Publications by authors named "Shakun Malik"

33 Publications

Integration of immunotherapy into adjuvant therapy for resected non-small-cell lung cancer: ALCHEMIST chemo-IO (ACCIO).

Immunotherapy 2021 06 21;13(9):727-734. Epub 2021 Apr 21.

Department of Hematology and Oncology, Emory University, Atlanta, GA 30322, USA.

Non-small-cell lung cancer (NSCLC) causes significant mortality each year. After successful resection of disease stage IB (>4 cm) to IIIA (per AJCC 7), adjuvant platinum-based chemotherapy improves median overall survival and is the standard of care, but many patients still experience recurrence of disease. An adjuvant regimen with greater efficacy could substantially improve outcomes. Pembrolizumab, a programmed cell death-1 inhibitor, has become an important option in the treatment of metastatic NSCLC. ALCHEMIST is a clinical trial platform of the National Cancer Institute that includes biomarker analysis for resected NSCLC and supports therapeutic trials including A081801 (ACCIO), a three-arm study that will evaluate both concurrent chemotherapy plus pembrolizumab and sequential chemotherapy followed by pembrolizumab to standard of care adjuvant platinum-based chemotherapy. NCT04267848 (ClinicalTrials.gov).
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http://dx.doi.org/10.2217/imt-2021-0019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8293026PMC
June 2021

Molecular Features of Cancers Exhibiting Exceptional Responses to Treatment.

Cancer Cell 2021 01 19;39(1):38-53.e7. Epub 2020 Nov 19.

Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA.

A small fraction of cancer patients with advanced disease survive significantly longer than patients with clinically comparable tumors. Molecular mechanisms for exceptional responses to therapy have been identified by genomic analysis of tumor biopsies from individual patients. Here, we analyzed tumor biopsies from an unbiased cohort of 111 exceptional responder patients using multiple platforms to profile genetic and epigenetic aberrations as well as the tumor microenvironment. Integrative analysis uncovered plausible mechanisms for the therapeutic response in nearly a quarter of the patients. The mechanisms were assigned to four broad categories-DNA damage response, intracellular signaling, immune engagement, and genetic alterations characteristic of favorable prognosis-with many tumors falling into multiple categories. These analyses revealed synthetic lethal relationships that may be exploited therapeutically and rare genetic lesions that favor therapeutic success, while also providing a wealth of testable hypotheses regarding oncogenic mechanisms that may influence the response to cancer therapy.
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http://dx.doi.org/10.1016/j.ccell.2020.10.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478080PMC
January 2021

Biomarker-driven therapies for previously treated squamous non-small-cell lung cancer (Lung-MAP SWOG S1400): a biomarker-driven master protocol.

Lancet Oncol 2020 12 27;21(12):1589-1601. Epub 2020 Oct 27.

Department of Medicine, Yale Cancer Center, New Haven, CT, USA.

Background: The Lung Cancer Master Protocol (Lung-MAP; S1400) is a completed biomarker-driven master protocol designed to address an unmet need for better therapies for squamous non-small-cell lung cancer. Lung-MAP (S1400) was created to establish an infrastructure for biomarker screening and rapid regulatory intent evaluation of targeted therapies and was the first biomarker-driven master protocol initiated with the US National Cancer Institute (NCI).

Methods: Lung-MAP (S1400) was done within the National Clinical Trials Network of the NCI using a public-private partnership. Eligible patients were aged 18 years or older, had stage IV or recurrent squamous non-small-cell lung cancer, had previously been treated with platinum-based chemotherapy, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. The study included a screening component using the FoundationOne assay (Foundation Medicine, Cambridge, MA, USA) for next-generation sequencing, and a clinical trial component with biomarker-driven substudies and non-match substudies for patients who were ineligible for biomarker-driven substudies. Patients were pre-screened and received their substudy assignment upon progression, or they were screened at progression and received their substudy assignment upon completion of testing. Patients could enrol onto additional substudies after progression on a substudy. The study is registered with ClinicalTrials.gov, NCT02154490, and all research related to Lung-MAP (S1400) is completed.

Findings: Between June 16, 2014, and Jan 28, 2019, 1864 patients enrolled and 1841 (98·9%) submitted tissue. 1674 (90·9%) of 1841 patients had biomarker results, and 1404 (83·9%) of 1674 patients received a substudy assignment. Of the assigned patients, 655 (46·7%) registered to a substudy. The biomarker-driven substudies evaluated taselisib (targeting PIK3CA alterations), palbociclib (cell cycle gene alterations), AZD4547 (FGFR alteration), rilotumumab plus erlotinib (MET), talazoparib (homologous recombination repair deficiency), and telisotuzumab vedotin (MET). The non-match substudies evaluated durvalumab, and nivolumab plus ipilimumab for anti-PD-1 or anti-PD-L1-naive disease, and durvalumab plus tremelimumab for anti-PD-1 or anti-PD-L1 relapsed disease. Combining data from the substudies, ten (7·0%) of 143 patients responded to targeted therapy, 53 (16·8%) of 315 patients responded to anti-PD-1 or anti-PD-L1 therapy for immunotherapy-naive disease, and three (5·4%) of 56 responded to docetaxel in the second line of therapy. Median overall survival was 5·9 months (95% CI 4·8-7·8) for the targeted therapy groups, 7·7 months (6·7-9·2) for the docetaxel groups, and 10·8 months (9·4-12·3) for the anti-PD-1 or anti-PD-L1-containing groups. Median progression-free survival was 2·5 months (95% CI 1·7-2·8) for the targeted therapy groups, 2·7 months (1·9-2·9) for the docetaxel groups, and 3·0 months (2·7-3·9) for the anti-PD-1 or anti-PD-L1-containing groups.

Interpretation: Lung-MAP (S1400) met its goal to quickly address biomarker-driven therapy questions in squamous non-small-cell lung cancer. In early 2019, a new screening protocol was implemented expanding to all histological types of non-small-cell lung cancer and to add focus on immunotherapy combinations for anti-PD-1 and anti-PD-L1 therapy-relapsed disease. With these changes, Lung-MAP continues to meet its goal to focus on unmet needs in the treatment of advanced lung cancers.

Funding: US National Institutes of Health, and AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Genentech, and Pfizer through the Foundation for the National Institutes of Health.
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http://dx.doi.org/10.1016/S1470-2045(20)30475-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8109255PMC
December 2020

The Exceptional Responders Initiative: Feasibility of a National Cancer Institute Pilot Study.

J Natl Cancer Inst 2021 01;113(1):27-37

Nationwide Children's Hospital, Columbus, OH, USA; Van Andel Research Institute, Grand Rapids, MI, USA.

Background: Tumor molecular profiling from patients experiencing exceptional responses to systemic therapy may provide insights into cancer biology and improve treatment tailoring. This pilot study evaluates the feasibility of identifying exceptional responders retrospectively, obtaining pre-exceptional response treatment tumor tissues, and analyzing them with state-of-the-art molecular analysis tools to identify potential molecular explanations for responses.

Methods: Exceptional response was defined as partial (PR) or complete (CR) response to a systemic treatment with population PR or CR rate less than 10% or an unusually long response (eg, duration >3 times published median). Cases proposed by patients' clinicians were reviewed by clinical and translational experts. Tumor and normal tissue (if possible) were profiled with whole exome sequencing and, if possible, targeted deep sequencing, RNA sequencing, methylation arrays, and immunohistochemistry. Potential germline mutations were tracked for relevance to disease.

Results: Cases reflected a variety of tumors and standard and investigational treatments. Of 520 cases, 476 (91.5%) were accepted for further review, and 222 of 476 (46.6%) proposed cases met requirements as exceptional responders. Clinical data were obtained from 168 of 222 cases (75.7%). Tumor was provided from 130 of 168 cases (77.4%). Of 117 of the 130 (90.0%) cases with sufficient nucleic acids, 109 (93.2%) were successfully analyzed; 6 patients had potentially actionable germline mutations.

Conclusion: Exceptional responses occur with standard and investigational treatment. Retrospective identification of exceptional responders, accessioning, and sequencing of pretreatment archived tissue is feasible. Data from molecular analyses of tumors, particularly when combining results from patients who received similar treatments, may elucidate molecular bases for exceptional responses.
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http://dx.doi.org/10.1093/jnci/djaa061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781457PMC
January 2021

Radiologic Considerations and Standardization of Malignant Pleural Mesothelioma Imaging Within Clinical Trials: Consensus Statement from the NCI Thoracic Malignancy Steering Committee - International Association for the Study of Lung Cancer - Mesothelioma Applied Research Foundation Clinical Trials Planning Meeting.

J Thorac Oncol 2019 10 27;14(10):1718-1731. Epub 2019 Aug 27.

Department of Medicine, Sir Charles Gairdner Hospital and Faculty of Health and Medical Sciences, University of Western Australia, Perth, Australia.

Detailed guidelines pertaining to radiological assessment of malignant pleural mesothelioma are currently lacking due to the rarity of the disease, complex morphology, propensity to invade multiple planes simultaneously, and lack of specific recommendations within the radiology community about assessment, reporting, and follow-up. In March 2017, a multidisciplinary meeting of mesothelioma experts was co-sponsored by the National Cancer Institute Thoracic Malignancy Steering Committee, International Association for the Study of Lung Cancer, and the Mesothelioma Applied Research Foundation. One of the outcomes of this conference was the foundation of detailed, multidisciplinary consensus imaging and management guidelines. Here, we present the recommendations for radiologic assessment of malignant pleural mesothelioma in the setting of clinical trial enrollment. We discuss optimization of imaging parameters across modalities, standardized reporting, and response assessment within clinical trials.
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http://dx.doi.org/10.1016/j.jtho.2019.08.012DOI Listing
October 2019

Pathologic Considerations and Standardization in Mesothelioma Clinical Trials.

J Thorac Oncol 2019 10 28;14(10):1704-1717. Epub 2019 Jun 28.

Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota. Electronic address:

The accurate diagnosis of mesothelioma is critical for the appropriate clinical management of this cancer. Many issues complicate making the diagnosis of mesothelioma including the presence of reactive mesothelial cells in benign pleural effusions, the heterogeneity of mesothelioma histopathology, the relatively high incidence of other epithelial malignancies that metastasize to the pleura, and primary sarcomas that arise within the pleura. Given the rapidly evolving field of molecular profiling and the need for translational correlates in mesothelioma clinical trials, the National Cancer Institute (NCI)-International Association for the Study of Lung Cancer-Mesothelioma Applied Research Foundation Clinical Trials Planning Meeting was convened in March 2017 to develop a consensus on standard pathology guidelines for future NCI-sponsored clinical trials in mesothelioma. This consensus statement covers recommendations for specimen handling, pathologic classification and diagnosis, biobanking, and tissue correlative studies.
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http://dx.doi.org/10.1016/j.jtho.2019.06.020DOI Listing
October 2019

Current Treatment Landscape of Nasopharyngeal Carcinoma and Potential Trials Evaluating the Value of Immunotherapy.

J Natl Cancer Inst 2019 07;111(7):655-663

Department of Thoracic Oncology Therapeutics.

Nasopharyngeal carcinoma (NPC) is a type of head and neck cancer with a distinctive regional and racial prevalence. It is associated with Epstein-Barr virus infection and has a high propensity for regional and distant metastases, while it is very sensitive to radiation and chemotherapy. A common feature of Epstein-Barr virus-positive NPC is the dense infiltration of lymphocytes in the tumor stroma and positive programmed death-ligand 1 expression in tumor cells, making it an attractive target for immunotherapy, especially immune checkpoint inhibitors. As new immunotherapeutic agents are being rapidly adopted in many cancers, including head and neck cancer, the National Cancer Institute sponsored a clinical trial planning meeting to identify opportunities for developing phase II and III trials testing immunotherapy in different stages of NPC. The meeting started with the summary of the biology of the disease, current standards of care, and evidence of immunotherapy in this cancer. Three subcommittees were tasked to develop clinical trials: loco regionally advanced, nonmetastatic NPC; widely metastatic NPC; and either local recurrence after initial treatment or presenting with oligometastatic disease. This article summarizes the proceedings of this clinical trial planning meeting and provides a road map for future trials incorporating immune checkpoint inhibitors for therapeutic management of NPC. This road map, though specific for NPC, may also be applicable to other virally driven cancers that have similar ability to evade the host's immune system.
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http://dx.doi.org/10.1093/jnci/djz044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962891PMC
July 2019

Disease Labels and Clear Communication With Patients-A Rose by Any Other Name Would Smell as Sweet.

JAMA Oncol 2019 06;5(6):784-785

Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland.

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http://dx.doi.org/10.1001/jamaoncol.2019.0053DOI Listing
June 2019

Current Status and Future Perspectives on Neoadjuvant Therapy in Lung Cancer.

J Thorac Oncol 2018 Dec 27;13(12):1818-1831. Epub 2018 Sep 27.

Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.

This Review Article provides a multi-stakeholder view on the current status of neoadjuvant therapy in lung cancer. Given the success of oncogene-targeted therapy and immunotherapy for patients with advanced lung cancer, there is a renewed interest in studying these agents in earlier disease settings with the opportunity to have an even greater impact on patient outcomes. There are unique opportunities and challenges with the neoadjuvant approach to drug development. To achieve more rapid knowledge turns, study designs, endpoints, and definitions of pathologic response should be standardized and harmonized. Continued dialogue with all stakeholders will be critical to design and test novel induction strategies, which could expedite drug development for patients with early lung cancer who are at high risk for metastatic recurrence.
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http://dx.doi.org/10.1016/j.jtho.2018.09.017DOI Listing
December 2018

Current and Future Management of Malignant Mesothelioma: A Consensus Report from the National Cancer Institute Thoracic Malignancy Steering Committee, International Association for the Study of Lung Cancer, and Mesothelioma Applied Research Foundation.

J Thorac Oncol 2018 11 25;13(11):1655-1667. Epub 2018 Sep 25.

Department of Radiation Oncology, Mount Sinai Medical Center, New York, New York.

On March 28- 29, 2017, the National Cancer Institute (NCI) Thoracic Malignacy Steering Committee, International Association for the Study of Lung Cancer, and Mesothelioma Applied Research Foundation convened the NCI-International Association for the Study of Lung Cancer- Mesothelioma Applied Research Foundation Mesothelioma Clinical Trials Planning Meeting in Bethesda, Maryland. The goal of the meeting was to bring together lead academicians, clinicians, scientists, and the U.S. Food and Drug Administration to focus on the development of clinical trials for patients in whom malignant pleural mesothelioma has been diagnosed. In light of the discovery of new cancer targets affecting the clinical development of novel agents and immunotherapies in malignant mesothelioma, the objective of this meeting was to assemble a consensus on at least two or three practice-changing multimodality clinical trials to be conducted through NCI's National Clinical Trials Network.
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http://dx.doi.org/10.1016/j.jtho.2018.08.2036DOI Listing
November 2018

Steps forward for cancer precision medicine.

Nat Rev Drug Discov 2018 01 24;17(1):1-2. Epub 2017 Nov 24.

EORTC Headquarters, 1200 Brussels, Belgium.

The availability of targeted anticancer drugs and the relative affordability of genomic analyses has led to a growing expectation among patients with cancer that they can receive personalized treatment based on the genomic signature of their tumour. Here, we discuss some of the challenges and steps needed to bring such approaches into routine practice.
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http://dx.doi.org/10.1038/nrd.2017.218DOI Listing
January 2018

Societal challenges of precision medicine: Bringing order to chaos.

Eur J Cancer 2017 10 4;84:325-334. Epub 2017 Sep 4.

EORTC Headquarters, Brussels, Belgium. Electronic address:

The increasing number of drugs targeting specific proteins implicated in tumourigenesis and the commercial promotion of relatively affordable genome-wide analyses has led to an increasing expectation among patients with cancer that they can now receive effective personalised treatment based on the often complex genomic signature of their tumour. For such approaches to work in routine practice, the development of correspondingly complex biomarker assays through an appropriate and rigorous regulatory framework will be required. It is becoming increasingly evident that a re-engineering of clinical research is necessary so that regulatory considerations and procedures facilitate the efficient translation of these required biomarker assays from the discovery setting through to clinical application. This article discusses the practical requirements and challenges of developing such new precision medicine strategies, based on leveraging complex genomic profiles, as discussed at the Innovation and Biomarkers in Cancer Drug Development meeting (8th-9th September 2016, Brussels, Belgium).
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http://dx.doi.org/10.1016/j.ejca.2017.07.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888555PMC
October 2017

Immunotherapy of head and neck cancer: Emerging clinical trials from a National Cancer Institute Head and Neck Cancer Steering Committee Planning Meeting.

Cancer 2017 Apr 1;123(7):1259-1271. Epub 2016 Dec 1.

Cancer Therapeutics Evaluation Program.

Recent advances have permitted successful therapeutic targeting of the immune system in head and neck squamous cell carcinoma (HNSCC). These new immunotherapeutic targets and agents are being rapidly adopted by the oncologic community and hold considerable promise. The National Cancer Institute sponsored a Clinical Trials Planning Meeting to address the issue of how to further investigate the use of immunotherapy in patients with HNSCC. The goals of the meeting were to consider phase 2 or 3 trial designs primarily in 3 different patient populations: those with previously untreated, human papillomavirus-initiated oropharyngeal cancers; those with previously untreated, human papillomavirus-negative HNSCC; and those with recurrent/metastatic HNSCC. In addition, a separate committee was formed to develop integrative biomarkers for the clinical trials. The meeting started with an overview of key immune components and principles related to HNSCC, including immunosurveillance and immune escape. Four clinical trial concepts were developed at the meeting integrating different immunotherapies with existing standards of care. These designs were presented for implementation by the head and neck committees of the National Cancer Institute-funded National Clinical Trials Network. This article summarizes the proceedings of this Clinical Trials Planning Meeting, the purpose of which was to facilitate the rigorous development and design of randomized phase 2 and 3 immunotherapeutic trials in patients with HNSCC. Although reviews usually are published immediately after the meeting is held, this report is unique because there are now tangible clinical trial designs that have been funded and put into practice and the studies are being activated to accrual. Cancer 2017;123:1259-1271. © 2016 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705038PMC
April 2017

Overview of Thoracic Oncology Trials in Cooperative Groups Around the Globe.

Clin Lung Cancer 2017 01 27;18(1):5-12. Epub 2016 Jun 27.

Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA. Electronic address:

Survival rates of patients with either early and advanced stage non-small-cell lung cancer (NSCLC) have improved with newer systemic therapy and radiation techniques, including combination regimens, targeted therapies, and immunotherapies. The cancer cooperative groups have historically played a critical role in the advancement of NSCLC therapy. Annually, representatives from cooperative groups worldwide convene at the International Lung Cancer Congress (ILCC). In summer 2015, the ILCC reached its 16th anniversary. This article highlights the NSCLC studies presented by participating groups in 2015.
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http://dx.doi.org/10.1016/j.cllc.2016.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5361177PMC
January 2017

Consensus Report of the 2015 Weinman International Conference on Mesothelioma.

J Thorac Oncol 2016 08;11(8):1246-1262

Cancer Therapy Evaluation Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

On November 9 and 10, 2015, the International Conference on Mesothelioma in Populations Exposed to Naturally Occurring Asbestiform Fibers was held at the University of Hawaii Cancer Center in Honolulu, Hawaii. The meeting was cosponsored by the International Association for the Study of Lung Cancer, and the agenda was designed with significant input from staff at the U.S. National Cancer Institute and National Institute of Environmental Health Sciences. A multidisciplinary group of participants presented updates reflecting a range of disciplinary perspectives, including mineralogy, geology, epidemiology, toxicology, biochemistry, molecular biology, genetics, public health, and clinical oncology. The group identified knowledge gaps that are barriers to preventing and treating malignant mesothelioma (MM) and the required next steps to address barriers. This manuscript reports the group's efforts and focus on strategies to limit risk to the population and reduce the incidence of MM. Four main topics were explored: genetic risk, environmental exposure, biomarkers, and clinical interventions. Genetics plays a critical role in MM when the disease occurs in carriers of germline BRCA1 associated protein 1 mutations. Moreover, it appears likely that, in addition to BRCA1 associated protein 1, other yet unknown genetic variants may also influence the individual risk for development of MM, especially after exposure to asbestos and related mineral fibers. MM is an almost entirely preventable malignancy as it is most often caused by exposure to commercial asbestos or mineral fibers with asbestos-like health effects, such as erionite. In the past in North America and in Europe, the most prominent source of exposure was related to occupation. Present regulations have reduced occupational exposure in these countries; however, some people continue to be exposed to previously installed asbestos in older construction and other settings. Moreover, an increasing number of people are being exposed in rural areas that contain noncommercial asbestos, erionite, and other mineral fibers in soil or rock (termed naturally occurring asbestos [NOA]) and are being developed. Public health authorities, scientists, residents, and other affected groups must work together in the areas where exposure to asbestos, including NOA, has been documented in the environment to mitigate or reduce this exposure. Although a blood biomarker validated to be effective for use in screening and identifying MM at an early stage in asbestos/NOA-exposed populations is not currently available, novel biomarkers presented at the meeting, such as high mobility group box 1 and fibulin-3, are promising. There was general agreement that current treatment for MM, which is based on surgery and standard chemotherapy, has a modest effect on the overall survival (OS), which remains dismal. Additionally, although much needed novel therapeutic approaches for MM are being developed and explored in clinical trials, there is a critical need to invest in prevention research, in which there is a great opportunity to reduce the incidence and mortality from MM.
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http://dx.doi.org/10.1016/j.jtho.2016.04.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5551435PMC
August 2016

Clinician Perspectives on Current Issues in Lung Cancer Drug Development.

J Thorac Oncol 2016 09 9;11(9):1387-96. Epub 2016 Jul 9.

U.S. Food and Drug Administration, Silver Spring, Maryland. Electronic address:

Recent advances in molecularly targeted therapy and immunotherapy offer a glimmer of hope for potentially realizing the dream of personalized therapy for lung cancer. This article highlights current questions in clinical trial design, enrollment strategies and patient focused drug development, with particular emphasis on unique issues in trials of targeted therapy and immunotherapy.
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http://dx.doi.org/10.1016/j.jtho.2016.05.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5131641PMC
September 2016

Small Cell Lung Cancer Screen of Oncology Drugs, Investigational Agents, and Gene and microRNA Expression.

J Natl Cancer Inst 2016 10 31;108(10). Epub 2016 May 31.

Affiliations of authors: Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD (DE, TS, RD, JL, CO, RR, MS, JC, EH, NF, AM); Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis (MK, GK, JM, BAT), Biometric Research Program, Division of Cancer Treatment and Diagnosis (EP, DS), and Cancer Therapy Evaluation Program (SM), National Cancer Institute, Rockville, MD.

Background: Small cell lung carcinoma (SCLC) is an aggressive, recalcitrant cancer, often metastatic at diagnosis and unresponsive to chemotherapy upon recurrence, thus it is challenging to treat.

Methods: Sixty-three human SCLC lines and three NSCLC lines were screened for response to 103 US Food and Drug Administration-approved oncology agents and 423 investigational agents. The investigational agents library was a diverse set of small molecules that included multiple compounds targeting the same molecular entity. The compounds were screened in triplicate at nine concentrations with a 96-hour exposure time using an ATP Lite endpoint. Gene expression was assessed by exon array, and microRNA expression was derived by direct digital detection. Activity across the SCLC lines was associated with molecular characteristics using pair-wise Pearson correlations.

Results: Results are presented for inhibitors of targets: BCL2, PARP1, mTOR, IGF1R, KSP/Eg5, PLK-1, AURK, and FGFR1. A relational map identified compounds with similar patterns of response. Unsupervised microRNA clustering resulted in three distinct SCLC subgroups. Associating drug response with micro-RNA expression indicated that lines most sensitive to etoposide and topotecan expressed high miR-200c-3p and low miR-140-5p and miR-9-5p. The BCL-2/BCL-XL inhibitors produced similar response patterns. Sensitivity to ABT-737 correlated with higher ASCL1 and BCL2. Several classes of compounds targeting nuclear proteins regulating mitosis produced a response pattern distinct from the etoposide response pattern.

Conclusions: Agents targeting nuclear kinases appear to be effective in SCLC lines. Confirmation of SCLC line findings in xenografts is needed. The drug and compound response, gene expression, and microRNA expression data are publicly available at http://sclccelllines.cancer.gov.
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http://dx.doi.org/10.1093/jnci/djw122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279282PMC
October 2016

ALCHEMIST Trials: A Golden Opportunity to Transform Outcomes in Early-Stage Non-Small Cell Lung Cancer.

Clin Cancer Res 2015 Dec;21(24):5439-44

Department of Medicine, Section of Hematology/Oncology, The University of Chicago, Chicago, Illinois. The University of Chicago Comprehensive Cancer Research Center, Chicago, Illinois.

The treatment of patients with metastatic non-small cell lung cancer (NSCLC) is slowly evolving from empirical cytotoxic chemotherapy to personalized treatment based on specific molecular alterations. Despite this 10-year evolution, targeted therapies have not been studied adequately in patients with resected NSCLC who have clearly defined actionable mutations. The advent of next-generation sequencing has now made it possible to characterize genomic alterations in unprecedented detail. The efforts begun by The Cancer Genome Atlas project to understand the complexities of the genomic landscape of lung cancer will be supplemented further by studying a large number of tumor specimens. The Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial (ALCHEMIST) is an NCI-sponsored national clinical trials network (NCTN) initiative to address the needs to refine therapy for early-stage NSCLC. This program will screen several thousand patients with operable lung adenocarcinoma to determine whether their tumors contain specific molecular alterations [epidermal growth factor receptor mutation (EGFR) and anaplastic lymphoma kinase rearrangement (ALK)], making them eligible for treatment trials that target these alterations. Patients with EGFR mutation or ALK gene rearrangement in their tumor will be randomized to placebo versus erlotinib or crizotinib, respectively, after completion of their standard adjuvant therapy. ALCHEMIST will also contain a large discovery component that will provide an opportunity to incorporate genomic studies to fully understand the clonal architecture, clonal evolution, and mechanisms of resistance to therapy. In this review, we describe the concept, rationale, and outline of ALCHEMIST and the plan for genomic studies in patients with lung adenocarcinoma. Clin Cancer Res; 21(24); 5439-44. ©2015 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-0354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4683399PMC
December 2015

Lung Master Protocol (Lung-MAP)-A Biomarker-Driven Protocol for Accelerating Development of Therapies for Squamous Cell Lung Cancer: SWOG S1400.

Clin Cancer Res 2015 Apr 13;21(7):1514-24. Epub 2015 Feb 13.

University of Texas MD Anderson Cancer Center, Houston, Texas.

The Lung Master Protocol (Lung-MAP, S1400) is a groundbreaking clinical trial designed to advance the efficient development of targeted therapies for squamous cell carcinoma (SCC) of the lung. There are no approved targeted therapies specific to advanced lung SCC, although The Cancer Genome Atlas project and similar studies have detected a significant number of somatic gene mutations/amplifications in lung SCC, some of which are targetable by investigational agents. However, the frequency of these changes is low (5%-20%), making recruitment and study conduct challenging in the traditional clinical trial setting. Here, we describe our approach to development of a biomarker-driven phase II/II multisubstudy "Master Protocol," using a common platform (next-generation DNA sequencing) to identify actionable molecular abnormalities, followed by randomization to the relevant targeted therapy versus standard of care.
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http://dx.doi.org/10.1158/1078-0432.CCR-13-3473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4654466PMC
April 2015

Consensus report of a joint NCI thoracic malignancies steering committee: FDA workshop on strategies for integrating biomarkers into clinical development of new therapies for lung cancer leading to the inception of "master protocols" in lung cancer.

J Thorac Oncol 2014 Oct;9(10):1443-8

*Clinical Investigations Branch, Cancer Therapy Evaluation Program, National Cancer Institute, National Institutes of Health, Bethesda, MD; †Offices of Hematology and Oncology Products, Center for Drug Evaluation and Research U.S. Food and Drug Administration, Silver Spring, MD; ‡University of Pittsburgh Medical Center, Pittsburgh, PA; §University of Utah, Salt Lake City, UT; ‖Duke University Medical Center, Durham, NC; ¶Biometric Research Branch, Cancer Therapy Evaluation Program, National Cancer Institute, National Institutes of Health, Bethesda, MD; and #University of Colorado, School of Medicine, Denver, CO.

On February 2, 2012, the National Cancer Institute (NCI) sponsored a 2-day workshop with the NCI Thoracic Malignancies Steering Committee and the Food and Drug Administration to bring together leading academicians, clinicians, industry and government representatives to identify challenges and potential solutions in the clinical development of novel targeted therapies for lung cancer. Measures of success are rapidly evolving from a scientific and regulatory perspective and the objectives of this workshop were to achieve initial consensus on a high priority biomarker-driven clinical trial designed to rapidly assess the activity of targeted agents in molecularly defined lung cancer subsets and to facilitate generation of data leading to approval of these new therapies. Additionally, the meeting focused on identification of the barriers to conduct such a trial and the development of strategies to overcome those barriers. The "Lung Master Protocols" recently launched by NCI were the direct outcome of this workshop.
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http://dx.doi.org/10.1097/JTO.0000000000000314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4165474PMC
October 2014

National Cancer Institute's Precision Medicine Initiatives for the new National Clinical Trials Network.

Am Soc Clin Oncol Educ Book 2014 :71-6

From the Division of Cancer Treatment and Diagnosis, National Cancer Institute at the National Institutes of Health, Bethesda, MD; Center for Cancer Genomics, National Cancer Institute at the National Institutes of Health, Bethesda, MD; and Leidos Corporation, Frederick, MD.

The promise of precision medicine will only be fully realized if the research community can adapt its clinical trials methodology to study molecularly characterized tumors instead of the traditional histologic classification. Such trials will depend on adequate tissue collection, availability of quality controlled, high throughput molecular assays, and the ability to screen large numbers of tumors to find those with the desired molecular alterations. The National Cancer Institute's (NCI) new National Clinical Trials Network (NCTN) is well positioned to conduct such trials. The NCTN has the ability to seamlessly perform ethics review, register patients, manage data, and deliver investigational drugs across its many sites including both in cities and rural communities, academic centers, and private practices. The initial set of trials will focus on different questions: (1) Exceptional Responders Initiative-why do a minority of patients with solid tumors or lymphoma respond very well to some drugs even if the majority do not?; (2) NCI MATCH trial-can molecular markers predict response to targeted therapies in patients with advanced cancer resistant to standard treatment?; (3) ALCHEMIST trial-will targeted epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) inhibitors improve survival for adenocarcinoma of the lung in the adjuvant setting?; and (4) Lung Cancer Master Protocol trial for advanced squamous cell lung cancer-is there an advantage to developing drugs for small subsets of molecularly characterized tumors in a single, multiarm trial design? These studies will hopefully spawn a new era of treatment trials that will carefully select the tumors that may respond best to investigational therapy.
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http://dx.doi.org/10.14694/EdBook_AM.2014.34.71DOI Listing
November 2015

U.S. Food and Drug Administration approval: crizotinib for treatment of advanced or metastatic non-small cell lung cancer that is anaplastic lymphoma kinase positive.

Clin Cancer Res 2014 Apr 26;20(8):2029-34. Epub 2014 Feb 26.

Authors' Affiliations: Clinical Investigations Branch, Cancer Therapy Evaluation Program, National Cancer Institute, National Institutes of Health, Bethesda; Offices of Hematology and Oncology Products, Biostatistics, and Clinical Pharmacology, Center for Drug Evaluation and Research; and Office of In Vitro Diagnostics and Radiological Health, Center for Devices and Radiologic Health; U.S. Food and Drug Administration, Silver Spring, Maryland.

On August 26, 2011, the U.S. Food and Drug Administration (FDA) approved crizotinib (XALKORI Capsules, Pfizer Inc.) for treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK) positive as detected by an FDA-approved test. The Vysis ALK Break-Apart FISH Probe Kit (Abbott Molecular, Inc.) was approved concurrently. In two multicenter, single-arm trials, patients with locally advanced or metastatic ALK-positive NSCLC previously treated with one or more systemic therapies received crizotinib orally at a dose of 250 mg twice daily. In 119 patients with ALK-positive NSCLC by local trial assay, the objective response rate (ORR) was 61% [95% confidence intervals (CI), 52%-70%] with a median response duration of 48 weeks. In 136 patients with ALK-positive NSCLC by the to-be-marketed test, the ORR was 50% (95% CI, 42%-59%) with a median response duration of 42 weeks. The most common adverse reactions (≥25%) were vision disorder, nausea, diarrhea, vomiting, edema, and constipation. Accelerated approval was granted on the basis of the high ORRs and durable responses. On November 20, 2013, crizotinib received full approval based on an improvement in progression-free survival in patients with metastatic ALK-positive NSCLC previously treated with one platinum-based chemotherapy regimen.
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http://dx.doi.org/10.1158/1078-0432.CCR-13-3077DOI Listing
April 2014

Obatoclax mesylate, a pan-bcl-2 inhibitor, in combination with docetaxel in a phase 1/2 trial in relapsed non-small-cell lung cancer.

J Thorac Oncol 2014 Jan;9(1):121-5

*H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida; †Arlington Cancer Center, Arlington, Texas; ‡Mayo Clinic Arizona, Scottsdale, Arizona; §Georgetown University Hospital, Washington, District of Columbia; ‖University of Maryland, Greenebaum Cancer Center, Baltimore, Maryland; ¶Tower Cancer Research Foundation, Beverly Hills, California; #MedStar Research Institute, Hyattsville, Maryland; and **formerly Gemin X Pharmaceuticals, an indirect wholly owned subsidiary of Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel.

Introduction: The proapoptotic small-molecule pan-Bcl-2 inhibitor obatoclax mesylate (GX15-070) may enhance the cytotoxicity of chemotherapy in relapsed/refractory non-small-cell lung cancer (NSCLC).

Methods: Obatoclax was administered with docetaxel in patients with relapsed or refractory NSCLC- docetaxel as a 1-hour infusion on day 1 and obatoclax as a 24-hour infusion on days 1 and 2-every 3 weeks for up to eight cycles. Four dose levels were evaluated in phase 1 (level 1: docetaxel 55 mg/m × 1 and obatoclax 30 mg × 2; levels 2-4: docetaxel 75 mg/m and obatoclax 30 mg, 45 mg, or 60 mg × 2) to identify dose-limiting toxicity and a phase 2 dose. In phase 2, response and tolerability were evaluated.

Results: Eighteen patients were included in phase 1. Two dose-limiting toxicities occurred during cycle 1: one febrile neutropenia each at dose levels 3 and 4. Maximum tolerated dose was not reached; 32 patients (including 3 from phase 1) were treated in phase 2 with docetaxel 75 mg/m and obatoclax 60 mg (median 2 cycles). Three patients (11%) had partial responses in phase 2; two demonstrated stable disease lasting 12 weeks or more. Median duration of response was 4.8 months. Overall, median progression-free survival was 1.4 months. Neutropenia (31%), febrile neutropenia (16%), and dyspnea (19%) were the most common grade 3/4 adverse events observed.

Conclusions: Combined obatoclax mesylate plus docetaxel is tolerable in patients with NSCLC, but response was minimal and neutropenia was a common adverse event.
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http://dx.doi.org/10.1097/JTO.0000000000000027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4666503PMC
January 2014

A Phase I, open-label, dose escalation study of afatinib, in a 3-week-on/1-week-off schedule in patients with advanced solid tumors.

Invest New Drugs 2013 Apr 17;31(2):399-408. Epub 2012 Nov 17.

Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, USA.

Background: A Phase I study to determine the maximum tolerated dose (MTD) and pharmacokinetics of afatinib (BIBW 2992), a novel irreversible ErbB Family Blocker, administered orally once daily in a 3-week-on/1-week-off dosing schedule.

Methods: Patients with advanced solid tumors received single-agent afatinib at 10, 20, 40, 55 or 65 mg/day. Safety, antitumor activity, pharmacokinetics and pharmacodynamic modulation of biomarkers were assessed.

Results: Forty-three patients were enrolled. Dose-limiting toxicities (DLTs) occurred in five patients in the dose escalation phase (1/8 at 40 mg/day; 1/6 at 55 mg/day; 3/6 at 65 mg/day). The MTD was established at 55 mg/day. In the expansion cohort at the MTD, 6 patients experienced a DLT in the first 28-day treatment period. The most frequent DLT was diarrhea. The most common adverse events were diarrhea, rash, nausea, vomiting and fatigue. Overall, the afatinib safety profile in a 3-week-on/1-week-off dose schedule was similar to that of our daily-continuous schedule. Afatinib displayed dose-dependent pharmacokinetics at doses up to and including 55 mg/day, with a terminal half-life suitable for once-daily dosing. Signs of clinical antitumor activity were observed. In biopsies taken from clinically normal forearm skin, afatinib caused a reduced proliferation rate, with a concomitant increase in differentiation of epidermal keratinocytes.

Conclusion: Afatinib in a 3-week-on/1-week-off schedule showed a good safety profile. The MTD was 55 mg/day, although excess DLTs in the expansion cohort indicated that the 40 mg/day dose would have an acceptable safety profile for future studies. Dose cohorts between 40 and 55 mg/day were not examined in this study.
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http://dx.doi.org/10.1007/s10637-012-9890-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3589659PMC
April 2013

A Phase I clinical trial of the combination of imatinib and paclitaxel in patients with advanced or metastatic solid tumors refractory to standard therapy.

Cancer Chemother Pharmacol 2012 Dec 27;70(6):843-53. Epub 2012 Sep 27.

Lombardi Comprehensive Cancer Center, Developmental Therapeutics Program, Washington, DC 20007, USA.

Purpose: Pre-clinical data suggest that combining imatinib with traditional cytotoxic chemotherapy may improve imatinib efficacy. We conducted a Phase I study of imatinib in combination with paclitaxel in patients with advanced or metastatic solid tumors.

Methods: Patients were accrued to the study in a standard 3 + 3 design. Patients were restaged every two cycles, and those with stable disease (SD), or better, continued study treatment without interruption. Maximally tolerated doses (MTDs) and pharmacokinetic profiles of combination imatinib and paclitaxel were assessed.

Results: Fifty-eight patients were enrolled, including 40 in the Phase I dose escalation portion. Alternating dose escalation of imatinib and paclitaxel on a 28-day cycle resulted in MTDs of 800 mg imatinib daily, on days 1-4, 8-11, 15-18, and 22-25, and 100 mg/m(2) paclitaxel weekly, on days 3, 10, and 17. Two expansion cohorts, comprising 10 breast cancer patients and 8 patients with soft-tissue sarcomas, were enrolled at the MTDs. The most common adverse events were flu-like symptoms (64 %) and nausea/vomiting (71 %). The most common Grade 3/4 toxicities were neutropenia (26 %), flu-like symptoms (12 %), and pain (12 %). There were no relevant differences in the pharmacokinetic profiles of either drug when given in combination compared with alone. Thirty-eight subjects were evaluable for response, 18 (47.4 %) of whom experienced clinical benefit. Five patients (13.2 %) had a partial response (PR) and 13 patients (34.2 %) had SD; the average time to progression in those with clinical benefit was 17 weeks (range: 7-28 weeks).

Conclusions: This combination of imatinib and paclitaxel was reasonably safe and tolerable, and demonstrated evidence of anti-tumor activity. Further exploration in disease-specific Phase II trials is warranted.
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http://dx.doi.org/10.1007/s00280-012-1969-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3703247PMC
December 2012

A phase 1 study of efatutazone, an oral peroxisome proliferator-activated receptor gamma agonist, administered to patients with advanced malignancies.

Cancer 2012 Nov 8;118(21):5403-13. Epub 2012 May 8.

Lombardi Comprehensive Cancer Center, Developmental Therapeutics Program, Georgetown University Medical Center, Washington, DC 20007, USA.

Background: Efatutazone (CS-7017), a novel peroxisome proliferator-activated receptor gamma (PPARγ) agonist, exerts anticancer activity in preclinical models. The authors conducted a phase 1 study to determine the recommended phase 2 dose, safety, tolerability, and pharmacokinetics of efatutazone.

Methods: Patients with advanced solid malignancies and no curative therapeutic options were enrolled to receive a given dose of efatutazone, administered orally (PO) twice daily for 6 weeks, in a 3 + 3 intercohort dose-escalation trial. After the third patient, patients with diabetes mellitus were excluded. Efatutazone dosing continued until disease progression or unacceptable toxicity, with measurement of efatutazone pharmacokinetics and plasma adiponectin levels.

Results: Thirty-one patients received efatutazone at doses ranging from 0.10 to 1.15 mg PO twice daily. Dose escalation stopped when maximal impact on PPARγ-related biomarkers had been reached before any protocol-defined maximum-tolerated dose level. On the basis of a population pharmacokinetic/pharmacodynamic analysis, the recommended phase 2 dose was 0.5 mg PO twice daily. A majority of patients experienced peripheral edema (53.3%), often requiring diuretics. Three episodes of dose-limiting toxicities, related to fluid retention, were noted in the 0.10-, 0.25-, and 1.15-mg cohorts. Of 31 treated patients, 27 were evaluable for response. A sustained partial response (PR; 690 days on therapy) was observed in a patient with myxoid liposarcoma. Ten additional patients had stable disease (SD) for ≥60 days. Exposures were approximately dose proportional, and adiponectin levels increased after 4 weeks of treatment at all dose levels. Immunohistochemistry of archived specimens demonstrated that PPARγ and retinoid X receptor expression levels were significantly greater in patients with SD for ≥60 days or PR (P = .0079), suggesting a predictive biomarker.

Conclusions: Efatutazone demonstrates acceptable tolerability with evidence of disease control in patients with advanced malignancies.
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http://dx.doi.org/10.1002/cncr.27526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3726261PMC
November 2012

A phase I trial of bexarotene in combination with docetaxel in patients with advanced solid tumors.

Clin Lung Cancer 2011 Jul 24;12(4):231-6. Epub 2011 Apr 24.

FDA, Office of Oncology Drug Products, Silver Spring, MD, USA.

Background: The purpose of this study was to identify dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of docetaxel with a fixed-dose of bexarotene.

Patients And Methods: This was a phase I, single-center and open-label trial of dose-escalating docetaxel with a fixed-dose oral bexarotene. Successive cohorts of 3 patients (pts), with confirmed solid tumors refractory to standard therapy or for whom no standard therapy existed, received fixed-dose oral bexarotene (400 mg/m(2) daily) with escalating doses of docetaxel weekly (25, 30, or 35 mg/m(2)) for 3 weeks on a 4-week cycle. Cohorts were expanded to 6 pts if a DLT was noted. The MTD was determined based on the occurrence of DLT in at least 2 of 6 pts during the first cycle.

Results: Nineteen pts were enrolled. Seven pts were treated at 25 mg/m(2), 6 at 30 mg/m(2), and 6 at 35 mg/m(2) of docetaxel. The MTD for docetaxel was 30 mg/m(2) with 400 mg/m(2) of daily bexarotene. Hypothyroidism, hypertriglyceridemia, and fatigue were common toxicities. Three pts developed pulmonary toxicity (possible radiation recall pneumonitis [n = 2] and pulmonary hypertension because of tumor emboli [n = 1]). Two pts withdrew consent because of Grade 3 fatigue. Ten of 19 pts were noted to have stable disease and received more than 2 cycles of therapy. Of the 10 pts with stable disease, 5 had non-small-cell lung cancer (NSCLC), and of those 5 pts, 1 had a partial response that persisted for eight cycles. conclusion: The MTD of docetaxel was 30 mg/m(2) in combination with daily bexarotene at 400mg/m(2). Careful monitoring may be indicated in pts with previously irradiated lung tumors.
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http://dx.doi.org/10.1016/j.cllc.2011.03.024DOI Listing
July 2011

Folotyn (pralatrexate injection) for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma: U.S. Food and Drug Administration drug approval summary.

Clin Cancer Res 2010 Oct 25;16(20):4921-7. Epub 2010 Aug 25.

Office of Oncology Drug Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.

Purpose: On September 24, 2009, the U.S. Food and Drug Administration granted accelerated approval for Folotyn (pralatrexate injection, Allos Therapeutics, Inc.) as a single agent for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL); it is the first drug approved for this indication.

Experimental Design: This review was based on study PDX-008, a phase II, single-arm, nonrandomized, open-label, international, multicenter trial, designed to evaluate the safety and efficacy of pralatrexate when administered concurrently with vitamin B(12) and folic acid supplementation in patients with relapsed or refractory PTCL.

Results: The overall response rate was 27% in 109 evaluable patients [95% confidence interval (CI), 19-36%]. Twelve percent of 109 evaluable patients (95% CI, 7-20%)] had a response duration of ≥14 weeks. Six of these 13 patients achieved a complete response, and one patient had complete response unconfirmed. The most common grade 3 and 4 toxicities were thrombocytopenia, mucositis, and neutropenia.

Conclusion: This accelerated approval was based on a response rate that is reasonably likely to predict clinical benefit in this heavily pretreated patient population with this rare disease. The applicant has committed to conducting postmarketing clinical trials to assess clinical benefit. The recommended starting dose of pralatrexate in patients with relapsed or refractory PTCL is 30 mg/m(2) via intravenous push over 3 to 5 min weekly for 6 weeks followed by a one-week rest (one cycle). Intramuscular injection of 1 mg vitamin B(12) should be administered every 8 to 10 weeks along with 1.0 mg folic acid given orally once a day.
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http://dx.doi.org/10.1158/1078-0432.CCR-10-1214DOI Listing
October 2010

HIV-related large B-cell lymphoma confined to the bone marrow with a fulminant clinical course: a case report and literature review.

Clin Adv Hematol Oncol 2007 Aug;5(8):622-4; discussion 625-6

Lombardi Cancer Center, Georgetown University Hospital, Washington, DC 20007, USA.

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August 2007
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