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Background: Despite the rising incidence of sarcoma in the geriatric population, there is a paucity of older adults enrolled on clinical trials. Whether older sarcoma patients treated on early phase clinical trials have any meaningful differences in clinical benefit or survival outcomes compared to younger patients remains unknown. Methods: We analyzed clinical and next generation sequencing data from sarcoma patients treated on phase 1 trials at MD Anderson Cancer Center (MDACC) and performed logistic and Cox proportional hazards regression analyses to compare response rate (RR), median time to progression (mTTP), clinical benefit rate (CBR; defined as CR, PR, or SD > 6 months), and median overall survival (mOS) between patients younger and older than 65 years of age. Results: Among the 406 patients with advanced sarcomas (321 soft tissue sarcoma, 85 bone sarcomas) treated on phase 1 trials at MDACC from May 2006 to May 2018, median age was 53 (range 11-84), 48% were female, and patients had a median 3 prior lines of therapy (range 0-9). The most commonly treated soft tissue sarcoma subtypes included leiomyosarcoma (n=66; 16%), liposarcoma (n=52; 13%), GIST (n=44; 11%), UPS (n=14; 3%), and synovial sarcoma (n=11; 3%) and most commonly treated bone sarcomas included osteosarcoma (n=34; 8%), chondrosarcoma (n=28; 7%), and Ewing’s sarcoma (n=25; 6%). 25% (n=102) of sarcoma patients treated on phase 1 protocols were age 65 or older. RR in patients younger than 65 years was 7% compared to 8% in those 65 or older, odds ratio 1.21 (95% CI 0.52, 2.83), p=0.66. mTTP for patients younger than 65 was 2.7 months compared to 3.7 months in those 65 or older, hazard ratio 0.90 (95% CI 0.72, 1.14), p=0.39. CBR in patients younger than 65 years was 22% compared to 31% in those 65 or older, odds ratio 1.65 (95% CI 1.00, 2.72), p=0.05. mOS in patients younger than 65 years was 16.1 months compared to 20.0 months in those 65 years or older, hazard ratio 1.08 (95% CI 0.80, 1.46), p=0.61. Conclusion: Heavily pretreated, metastatic sarcoma patients aged 65 or older enrolled on phase 1 studies at MDACC had no significant differences in response rate, time to progression, and overall survival compared to their younger counterparts. In fact, older sarcoma patients demonstrated an improved clinical benefit rate compared to younger patients. Older patients should be encouraged to enroll on early phase clinical trials when clinically appropriate and broad eligibility criteria for such studies are needed to ensure older sarcoma patients are not excluded from these trials. Citation Format: Shiraj Sen, Roberto C. Pestana, Kenneth Hess, David S. Hong, Ishwaria M. Subbiah, Anthony Conley, Gerald S. Falchook, Robert S. Benjamin, Shreyas Patel, Funda Meric-Bernstam, Vivek Subbiah. Outcomes of geriatric sarcoma patients enrolled in phase 1 clinical trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3997.

Background: Patients with advanced carcinoma of unknown primary (CUP) have limited effective therapeutic options given the challenges of phenotypic and genotypic diversity. To identify future novel therapeutic strategies we conduct an ongoing exploratory analysis of next-generation sequencing (NGS) of relapsed, refractory CUP. Methods: We identified CUP patients referred to our phase I clinic with adequate FFPE sections from archival tissue for a targeted CLIA-certified NGS assay (Foundation One, MA). Over 2000 exons of 186 cancer-related genes plus over 30 introns from 14 genes often rearranged in cancer were fully sequenced for point mutations, insertions/deletions, copy number alterations (CNAs) and select gene fusions. Results: Of 19 patients seen (10 male, 9 female; median age at diagnosis 49 years), 17 demonstrated genomic alterations (median 3 aberrations/tumor, range 0 - 10); two patients had no reportable genomic alterations. Of the 71 detected aberrations, 17 (24%) have been implicated in impaired cell cycle regulation and arrest; specifically in genes which encode the cyclin-dependent kinases (CDK12 Q570*, CDKN2A/B loss, CDKN2A p16INK4a loss and p14ARF exon 2-3 loss) or their associated proteins including amplification of CCND1 and CCNE1 (n = 3). Of these 8 patients with impaired cell cycle regulation, 5 (63%) demonstrated concurrent mutations associated with epigenetic deregulation and impaired DNA methylation, most commonly ARID1A Y1211fs*5 and S1929fs*25, which encodes the AT-rich interactive domain-containing protein 1A, Arid1a, a member of the SWI/SNF chromatin remodeling complex); other mutations observed are CREBBP S893L (encoding a ubiquitously expressed transcriptional coregulatory protein controlling chromatin remodeling via its histone acetyltransferase activity); MLL2 R4904* (encoding an H3K4-specific histone methyltransferase) and KDM6A S466* (encoding the histone H3 lysine 27 demethylase UTX). Overall 5 of 19 (26%) patients with advanced relapsed CUP demonstrated a profile of aberrations that concurrently impact cell cycle arrest and epigenetic regulation. Conclusion: Through NGS-based molecular profiling, we can a subset of patients with advanced carcinoma of unknown primary with coexisting mutations leading to impaired cell cycle arrest and epigenetic deregulation, highlighting a therapeutic combination with a cell cycle inhibitor (such as Cdk4/6 inhibitors currently in clinical trial) and histone deacetylase inhibitors. Note: This abstract was not presented at the meeting. Citation Format: Ishwaria M. Subbiah, Gauri Varadhachary, Apostolia M. Tsimberidou, Jennifer J. Wheler, Vivek Subbiah, Filip Janku, Sinchita Roy Chowdhuri, Ralph Zinner, David S. Hong. Impaired cell cycle arrest with concurrent epigenetic deregulation identified through next generation sequencing in patients with advanced carcinoma of unknown primary: Implications for personalized medicine. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 604. doi:10.1158/1538-7445.AM2015-604

Background: Relapsed refractory colorectal adenocarcinoma (CRC) is evolving as a disease with distinct molecular subsets rather than a singular histology. Given the varied outcomes of CRC patients treated on clinical trials particularly with targeted therapies, we aimed to identify a molecular phenotype for future therapeutic targeting. Methods: We identified CRC patients referred to our Phase I clinic with adequate tissue for next generation sequencing (NGS) on a commercially available platform (FoundationOne, Boston, MA). Over 2000 exons of 186 cancer-related genes plus over 30 introns from 14 genes often rearranged in cancer were fully sequenced for point mutations, insertions/deletions, copy number alterations (CNAs) and select gene fusions. Results: Overall, 60 relapsed CRC patients (31 male, 29 female; median age 55 years; 56 colon primary, 4 rectum primary). 48 (80%) patients had a mutation linked to aberrant Wnt pathway signaling (most commonly, APC 43 pts, 90%). Of these 48 patients, over half (n = 26, 54%) demonstrated a concurrent mutation affecting the PI3K cascade (PIK3CA in 12 patients [4 E545K, 3 Q546K, 2 E542K, 1 H1047Y, 1 E453K, 1 R38C]). Of these 26 pts with concurrent aberrant Wnt and PI3K pathways, 22 also demonstrated a concomitant MAPK pathway mutation (17 KRAS and 3 BRAF). Of the 60 CRC pts overall, 22 (37%) patients had coexisting aberrations linked to in all three (Wnt, PI3K, and MAPK) cascades. Conclusions: Concomitant mutations in three pathways (Wnt, MAPK, PI3K) implicated in cancer occur frequently in patients with advanced CRC, emphasizing the need for a combinatorial therapeutic strategy ideally targeting all three cascades. Note: This abstract was not presented at the meeting. Citation Format: Ishwaria M. Subbiah, Filip Janku, Apostolia M. Tsimberidou, Aung Naing, Vivek Subbiah, Jennifer J. Wheler, Ralph Zinner, Cathy Eng, Michael J. Overman, Scott Kopetz, David S. Hong. Concurrent aberrations in the Wnt, MAPK and PI3K pathways identified through next generation sequencing of relapsed refractory colorectal adenocarcinoma (CRC): Implications for future therapeutic trials. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4263. doi:10.1158/1538-7445.AM2015-4263

Background: Carcinoma of unknown primary (CUP) represents a heterogeneous group of cancers without an identifiable primary disease site where staining for a vast array of immunohistochemical markers is undertaken to identify tumor lineage. Given rapid advances in characterizing cancer genomes, we sought to describe the molecular profiles of patients with advanced CUP treated with novel targeted therapies on phase I clinical trials to identify pathways of interest to drive future therapeutic strategies. Methods: Of patients with advanced malignancies seen in the Phase I clinic, we identified 16 CUP patients on whom adequate tissue was available to perform next-generation sequencing (NGS) from FFPE sections using a targeted NGS assay in a CLIA laboratory (Foundation One, MA). Over 2000 exons of 186 cancer-related genes plus over 30 introns from 14 genes often rearranged in cancer were fully sequenced for point mutations, insertions/deletions, copy number alterations (CNAs) and select gene fusions. Results: Of 16 tumor specimen, 14 demonstrated genomic alterations with a median of 4 aberrations within each specimen (range 0 - 10, total of 69 alterations); two patients did not demonstrate any tested changes. All patients with detected mutations possessed an exclusive unique molecular profile of aberrations with no two patients demonstrating an identical panel of mutations. A total of 69 alterations were identified of which 18 (26%) led to aberrant cell signaling within the PI3K/AKT/MTOR (including 4 with PIK3CA mutations) or the MAPK signaling cascades, primarily KRAS mutations in 3 patients. Also noted were 13 (19%) alterations impairing cell cycle arrest most commonly affecting cyclin dependent kinases, 10 (14%) impacting epigenetic regulation and DNA methylation, 10 (14%) affecting known tumor suppressor genes including TP53 in 8 patients, and 10 (14%) unique alternations in transcriptional regulators. Conclusion: With thorough molecular profiling, we can identify the unique fingerprint of potential actionable aberrations in a subset of advanced CUP patients. Herein we identified activation of the PI3K/AKT/MTOR and RAS/RAF/MEK signaling pathways combined with impaired cell cycle arrest in 8 of 16 (50%) tested patients, suggesting that a combination of PI3K and MAPK cascade inhibitors in combination with a cell cycle inhibitor may be of therapeutic value to these patients. Further matching patients to these actionable aberrations is underway, thereby translating these therapeutic targets to the bedside with the development of novel targeted therapies. Note: This abstract was not presented at the meeting. Citation Format: Ishwaria M. Subbiah, Gauri Varadhachary, Apostolia M. Tsimberidou, Jennifer J. Wheler, Vivek Subbiah, Filip Janku, Sinchita Roy Chowdhury, Ralph Zinner, Funda Meric-Bernstam, David S. Hong. One size does not fit all: Fingerprinting advanced carcinoma of unknown primary through comprehensive profiling identifies aberrant activation of the PI3K and MAPK signaling cascades in concert with impaired cell cycle arrest. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4700. doi:10.1158/1538-7445.AM2014-4700

Introduction: Patients with advanced cancer have limited therapeutic options. We conducted an investigator-initiated 4-arm phase I study of lenalidomide (len) combined with bevacizumab (bev), sorafenib (soraf), temsirolimus (tem), or 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX) in patients with advanced cancers. Patients and Methods: Patients were treated with escalating doses of len (5, 10, 20 mg daily) combined with bev (5, 7.5, 10 mg/m2 on days 1, 15); soraf (200, 400mg daily); tem (15, 20, 25mg on days 1, 8, 15, 22); or FOLFOX (oxaliplatin 65, 85 mg/m2 on day 1). The escalation phase (“3+3”) was followed by an expansion phase per arm. Response was assessed by RECIST v.1. Patients were to receive enoxaparin prophylaxis. Results: Overall, 101 patients were enrolled; and 59 were treated in the dose escalation phase (4 arms) and are included in this analysis (169 cycles to date). Diagnoses were colorectal cancer (n=19), sarcoma (n=5), ovarian (n=4), lung (n=3), hepatocellular carcinoma (n=3), melanoma (n=4), neuroendocrine (n=2), prostate (n=2) and other (n=17). The median number of cycles/patient was 2 (range, 1-10). Pretreatment characteristics and outcomes are shown in Table. Two DLTs were noted: Grade 3 transient ischemic attack (TIA) while on enoxaparin in the len + FOLFOX arm and Grade 3 acute renal failure (ARF) in the len + tem arm. Three pts (two on enoxaparin prophylaxis and one not) had venous thrombosis while on study. Fifteen of 59 (25%) pts had prolonged stable disease (SD) for > 4 months, including 7 (12%) for > 6 mos. The len+soraf and len+tem arms have reached the maximum dose level tested; currently, expansion phase). The lev+bev and len+FOLFOX arms are in the dose escalation phase. Conclusion: Lenalidomide combined with bev, soraf, tem or FOLFOX is well tolerated and it is associatd with antitumor activity in patients with advanced solid tumors. Anticoagulation phophylaxis is needed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1751. doi:1538-7445.AM2012-1751

BACKGROUND: Patients with cholangiocarcinoma (CC) and gallbladder carcinoma (GC) have few effective therapeutic options in the relapsed and/or metastatic setting. With that purpose, we analyzed the characteristics and outcomes of patients with advanced CC and GC treated on early-phase clinical trials in the Clinical Center for Targeted Therapy at MD Anderson Cancer Center. METHODS: We searched an electronic database of consecutive pts with GC and CC referred to the Clinical Center for Targeted Therapy starting in November 2004. We assessed the relationship between types of clinical trial and pts’ tumor types, progression-free survival, and mutations. RESULTS: Of the 72 patients with CC and GC referred to the clinic, 32 (44%) were not enrolled in a clinical trials mainly due to deterioration of performance status (n=25), decision to pursue alternate therapies (n=6), and insurance denial (n=1). Forty pts (5 w GC; 35 w CC) who received treatment on early clinical trials are included in this analysis. The median age was 60.2 yrs (range, 41.4-73.6 yrs). ECOG performance status (PS) was 0-1 in 36 pts (90%) and 2 in 4 (10%). Median number of prior therapies was 3 (range 0-17). Six pts were not restaged due to early disease progression. Of the 40 pts evaluable for response, 8 (20%) had stable disease (SD) > 6 months and 3 (8%) had a partial response (PR) (total SD > 6 mos/PR = 28%). Highest rates of SD > 6 mos/PR were observed in patients treated with protocols that included hepatic arterial infusion drug administration (7/17 = 41%) or anti-angiogenic agents (9/24 = 38%) (with 6 of these pts receiving treatment that included hepatic arterial infusion chemotherapy combined with a systemic anti-angiogenic agent). SD lasting 9 months was also seen in 1 pt treated with a MEK inhibitor. Median progression-free survival for the 40 pts was 2.0 months 9 (95% CI 1.7, 2.8) on early-phase clinical trials versus 3.0 months on their last FDA-approved treatment before Phase I referral (95% CI 2.3, 3.7). CONCLUSIONS: About one-third of patients with CC and GC referred for early-phase trials cannot be enrolled because of poor performance status. Twenty-eight percent of patients who met eligibility criteria achieved SD > 6 mos/PR, with responses predominantly observed in regimens that contained locoregional treatment, anti-angiogenic agents, or a targeted MEK inhibitor. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2669. doi:1538-7445.AM2012-2669