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118 Background: To date, immune-checkpoint inhibition for microsatellite stable (MSS) mCRC has been ineffective, though targeted therapy combination strategies may be promising. This phase II, investigator-initiated trial (NCT03475004) was designed to evaluate the efficacy and safety of the three-drug combination of pembrolizumab (pembro), binimetinib, and bevacizumab in patients with advanced, MSS treatment-refractory colorectal cancer. Methods: Patients with mCRC locally determined to be MSS and whom have progressed on two prior lines of therapy were enrolled. Treatment consists of pembro (200 mg every 3 weeks), binimetinib (45 mg BID) and bevacizumab (7.5 mg/kg every 3 weeks) until disease progression or unacceptable toxicity. The primary endpoint is PFS using RECIST v1.1 by investigator review. Additional endpoints include objective response rate, disease control rate at time of first re-staging (2 mo), duration of response, and safety and tolerability. Results: 50 patients have been enrolled (accrual is completed). 53% of patients are male and the mean age is 53.6 (range 31-79). The mean number of prior therapies is 5.3. At the time of preliminary data review, 39 patients are evaluable for response data. The median PFS was 5.8 mo (95% CI 4.2 to 8.9). The objective response rate was 13% with 5 partial responses. 24 patients (62%) had stable disease and 10 (26%) had progressive disease as the best response. The disease control rate at the time of first re-staging was 74%. Median duration of response was 6.5 mo. 19 (40%) patients experienced serious adverse events; the most common grade ≥3 adverse events included transaminase elevation (15%), diarrhea (11%), acneiform rash (9%), hypertension (9%), and anemia (9%). Conclusions: Preliminary results from this phase II study indicate that this regimen of pembrolizumab, binimetinib, and bevacizumab has promising activity and acceptable tolerability in this heavily pre-treated population of patients with MSS metastatic colorectal cancer. Final results will be presented as well as ongoing correlative studies. Clinical trial information: NCT03475004.

3075 Background: OKI-179 is a novel, oral pro-drug analog of largazole, a compound in the romidepsin-depsipeptide class of natural products. OKI-006, the active metabolite of OKI-179, inhibits HDAC 1,2,3 (IC50 = 1.2, 2.4, 2.0 nM, respectively), with no significant inhibition of Class IIa HDACs and has shown promising activity in preclinical models of solid tumors. We conducted a first-in-human dose escalation study of OKI-179 in patients with advanced solid tumors. Methods: Patients with advanced solid tumors, ECOG ≤1, normal QTc, and disease refractory to or with no available standard therapy options were treated with OKI-179 with either intermittent dosing (once daily for 4 days on 3 days off) or continuous dosing (once daily). Dose escalation was conducted using a standard 3+3 design. Pharmacokinetic (PK) and pharmacodynamic (PD) testing was performed at various time points after dosing. Results: As of Feb 4, 2021, 26 patients (19 female, 7 male) were enrolled with mean age of 63 (range 41-83). Patients received a median of 5 (range 1-11) prior lines of therapy and most common tumor types included pancreatic (N = 5), breast (N = 4), lung (N = 4), and ovarian cancer (N = 4). Twenty patients were treated in intermittent dosing cohorts from 30-450 mg. One DLT (Grade 2 [G2] thrombocytopenia) occurred in the 450 mg cohort which was expanded to 6 patients without subsequent DLTs. Six patients were treated in 2 continuous dosing cohorts of 200 mg and 300 mg. Two of 3 patients in the 300 mg cohort had DLTs of G3-4 thrombocytopenia and no DLTs were observed in 3 patients treated at 200 mg PO daily. The most common adverse events (AEs) were nausea (62%), fatigue (42%), anemia (39%), anorexia (27%), and vomiting (23%). These AE’s were G1-2 except for G3 anemia (12%), G3 fatigue (12%), and G3 anorexia (4%). No other G4-5 treatment-related AEs occurred. Median time on study was 79 days and best response was stable disease (SD) in 10 of 24 patients evaluable for efficacy (42%). Prolonged SD was observed in patients with platinum-resistant serous ovarian cancer (446 days) and adenoid cystic nasopharyngeal carcinoma (256 days). OKI-006 achieved consistent exposure with Cmax > 2,000 ng/ml and AUC > 8,000 hr*ng/ml, well above the targeted exposure for efficacy based on pre-clinical studies in murine models. Tmax was 2 hours and T1/2 was 6-8 hours. OKI-179 treatment resulted in > 3X increased T cell histone H3K9 and H3K27 acetylation within circulating PBMCs at doses of 180 - 450 mg. Conclusions: OKI-179 has a manageable safety profile, with thrombocytopenia being the on-target DLT. It has a favorable PK profile and demonstrated on-target PD effects at tolerable doses. The MTD and RP2D for OKI-179 was 450 mg daily for intermittent dosing and 200 mg daily for continuous dosing. Phase 2 studies are being designed, with a focus on combination with endocrine therapy in ER+ breast cancer and in NRAS-mutant melanoma. Clinical trial information: NCT03931681.

126 Background: In microsatellite stable (MSS) colorectal cancer (CRC) cases, frequent amplifications in 13q and 20q regions have been reported with limited understanding of their potential role for prognosis and treatment. Based on an internal research molecular tumor board case analysis of a KRAS WT, MSS left-sided (LS), metastatic CRC patient, we noted 50% of the 11 listed variants of unknown significance were on 20q. This study aims to investigate the potential prognostic role for gain of 20q chromosomal regions relative to other chromosomal imbalances using a retrospective cohort. Methods: We performed a genome-wide CN cluster analysis using the TCGA data with resulting patient clusters compared based on Kaplan-Meier estimated disease-free interval (DFI) in months (mos) using a log-rank. We examined associations between CN-derived clusters and CRC phenotypes. Results: Using TCGA data, we identified four CN-derived patient clusters of which two had significantly different DFI’s. One longer DFI cluster (n = 83; median DFI = 28mos) was defined by a signature of copy neutral genes along Chr8p and 18q regions. The shorter DFI cluster (n = 46; median DFI = 20mos) was defined by a signature of Chr8p and 18q regions of loss. The two clusters significantly differed in terms of site (85% right-sided in the shorter vs. 85% LS in the longer DFI cluster) and MS status (81% MSS in the shorter vs. 72% MSI in the longer DFI cluster) with no significant differences in age (mean of 70 years at diagnosis) and KRAS status (around 50% WT) between clusters. The shorter DFI was able to be further differentiated based on gain of chromosomal regions 20q (n = 26; median DFI = 24mos) and 13q (n = 20; median DFI = 18mos). No significant differences in mean age, tumor stage, site, and MS status between the shorter DFI subgroups were noted. Enriched pathways in the Chr20q gain sub-cluster include cell differentiation (Hippo, Rap1, VEGF), whereas metabolic signaling pathways via AGE-RAGE and AMPK, as well as cell growth and malignant transformation via RAS are enriched in the Chr13q gain sub-cluster. Conclusions: Clinical sequencing is able to identify regions of gain in Chr20q and Chr13q as part of VUS’s. Gain of Chr20q has been reported with better survival in mCRC patients. Gain of chromosomal region 20q and loss of 18q has been reported to discriminate between Lynch Syndrome and familial colorectal cancer. Herein, we show that gain of the 20q region with 18q and 8p regions of loss is associated with shorter DFI and gain of 13q region with loss of 8p even worse prognosis.

4031 Background: The majority of pts with mCRC have microsatellite stable (MSS) tumors with minimal response to PD-L1/PD-1 blockade. MEK inhibition and VEGF inhibition have immunomodulatory effects (upregulation of tumor major histocompatibility complex-I expression, enhanced T-cell infiltration, reduced MDSCs and Tregs in tumors) supporting clinical evaluation of combined MEKi (B), anti–PD-1 (P), and anti-VEGF (BV) in pts with mCRC. We hypothesize that the combination of binimetinib, pembrolizumab, and bevacizumab (BPBV) will result in greater clinical benefit than pembrolizumab alone. Methods: Patients with chemotherapy-refractory mCRC were evaluated (20 planned in the safety lead-in and 50 planned for total accrual). B was dosed at 45mg PO BID, P was administered at 200mg IV Q21 days, and BV was administered at 7.5mg/kg IV Q21 days. Primary objectives were safety, tolerability, and investigator-assessed ORR by RECIST 1.1. Clinical benefit rate (CR+PR+SD) and progression-free survival were secondary endpoints. Descriptive statistics were used to summarize safety and clinical activity. Results: As of January 9, 2020, 21 pts (10 KRAS/NRASmt, 11 RASwt, 21 MSS) were enrolled into the safety lead-in and were evaluable. The median number of prior therapies was 6. The BPBV combination was tolerable. Treatment-related Gr 1-2 and Gr 3-4 AEs occurred at 60% and 38%, respectively. The most frequent related Gr 3-4 AEs were aceniform rash, diarrhea, and hypertension (19%, 14%, 14% respectively). No treatment-related Gr 5 AEs occurred. A total of 17 patients were evaluable for response. Confirmed PR was observed in 2 pts (12%). SD was noted in 14 patients (82%) leading to a clinical benefit rate of 94%. 1 patient had PD as the best response to treatment. Median PFS was 6.4 months (95% CI 4.2-8.9). Molecular determinants, immune biomarkers, and updated tumor assessments of response will be presented. Conclusions: B + P + BV demonstrated a tolerable safety profile and improvements in ORR and clinical benefit rate compared to those reported with SOC in heavily pretreated pts with mCRC. Objective responses observed in pts were durable, suggesting benefit of this novel combination in a patient population refractory to immune therapies. Clinical trial information: NCT03475004 .

74 Background: Despite advances in cancer treatment, the orientation of our health system does not address the whole cancer patient or support the wellbeing of the heart, soul, and mind. We launched the CaLM Model of Whole Person Cancer Care, an oncology medical home approach that integrates high acuity, sub-specialty clinical cancer care with comprehensive, ongoing supportive care. The CaLM Model operationalizes the six components in the conceptual framework set forth in the NASEM’s 2013 report. Delivering High-Quality Cancer Care. Methods: Beginning December 2018, we piloted a “flipped” ambulatory care model in GYN and GI oncology delivering daily care through a subset of providers, the SWAT Team: a palliative NP, med onc NP, clinical social worker, and navigator. The SWAT Team triages all physical and social needs. As opposed to anchoring care with the oncologist and referring the patient out to social services, the SWAT team anchors care and the oncologist plugs in for treatment planning. The CaLM Model also utilizes coordinated, interdisciplinary care including financial and fertility navigation, nutrition, genetic counseling, pharmacy, and psychiatry, to manage the patient’s needs via a team-based approach by assessing and addressing the patient’s needs according to their values and preferences. We designed a new clinical and psychosocial assessment tool and patient-facing care plan; launched a Multi-Disciplinary “whole-person” case review process with all interdisciplinary providers and measured patient reported outcomes using the FACT-G, PHQ, GAD, and MD Anderson Symptom Inventory at baseline (initial visit) and every clinical visit. Measured at initial visit and every 6 months. Results: Early data show that the CaLM Model reduces patient symptom burden while improving quality of life. Conclusions: The CaLM Model is an efficient use of resources, compared to a traditional oncologist-focused model of cancer care. Further research is underway to assess cost benefit to the system, the patient and the payers. Ultimately, the CaLM Model may shift the paradigm of cancer care by demonstrating the feasibility and effectiveness of a patient-centered model of care delivery that builds a foundation for a value-based payment model.

5559 Background: Ovarian cancer patients who enroll in Phase I clinical trials are typically platinum resistant, heavily pretreated patients with a poor prognosis. Historically, clinical benefit of Phase I trials in this patient population has been uncertain. We assessed prognostic factors and survival in women with recurrent, previously treated ovarian cancer who enrolled in Phase I clinical trials. Methods: We performed a retrospective analysis of all ovarian cancer patients who were treated on Phase I clinical trials from 2008 through 2018 at the University of Colorado Cancer Center. Patient characteristics, treatment-related toxicities and survival data were assessed. Descriptive statistics and Cox proportional hazards models were utilized to identify risk factors associated with survival time. Results: A total of 132 individual patients were treated on Phase I clinical trials. Patients had a median age of 59 years (range 33-88) with a median of 5.5 (range 1-13) previous chemotherapy lines. 53/132 (40%) of patients were treated on multiple Phase I trials with a median of 1 (range 0-5) prior Phase 1 clinical trial enrollments. All patients had an ECOG performance status of 0 or 1. Overall response rate (defined as complete or partial response) was 9% and disease control rate (defined as complete or partial response or stable disease as best response) was 33%. Median overall survival (OS) was 11.5 months (95% CI: 9.3-13.7). Two patients died on trial due to progression of disease while no patients died due to treatment-related toxicity. In multivariate analysis, independent risk factors predicting shorter survival were elevated CA-125 (HR 2.8; 95% CI: 1.6-5.2) and albumin < 3.5 g/dL (HR 2.5; 95% CI: 1.65-3.79). BMI > 25 predicted longer survival (HR 0.65; 95% CI: 0.44-0.96). Conclusions: Phase I clinical trials for heavily pretreated ovarian cancer patients are safe by a standard of no patients experiencing toxicity-related deaths in our study. They are clinically efficacious with patients experiencing OS of 11.5 months, which is comparable to existing approved therapies. Elevated CA-125 and low albumin levels predict shorter survival, while BMI > 25 predicts longer survival. Phase I clinical trial options should be considered for all heavily pretreated ovarian cancer patients if available to them.

PurposeApoptosis ligand 2/tumor necrosis factor–related apoptosis-inducing ligand (Apo2L/TRAIL)—a member of the tumor necrosis factor cytokine family—induces apoptosis by activating the extrinsic pathway through the proapoptotic death receptors DR4 and DR5. Recombinant human Apo2L/TRAIL (rhApo2L/TRAIL) has broad potential as a cancer therapy. To the best of our knowledge, this is the first in-human clinical trial to assess the safety, tolerability, pharmacokinetics, and antitumor activity of multiple intravenous doses of rhApo2L/TRAIL in patients with advanced cancer.Patients and MethodsThis phase I, open-label, dose-escalation study treated patients with advanced cancer with rhApo2L/TRAIL doses ranging from 0.5 to 30 mg/kg/d, with parallel dose escalation for patients without liver metastases and with normal liver function (cohort 1) and for patients with liver metastases and normal or mildly abnormal liver function (cohort 2). Doses were given daily for 5 days, with cycles repeating every 3 weeks. Assessments included adverse events (AEs), laboratory tests, pharmacokinetics, and imaging to evaluate antitumor activity.ResultsSeventy-one patients received a mean of 18.3 doses; seven patients completed all eight treatment cycles. The AE profile of rhApo2L/TRAIL was similar in cohorts 1 and 2. The most common AEs were fatigue (38%), nausea (28%), vomiting (23%), fever (23%), anemia (18%), and constipation (18%). Liver enzyme elevations were concurrent with progressive metastatic liver disease. Two patients with sarcoma (synovial and undifferentiated) experienced serious AEs associated with rapid tumor necrosis. Two patients with chondrosarcoma experienced durable partial responses to rhApo2L/TRAIL.ConclusionAt the tested schedule and dose range, rhApo2L/TRAIL was safe and well tolerated. Dose escalation achieved peak rhApo2L/TRAIL serum concentrations equivalent to those associated with preclinical antitumor efficacy.

Recent retrospective evidence from several randomized studies has established that advanced colorectal cancer patients with tumors harboring a mutation in the KRAS gene do not derive benefit from the administration of epidermal growth factor receptor–directed monoclonal antibodies, such as cetuximab or panitumumab. This represents a paradigm-changing event and will have substantial impact on current and future anticancer drug development. These results add to the economic and ethical considerations involved in the development of novel targeted therapies and should increase our scrutiny of mechanisms of resistance and predictive biomarkers while in earlier developmental stages. In this article we will review the available clinical data, discuss the potential implications for future drug development in colorectal cancer, and provide a comprehensive overview of the technical aspects of KRAS mutation testing. In particular we aimed at enumerating the available procedures for mutation detection and their main characteristics, as well as comparing them from a clinical feasibility standpoint. While the true specificity and sensitivity of these methods have yet to be fully characterized, a better understanding of the differences between tests will be critical so that clinicians and pathologists can fully integrate this testing into the routine care of patients with colorectal cancer.

Purpose To establish the safety and toxicity profile of daily gefitinib with radiation alone or with concurrent chemoradiotherapy in previously untreated patients with locally advanced squamous cell head and neck cancer (LAHNC). Patients and Methods Patients with intermediate-stage LAHNC were treated with concomitant boost radiation (RT) alone with escalating doses of daily gefitinib (250 or 500 mg; cohort I). Once a safety profile was determined with RT alone, patients with high-risk disease were then treated with daily gefitinib (250 or 500 mg), weekly cisplatin (CDDP; 30 mg/m2), and once-daily RT (cohort II). Patients also received post-RT gefitinib at 250 mg daily for a period of up to 2 years. Results Twenty-three patients were enrolled and assessable for toxicity. No dose-limiting toxicities (DLTs) were observed in patients treated in cohort I at either 250 or 500 mg of gefitinib daily with concomitant boost RT to 72 Gy. In patients receiving chemoradiotherapy and gefitinib (cohort II), DLTs included one grade 4 diarrhea and one grade 4 neutropenic fever. Fifteen patients started maintenance gefitinib, and eight (53%) experienced grade 1 to 2 acne-like skin rash and diarrhea, but no grade 3 or 4 toxicity occurred. Conclusion Gefitinib (250 or 500 mg daily) was well tolerated with concomitant boost RT or concurrent chemoradiotherapy with weekly CDDP. Protracted administration of gefitinib for up to 2 years at 250 mg daily was also tolerated well.

Sunitinib (SU011248) is an oral small molecular tyrosine kinase inhibitor that exhibits potent antiangiogenic and antitumor activity. Tyrosine kinase inhibitors such as SU6668 and SU5416 (semaxanib) demonstrated poor pharmacologic properties and limited efficacy; therefore, sunitinib was rationally designed and chosen for its high bioavailability and its nanomolar-range potency against the antiangiogenic receptor tyrosine kinases (RTKs)—vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR). Sunitinib inhibits other tyrosine kinases including, KIT, FLT3, colony-stimulating factor 1 (CSF-1), and RET, which are involved in a number of malignancies including small-cell lung cancer, GI stromal tumors (GISTs), breast cancer, acute myelogenous leukemia, multiple endocrine neoplasia types 2A and 2B, and familial medullary thyroid carcinoma. Sunitinib demonstrated robust antitumor activity in preclinical studies resulting not only in tumor growth inhibition, but tumor regression in models of colon cancer, non–small-cell lung cancer, melanoma, renal carcinoma, and squamous cell carcinoma, which were associated with inhibition of VEGFR and PDGFR phosphorylation. Clinical activity was demonstrated in neuroendocrine, colon, and breast cancers in phase II studies, whereas definitive efficacy has been demonstrated in advanced renal cell carcinoma and in imatinib-refractory GISTs, leading to US Food and Drug Administration approval of sunitinib for treatment of these two diseases. Studies investigating sunitinib alone in various tumor types and in combination with chemotherapy are ongoing. The clinical benchmarking of this small-molecule inhibitor of members of the split-kinase domain family of RTKs will lead to additional insights regarding the biology, potential biomarkers, and clinical utility of agents that target multiple signaling pathways in tumor, stromal, and endothelial compartments.

There is no question that the treatment of cancer 10 years from now will be very different from that employed 10 years ago. Are we at the beginning of a series of rapid breakthroughs, or are we making slow progress? Only time will tell. We have many new “druggable” targets, and maybe the results really will be different from the past, with major advances in the treatment of traditionally refractory malignancies. Let us first briefly recapitulate the history of anticancer agents, to understand that the more things change, the more they stay the same. The pharmacologic management of cancer can be traced back to the Manhattan Project (1945), with a number of laboratories developing alkylating agents. These were clearly targeted agents, directed toward alkylating DNA, albeit in a diffuse manner. The next drugs were the antimetabolites, including the antifols, such as methotrexate, and the purine and pyrimidine analogs, such as 6-mercaptopurine and fluorouracil. Again, these drugs were clearly targeted against specific pathways and even specific enzymes, such as dihydrofolate reductase for methotrexate. Even then, we implicitly understood the concept of biomarkers, and myelosuppression was considered to be pharmacodynamic evidence of effects on the target—DNA. Now, approximately a half century (and hundreds of drugs) later, we are engrossed in a new era of oncology therapeutics, that many call “targeted therapies.” To paraphrase one perennially asked question, why are these drugs different from all other drugs? They are meant to be different because we believe that we can preferentially target the tumor rather than normal tissue. This belief is partially supportable, as particularly exemplified by the fantastic results achieved in chronic myelogenous leukemia with imatinib. The drugs are different because we have identified new signaling pathways and tumor biology, which we must learn and understand. They are different because we can’t remember or spell the generic names. They are not different, however, in that we have always had targets, and we have generally known that we have hit a target (which may be different from the intended target). As one example, estramustine was developed as an estrogen-receptor targeted–alkylating agent. However, it was subsequently demonstrated to be an antimitotic agent with activity in prostate cancer independent of the estrogen receptor. Furthermore, we have demonstrated that targeted agents, both old and new, can exhibit mechanism-based effects on normal tissue (myelosuppression, skin rash, diarrhea) that may or may not be associated with a beneficial effect on the patient. With a plethora of new targets, we also have a plethora of new drugs and sponsors, some of whom only have one drug to develop. There is immense competition among companies for patient resources, particularly in the United States and Europe, though many investigators in Asia and South America are equally inundated with requests for trials. Thus, many sponsors and investigators have attempted to minimize the number of patients treated in early clinical trials because of concerns relating to imbalances in patient resources, and financial incentives to move quickly toward phase III trials. Phase I trials have become smaller, in large part because of the recognition that newer targeted agents are less toxic, and are therefore less likely to result in serious toxic effects. This has led to the widespread adaptation of a variety of accelerated titration designs, which have in common, aggressive dose escalations and small patient cohorts, in the absence of toxicity. Such designs are very efficient for defining the maximum-tolerated dose, but are less useful for obtaining a full understanding of a new agent’s clinical pharmacology. In JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 22 NOVEMBER 15 2004

2587 Background: MEK inhibition is of interest in cancer drug development. However, better strategies are needed to overcome acquired resistance to MEK inhibitors. Preclinical studies have shown Wnt pathway overexpression in KRAS mutant cell lines resistant to the MEK inhibitor, selumetinib. The combination of selumetinib and cyclosporin A (CsA), a non-canonical Wnt pathway modulator, demonstrated antitumor activity in patient-derived xenograft (PDX) models. We conducted an NCI CTEP-approved Phase I/IB trial (NCI # 9571/COMIRB # 13-2628/NCT02188264) of selumetinib and CsA combination. Biomarkers of response are being co-developed. Methods: Patients with advanced solid tumors were treated with the combination of selumetinib and CsA in dose escalation followed by an expansion cohort in patients with irinotecan and oxaliplatin-refractory mCRC (n = 20). The expansion cohort utilized a selumetinib “run-in” to evaluate efficacy in RAS-WT and RAS-MT mCRC to identify those patients most likely to respond to the combination. Results: As of January 2017, 18 patients were enrolled in the dose escalation phase and 20 patients were enrolled in the dose expansion phase. The most common adverse events and grade 3/4 toxicities were rash, hypertension, and edema. Three DLTs - Grade 3 hypertension, rash and increased creatinine were reported. The maximum tolerated dose was identified as selumetinib 75 mg BID and CsA 2 mg/kg BID on a 28-day cycle. The selumetinib “run-in” did not favor a specific RAS type. Two partial responses were noted. Sixteen patients had stable disease, and 6 patients had progression of disease as their best response to therapy. Conclusions: Selumetinib in combination with cyclosporin A appears to be well tolerated with evidence of activity in mCRC. Tumor response data are currently being updated. FZD will be evaluated as a potential biomarker of response. Clinical trial information: NCT02188264.

e14604 Background: There is great interest in investigating immune checkpoint inhibition in combination with novel agents, however, preclinical studies are limited by the lack of immune-competent human cancer cell line xenograft models. We developed a “hematopoietic” humanized mouse model to address this unmet need. HDAC inhibitors (HDACi) induce T-cell chemokine expression and enhance response to PD1 inhibitors in lung cancer models. We evaluated the combination of OKI-179, a novel Class I HDACi and nivolumab in our humanized mouse model. Methods: BRGS newborn pups were transplanted with CD34+ cells purified from umbilical cord blood. At 16 weeks, MDA-MB-231 cells were implanted in the flanks of the mice. When the average tumor size reached ~150-300 mm3, the mice were randomized into vehicle, nivolumab, OKI-179, or the combination treatment according to % chimerism. At the end of the treatment, mice were euthanized and tissues were collected for further analysis. Results: We observed a statistically significant improvement in tumor growth inhibition with the combination of OKI-179 and nivolumab (%TGI = 77%) as compared to single agent nivolumab (45%TGI). Nivolumab treatment led to a significant decrease in PD-1 expression on T cells. We also observed an increased number of TILs (CD8+ T cells) and T cells in the lymph nodes of treated mice suggesting T cell expansion. All mice were highly chimeric and responding tumors exhibited an increase in CD44 high IFN+ T cells. We observed a higher CD8% and a higher effector memory % (HLADR+, CD45RO+) in these mice. Conclusions: We successfully established a humanized TNBC human cancer cell line xenograft model, with tumor engraftment occurred in all humanized mice. Mice treated with nivolumab demonstrating the development of lymph nodes that were populated by activated T cells. The combo resulted in superior tumor growth inhibition. These preliminary results demonstrate that human immunity and PD-1 expressing T cells exist in these models and provide the basis for planned immunotherapy combination studies.

PURPOSE: To determine the toxicity, maximum-tolerated dose (MTD), and pharmacokinetics of recombinant human CD40 ligand (rhuCD40L) (Avrend; Immunex Corp, Seattle, WA), suggested in preclinical studies to mediate cytotoxicity against CD40-expressing tumors and immune stimulation. PATIENTS AND METHODS: Patients with advanced solid tumors or intermediate- or high-grade non-Hodgkin’s lymphoma (NHL) received rhuCD40L subcutaneously daily for 5 days in a phase I dose-escalation study. Subsequent courses were given until disease progression. RESULTS: Thirty-two patients received rhuCD40L at three dose levels. A total of 65 courses were administered. The MTD was 0.1 mg/kg/d based on dose-related but transient elevations of serum liver transaminases. Grade 3 or 4 transaminase elevations occurred in 14%, 28%, and 57% of patients treated at 0.05, 0.10, and 0.15 mg/kg/d, respectively. Other toxicities were mild to moderate. At the MTD, the half-life of rhuCD40L was calculated at 24.8 ± 22.8 hours. Two patients (6%) had a partial response on study (one patient with laryngeal carcinoma and one with NHL). For the patient with laryngeal cancer, a partial response was sustained for 12 months before the patient was taken off therapy and observed on no additional therapy. Three months later, the patient was found to have a complete response and remains biospy-proven free of disease at 24 months. Twelve patients (38%) had stable disease after one course, which was sustained in four patients through four courses. CONCLUSION: The MTD of rhuCD40L when administered subcutaneously daily for 5 days was defined by transient serum elevations in hepatic transaminases. Encouraging antitumor activity, including a long-term complete remission, was observed. Phase II studies are warranted.

PURPOSE: To assess the feasibility of administering OSI-774, to recommend a dose on a protracted, continuous daily schedule, to characterize its pharmacokinetic behavior, and to acquire preliminary evidence of anticancer activity. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of OSI-774 in three study parts (A to C) to evaluate progressively longer treatment intervals. Part A patients received OSI-774 25 to 100 mg once daily, for 3 days each week, for 3 weeks every 4 weeks. Part B patients received OSI-774 doses ranging from 50 to 200 mg given once daily for 3 weeks every 4 weeks to establish the maximum tolerated dose (MTD). In part C, patients received this MTD on a continuous, uninterrupted schedule. The pharmacokinetics of OSI-774 and its O-demethylated metabolite, OSI-420, were characterized. RESULTS: Forty patients received a total of 123 28-day courses of OSI-774. No severe toxicities precluded dose escalation of OSI-774 from 25 to 100 mg/d in part A. In part B, the incidence of severe diarrhea and/or cutaneous toxicity was unacceptably high at OSI-774 doses exceeding 150 mg/d. Uninterrupted, daily administration of OSI-774 150 mg/d represented the MTD on a protracted daily schedule. The pharmacokinetics of OSI-774 were dose independent; repetitive daily treatment did not result in drug accumulation (at 150 mg/d [average]: minimum steady-state plasma concentration, 1.20 ± 0.62 μg/mL; clearance rate, 6.33 ± 6.41 L/h; elimination half-life, 24.4 ± 14.6 hours; volume of distribution, 136. 4 ± 93.1 L; area under the plasma concentration-time curve for OSI-420 relative to OSI-774, 0.12 ± 0.12 μg/h/mL). CONCLUSION: The recommended dose for disease-directed studies of OSI-774 administered orally on a daily, continuous, uninterrupted schedule is 150 mg/d. OSI-774 was well tolerated, and several patients with epidermoid malignancies demonstrated either antitumor activity or relatively long periods of stable disease. The precise contribution of OSI-774 to these effects is not known.

PURPOSE To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic profile of the dolastatin 15 analog LU103793 when administered daily for 5 days every 3 weeks. PATIENTS AND METHODS Fifty-six courses of LU103793 at doses of 0.5 to 3.0 mg/m2 were administered to 26 patients with advanced solid malignancies. Pharmacokinetic studies were performed on days 1 and 5 of course one. Pharmacokinetic variables were related to the principal toxicities. RESULTS Neutropenia, peripheral edema, and liver function test abnormalities were dose-limiting at doses greater than 2.5 mg/m2 per day. Four of six patients developed DLT at 3.0 mg/m2 per day, whereas two of 12 patients treated at 2.5 mg/m2 per day developed DLT. Pharmacokinetic parameters were independent of dose and similar on days 1 and 5. Volume of distribution at steady-state (Vss) was 7.6 +/- 2.0 L/m2, clearance 0.49 +/- 0.18 L/h/m2, and elimination half-life (t1/2) 12.3 +/- 3.8 hours. Peak concentrations (Cmax) on day 1 related to mean percentage decrement in neutrophils (sigmoid maximum effect (Emax) model). Patients who experienced dose-limiting neutropenia had significantly higher Cmax values than patients who did not, whereas nonhematologic DLTs were more related to dose. CONCLUSION The recommended dose for phase II evaluations of LU103793 daily for 5 days every 3 weeks is 2.5 mg/m2 per day. The lack of prohibitive cardiovascular effects and the generally acceptable toxicity profile support the rationale for performing disease-directed evaluations of LU103793 on the schedule evaluated in this study.

609 Background: Targeting MEK is of interest in the development of novel agents for treatment of many malignancies. However, better strategies are needed to overcome acquired resistance to MEK inhibitors. Preclinical studies have shown Wnt pathway overexpression in KRAS mutant cell lines resistant to the MEK inhibitor, Selumetinib. The combination of selumetinib and cyclosporin A (CsA), a non-canonical WnT pathway modulator, demonstrated antitumor activity in patient-derived xenograft (PDX) models. We are conducting an NCI CTEP-approved Phase I/IB trial (NCI # 9571/COMIRB # 13-2628) of selumetinib and CsA combination. Biomarkers of response to therapy are being co-developed. We hypothesize that this combination will be safe and potentially effective in patients with mCRC and that upregulation of FZD2 may predict for sensitivity. Methods: Phase I trial with initial dose escalation investigating the combination of selumetinib and CsA in patients with advanced solid tumors (n = 18) followed by an expansion cohort in patients with irinotecan and oxaliplatin-refractory mCRC (n = 20). The expansion cohort utilizes a selumetinib “run-in” to evaluate efficacy in RAS-WT and RAS-MT mCRC to identify those patients most likely to respond to the combination. Results: 18 patients were enrolled in the dose escalation phase and 10 patients have been enrolled in the dose expansion phase as of September 2016. Grade 1 or 2 nausea and rash were reported as the most common AEs. Most commonly reported Grade 3 or 4 toxicities were hypertension, elevated liver enzymes and rash. Three DLTs were reported with Grade 3 hypertension noted at dose level 1 and 2 and grade 3 rash reported at dose level 2. The maximum tolerated dose was defined as Selumetinib 75 mg BID and CsA 2 mg/kg BID on a 28-day cycle. Two partial responses and sixteen stable disease responses have been observed. Six patients have exhibited progressive disease. Conclusions: Selumetinib in combination with cyclosporin A appears to be well-tolerated with evidence of activity in solid tumors. Expansion cohort will complete enrollment this month. Clinical trial information: NCT02188264.