ALBERT

Description: Abstract 48 Elevated expression of BAALC (brain and acute leukemia, cytoplasmic) is an adverse prognostic factor in patients with cytogenetically normal acute myeloid leukemia (CNAML). However, its precise role in normal hematopoiesis and leukemogenesis remains to be elucidated. To address this issue, we evaluated the effect of BAALC overexpression upon hematopoiesis and leukemogenesis and generated BAALC-deficient mice. First, we examined the effect of BAALC overexpression upon hematopoiesis. BAALC-transduced bone marrow (BM) cells had decreased colony-forming capacity. Bone marrow transplantation (BMT) assay demonstrated that the donor chimerism was lower in transplanted mice with BAALC-overexpressed cells than with control cells. To examine the mechanism, we performed gene expression analysis. This revealed that p53 pathway is up-regulated in BAALC-overexpressed cells. Colony-forming assay and BMT assay using p53-deficient BM cells demonstrated that the blockage of proliferation by BAALC overexpression is canceled in p53-deficient cells in vitro and in vivo, suggesting that the inhibition of proliferation by BAALC overexpression is dependent on p53 pathway. Next, we generated BAALC-conventionally deficient mice. Most BAALC-deficient female mice died between E11.5 and E12.5 because of defects of placental development. BAALC-deficient E11.5 yolk sac cells had increased colony-forming capacity. Transplantation assay showed that the donor chimerism at 4 weeks after transplantation was higher in transplanted mice with BAALC-deficient E12.5 fetal liver cells than with wild fetal liver cells. Moreover, the frequency of G0/G1 phase cells was decreased in BAALC-deficient yolk sac. Thus, the proliferation is activated and the frequency of quiescent cells is reduced in BAALC-deficient embryonic hematopoietic cells. In addition, we examined the role of BAALC in adult hematopoiesis using BAALC-conditionally deficient mice with Mx-Cre system. In BAALC-deficient (Mx-Cre+BAALC flox/flox) BM, long-term hematopoietic stem cells (HSCs), identified as CD34−Flt3−cKit+Sca1+Lin− cells, were reduced as compared with control (Mx-Cre−BAALC flox/flox) BM. BAALC-deficient adult BM had impaired long-term repopulating ability in serial competitive BMT. Moreover, BAALC-deficient mice showed higher mortality rates after weekly 5-FU injections. On the other hand, the ability of colony forming unit spleen (CFU-S) was enhanced and the recovery after myelosuppression induced by single 5-FU injection was faster in BAALC-deficient mice, indicating that BAALC-deficient HSCs have enhanced short-term repopulating ability. Next, to address the relationship between BAALC and p53 protein levels, we performed intracellular flow cytometric analysis and immunocytochemical staining. These experiments revealed that p53 protein is reduced in BAALC-deficient HSCs. Immunoprecipitation revealed that BAALC interferes with the binding of MDM2 to p53, which leads to stabilization of p53 protein. Finally, we tested the effect of BAALC overexpression in leukemia mouse models. BAALC overexpression promoted leukemia in mice in cooperation with TEL/PDGFBR-AML1/ETO (TPAE). BM cells transduced with TPAE and BAALC had increased colony-forming capacity as compared with TPAE and mock-transduced cells. By contrast, BAALC cannot accelerate myc/BCL2-induced leukemia. Western blot showed that p53 is inactivated in TPAE leukemic cells but not in myc/BCL2 leukemic cells. BM cells transduced with myc/BCL2 and BAALC had decreased colony-forming capacity as compared with myc/BCL2 and mock-transduced cells. However, BAALC overexpression promoted colony-forming capacity of p53-deficient cells transduced with myc/BCL2. Similarly, BAALC overexpression promoted the colony-forming capacity of BM cells transduced with BCR/ABL which is known to inactivate p53. Promoted proliferation of BCR/ABL-transduced cells by BAALC overexpression was canceled by the MDM2 antagonist, Nutlin-3. Taken together, BAALC overexpression accelerates leukemia with impaired p53 pathway. In conclusion, these data suggest that BAALC activates p53 pathway and maintains the stemness in normal HSCs. Once p53 pathway is impaired, however, BAALC promotes proliferation of leukemic cells. Our data for the first time uncovered a novel function of BAALC, which may lead to novel therapeutic strategy for CNAML with poor prognosis. Disclosures: No relevant conflicts of interest to declare.

Description: Background: Accelerated approval regulation was instituted in 1992 in the US. Principally, accelerated approval is granted based on a surrogate endpoint that is reasonably likely to predict clinical benefit and postmarketing confirmatory clinical trials are required to verify clinical benefit and convert accelerated approval to regular approval. However, it is a big challenge in terms of feasibility to conduct randomized phase 3 trials for relapsed or refractory hematological malignancy. Methods: We examined indications of accelerated approval and target population and development status of postmarketing confirmatory clinical trials regarding all drugs for hematological malignancy that were granted accelerated approval during December, 1992 and July, 2016. In addition, we searched Pubmed for results of randomized phase 3 trials that were published after the year of 2000 and Clinicaltrials.gov database for information on ongoing or terminated randomized phase 3 trials for adult patients with relapsed or refractory lymphoid malignancies other than chronic lymphocytic leukemia and multiple myeloma. Results: As of July 31, 2016, 37 indications of 31 drugs for hematological malignancy were granted accelerated approval. Of these, 31 indications were relapsed or refractory hematological malignancy. Although postmarketing clinical trials for verifying clinical efficacy were completed regarding the other 6 indications, accelerated approval regarding only 13 of the 31 indications for relapsed or refractory hematological malignancy was converted to regular approval and this conversion took median 1155 (166-3220) days. Moreover, 5 of the 13 indications were granted regular approval based on clinical data in different population from (earlier treatment line than) the indications granted accelerated approval as follows: ibritumomab tiuxetan for follicular lymphoma, alemtuzumab for chronic lymphocytic leukemia, imatinib for pediatric chronic myeloid leukemia, ofatumumab for chronic lymphocytic leukemia and brentuximab vedotin for Hodgkin lymphoma. The other 8 of 13 indications were grated regular approval for very similar population to the indications granted accelerated approval as follows: relapsed or refractory cutaneous T-cell lymphoma (denileukin), relapsed or refractory chronic myeloid leukemia (dasatinib, nilotinib and omacetaxin), relapsed or refractory multiple myeloma (bortezomib, carfilzomib and pomalidomide) and relapsed or refractory chronic lymphocytic leukemia (ibrutinib). Therefore, accelerated approval of any drugs has never been converted to regular approval based on clinical trials for relapsed or refractory B-cell lymphoma, relapsed or refractory peripheral T-cell lymphoma and relapsed or refractory acute lymphoblastic leukemia. In fact, regarding phase 3 trials for adult patients with relapsed or refractory lymphoid malignancies other than multiple myeloma and chronic lymphocytic leukemia, we found 20 trials published in international journals and 32 trials in clinicaltrials.gov. The details are 23 trials for indolent B-cell non-Hodgkin's lymphoma including follicular lymphoma, 13 for autologous stem cell transplantation (ASCT)-eligible aggressive non-Hodgkin's lymphoma, 4 for ASCT-ineligible aggressive non-Hodgkin's lymphoma, 4 for mantle cell lymphoma, 4 for Hodgkin's lymphoma, 2 for acute lymphoblastic leukemia, 1 for peripheral T-cell lymphoma and 1 for cutaneous T-cell lymphoma. In total, 11 trials were stopped due to low accrual. The median (Min, Max) number of actual or anticipated enrolled patients in the other 41 trials was 317 (143, 800). Negative results were reported regarding 9 trials including 7 trials for ASCT-eligible aggressive non-Hodgkin's lymphoma. There were no trials in which result of overall survival as single primary endpoint was positive. Conclusions: Our analysis indicates that drug approval based on phase 3 trials for patients with relapsed or refractory lymphoid malignancies other than multiple myeloma and chronic lymphocytic leukemia remains a big challenge. Therefore, how to evaluate results of single-arm trials for these patients and how to enroll these patients to clinical trials efficiently are important. Disclosures Nagai: Takara Bio Inc.: Consultancy. Ozawa:Celgene Japan: Consultancy; Takara Bio Inc: Research Funding; Sumitomo Dainippon Pharma Co. Ltd: Research Funding; JCR Pharmaceutical Inc: Consultancy.

Description: Abstract 4243 Background: Both the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan and the US Food and Drug Administration (FDA) review drug applications for market approval. In 1992, the FDA instituted accelerated approval (AA) regulations based on surrogate endpoints including response rate, and it allows distribution of drugs for serious diseases before granting regular approval (RA) based on confirmed clinical benefit including improved survival. The PMDA has not adopted such regulations. Differences in the total review time and the approval date of drug applications between regulatory agencies of some countries have recently attracted considerable attention. (N Engl J Med. 2012; 366:2284-93) Few studies have examined the differences in review process, however, from the point of view of AA regulations and primary endpoints in pivotal trials. Methods: 38 indications of 28 hematologic anticancer drugs approved in Japan after the year of 2000 were studied in order to analyze the influence of the differences in regulations and primary endpoints in registration trials between the PMDA and the FDA. Information concerning regulatory decisions made by the PMDA and the FDA was obtained from publicly accessible data including the PMDA's review reports, the FDA's review reports, the Drugs@FDA website, and articles written by the FDA. (J Natl Cancer Inst. 2010; 102:230-43, J Natl Cancer Inst. 2011; 103:636-44, and so on). Results: Thirteen indications have not been approved by the FDA. One indication (rituximab for CD20-positive aggressive B-cell non-Hodgkin's lymphoma) was approved by the PMDA earlier than the FDA. Three indications were approved by the PMDA with clinical data of off-label drug use but not trials in Japan after RA without AA by the FDA, and the median of delay was 64 months. Ten indications were approved by the PMDA with trials in Japan after RA without AA by the FDA, and the median of delay was 52 months. Eleven indications were approved by the PMDA with trials in Japan after AA by the FDA, and the median of delay was 24 months. Of these, AA converted to RA in one indication (bortezomib for relapsed or refractory multiple myeloma) before the PMDA's approval in Japan, and in four indications after the PMDA's approval. All trials in Japan were carried out aiming for response rate or safety data, but not survival, and these included only two comparative trials. Both of these trials were international trials of nilotinib or dasatinib for newly diagnosed chronic myeloid leukemia compared with imatinib. These indications of the drugs were approved by the PMDA later than AA by the FDA by 6 and 8 months, respectively. Next, the targeted population and the primary endpoints of the comparative clinical trials conducted for the FDA's approval of these indications were examined. In most of these comparative trials, patients with newly diagnosed hematological malignancies were targeted and progression-free survival or time to progression was investigated as the primary endpoint. It should be noted that there were no comparative trials in which improved time-to-event endpoints led to RA by the FDA for patients with relapsed/refractory disease other than multiple myeloma. Moreover, overall survival has been adopted as the primary endpoint in none of these trials although improved overall survival which was not adopted as the primary endpoint has been shown in some trials for multiple myeloma. Conclusions: Japanese registration trials of hematological malignancy drugs have frequently been conducted aiming for response rate or safety data after foreign pivotal trials were completed. Whether the FDA grants AA or RA, therefore, it is important to participate in appropriate international trials for timely approval in Japan. Moreover, from the global point of view, it is desirable that improved overall survival is demonstrated in comparative trials for patients with relapsed/refractory disease before market approval of new hematological malignancy drugs as well as solid malignancy drugs. Disclosures: Off Label Use: I will tell that the PMDA approved a few indications with Japanese clinical data of off-label drug use.

Description: Background: Pharmaceuticals and Medical Devices Agency (PMDA) in Japan, the US Food and Drug Administration (FDA) in the US and the European Medicines Agency (EMA) in the EU review drug applications for market approval. It was shown that most new molecular entity (NME) agents were first approved in the US because the FDA has reviewed applications more quickly (N Engl J Med. 2012; 366: 2284-93). However, differences in regulatory actions among Japan, the US and the EU in terms of relationship between the approval date and primary endpoints of pivotal trials in marketing applications including supplemental applications for additional indications have never been analyzed comprehensively. Methods: 93 indications of 55 hematologic anticancer drugs approved in Japan, the US or the EU (only central marketing authorization by the European Commission) between August 2000 and June 2014 were examined in this research. Information concerning regulatory decisions made by PMDA, the FDA and the EMA was obtained from publicly accessible data only such as PMDA’s review reports, the PMDA website, the FDA’s review reports, the Drugs@FDA website, the European public assessment reports published by the EMA’s Committee for Medicinal Products for Human Use (CHMP) and the EMA website. Results: 24, 60, and 9 indications were first approved in Japan, the US, and the EU, respectively. 2 NME agents were first approved in Japan and the EU each; mogamulizumab for relapsed CCR4-positive adult T-cell leukemia/lymphoma as well as relapsed CCR4-positive peripheral T-cell lymphoma/cutaneous T-cell lymphoma and tamibarotene for relapsed acute promyelocytic leukemia in Japan and pixantrone dimaleate for relapsed aggressive non-Hodgkin B-cell lymphoma and histamine dihydrochloride for acute myeloid leukemia in the EU. 17 indications were approved only in the US and 13 of these were approved based on response rate in single-arm trials. The other 4 indications were approved based on results of comparative trials. Of the 13 indications approved based on single-arm trials, 8 indications were approved through the accelerated approval scheme in the US. 5 indications (pixantrone dimaleate, histamine dihydrochloride, temsirolimus for relapsed mantle cell lymphoma, rituximab as maintenance therapy for relapsed follicular lymphoma and decitabine for acute myeloid leukemia) were approved only in the EU and 4 other indications (ibritumomab tiuxetan as consolidation therapy for follicular lymphoma and rituximab for diffuse large B-cell lymphoma, newly diagnosed chronic lymphocytic leukemia, and relapsed chronic lymphocytic leukemia) were approved the earliest in the EU. All these 9 indications were approved based on results of comparative trials. Of these 9 indications, only pixantrone dimaleate was approved through the conditional approval scheme and only histamine dihydrochloride was approved through the approval under exceptional circumstances scheme. Although 23 indications were approved only in Japan, most of them were additional indications of old drugs and not based on results of comparative trials. Primary endpoints were different between the US and the EU in 3 of 41 indications approved in both the US and the EU. All these 3 indications were approved earlier in the US and response rate or time to progression (TTP) in the US instead of progression-free survival (PFS) or overall survival (OS) in the EU was adopted as the primary endpoints as follows; thalidomide for newly diagnosed multiple myeloma (TTP in the US and OS in the EU), pomalidomide for relapsed multiple myeloma (overall response rate in the US and PFS in the EU), and azacitidine for myelodysplastic syndrome (complete remission rate in the US and OS in the EU). Conclusions: The conditional approval scheme or the approval under exceptional circumstances scheme in the EU and the accelerated approval scheme in the US are available, while there are no similar schemes for oncologic drugs in Japan. However, this analysis suggests that the FDA has taken a more active attitude to acceptance of surrogate endpoints. Therefore, not only shorter review time but also this attitude may lead to earlier marketing authorization of drugs for hematologic malignancy in the US. Disclosures Off Label Use: I will discuss off-label drug use in the US which has been approved in the EU or Japan..

Description: Several expedited regulatory review projects for innovative drugs and regenerative medical products have been developed in the US, the EU, and Japan. Each regulatory agency has elaborated an original regulatory framework and adopted regulatory projects developed by the other regulatory agencies. For example, the Food and Drug Administration (FDA) first developed the breakthrough therapy designation, and then the Pharmaceuticals and Medical Devices Agency (PMDA) and European Medicines Agency (EMA) introduced the Sakigake designation and the priority medicines (PRIME) designation, respectively. In addition, the necessity of the product being first development in Japan is the original feature of the Sakigake designation, while actively supporting the development of advanced-therapy medicinal products (ATMPs) by academia or small/medium-sized sponsors is the original feature of the PRIME; these particular features are different from the breakthrough therapy designation in the US. In this review article, flexible and expedited review processes for new drugs, and cell and gene therapies in the US, the EU, and Japan are described. Moreover, all the drugs and regenerative medical products that were granted conditional approval or Sakigake designation in Japan are listed and analyzed herein.