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Accelerated Approval to Zanubrutinib for Mantle Cell Lymphoma

The FDA granted accelerated approval to zanubrutinib for adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

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Efficacy was evaluated in BGB-3111-206 (NCT03206970), a phase II, open-label, multicenter, single-arm trial of 86 patients with MCL who received at least one prior therapy. Zanubrutinib was given orally at 160 mg twice daily until disease progression or unacceptable toxicity. Efficacy was also assessed in BGB-3111-AU-003 (NCT 02343120), a phase I/II, open-label, dose-escalation, global, multicenter, single-arm trial of B-cell malignancies, including 32 previously treated MCL patients treated with zanubrutinib administered orally at 160 mg twice daily or 320 mg once daily.


The primary efficacy outcome measure in both trials was overall response rate (ORR), as assessed by an independent review committee. In trial BGB-3111-206, FDG-PET scans were required and the ORR was 84 percent (95% CI: 74, 91), with a complete response rate of 59 percent (95% CI 48, 70) and a median response duration of 19.5 months (95% CI: 16.6, not estimable). In trial BGB-3111-AU-003, FDG-PET scans were not required and the ORR was 84 percent (95% CI: 67, 95), with a complete response rate of 22 percent (95% CI: 9, 40) and a median response duration of 18.5 months (95% CI: 12.6, not estimable).


The most common adverse reactions (>=20%) included decreased neutrophil count, decreased platelet count, upper respiratory tract infection, decreased white blood cell count, decreased hemoglobin, rash, bruising, diarrhea, and cough. The most common serious adverse reactions were pneumonia in 11 percent and hemorrhage in 5 percent of patients.


The recommended zanubrutinib dose is 160 mg orally twice daily or 320 mg orally once daily.


Priority Review for Nivolumab + Ipilimumab in Advanced Hepatocellular Carcinoma

The FDA accepted a supplemental Biologics License Application and granted Breakthrough Therapy Designation for nivolumab in combination with ipilimumab for the treatment of patients with advanced hepatocellular carcinoma (HCC) previously treated with sorafenib. The FDA granted the application Priority Review with a Prescription Drug User Fee Act goal date of March 10, 2020.


This application is based on data from the nivolumab plus ipilimumab cohort of the phase I/II CheckMate-040 study evaluating the immuno-oncology combination in patients with advanced HCC previously treated with sorafenib. Data from this study were presented at the 2019 ASCO Annual Meeting.


FDA Office of Hematology Oncology Products Renamed Office of Oncologic Diseases

The FDA's office responsible for reviewing applications for new and existing cancer therapies has reorganized and been renamed as part of modernization plans approved in September 2019.


The Center for Drug Evaluation and Research Office of Hematology and Oncology Products has been reorganized and renamed the Office of Oncologic Diseases. Richard Pazdur, MD, is the Acting Director of Office of Oncologic Diseases.


"As the practice of oncology and the treatments for these life-threatening diseases have become more complex, we recognized the need to flatten the organization with additional but smaller review divisions to enable more efficient drug review," Pazdur said. "Reorganizing the office in this manner will allow for greater stakeholder engagement in the various disease programs."


Pazdur also directs the FDA's Oncology Center of Excellence (OCE), established in 2017 to help expedite the development of oncology and hematology medical products and to support an integrated approach in the clinical evaluation of drugs, biologics, and devices for the treatment of cancer. The OCE is not affected by the reorganization.


The Office of Hematology and Oncology Products contained three clinical divisions and one nonclinical division: Division of Oncology Products 1 (DOP1), Division of Oncology Products 2 (DOP2), Division of Hematology Products (DHP), and Division of Hematology Oncology Toxicology (DHOT).


The new Office of Oncologic Diseases structure consists of six divisions:


* DOP1 is re-named Division of Oncology 1 (DO1).


* DOP2 will be split into two divisions: Division of Oncology 2 (DO2) and Division of Oncology 3 (DO3).


* DHP will be split into two divisions to review products intended to treat hematologic malignancies: Division of Hematologic Malignancies 1 (DHM1) and Division of Hematologic Malignancies 2 (DHM2). DHP's review of products to treat non-malignant hematologic conditions will move to another office within the Center for Drug Evaluation and Research.


* DHOT remains the same.



DO1 will retain its responsibilities for products for breast, gynecologic, and genitourinary cancers as well as supportive care.


DO2 will review products for thoracic and head and neck cancers, central nervous system cancers, pediatric solid tumors, and rare cancers.


DO3 will review products for gastrointestinal malignancies, melanoma and other advanced skin cancers, and sarcomas.


DHM1 will be responsible for products for acute leukemia and myelodysplasia (includes myelodysplastic-myeloproliferative overlap syndromes), chronic myeloid leukemia and other myeloproliferative neoplasms with the term "leukemia," blastic plasmacytoid dendritic cell neoplasm, conditioning regimens for DHM1 indications, graft-versus-host disease, tumor lysis syndrome, cytokine release syndrome, and CAR-T neurotoxicity.


DHM2 will review for products for lymphoma, chronic lymphocytic leukemia, multiple myeloma, and other plasma cell malignancies.


Products for non-malignant hematologic diseases and conditions that DHP previously covered will be reviewed in the newly formed Division of Non-malignant Hematology in the Office of Cardiology, Hematology, Endocrinology and Nephrology.


The Regulatory Project Management Staff are reorganized under the newly formed Office of Regulatory Operations within the Center for Drug Evaluation and Research's Office of New Drugs. Regulatory project management staff supporting Office of Oncologic Diseases will be in the newly formed Division of Regulatory Operations-Oncologic Diseases, with individual branches supporting each of the five clinical review divisions in the Office of Oncologic Diseases.


In addition, a centralized Safety Team has been created in the Office of Oncologic Diseases to work with the review divisions to provide for consistent review, management, and communication of safety information across development programs and throughout the pre- and post-market life cycle of oncology drugs. A centralized labeling team will standardize and harmonize labeling efforts across the new division.