Philip J. Gold

Multicenter Phase II and Translational Study of Cetuximab in Metastatic Colorectal Carcinoma Refractory to Irinotecan, Oxaliplatin, and Fluoropyrimidines

PURPOSE This multicenter study evaluated the antitumor activity of cetuximab, an immunoglobulin G1 antibody directed at the epidermal growth factor receptor (EGFR), in metastatic colorectal carcinoma (CRC) refractory to irinotecan, oxaliplatin, and a fluoropyrimidine. It also evaluated the safety, pharmacokinetics, immunokinetics, and biologic determinants of activity. PATIENTS AND METHODS Patients with metastatic CRC, whose tumors demonstrated EGFR immunostaining and were refractory to irinotecan, oxaliplatin, and fluoropyrimidines, were treated with cetuximab at a loading dose of 400 mg/m2 followed by 250 mg/m2 weekly. An independent review committee (IRC) reviewed responses. Blood was collected for cetuximab pharmacokinetics and to detect antibodies to cetuximab. EGFR gene sequencing of the tyrosine kinase domain and gene copy number assessments were performed. RESULTS The response rates in 346 patients, as determined by the investigators and IRC, were 12.4% (95% CI, 9.1 to 16.4) and 11.6% (95% CI, 8.4 to 16.4). The median progression-free survival (PFS) and survival times were 1.4 months (95% CI, 1.4 to 2.1) and 6.6 months (95% CI, 5.6 to 7.6), respectively. An acneiform rash occurred in 82.9% of patients; grade 3 rash was observed in 4.9%. Response and survival related strongly to the severity of the rash. In contrast, clinical benefit did not relate to EGFR immunostaining. EGFR tyrosine kinase domain mutations were not identified, and EGFR gene copy number did not relate to response or PFS, but to survival (P = .03). CONCLUSION Cetuximab is active and well tolerated in metastatic CRC refractory to irinotecan, oxaliplatin, and fluoropyrimidines. The severity of rash was related to efficacy. Neither EGFR kinase domain mutations nor EGFR gene amplification appear to be essential for response to cetuximab in this setting.

First-in-Man Phase I Study of GC33, A Novel Recombinant Humanized Antibody against Glypican-3, in Patients with Advanced Hepatocellular Carcinoma

Purpose: GC33 is a novel recombinant fully humanized monoclonal antibody that binds to human glypican-3 (GPC3). The antitumor activity of GC33 was shown in preclinical models of hepatocellular carcinoma (HCC). This first-in-man clinical trial was conducted to evaluate the safety, pharmacokinetic characteristics, and preliminary efficacy of GC33 in patients with advanced HCC. Experimental Design: Patients with measurable, histologically proven, advanced HCC were enrolled to a dose-escalation study of GC33 (2.5–20 mg/kg) given intravenously weekly. The primary endpoint was to determine the maximum tolerated dose of GC33 for further development. Pharmacokinetic characteristics were measured in serum samples. Immunohistochemistry was conducted on tumor biopsies to evaluate GPC3 expression. Tumor response was assessed every 8 weeks using Response Evaluation Criteria in Solid Tumors criteria. Results: Twenty patients were enrolled and treated with GC33. A maximum tolerated dose was not reached as there were no dose-limiting toxicities (DLT) up to the highest planned dose level. Common adverse events with all grades included fatigue (50%), constipation (35%), headache (35%), and hyponatremia (35%). The incidence of adverse events seemed not to be dose dependent. Trough serum concentrations at steady state were in excess of target concentration at doses of 5 mg/kg or greater. Median time to progression (TTP) was 26.0 weeks in the GPC3 high expression group and 7.1 weeks in the low expression group (P = 0.033). Conclusion: This study shows that GC33 was well tolerated in advanced HCC and provides preliminary evidence that GPC3 expression in HCC may be associated with the clinical benefit to GC33 that warrants prospective evaluation. Clin Cancer Res; 19(4); 920–8. ©2012 AACR.

Thymidine Phosphorylase Expression Is Associated With Response to Capecitabine Plus Irinotecan in Patients With Metastatic Colorectal Cancer

PURPOSE To evaluate the clinical activity and toxicity of capecitabine plus irinotecan as first-line therapy for patients with metastatic colorectal cancer (mCRC), and to describe the association of expression of thymidine phosphorylase (TP), thymidylate synthase (TS), and dihydropyrimidine dehydrogenase (DPD) with antitumor activity. PATIENTS AND METHODS Patients with previously untreated mCRC received irinotecan days 1 and 8 intravenously, and capecitabine days 2 to 15 orally in 21-day cycles. Doses were irinotecan 125 mg/m2 and capecitabine 1,000 mg/m2 bid (n = 15; cohort 1), or irinotecan 100 mg/m2 and capecitabine 900 mg/m2 bid (n = 52; cohort 2). Tissues from primary and metastatic sites were assessed for TP, TS, and DPD gene and protein expression. RESULTS An unacceptable level of GI toxicity in the first 15 patients led to a protocol modification in starting doses. The response rate was 45% (30 of 67 patients). Overall survival was associated with TP expression assessed by immunohistochemistry in both primary tumors (P = .045) and metastases (P = .001). Objective tumor response was associated with TP expression in primary tumors (odds ratio, 4.77; 95% CI, 1.25 to 18.18), with a similar trend in metastases (odds ratio, 8.67; 95% CI, 0.95 to 79.1). TP gene expression in primary tumors was also associated with response. CONCLUSION These data indicate that capecitabine plus irinotecan is an active regimen against mCRC. The biomarker analysis (including metastatic tissue) was feasible in a multicenter setting, and provides preliminary evidence that TP expression may be a predictive marker for response.

Cetuximab as Second-Line Therapy in Patients with Metastatic Esophageal Adenocarcinoma: A Phase II Southwest Oncology Group Study (S0415)

Introduction: Esophageal adenocarcinomas commonly express the epidermal growth factor receptor. This trial assessed the 6-month overall survival probability in metastatic esophageal cancer patients treated with cetuximab as second-line therapy. Methods: This was a multicenter, open-label phase II study of single-agent cetuximab for metastatic esophageal adenocarcinoma patients who failed one prior chemotherapy regimen. Adequate organ function and Zubrod performance status of 0 to 2 were required. Patients received cetuximab 400 mg/m2 intravenously (IV) on week 1 and 250 mg/m2 IV weekly thereafter. The primary objective was to determine 6-month overall survival. Secondary end points included progression-free survival, response rate, and toxicity. Tumor tissue was collected for correlative studies. Results: Sixty-three patients were registered, with eight ineligible or never treated. Fifty-five eligible patients (49 men, 6 women; median age = 61.2 years [range, 30.7–88.5]) were enrolled. Twenty patients survived more than 6 months for a 6-month overall survival rate of 36% (95% confidence interval [CI]: 24–50%). The median overall survival was 4.0 months (95% CI: 3.2–5.9). Median progression-free survival was 1.8 months (95% CI: 1.7–1.9). One partial response and two unconfirmed partial responses were observed. Two patients experienced grade 4 fatigue. There was one treatment-related death due to pneumonitis. Germline polymorphisms of epidermal growth factor receptor, epidermal growth factor, interleukin (IL)-8, cyclooxygenase (COX)-2, vascular epidermal growth factor receptor (VEGF), CCND1, neuropilin 1 (NRP1), and K-ras mutational status were not associated with response or survival. Conclusions: The 6-month overall survival rate of 36% observed on this study failed to meet the primary survival objective. Thus, cetuximab alone cannot be recommended in the second-line treatment of metastatic esophageal cancer.

S0356: A Phase II Clinical and Prospective Molecular Trial With Oxaliplatin, Fluorouracil, and External-Beam Radiation Therapy Before Surgery for Patients With Esophageal Adenocarcinoma

PURPOSE Pathologic complete response (pCR) after neoadjuvant therapy for locally advanced esophageal adenocarcinoma is associated with improved survival. The Southwest Oncology Group designed a trimodality, phase II, single-arm trial with objectives of achieving a pCR rate of 40% with prospective exploratory analyses of intratumoral molecular markers postulated to affect response and survival. PATIENTS AND METHODS Patients with clinically staged II or III esophageal adenocarcinoma received oxaliplatin 85 mg/m(2) on days 1, 15, and 29; protracted-infusion fluorouracil (PI-FU) 180 mg/m(2)/d on days 8 through 43; and external-beam radiation therapy (EBRT) 5 days a week at 1.8 Gy/d for 25 fractions; surgery was performed 28 to 42 days after neoadjuvant therapy. Chemotherapy was planned after surgery. Tumors were analyzed for mRNA expression and polymorphisms in genes involved in drug metabolism and DNA repair. RESULTS Ninety-three patients were evaluable. Two deaths (2.2%) were attributable to preoperative therapy, and two deaths (2.2%) were attributable to surgery. Grade 3 and 4 toxicities were recorded for 47.3% and 19.4% of patients, respectively. Seventy-nine patients (84.9%) underwent surgery; 67.7% of patients had R0 resections. Twenty-six patients (28.0%) had confirmed pCR (95% CI, 19.1% to 38.2%). At a median follow-up of 39.2 months, estimates of median and 3-year overall survival (OS) were 28.3 months and 45.1%, respectively. Intratumoral ERCC-1 gene expression was inversely related to progression-free survival and OS. CONCLUSION Neoadjuvant oxaliplatin, PI-FU, and EBRT for esophageal adenocarcinoma is active and tolerable. Because the regimen failed to meet the primary end point, it does not define a new standard. However, future trials can be built on this platform to validate the role of ERCC-1 in determining the best systemic regimen for individual patients.

Cetuximab Plus Cisplatin, Irinotecan, and Thoracic Radiotherapy as Definitive Treatment for Locally Advanced, Unresectable Esophageal Cancer: A Phase-II Study of The SWOG (S0414)

Introduction: The specific aims of the study were to evaluate the 2-year overall survival (OS) and progression-free survival (PFS), toxicity profile, and best objective response rate in patients with locally advanced, clinically unresectable esophageal cancer receiving cetuximab, cisplatin, irinotecan, and thoracic radiotherapy (TRT) within a multi-institutional cooperative-group setting. Methods: Eligible patients (cT4 M0 or medically unresectable, biopsy proven, and noncervical esophageal cancer) were to receive four 21-day cycles of cetuximab 400 mg/m2 (day 1, cycle 1), cetuximab 250 mg/m2 (day 8, 15, cycle 1; then days 1, 8, and 15 for subsequent cycles), cisplatin 30 mg/m2 (days 1 and 8, all cycles), and irinotecan 65 mg/m2 (days 1 and 8, all cycles). TRT was administered at 1.8 Gy in 28 daily fractions to a total dose of 50.4 Gy, to begin with on day 1 of cycle 3. The primary endpoint was 2-year OS, with an accrual goal of 75 patients with adenocarcinoma. Results: The study was closed because of slow accrual, with 21 eligible patients (11 squamous, 10 adenocarcinoma) enrolled from May 2005 to September 2007. Two-year OS and PFS (95% confidence interval [CI]) were 33.3% (14.6–57.0%) and 23.8% (8.2–47.2%), respectively. Kaplan–Meier estimates of median (95% CI) OS and PFS were 11.2 (6.4–43.6) and 6.4 (3.7–12.0) months, respectively. The overall response rate (95% CI) among 17 evaluable patients was 17.6% (3.8–43.4%), including 6% confirmed complete responders and 12% unconfirmed partial responders. Two deaths resulted from protocol treatment (sudden death and gastrointestinal necrosis). Ten (47.6%) and 6 (28.6%) patients had grade-3 or -4 toxicity, respectively: 52.4% were hematologic, 23.8% had fatigue, 19.0% had nausea, 19.0% had dehydration, and 19.0% had anorexia. Conclusions: Concomitant cetuximab, cisplatin, irinotecan, and TRT were poorly tolerated in the first North American cooperative group trial testing this regimen for locally advanced esophageal cancer as treatment-related mortality approached 10%. Single-institution phase-II cetuximab-based combined modality trials have yielded encouraging results in preliminary analyses. The SWOG GI Committee endorses enrollment to open clinical trials to clarify the therapeutic ratio of cetuximab-based combined modality approaches for esophageal cancer.

Phase II Study of Olaparib (AZD-2281) After Standard Systemic Therapies for Disseminated Colorectal Cancer.

BACKGROUND Effective new agents for patients with colorectal cancer (CRC) with disease progression during standard therapy regimens are needed. We hypothesized that poly ADP ribose polymerase (PARP) inhibitor therapy in patients with CRC and inefficient tumor DNA repair mechanisms, such as those with high-level microsatellite instability (MSI-H), would result in synthetic lethality. METHODS This was an open-label phase II trial testing olaparib 400 mg p.o. b.i.d. for patients with disseminated, measurable CRC failing standard therapies with centrally confirmed tumor MSI status. The primary endpoint was the tumor response, assessed by RECIST, version 1.0. The secondary endpoints were safety/toxicity, progression-free survival (PFS), and overall survival (OS). RESULTS Thirty-three patients (20 microsatellite stable [MSS], 13 MSI-H) were enrolled. The median age for all patients was 57 years and for MSS and MSI-H patients was 51 and 61 years, respectively. All patients received at least one 28-day cycle of olaparib. No patient had a complete or partial response. Nausea (48%), fatigue (36%), and vomiting (33%) were the most commonly reported treatment-related adverse events. The median PFS for all patients was 1.84 months. No statistically significant differences were found in the median PFS or OS for the MSS group compared with the MSI-H group. CONCLUSION Single-agent olaparib delivered after failure of standard systemic therapy did not demonstrate activity for CRC patients, regardless of microsatellite status. Future trials, testing PARP inhibitors in patients with CRC should focus on the use of DNA-damaging chemotherapy and/or radiation therapy, combined with PARP inhibitors, remembering the toxicity reported in the present study. IMPLICATIONS FOR PRACTICE Microsatellite instability (MSI-H) colorectal tumors exhibit hypermethylation in tumor mismatch repair genes, or have mutations in one or more of these genes resulting from a germ-line defect (Lynch syndrome). PARP inhibitors such as olaparib are most effective in tumors associated with inability to repair DNA damage. However, in this trial, single agent olaparib failed to elicit responses in patients with MSI-H colorectal tumors, and in those with microsatellite-stable tumors. It is possible that by adding olaparib to radiation therapy, or to a systemic DNA damaging agent, tumor lethality could be obtained. However, the price would be increased toxicity.

Higher capecitabine AUC in elderly patients with advanced colorectal cancer (SWOGS0030)

Background:The aging process is accompanied by physiological changes including reduced glomerular filtration and hepatic function, as well as changes in gastric secretions. To investigate what effect would aging have on the disposition of capecitabine and its metabolites, the pharmacokinetics between patients ⩾70 years and <60 years were compared in SWOG0030.Methods:Twenty-nine unresectable colorectal cancer patients were stratified to either ⩾70 or <60 years of age, where the disposition of capecitabine and its metabolites were compared.Results:Notable increase in capecitabine area under the curve (AUC) was accompanied by reduction in capecitabine clearance in ⩾70 years patients (P<0.05). No difference in 5’-deoxy-5-fluorocytidine, 5’-deoxy-5-fluorouridine (DFUR), and 5-fluorouracil (5FU) AUCs between the two age groups, suggesting that carboxylesterase and cytidine deaminase (CDA) activity was similar between the two age groups. These results suggest that metabolic enzymes involved in converting capecitabine metabolites are not altered by age. An elevation in capecitabine Cmax and reduction in clearance was seen in females, where capecitabine AUC was 40.3% higher in women. Elevation of DFUR Cmax (45%) and AUC (46%) (P<0.05) was also noted, suggesting that CDA activity may be higher in females.Conclusion:Increases in capecitabine Cmax and AUC was observed in patients ⩾70 years when compared with younger patients who were >60 years.

Abstract CT032: A Phase 1b study of PEGPH20 plus pembrolizumab in patients with selected hyaluronan-high solid tumors

Background: Hyaluronan (HA) accumulation in the tumor microenvironment increases tumor interstitial fluid pressure, promoting vascular collapse and limiting access of chemotherapy and immune cells to tumor sites. In animal models, HA-High tumors exhibit increased growth and metastasis, treatment resistance, and reduced survival. PEGPH20 is a PEGylated recombinant human hyaluronidase that enzymatically degrades tumor HA. Pembrolizumab (PEM) is a humanized monoclonal antibody targeting PD-1, demonstrating tolerability and activity in patients (pts) with non-small cell lung cancer (NSCLC). This study evaluates the safety and activity of PEGPH20 plus PEM in pts with NSCLC or gastric cancer. Methods: This Phase 1b study comprises dose escalation (up to 30 pts regardless of HA status) and cohort expansion (up to 51 pts with tumors accumulating high levels of HA). HA staining is performed using the VENTANA HA RxDX Assay, which indicates HA in the extracellular matrix. HA-High status (ie, patients who may achieve clinical benefit) was determined by Halozyme to be ≥50% staining based on clinical outcome data from a phase 2 study. For dose escalation, eligible pts (ECOG 0-1) had stage IIIB/IV NSCLC failing ≥1 prior platinum-based regimen or locally advanced or metastatic gastric adenocarcinoma failing ≥1 previous chemotherapy regimen. NSCLC pts known to be epidermal growth factor receptor (EGFR)- or anaplastic lymphoma kinase (ALK)-positive must have received an EGFR inhibitor or ALK inhibitor, respectively. For cohort expansion, previously treated or untreated NSCLC is allowed; gastric cancer pts must have failed 1-2 prior treatments. PEGPH20 (1.6, 2.2, 2.6, 3.0, 4.0 µg/kg) is administered IV on D1, 8, 15 of each 21-day cycle followed by PEM 200 mg IV on D1, 4 to 6 hours after PEGPH20. Due to increased thromboembolic risk in gastric cancer, these pts receive prophylactic enoxaparin. Additional prophylaxis with piroxicam (possible musculoskeletal events) and proton pump inhibitors are given to all patients. The primary endpoint for dose escalation is the recommended Phase 2 dose for PEGPH20 in combination with PEM. The primary endpoint for cohort expansion is objective response rate per RECIST v1.1. Secondary endpoints are duration of response, disease control rate, progression-free survival per RECIST and immune-related response criteria, pharmacokinetics, and adverse events. Exploratory endpoints include secondary efficacy endpoints by PD-LI status, plasma and tumor HA levels, and imaging parameters of tumor blood flow (dynamic contrast-enhanced magnetic resonance imaging [DCE-MRI]) and tumor metabolic activity (positron emission tomography/computed tomography [PET/CT] scans). ClinicalTrials.gov Identifier: NCT02563548. Citation Format: Lyudmila Bazhenova, Philip J. Gold, R. Donald Harvey, Alexander I. Spira, John Nemunaitis, Joaquina C. Baranda, Shirish Gadgeel. A Phase 1b study of PEGPH20 plus pembrolizumab in patients with selected hyaluronan-high solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT032. doi:10.1158/1538-7445.AM2017-CT032

Abstract 997: Impact of a personalized medicine research program (PMRP), using targeted tumor profiling and a cloud based clinical trials matching platform, on clinical decision-making

Background: Cancer care is evolving to a model of precision medicine where genomic changes in a patient9s tumor are used to inform individualized management (mgmt). The optimal approach and impact of tumor profiling on cancer care remain important research questions. We report the impact on clinical decision-making by results from a PMRP in a research practice. Methods: A custom designed next generation sequencing (NGS) 68 gene alteration (GA) panel, covering clinically relevant genes and regions was developed in 2014. The NGS results were used to: 1) prioritize standard therapies; 2) match patients (pts) with clinical trials (CT); and 3) serve as a data mining resource. NGS testing was offered early in the course of mgmt. An Institutional Review Board approved prospective registration protocol (PMRP) was activated in 2014, with the objective of establishing a centralized longitudinal, molecular phenotypic, and research data repository. Primary endpoints include proportion of pts where NGS impacted mgmt, to include enrollment onto CT. A cloud-based informatics platform was developed to: manage PMRP; facilitate CT matching; perform quality assurance/quality improvement; pursue research initiatives. Results: As of 11/15/2016, 869 pts gave informed consent, with 844 pts enrolled. The top primary sites included: breast (115); colorectal (111); central nervous system (103); lung (91); ovary (49); hematologic malignancies (46); pancreas (37); uterus (28); esophagus (25); skin (21). Of solid tumor pts with documented clinical stage, 130 (40%) pts had early stage cancer (I, II and III), and 193 (60%) pts had advanced stage (IV) cancer. NGS results: 739 (88%) pts with GA found; 27 (3%) pts without GA. Of pts with GA, 178 (24%) pts had actionable (on-label drugs) GA and 476 (64%) pts had applicable (off-label or CT) GA, for a total of 546 (74%) pts with actionable and/or applicable GA. The top actionable GA were: KRAS (125); PIK3CA (17); BRAF (13); EGFR (12); NRAS (11); AKT1 (3); TET2 (2); ERBB2 (2); HRAS (2). The top applicable GA, included: TP53 (225); TPMT (78); TYMS (78); PIK3CA (77); APC (56); PTEN (52); IDH1 (34); CDNK2A (22); CTNNB1 (18); TET2 (16). Care mgmt impact was reported by physicians for 508 pts with actionable/applicable GA. Physicians reported mgmt impact, at time of reporting, for 105 (21%) pts, to include: new treatment (Tx) in 30 (6%) pts; no Tx given in 18 (4%) pts; Tx changed in 12 (2%) pts; Tx stopped in 1 ( Conclusions: NGS profiling of tumors with this 68 GA panel has an impact on clinical decision- making in a minority, though substantial number, of pts. Impact on CT participation remains modest. Access to drugs and CT remains an important barrier. Citation Format: Thomas D. Brown, Paul D. Tittel, Philip J. Gold, Charles W. Drescher, John M. Pagel, J D. Beatty, Patra Grevstad, Desiree Iriarte, Shlece Alexander, Madeleine Brindle, Xiaoyu Liu, Donielle O9connor, Mariko Tameishi, Danbin Xu, Anna B. Berry. Impact of a personalized medicine research program (PMRP), using targeted tumor profiling and a cloud based clinical trials matching platform, on clinical decision-making [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 997. doi:10.1158/1538-7445.AM2017-997