each arm . Peripheral neuropathy occurred in significantly more patients treated with BV ( 67 % vs . 6 %; p value not reported ). The most common any-grade AEs in both the BV and control cohorts included nausea ( 36 % and 13 %), diarrhea ( 29 % and 6 %), fatigue ( 29 % and 27 %), vomiting ( 17 % and 5 %), alopecia ( 15 % and 3 %), pruritus ( 17 % and 13 %), pyrexia ( 17 % and 18 %), decreased appetite ( 15 % and 5 %), and hypertriglyceridemia ( 2 % and 18 %).

Twenty-four percent of BV-treated patients experienced AEs that led to treatment discontinuation , compared with 8 percent of patients in the control arm ( p value not reported ). Four deaths were reported in the BV cohort , three of which were deemed unrelated to treatment .

The FDA ’ s decision on the drug ’ s approval is expected on or before December 16 , 2017 .

The drug is already approved for the treatment of Hodgkin lymphoma and systemic ALCL .

Sources : Seattle Genetics press release , August 16 , 2017 ; Kim YH , Whittaker S , Horwitz SM , et al . 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 . Presented at the 2016 ASH Annual Meeting , December 4 , 2016 ; San Diego , CA .

Alnylam Pharmaceuticals , Inc ., suspended a phase II trial of its investigational RNA inhibitor fitusiran for patients with hemophilia after a patient with hemophilia A experienced a fatal thrombotic event while enrolled in the open-label extension study , which was assessing fitusiran in patients with hemophilia A or B with or without inhibitors . The hold also affects the phase III ATLAS study , which was recently initiated but had not yet started dosing .

The drug ’ s manufacturer did not indicate whether the death was directly related to fitusiran use . Approximately nine days prior to hospital admission , the patient developed exercise-induced right hip pain that was treated with a total of three doses of factor VIII ( FVIII ) concentrate ( 31-46 IU / kg ) on three separate days . Over a 14-day hospitalization , the patient ’ s medical condition worsened despite receiving FVIII , and the patient died from subsequent cerebral edema . The investigators reported the initial diagnosis of subarachnoid hemorrhage as unrelated to fitusiran

treatment , but further analysis of computed tomography scans confirmed that the triggering event was a cerebral venous sinus thrombosis , according to Alnylam .

The company is conducting a safety review of the trial with the FDA to investigate a possible connection between the drug and serious thrombotic events and to develop a risk-mitigation plan .

Source : Alnylam press release , September 7 , 2017 .

The FDA approved gemtuzumab ozogamicin ( GO ) for two patient populations : adults with newly diagnosed CD33-positive acute myeloid leukemia ( AML ) and children ≥2 years old with relapsed or refractory CD33- positive AML .

GO originally received accelerated approval in May 2000 as monotherapy for older patients with relapsed CD33-positive AML . In June 2010 , the drug was voluntarily withdrawn from the market after subsequent confirmatory trials failed to verify clinical benefit and demonstrated safety concerns , including early deaths .

This recent approval includes a lower recommended dose , as well as new patient populations and a different dosing schedule , in combination with chemotherapy or as monotherapy . “ We are approving [ GO ] after a careful review of the new dosing regimen , which has shown that the benefits of this treatment outweigh the risk ,” said Richard Pazdur , MD , director of the FDA ’ s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA ’ s Center for Drug Evaluation and Research .

The approval was based on outcomes from three clinical trials – one investigated GO in combination with chemotherapy , and two investigated GO as a single agent . In the combination study , 271 adult patients with newly diagnosed CD33- positive AML were randomized to receive daunorubicin and cytarabine with or without GO ; patients who received GO plus daunorubicin and cytarabine had a median event-free survival of 17.3 months ( range not provided ), compared with 9.5 months ( range not provided ) in those who received chemotherapy alone ( p value not reported ). In the first monotherapy study , 237 patients with newly diagnosed AML who could not tolerate or chose not to receive intensive chemotherapy were randomized to receive GO or best supportive care . The median overall survival ( OS ) was 4.9 months in those receiving GO , compared