James A. Zwiebel

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

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 Institutes (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.

Phase II trial of the histone deacetylase inhibitor belinostat in women with platinum resistant epithelial ovarian cancer and micropapillary (LMP) ovarian tumours

AIMnMicropapillary/borderline (LMP) ovarian tumours are rarely included in clinical trials and are intrinsically resistant to radiation and chemotherapy. Platinum resistant epithelial ovarian cancer (EOC) has a poor prognosis. The histone deacetylase inhibitor belinostat demonstrated antitumour activity in pre-clinical ovarian cancer models.nnnMETHODSnA phase II study was performed to evaluate the activity of belinostat in two patient populations: women with metastatic or recurrent platinum resistant (progression within 6 months) EOC and LMP ovarian tumours, both groups had received no more than 3 prior lines of chemotherapy. Belinostat 1000 mg/m(2)/d was administered iv days 1-5 of a 21 d cycle. Peripheral blood mononuclear cells (PBMCs) and tumour biopsies, where possible, for correlative studies were obtained prior to and following treatment.nnnRESULTSnEighteen patients with EOC and 14 patients with LMP tumours were enrolled on study. Belinostat was well tolerated with no grade four toxicity (179 cycles). Grade 3 toxicity consisted of thrombosis (3 patients), hypersensitivity (1) and elevated ALP (1). One patient with LMP tumour had a partial response (unconfirmed) and 10 had stable disease (SD), 3 were non-evaluable. Median progression-free survival (PFS) was 13.4 months (95% confidence interval (CI), 5.6--not reached). Best response in patients with EOC was SD (nine patients) and median PFS was 2.3 months (95% CI, 1.2-5.7 months). An accumulation of acetylated histones H3 and H4 was noted in PBMCs and in tumour tissue.nnnCONCLUSIONSnBelinostat is well tolerated in both patient groups and shows some activity in patients with micropapillary (LMP) disease.

Breast cancer gene therapy : transgenic immunotherapy

SummaryA number of studies have demonstrated that potent anti-tumor immunity can be induced using cytokine gene transfer, a strategy termed transgenic immunotherapy. Our aim is to express cytokine genes in the vicinity of tumor cells, either by transducing tumor cells themselves, or by delivering cytokine-expressing endothelial cells to tumor sites. We compared the ability of cytokine-expressing tumor cells or endothelial cells to inhibit the tumorigenesis of MDA-MB-435 breast cancer cells in athymic nude mice. Retroviral vectors containing either human interleukin 2 (hIL-2) or interleukin 1 (hIL-1α) were used to transduce MDA-MB-435 cells or human umbilical vein endothelial cells (HUVEC). Using a modified MTT bioassay and an ELISA specific for hIL-2, 43 of 70 MDA-MB-435 clones transduced with IL-2 were found to secrete between 100–800 units of IL-2/106 cells/24 hr. hIL-2 and hIL-1α-transduced HUVEC secreted 40 ng/IL-2/106/24 hr and 1.8 ng/106/24 hr, respectively. To facilitatein vivo tracking of tumor cells, both nontransduced and IL-2-expressing MDA-MB-435 cells were genetically-marked with the E. colilacZ gene and selected using flow cytometry. To studyin vivo tumorigenicity, cells were injected into the mammary fat pad of athymic nude mice: (1)lacZ/MDA-MB-435 cells injected alone formed tumors in all animals ;(2) IL-2-expressinglacZ/MDA-MB-435 cells did not form any tumors; (3) co-inoculation of MDA-MB-435/IL-2, HUVEC/IL-2, or HUVEC/IL-1α withlacZ/MDA-MB-435 cells prevented or delayed tumor growth. These results suggest that local cytokine secretion was capable of activating natural killer cell activity in host animals. Transgenic immunotherapy is a promising approach that may be useful for the eradication of minimal residual disease.

Abstract 2594: Reovirus replication in ovarian and peritoneal tumors after intravenous administration

Background: Reovirus Serotype 3 - Dearing Strain is an oncolytic virus under clinical evaluation for treatment of solid tumor malignancies. We initiated a phase 1/2 study with reovirus in patients with ovarian, primary peritoneal and fallopian tube carcinoma. The objectives of the correlative studies in this trial include the verification of reovirus penetration and replication in ovarian and peritoneal tumors after IV and IP reovirus administration and to evaluate tumor RAS pathway activation status as a marker for reovirus activity in this patient population. Methods: Percutaneous tumor biopsies and ascites fluid were collected at various times during therapy from patients receiving reovirus via both IV and IP routes. Biopsied tissue and cell preparations from ascites were evaluated for reovirus capsid particles via electron microscopy (EM) and viral protein via immunohistochemistry (IHC). The presence of viral RNA and transcribed DNA are evaluated via reverse-transcriptase in situ PCR (RTISPCR). IHC for phosphorylated ERK (pERK) is applied to determine RAS pathway activation status. Results: To date, 5 patients have been accrued and treated on trial. Preliminary evaluation with IHC indicates the presence of viral protein in the biopsied ovarian and peritoneal tissue samples from a subset of these patients after IV administration of reovirus. Completion of EM, RTISPCR, and pERK IHC on biopsied tissues and ascites samples is in progress. Conclusions: Results to date display evidence of viral replication in peritoneal and ovarian cancer cells after IV administration of reovirus. This data represents the first observation of reovirus penetration into the peritoneal space after systemic drug administration. Completion of correlative analyses will further characterize the ability of reovirus to penetrate and replicate within the IP space and ascites after IV and IP administration. Furthermore, the selective viral infection and replication within RAS-pathway-activated tumor cells will be assessed. Results of all correlatives will be presented at the meeting. This work is supported by the NCI, grant U01CA076576 and contract NO1CM62207. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2594.

Abstract CT101: NCI-molecular analysis for therapy choice (NCI-MATCH) clinical trial: interim analysis

The NCI MATCH is an efficacy signal-finding trial to identify molecular alterations that can be matched to targeted treatments in tumor biopsies from patients (pts) with refractory solid tumors or lymphomas.br />METHODS: An Ion Torrent Oncomine panel sequencing assay and a binary PTEN immunohistochemistry assay were employed. NCI-MATCH opened in August 2015. A protocol-directed pause in screening for interim analysis occurred in November 2015 with goals to assess tumor biopsy feasibility and quality, performance of the CLIA-accredited laboratories, any unanticipated concerns with the study, the match rate for the first activated 10 arms and for planned arms, the spectrum of molecular abnormalities identified, histologic tumor types and demographics. RESULTS: Between 8-12-15 and 11-11-15, 795 pts enrolled for screening and 739 biopsies were submitted. Biopsies were submitted from community (2/3) and academic (1/3) sites. Sequencing was completed on 645 of these specimens (87%). Median turn around time was 27 days but increased from 14 days in the first month to 36 days in the last month, correlating with marked increase in weekly accrual. The highest toxicity (Grade 3) possibly related to biopsy was < 1%. The most frequent tumor types sequenced were colorectal (13%), breast (13%), ovarian (11%), non-small cell lung (7.4%), endometrial (7%), pancreatic (5%), head/neck (5%) esophageal/gastric (4%), cholangiocarcinoma and neuroendocrine (3% each), and small cell lung, prostate, bladder, and unknown primary (<3% each). Fifty-six patients (9%) had actionable mutations of interest (aMOIs); of these, 33 pts (5.1%, 95%CI 3.5, 7.1%) met molecular eligibility for assignment to one of 10 treatment arms. The most common genetic mutations, amplifications or translocations were:n CONCLUSIONS: Accrual was brisk and biopsies were feasible and safe with adequate tumor yield and results. The match rate was lower than predicted for the first 10 treatment arms. Accrual of less common tumor histologic types exceeded expectations. Results from the interim analysis will inform the types of treatment and predicted match rate for additional MATCH arms. NCI-MATCH will re-open with increased capacity and additional treatment arms with a match rate goal of at least 20%. Citation Format: Barbara A. Conley, Robert Gray, Alice Chen, Peter O’Dwyer, Carlos Arteaga, Brent Coffey, David Patton, Shuli Li, Lisa M. McShane, Larry Rubinstein, Robert Comis, Jeffrey Abrams, Paul M. Williams, Chih-Jian Lih, Stanley Hamilton, Edith Mitchell, James Zwiebel, Keith Flaherty, NCI MATCH team. NCI-molecular analysis for therapy choice (NCI-MATCH) clinical trial: interim analysis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT101.

National Cancer Institute Formulary: A Public‐Private Partnership Providing Investigators Access to Investigational Anticancer Agents

As part of the White House Cancer Moonshot Initiative, the National Cancer Institute (NCI) has developed a drug formulary to provide investigational anticancer agents to the extramural research community. This article describes how the NCI Formulary functions, how researchers may apply for access to drugs in the formulary, and the NCIs initial goals for formulary participation. Approved investigators may apply for access to formulary agents at: https://nciformulary.cancer.gov.

Abstract PL03-01: NCI-MATCH: A new paradigm in the era of genomic oncology

Oncology has undergone major changes in systemic treatment options, from chemotherapy to antiangiogenic agents to tyrosine-kinase inhibitors to immunotherapy. Historically, a therapeutic agent is tested in separate trials as monotherapy or combined with investigational or approved agents/modalities, to determine antitumor activity in each histology based on the premise that each histology responds differently to the same treatment. This paradigm is time consuming and may or may not make use of molecular characterization to test each agent in each histology. However, with the expansion of biologic understanding and development of various biomarkers, e.g., estrogen receptor and Her 2 amplification, we move beyond the basic paradigm of general histology to one in which treatment is based upon molecular characteristics of the tumor. Examples of recent discoveries from this more modern paradigm are (1) multiple histologies sharing a common molecular profile and (2) a subset within a single histology having a given molecular characteristic. Various agents have been tested singularly in terms of molecular aberrations and histology, e.g., ALK inhibitors and NSCLC. However, with the rapid increase in the number of targeted agents in development, more facile and efficient clinical trial designs are needed. The National Cancer Institute (NCI) and ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) collaborated in designing the Molecular Analysis for Therapy Choice trial (NCI-MATCH or EAY131), the first large-scale signal-finding precision medicine oncology trial in the United States to incorporate centralized NGS testing to direct patients to parallel (nonrandomized) phase II treatment arms under a master protocol. The trial is being conducted by the NCI National Clinical Trials Network (NCTN), with ECOG-ACRIN leading the trial. More than 100 investigators from across the NCTN adult cancer-oriented member groups (Alliance for Clinical Trials in Oncology, ECOG-ACRIN, NRG Oncology, and SWOG) have worked collaboratively to design and lead what is currently 30 treatment arms (subprotocols), with more arms in development. Wide-scale NCTN investigator involvement ensures use of the latest knowledge to define the actionable mutations required for eligibility and to make evidence-based selections of experimental agents. In NCI-MATCH, patients are assigned treatment based on the genomic alterations found in their tumors through genomic sequencing and other tests at the time of initial enrollment for screening. Unlike other phase II trials, each arm is open to advanced solid tumors, lymphomas, or myeloma that share a set of molecular aberrations, not restricted to a single histology. This strategy accommodates and encourages enrollment of rare tumors for which there are often no standard treatments and limited clinical trial options. NCI-MATCH has 10-30 concurrent treatment arms available to patients at any given time, testing both investigational agents and FDA-approved drugs for new indications. Most treatment arms have an enrollment goal of 35 patients, with some arms that address tumor gene variants of higher prevalence expanded to 70 patients. Together, the NCTN and NCI Community Oncology Research Program provide infrastructure for many clinical sites (>1100) to participate, providing ready access to physicians and patients; screening enrollment has occurred in all 50 states in the U.S, the District of Columbia, and Puerto Rico. A specific assay was developed for the trial (the MATCH assay), and a laboratory network was organized to rapidly process the tissue and efficiently interrogate for mutations. NCI and ECOG-ACRIN statisticians developed the analysis plan and are currently maintaining data that are closely monitored by safety experts for any adverse event signals. Lastly, a bioinformatics system (MATCHbox) was developed to coordinate molecular data collection and support rule-based decision-making based on those data. Because genomics in oncology is rapidly expanding and evolving, NCI-MATCH required flexibility to accommodate brisker screening accrual than anticipated, and adaptation to constantly emerging information about new drugs and new molecular alterations. The goal to sequence the tumors of 6,000 patients with NCI funding was achieved two years ahead of schedule, but that cohort was not sufficient to fill all the arms—in particular, those aimed at the most rarely occurring tumor gene aberrations. Currently, the goal for the trial is to complete the open treatment arms by allowing for designated commercial and academic laboratories to notify ordering physicians when genomic tests they ordered to guide clinical care indicate a potential eligibility to a NCI-MATCH arm with a rare variant and allow for enrollment to the relevant treatment subprotocol if the patient meets all subprotocol eligibility criteria. The tissue confirmation of the molecular abnormality on the MATCH assay by the central laboratories will be accomplished after subprotocol enrollment so that patient treatment will not be delayed for confirmation. A demonstration project is now under way to test the applicability of this approach and potentially develop common standards for future use. With tumor sequencing becoming a more and more common practice in oncology, this may allow patients with mutations of low prevalence to have investigational treatment options. NCI-MATCH is expanding its panel and definition of actionable mutations to allow greater flexibility to incorporate in real time new mutations supported with adequate levels of evidence. The valuable genomic and clinical outcome data collected in the trial will permit evaluation of efficacy of targeting certain actionable mutations with a specific agent. In addition, biospecimens are being collected to build a rich resource for conducting auxiliary biology studies that may answer questions about prevalence of mutations in the metastatic setting, prevalence of mutations in rare histologies, and resistance mechanisms of various targeted therapy. At this meeting, two abstracts will provide an overall trial update and present information about the prevalence of mismatch repair deficiency (dMMR) in the centrally screened population. Citation Format: Alice P. Chen, Peter J. O9Dwyer, Lyndsay Harris, Barbara A. Conley, Stanley R. Hamilton, Mickey Williams, Robert J. Gray, Shuli Li, Lisa M. McShane, Lawrence V. Rubinstein, Susanna I. Lee, Shaji Kumar, Edith P. Mitchell, James A. Zwiebel, Constantine A. Gatsonis, Lalitha K. Shankar, Paolo F. Caimi, Carlos L. Arteaga, A John Iafrate, Jeffrey Sklar, Richard F. Little, Keith T. Flaherty. NCI-MATCH: A new paradigm in the era of genomic oncology [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr PL03-01.

20 – Structures Supporting Cancer Clinical Trials

Abstract Cancer clinical trials provide the evidence on which sound oncology practice is based. Assuring rapid enrollment to clinical trials is a major goal of all sponsors and funders and depends to a great extent on the efficiency of the infrastructure that supports this research. Increasingly, National Cancer Institute- and biopharmaceutical-sponsored trials encourage the participation of physicians engaged in community practice, in addition to the more traditional involvement of academic institutions. The characteristics that ensure quality research in these varied practice settings are reviewed in this chapter and tools that facilitate enrollment are described.

Cell-Based Vascular Gene Delivery: Endothelial Cells as Carriers

The endothelium exists within the cardiovascular tree in two principal settings: (1) the microvasculature, constituting the major surface interfacing with the blood, and (2) the large vessel arterial and venous circulation communicating between the heart and capillary beds. Each of these regions of the vascular system presents unique opportunities for both vascular biologists and gene therapists for the study and treatment of disorders that are either vascular or nonvascular in origin.