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U.S. FDA Expands IMBRUVICA® (ibrutinib) Label to Include Overall Survival Data in Previously Untreated Chronic Lymphocytic Leukemia (CLL) and New Indication for Small Lymphocytic Lymphoma (SLL) Patients

On May 9, 2016 AbbVie (NYSE: ABBV), a global biopharmaceutical company, reported the U.S. Food and Drug Administration (FDA) updated the IMBRUVICA (ibrutinib) Prescribing Information (PI) to include new data from two Phase 3 trials supporting its expanded use in patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) (Press release, AbbVie, MAY 9, 2016, View Source [SID:1234512091]).[1] The label now includes overall survival (OS) results in previously-untreated CLL/SLL patients from the Phase 3 RESONATETM-2 (PCYC-1115) trial.

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The IMBRUVICA label has also been updated with safety and efficacy data from the Phase 3 HELIOS (CLL3001) trial assessing the use of IMBRUVICA in combination with bendamustine and rituximab (BR) versus placebo plus BR in relapsed/refractory patients with CLL/SLL. As well, following a review of the November 2015 supplemental New Drug Application (sNDA), the FDA has approved a new IMBRUVICA indication to include the treatment of patients with SLL with or without the deletion of chromosome 17p (del 17p).1 IMBRUVICA is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie Company, and Janssen Biotech, Inc.

The RESONATE-2 trial served as the basis for the March 2016 FDA approval of IMBRUVICA for the first-line treatment of CLL patients. Notably, the OS data now included in the IMBRUVICA PI provide a longer-term update to results published in The New England Journal of Medicine, with a median follow-up of 28.1 months. The label updates based on HELIOS represent the first-ever data demonstrating an improvement in progression-free survival (PFS) and overall response rate (ORR) with IMBRUVICA when combined with BR versus placebo plus BR in patients with relapsed/refractory CLL/SLL.

"This update helps to affirm the established efficacy, safety and tolerability of this therapy for treatment of patients with CLL/SLL, both as a monotherapy or in combination with other agents," said Jan Burger, M.D., Ph.D., Associate Professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX and the RESONATE-2 lead study investigator.* "It reflects the growing body of clinical evidence supporting this therapy as a potential treatment option for people living with CLL/SLL."

"We are pleased the FDA has added the survival data observed with IMBRUVICA as a first-line therapy for CLL to its Prescribing Information and that the indication has been expanded to include patients with SLL. Moreover, the positive results seen in the HELIOS study provide additional evidence supporting the compelling safety and efficacy seen with IMBRUVICA in CLL and SLL patients," said Danelle James, M.D., M.S., Head of Oncology at Pharmacyclics. "We believe the IMBRUVICA label is very strong for the treatment of certain hematologic malignancies and is now reinforced not only by data evaluating its use as a single agent, but also in combination with other commonly used chemotherapy regimens."

Immune Design and Gritstone Oncology Announce Clinical Collaboration for Neoantigen Cancer Immunotherapy

On May 09, 2016 Immune Design (Nasdaq:IMDZ), a clinical-stage immunotherapy company focused on oncology, and Gritstone Oncology, a private cancer immunotherapy company developing next-generation, personalized cancer therapeutics, reported a clinical collaboration for development of novel, personalized immunotherapies combining both companies’ leading technologies (Press release, Immune Design, MAY 9, 2016, View Source [SID:1234512088]).

The collaboration will involve the application of Immune Design’s ZVexTM discovery platform with Gritstone’s proprietary genomics and proteomics platform for identification of patient-specific tumor antigens to develop neoantigen-based immunotherapies. Immune Design and Gritstone will be jointly responsible for development activities, with an initial likely focus in non-small cell lung cancer. The first clinical trial is expected to commence in 2017.

"The emerging tumor neoantigen field holds great potential for the successful application of cancer immunotherapies, and we are pleased to be working with Gritstone, a company that we believe is a pioneer in the field," said Carlos Paya, M.D., Ph.D., president and chief executive officer of Immune Design. "Having validated our two platforms in clinical trials targeting conserved tumor antigens, we believe their application to patient specific tumor antigens is a natural next step."

For the first trial of their technologies, the companies are evaluating combining the Gritstone and Immune Design neoantigen vaccine with a checkpoint inhibitor, to optimize the vaccine-induced immune response at several levels and maximize the likelihood of clinical efficacy.

"We are excited to work with Immune Design and their novel immunotherapy approach," said Andrew Allen, M.D., Ph.D., co-founder, president and chief executive officer of Gritstone Oncology. "There is good evidence that viral vectors are one of the most effective means of generating high titer CD8+ T cells that recognize encoded antigens, and so this is a logical move for our company, as our neoantigen prediction platform starts to deliver immune targets for individual patients with lung cancer."

Intravenous Busulfan-Based Myeloablative Conditioning Regimens Prior to Hematopoietic Cell Transplantation for Hematologic Malignancies.

Busulfan (Bu)-containing regimens are commonly used in myeloablative regimens prior to allogeneic hematopoietic cell transplantation (HCT). Yet, there is considerable variability on how Bu is administered related to frequency (four times a day, Q6 or daily, Q24) and the combination with other chemotherapeutic agents (cyclophosphamide, Cy or fludarabine, Flu). A prospective cohort study of recipients of Bu-based conditioning according to contemporary practices was used to compare different approaches in using Bu (BuCy Q6 N=495; BuFlu Q24 N=331; BuCy Q24 N=96; BuFlu Q6 N=91) in patients with myeloid malignancies from 2009 to 2011. BuFlu Q24 recipients were more likely to be older and tended to have worse performance status and higher comorbid burden. The cumulative incidence of hepatic veno-occlusive disease (p=0.4), idiopathic pneumonia (p=0.5) and seizures (p=0.5) did not differ across groups. One-year HCT related mortality ranged from 12% to 16% (P=0.8), three-year relapse incidences ranged from 32% to 36% (p=0.8) and three-year overall survival ranged from 51% to 58% (p=0.2) across groups. This study demonstrates that the use of intravenous Bu Q6 or Q24 or accompanied by Cy or Flu have similar outcomes in the myeloablative setting for treatment of myeloid malignancies.
Copyright © 2016 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Population Pharmacokinetic/Pharmacodynamic Modeling of Sunitinib by Dosing Schedule in Patients with Advanced Renal Cell Carcinoma or Gastrointestinal Stromal Tumor.

Sunitinib is a multi-targeted tyrosine kinase inhibitor used in the treatment of advanced renal cell carcinoma (RCC) and imatinib-resistant/intolerant gastrointestinal stromal tumors (GIST).
A meta-analysis of 10 prospective clinical studies in advanced RCC and GIST was performed to support the development of pharmacokinetic (PK) and PK/pharmacodynamic (PD) models that account for the effects of important covariates. These models were used to make predictions with respect to the PK, safety, and efficacy of sunitinib when administered on the traditional 4-weeks-on/2-weeks-off schedule (Schedule 4/2) versus an alternative schedule of 2 weeks on/1 week off (Schedule 2/1).
The covariates found to have a significant effect on one or more of the PK or PD parameter studies included, age, sex, body weight, race, baseline Eastern Cooperative Oncology Group performance status, tumor type, and dosing schedule. The models predicted that, in both RCC and GIST patients, Schedule 2/1 would have comparable efficacy to Schedule 4/2, despite some differences in PK profiles. The models also predicted that, in both indications, sunitinib-related thrombocytopenia would be less severe when sunitinib was administered on Schedule 2/1 dosing compared with Schedule 4/2.
These findings support the use of sunitinib on Schedule 2/1 as a potential alternative to Schedule 4/2 because it allows for the management of toxicity without loss of efficacy.

Response assessment in lymphoma: Concordance between independent central review and local evaluation in a clinical trial setting.

Independent central review of clinical imaging remains the standard for oncology clinical trials with registration potential. A limited independent central review strategy has been proposed for solid tumor trials based on concordance between central and local evaluation of response. Concordance between independent central review and local evaluation of response in hematological malignancies is not known.
We retrospectively evaluated concordance between prospectively performed central and local assessments of response using the Revised Response Criteria for Malignant Lymphoma across two international, open-label, single-arm, registration studies of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma (N = 102) or systemic anaplastic large-cell lymphoma (N = 58).
Overall objective response rates were similar between assessors for both the trial in Hodgkin lymphoma (75% independent central review, 72% local evaluation) and the trial in anaplastic large-cell lymphoma (86% independent central review, 83% local evaluation). Patient-specific objective response concordance was also substantial (Hodgkin lymphoma: kappa = 0.68; anaplastic large-cell lymphoma: kappa = 0.74). Median progression-free survival was similar between assessors for patients with anaplastic large-cell lymphoma (14.3 months by independent central review (95% confidence interval: 6.9, -); 14.5 months by local evaluation (95% confidence interval: 9.4, -)), but longer by local evaluation in patients with Hodgkin lymphoma (5.8 months by independent central review (95% confidence interval: 5.0, 9.0); 9.0 months by local evaluation (95% confidence interval: 7.1, 12.0)). Median duration of response was longer by local evaluation in both malignancies, which was primarily attributable to earlier computed tomography and positron emission tomography-based scoring of progression by independent central review.
A limited independent review audit strategy for clinical trials of some lymphomas appears feasible and practical based on substantial concordance in assessments of overall objective response by central and local evaluation in two international, prospective, registration trials in lymphoma. Some variability between assessors in the time-to-event endpoints was observed, which appeared attributable to earlier assignments of progression by independent central review compared with local evaluation.
© The Author(s) 2016.