Radiographic Stable Disease Research Articles

Immune checkpoint inhibition in locally advanced rectal adenocarcinoma at Mayo Clinic.

e15626 Background: Studies have shown the effectiveness of immune checkpoint inhibition (ICI) in patients with tumors demonstrating microsatellite instability (MSI-H) and an associated defect in DNA mismatch repair (dMMR). In particular, KEYNOTE-177 demonstrated significant survival benefit for patients with unresectable or metastatic colorectal cancer with MSI-H or dMMR. Recently published case reports and series have demonstrated similar outcomes for patients with locally advanced and resectable rectal cancer. We report on the experience of patients with locally advanced, resectable rectal adenocarcinoma treated across the Mayo Clinic Health System. Methods: We conducted a retrospective analysis of patients treated at Mayo Clinic since 2015 A search of the Mayo Clinic database was done to include parameters for confirmed rectal adenocarcinoma, dMMR in pathology reports. Patients receiving ICI treatment including pembrolizumab, nivolumab/ipilimumab and durvalumab in any combination with chemotherapy and/or radiation were included. Patients with metastatic disease at the time of surgical intervention or ICI were excluded. Clinical data was assimilated. Results: Twenty-one patients met criteria for inclusion in our analysis. Fifteen patients had de novo disease. Six patients had local recurrence and had been treated previously with chemotherapy, radiation (RT) and surgery. None of the patients included had prior ICI therapy. Fifteen patients had Lynch syndrome. The median age of diagnosis was 41.5 years. Seven patients underwent surgical intervention. of the seven patients received surgery upfront followed by immunotherapy. The remaining six had neoadjuvant immunotherapy alone or in combination with chemotherapy and/or radiation. Prior to surgery, all patients demonstrated radiographic partial response (rPR). 67% of these demonstrated a pathologic complete response (pCR) while 33% had residual disease. The patient who received surgery upfront and adjuvant ICI continues to have radiographic stable disease after 1 year of treatment. For patients who did not have surgery, 50% had radiographic “complete or near complete” response (rCR), 43% had rPR and 7% had radiographic stable disease. Ten patients received RT and ICI with 70% demonstrating rCR and 30% rPR. Overall, the objective response rate was 90 Response to treatment was observed upwards of 75 months. Only 1 person in the study had progression of disease that occurred after 14 months of therapy. Conclusions: Similar to KEYNOTE-177, patients with locally advanced MSI-H/dMMR rectal cancer have significant and durable response to immunotherapy alone or in combination with chemotherapy, radiation and surgery. Further large prospective trials are needed to validate these findings and determine a standardized approach.

Abstract 1236: Biomarkers of response to abiraterone and the polo-like kinase 1 (PLK1) inhibitor onvansertib in metastatic castration resistant prostate cancer (mCRPC) patients

Abstract Background: Abiraterone (abi), a widely-used standard of care for castration-sensitive and castration-resistant prostate cancers, inhibits the androgen receptor signaling pathway. While abi slows disease progression, extended treatment universally results in acquired resistance. PLK1 is a serine/threonine protein kinase, master regulator of the cell cycle. PLK1 is upregulated in prostate cancer following androgen-deprivation therapy and PLK1 inhibition synergizes with abi in CRPC models, providing a potential means to reverse or delay abi resistance. Onvansertib is an oral highly selective PLK1 inhibitor that showed synergistic anti-tumor activity with abi in in-vitro and in-vivo CRPC models. A phase 2 clinical trial (NCT03414034) is ongoing to assess the efficacy of onvansertib in combination with abi in mCRPC patients with early abi resistance. Genomic and transcriptomic analyses were performed to identify response biomarkers for the onvansertib/abi combination. Methods: Cell-free DNA isolated from patient plasma was analyzed by targeted sequencing using Guardant OMNI® (500-gene panel). RNA expression profiling was performed using archival tissues by Veracyte (formerly Decipher Biosciences). Genomic and transcriptomic profiles of patients who progressed within 12 weeks of treatment (“PD” patients) were compared to patients who had radiographic stable disease at 12 weeks (“SD” patients). Results: Genomic profiles were successfully obtained from 19 PD patients and 31 SD patients. On average, PD patients had more somatic alterations than SD patients (14 vs 7, p=0.017). SD was positively correlated with the presence of alterations affecting signaling pathways such as MTOR, NF1, PTEN and EGFR, and negatively correlated with gene alterations involved in cell migration and invasion such as APC, KDR, PREX2, NF2 and AKT3. Eight (26%) of the 31 SD patients had alterations either in MTOR (n=5) or PTEN (n=3), that were predicted to have functional impacts on the protein, while only 1 PD patient (5%) had an alteration in either of those 2 genes. Moreover, transcriptomic analyses performed on tissue from 8 patients revealed that SD patients (n=5) exhibited a gene expression signature of “PTEN loss” that was absent in PD patients (n=3) (p=0.016). Conclusions: Taken together, these data suggest that alterations in PTEN and MTOR, two key genes of the PI3K signaling pathway, are potential biomarkers for sensitivity to onvansertib/abi combination in mCRPC patients with early abi-resistance. Preclinical studies are underway to assess the activity of onvansertib/abi in combination with PI3K-pathway inhibitors. Citation Format: Maya Ridinger, Errin Samuelsz, Peter J. Croucher, Mark Erlander, Katherine Ruffner, David J. Einstein. Biomarkers of response to abiraterone and the polo-like kinase 1 (PLK1) inhibitor onvansertib in metastatic castration resistant prostate cancer (mCRPC) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1236.

Major pathologic response on biopsy (MPRbx) in patients with advanced melanoma treated with anti-PD-1: evidence for an early, on-therapy biomarker of response

BackgroundWith increasing anti-PD-1 therapy use in patients with melanoma and other tumor types, there is interest in developing early on-treatment biomarkers that correlate with long-term patient outcome. An understanding of the pathologic features of immune-mediated tumor regression is key in this endeavor. Materials and methodsHistologic features of immune-related pathologic response (irPR) following anti-PD-1 therapy were identified on hematoxylin and eosin (H&E)-stained slides in a discovery cohort of pre- and on-treatment specimens from n=16 patients with advanced melanoma. These features were used to generate an irPR score [from 0=no irPR features to 3=major pathologic response on biopsy (MPRbx, ≤10% residual viable tumor)]. This scoring system was then tested for an association with objective response by RECIST1.1 and overall survival in a prospectively collected validation cohort of pre- and on-treatment biopsies (n=51 on-treatment at 4-week timepoint) from melanoma patients enrolled on the nivolumab monotherapy arm of CA209-038 (NCT01621490). ResultsSpecimens from responders in the discovery cohort had features of immune-activation (moderate–high TIL densities, plasma cells) and wound-healing/tissue repair (neovascularization, proliferative fibrosis) compared to nonresponders, (P≤0.021, for each feature). In the validation cohort, increasing irPR score associated with objective response (P=0.009) and MPRbx associated with increased overall survival (n=51; HR 0.13; 95%CI, 0.054–0.31, P=0.015). Neither tumoral necrosis nor pretreatment histologic features were associated with response. Eight of 16 (50%) of patients with stable disease showed irPR features, two of which were MPRbx, indicating a disconnect between pathologic and radiographic features at the 4-week on-therapy timepoint for some patients. ConclusionsFeatures of immune-mediated tumor regression on routine H&E-stained biopsy slides from patients with advanced melanoma correlate with objective response to anti-PD-1 and overall survival. An on-therapy biopsy may be particularly clinically useful for informing treatment decisions in patients with radiographic stable disease. This approach is inexpensive, straightforward, and widely available.

Highlights of This Issue

This is the first published phase I neoadjuvant study of the WEE1 inhibitor, AZD1775, with cisplatin and docetaxel. This novel approach exploits the underlying biology of TP53-inactivated tumors, which are incapable of G1 arrest and reliant on the G2/M checkpoint for DNA repair following genotoxic therapy. WEE1′s inhibition of CDK2 maintains genomic stability in S-phase, thereby protecting cells against replication stress and subsequent cell death. Treatment was tolerable with encouraging antitumor activity. Pharmacodynamic data demonstrated evidence of replication stress and G2/M override, leading to apoptosis. Given favorable safety, AZD1775 could reduce morbidity of definitive therapy in borderline-resectable, advanced HNSCC.Diffuse gliomas include different subtypes with diverse prognosis ranging from 1 to 15 years median overall survival. Thus, the subclassification of this type of tumours is crucial for the clinical and surgical managing of patients. The anatomical localization of diffuse gliomas, however, challenges access to tumour specimens for diagnosis. Martínez-Ricarte and colleagues have developed a platform to rapidly genotype seven genes in CSF ctDNA that allow the subclassification of diffuse gliomas. They showed that CSF ctDNA can be used as a liquid biopsy to diagnose diffuse gliomas, avoiding high-risk surgical procedures and facilitating the management of CNS malignancies.Although IGF-1R is critically involved in pancreatic cancer pathophysiology, IGF-1R inhibitors failed to show clinical benefit. To explore mechanisms of resistance, Camblin and colleagues performed growth factor screening in pancreatic cancer cells and investigated the prevalence of activating growth factors and their receptors in patient samples. The studies reveal that HRG/ErbB3 axis is critical to pancreatic cancer progression and resistance to IGF-1R inhibition. Moreover, they demonstrate that dual IGF-1R and ErbB3 targeting with a novel bispecific antibody increases the activity of standard-of-care chemotherapies. These findings provide mechanistic insight into pancreatic cancer resistance to IGF-1R inhibitors and identify novel therapeutic strategies.Anaplastic lymphoma kinase (ALK) is an oncogenic kinase implicated in several tumors, including neuroblastoma. Carneiro and colleagues report the first case of small-cell neuroendocrine prostate cancer (NEPC) with ALKF1174C activating mutation. The patient responded to second-generation ALK inhibitor alectinib as reflected by declining circulating tumor DNA allele fraction and radiographic stable disease. Alectinib also inhibited the growth of prostate cancer cell lines and organoids expressing ALKF1174C. Furthermore, ALK amplification was associated with poor outcome in prostate adenocarcinoma. The findings indicate the involvement of ALK in de novo and treatment-emergent NEPC and the therapeutic potential of ALK inhibitors.

Anaplastic Lymphoma Kinase Mutation (ALK F1174C) in Small Cell Carcinoma of the Prostate and Molecular Response to Alectinib.

Purpose: Small cell carcinoma of the prostate (SCCP) is an aggressive disease that can arise de novo or by transdifferentiation from prostate adenocarcinoma. Alterations in anaplastic lymphoma kinase (ALK) gene are involved in neuroblastoma, lung cancer, and other malignancies, but its role in SCCP has not been documented. We describe a patient with refractory de novo SCCP with ALK F1174C-activating mutation who obtained clinical benefit from treatment with ALK inhibitor.Experimental Design: Next-generation sequencing (NGS) was used to analyze primary and circulating tumor DNA (ctDNA). Prostate cancer databases were queried for alterations in ALK gene, mRNA, and its impact in clinical outcomes. In vitro prostate cell line/organoid models were generated by lentiviral-mediated expression of ALK and ALK F1174C and assessed for response to ALK inhibitors crizotinib and alectinib.Results: NGS analysis of the primary tumor and ctDNA of a 39-year-old patient with refractory SSCP identified ALK F1174C mutation. Treatment with second-generation ALK inhibitor alectinib resulted in radiographic stable disease for over 6 months, symptomatic improvement, and significant molecular response as reflected by declining ctDNA allele fraction. Analysis of prostate cancer datasets showed that ALK amplification was associated with poor outcome. In prostate cancer cells and organoids, ALK F1174C expression enhanced growth and induced expression of the neuroendocrine marker neuron-specific enolase. Alectinib was more effective than crizotinib in inhibiting ALK F1174C-expressing cell growth.Conclusions: These findings implicate ALK-activating mutations in SCCP pathogenesis and suggest the therapeutic potential of targeting ALK molecular alterations in some patients with SCCP. Clin Cancer Res; 24(12); 2732-9. ©2018 AACR.

Phase II trial of pembrolizumab in patients with platinum refractory germ-cell tumors: a Hoosier Cancer Research Network Study GU14-206

Despite remarkable results with salvage standard-dose or high-dose chemotherapy ∼15% of patients with relapsed germ-cell tumors (GCT) are incurable. Immune checkpoint inhibitors have produced significant remission in multiple tumor types. We report the first study of immunotherapy in patients with GCT. Single arm phase II trial investigating pembrolizumab 200 mg i.v. Q3weeks until disease progression in patients with relapsed GCT and no curable options. Patients age ≥18 with GCT who progressed after first-line cisplatin-based chemotherapy and after at least one salvage regimen (high-dose or standard-dose chemotherapy) were eligible. Centrally assessed programmed death-ligand 1 (PD-L1) on tumor and infiltrating immune cells was scored. Primary end point was overall response rate using immune-related response criteria. Simon two-stage design with type I error 20% and power 80% was utilized. Twelve male patients were enrolled. Median age was 38 years. All patients had nonseminoma. Primary site was testis (11) or mediastinum (1). Median AFP 615 (range 1-32, 760) and hCG 4 (range 0.6-37, 096). Six patients had late relapse (>2 years). Median number of previous chemotherapy regimens was 3. Six patients received prior high-dose chemotherapy. Two patients had positive PD-L1 staining (H-score 90 and 170). Median number of pembrolizumab doses was 2 (range 1-8). There were six grade 3 adverse events. No immune-related adverse events were reported. No partial or complete responses were observed. Two patients achieved radiographic stable disease for 28 and 19 weeks, respectively; both had continued rising AFP level despite radiographic stability and had negative PD-L1 staining. This is the first reported trial evaluating immune checkpoint inhibitors in GCT. Pembrolizumab is well tolerated but does not appear to have clinically meaningful single-agent activity in refractory GCT. NCT02499952.

MABp1 to improve clinical outcomes of patients with symptomatic refractory metastatic colorectal cancer patients: Per-protocol population analysis of phase III study (PT026).

3530 Background: Refractory metastatic colorectal cancer (mCRC) patients derive minimal benefit from further exposure to toxic agents. MABp1 is an anti-interleukin 1 alpha antibody that is shown to prolong survival (NCT01767857) and improves outcomes when assessed with a primary endpoint based on a constellation of objective and patient self-reported measures (NCT02138422) (Hickish T. et al Lancet Oncology 2017). In the latter study, clinically advanced patients were enrolled (symptomatic, ECOG 1,2), and 18% of patients progressed prior to reaching the endpoint assessments. Here we present the outcomes in per-protocol population (PP), those patients completing week 8 assessments. Methods: 309 patients randomized 2:1 to receive MABp1 versus placebo. Patients were ECOG 1-2, with mCRC refractory to chemotherapy, any degree of weight loss, and cancer-associated symptoms. The composite primary endpoint assessed the rate of patients achieving stabilization or improvement in lean body mass (LBM) and two of three symptom measures (pain, fatigue, appetite loss) from screening to the week 8 assessment. The study was designed for placebo cross-over, thus OS analysis for MABp1 vs placebo was not possible. Results: 57 patients (38 MABp1 [18%] and 19 placebo [19%]) discontinued study prior to the week 8 assessment due to disease progression, including 17 (8%) and 11 (11%) deaths in MABp1 and placebo respectively. 62% of placebo patients received MABp1 after 8 weeks. 252 patients, 40% in MABp1 (68/169) vs 23% in placebo (19/83) met the primary endpoint (p = 0.003). 139 patients were available for PP survival analysis (90 MABp1 vs 49 Placebo). Median OS of those achieving the primary endpoint was 11.7 months vs 5.7 months for those that did not (HR 0.39; p < 0.0001). Radiographic stable disease was improved (42% vs 12%; p < 0.001) and incidence of SAEs (6% vs 15%; p = 0.11) reduced in those achieving the primary endpoint. Conclusions: Achieving the primary endpoint was associated with improvement in outcomes, RECIST stabilization, SAEs and survival. Further study should confirm the effect of MABp1 on survival in this population. Clinical trial information: NCT02138422.

A phase II study of cabozantinib in metastatic castration-resistant prostate cancer (mCRPC) with visceral metastases (VM) with very small nuclear circulating tumor cell (vsnCTC) association studies.

208 Background: Cabozantinib is a multi-targeted tyrosine kinase inhibitor (TKI) that has recognized clinical activity in mCRPC. While phase 3 studies did not show a significant improvement in overall survival (OS), patients with VM had improved OS compared to those with only osseous metastases in subgroup analysis. Our group has also identified a subgroup of CTCs strongly associated with the presence of VM (Chen, Cancer 2015). We hypothesized that cabozantinib would yield clinical benefit and changes in vsnCTC counts would reflect disease behavior. Methods: This study was designed as an open label study of cabozantinib 60 mg daily, for mCRPC patients with visceral disease. The primary endpoint is clinical benefit rate (radiographic stable disease + partial response (PR) by RECIST 1.1) at 12 weeks (CBR12). Serum PSA concentrations were not used as a primary endpoint. CTCs were enumerated by NanoVelcro CTC Assay and characterized using published methods. Results: Thirteen patients have completed at least 8 weeks of treatment. In this group, 38% had pulmonary metastases; 77% had hepatic metastases; CBR12 was 92% at the time of this report. A quarter of the patients experienced a PR. Mean time to radiographic progression for responders was 38 weeks (19-57). Discordant responses were noted between VM and bone scans. Grade 3 or higher toxicities were compatible with prior studies and observed in 50% of patients. In this advanced mCRPC and relatively heavily pre-treated population, treatment discontinuation due to toxicity was 33%. Eleven of 13 patients were assessable for CTC and imaging. Of the 11 patients, 7 had vsnCTCs detected at baseline. All 7 patients reported subjective improvement that was associated with a decrease in vsnCTCs by 6-8 weeks. In patients who had a PR, no vsnCTCs were detected at 6 weeks while on active treatment. An increase in vsnCTCs was seen prior to visceral progression. Conclusions: Cabozantinib is a TKI with activity in mCRPC with visceral metastases. Toxicity is consistent with previous reports and manageable. The NanoVelcro vsnCTC assay may be a predictive marker of response. Clinical trial information: NCT01834651.

Abstract C49: Phase 1 study of CB-839, a first-in-class, orally administered small molecule inhibitor of glutaminase in patients with refractory solid tumors

Abstract Background: CB-839 is a first-in-class highly selective inhibitor of glutaminase (GLS), a key enzyme in the utilization of glutamine by many cancer cells. Inhibition of GLS blocks the ability of tumor cells to use glutamine as a source of energy and anabolic building blocks. CB-839 has broad activity, inducing cell death or growth arrest in triple negative breast cancer (TNBC), KRAS-mutant non-small cell lung cancer (NSCLC), clear cell renal cell cancer (RCC), and mesothelioma cell lines. GLS inhibition with CB-839 has also been shown to synergistically combine with several standard of care (SOC) chemotherapies and signal transduction inhibitors. Methods: CX-839-001 is an ongoing Phase 1 study of escalating doses of CB-839 given continuously in 21 day cycles in advanced and/or treatment-refractory solid tumor patients (pts) to evaluate safety and tolerability, and to identify the recommended Phase 2 dose (R2PD). It was initially given three times daily (TID) without food, but based on PK and safety data, the drug is now being given twice daily (BID) with meals. Pharmacokinetics (PK) is monitored on Days 1 and 15; pharmacodynamics is measured in platelets and in tumor biopsies. Pts are currently being enrolled at the RP2D, 600 mg BID, with the tumor types noted above as well as pts receiving CB-839 in combination with SOC agents, including paclitaxel in TNBC, docetaxel in KRAS-mutant NSCLC, erlotinib in EGFR-mutant NSCLC, and everolimus in RCC. Results: Safety data from 85 pts enrolled in the trial revealed a low rate of Gr3/4 AEs, with 9.4% (8/85) of pts experiencing a Gr3/4 AE related to CB-839. One DLT occurred on study, a drug-related Gr3 creatinine elevation in a patient with diabetic nephropathy at the 250 mg TID dose level. Reversible, asymptomatic Gr3 elevations in transaminases occurred mostly on the TID schedule in 6/32 pts (18.8%), with only one Gr3 event occurring among 53 pts (1.9%) receiving the BID regimen. Clear exposure-dependent inhibition of GLS in platelets was seen 4 hr after the first dose of CB-839, with >90% inhibition at PK trough for most pts at the RP2D. A total of 93 pts have been enrolled on the monotherapy cohorts of the trial as of 24 July 2015, including 32 pts on TID dosing (100-800 mg) and 61 pts on BID dosing (600-1000 mg). Radiographic stable disease (SD) was observed in 6 (19%) of 31 efficacy-evaluable pts receiving CB-839 on the TID schedule and 17 (40%) of 43 efficacy-evaluable pts on the BID schedule. Pts with SD have been on study for a median of >5 cycles (range 3-18); 15 (65%) of these pts remain on treatment. Seven of 11 (64%) evaluable RCC pts on the BID dose schedule showed SD, 5 of whom remain on study. A TNBC patient has maintained SD for more than one year and has had a 23% reduction in tumor burden. GLS expression was evaluated by IHC and found to be moderate to high in most patient tumor samples. Additional correlative studies will also be presented. Conclusions: CB-839 has been well tolerated when administered BID with food at and above doses that produced robust inhibition of GLS in platelets and in tumors. Evidence of prolonged SD in pts receiving single agent CB-839, together with strong preclinical data in combination with SOC agents including paclitaxel, everolimus and erlotinib, provides a clear rationale for continued evaluation of CB-839 in several tumor types, as a single agent and in combination with SOC therapies. Citation Format: Funda Meric-Bernstam, Angela DeMichele, Melinda L. Telli, Pamela Munster, Keith W. Orford, George D. Demitri, Gary K. Schwartz, Othon Iliopoulos, James W. Mier, Taofeek K. Owonikoko, Mark K. Bennett, Manish R. Patel, Jeffery R. Infante, James J. Harding. Phase 1 study of CB-839, a first-in-class, orally administered small molecule inhibitor of glutaminase in patients with refractory solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C49.

Abstract C137: First-in-human dose escalation study of oral ONC201 in advanced solid tumors

Abstract Background: ONC201 is an orally active first-in-class small molecule with strong antitumor activity in preclinical models of advanced cancers. In cancer cell lines and patient samples ONC201 induces activation of the integrated stress response (Ishizawa et al ASH, 2014) resulting in upregulation of ATF4 and CHOP which in turn regulates several proapoptotic genes namely DR5. ONC201 also causes late-stage inactivation of Akt and ERK, which also results in downstream activation of the apoptotic TRAIL pathway as part of innate immune surveillance (Allen J et al, Sci Trans Med, 2013). Activity of ONC201 is independent of p53 status and mutation agnostic. ONC201 is well tolerated at efficacious doses in animal models, crosses the blood brain barrier, is particularly effective in refractory tumors, depletes cancer stem cells (Ishizawa et al, ASH 2014; Prabhu et al, Blood 2014; Zhao et al, ASCO 2014), and is effective with infrequent dosing preclinically. Based on the compelling efficacy and safety profile of ONC201 as well as the engagement of signaling pathways critical for many cancers, the clinical introduction ONC201 in advanced cancer patients is warranted. Methods: The first-in-human study of ONC201 (NCT02250781) began in January 2015 as an open-label single-site phase I trial enrolling adult patients with refractory advanced solid tumors and glioblastoma (GBM). Patients with symptomatic brain metastases or prior bevacizumab for treatment of GBM are excluded. The primary endpoint is determination of the recommended phase II dose (RP2D) of single agent ONC201 given orally once every 3 weeks (1 cycle). Secondary endpoints include assessment of pharmacodynamics using select biomarkers for ONC201 (Allen et al, 2015), pharmacokinetics, toxicity, and efficacy. The study employs an accelerated, single patient per cohort, dose escalation design with expansion to a standard 3+3 design if a subject has grade > / = grade 2 toxicity or dose limiting toxicity within cycle 1. The maximum tolerated dose is the highest dose level in which 6 patients have been treated with < / = 1 instance of DLT. Based on pre-clinical models doses for once every 3 week dosing were: dose leve1 (DL) 1- 125mg; 2- 250mg; 3- 375mg; 4- 500mg; 5- 626mg. Results: Single patient dose escalation was completed in cohorts 1 to 4 and 6 patients completed at least 3 weeks of level 5 without any > / = grade 2 drug related toxicity. At DL 6, Mean T1/2 = 7.91hours (7.01-9.42); Mean Cmax = 8.58 ug/mL (3.95 - 19.15) Mean AUC(0-24) = 28057 (15293 - 50597) hr-ng/mL. Ongoing radiographic stable disease is noted in a patient with metastatic castrate resistant prostate cancer. Conclusions: The RP2D of ONC201 is 625mg on a once every 3 week schedule. Evaluation of PD markers of response and enrollment to a dose expansion safety cohort are ongoing. Citation Format: Mark N. Stein, Rebecca Moss, Tina Mayer, Ann W. Silk, Nancy Chan, Ling Zheng, Yasmeen Beckett, Noelle Tenpenny, Edward Bentlyewski, Robert DiPaola, Rohinton Tarapore, Joshua Allen, Janice Mehnert. First-in-human dose escalation study of oral ONC201 in advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C137.

Chemoimmunotherapy of Advanced Non-Small Cell Lung Cancer (Nsclc) with Imprime Pgg (Ipgg) in Combination with Cetuximab, Carboplatin and Paclitaxel–Analysis of Secondary Endpoints of a Multicenter, Randomized Phase 2 Trial

ABSTRACT Aim: IPGG is a yeast-derived b-glucan that primes innate immune cells to kill monoclonal antibody-targeted cancer cells via complement receptor 3 (CR3). Subjects with anti-beta glucan antibodies (ABA) levels conducive to IPGG binding to CR3 are considered “biomarker positive” (BM+). We have previously reported significant improvements in objective responses with IPGG in combination with cetuximab, carboplatin and paclitaxel in patients (pts) with advanced NSCLC. Herein, we present the secondary endpoints of the clinical trial. Methods: Pts with Stage IV NSCLC received cetuximab (CET) 250 mg/m2 following initial 400 mg/m2 loading dose) without (Control, N = 30) or with IPGG 4mg/kg (IPGG, N = 60) on Days 1, 8 and 15 of each 3-week treatment cycle, and carboplatin (AUC 6) + paclitaxel (200 mg/m2) on Day 2 for the first 4 to 6 cycles. Pts achieving radiographic stable disease or tumor response (modified RECIST 1.0) received CET or CET/IPGG maintenance treatment. The primary endpoint was objective response rate. Secondary endpoints included disease control rate (DCR: CR + PR + SD), time to progression (TTP), overall survival (OS) and safety. Results: Best overall response (control vs IPGG) was PR in 23.1% vs 47.8% (p = 0.048), SD in 53.8% vs 30.4%, and PD in 23.1% vs 21.7%, respectively; DCR was 76.9% vs 78.3%, respectively (p = NS). ORR was 66.7% with IPGG in BM+ pts (p = 0.009 vs. Control) and 38.7% in the BM - group (p = NS vs. Control). Median TTP was 4.4 mo vs 4.3 mo respectively in the overall population and 5.6 mo in BM+ pts receiving IPGG (p = NS). OS was 11.3 mo vs 12.4 mo overall (p = NS), and 16.7 mo in BM+ pts vs. 9.4 mo in BM- pts receiving IPGG (p = 0.133). All subjects had at least one adverse event; grade III/IV adverse events occurred in 86.2% vs 78.0% of control vs. IPGG-treated pts. Conclusions: In patients with stage IV NSCLC receiving combination therapy with carboplatin, paclitaxel and CET, IPGG was well tolerated, improved objective responses and prolonged OS in BM+ pts. Disclosure: N. Bose, M.L. Patchen, J. Lowe, P. Mattson, M. Gargano, R.D. Huhn and A. Braun: Employee of Biothera, Inc.All other authors have declared no conflicts of interest.

Planned interim analysis of phase II study of sorafenib and capecitabine (SorCape) in previously treated metastatic colorectal cancer (mCRC): NCT01471353.

548 Background: Inhibition of the MEK/ERK pathway through Raf has been shown to resensitize tumor cells resistant to chemotherapy. Sorafenib (Sor) is an oral multi-tyrosine kinase inhibitor (TKI) affecting tumor proliferation and angiogenesis through inhibition of the Ras/Raf/MEK/ERK, VEGF, and PDGF pathways. A similar TKI, regorafenib, has efficacy as monotherapy in advanced mCRC. Demonstrating activity of this compound class with standard cytotoxic therapy represents a clinical unmet need. Methods: Eligible pts had progressive mCRC after prior oxaliplatin and irinotecan, at least 1 measurable target lesion by RECIST, ECOG PS 0-1, and adequate organ function. Pts received Cape (1000mg/m2 PO BID D1-14) and Sor (400mg PO BID max via dose escalation per cycle). Cycles were q21d with tumor assessments q9w. Endpoints included progression-free survival (PFS), objective and biochemical response rates, overall survival (OS), toxicity and quality of life. Sample size was based on a 50% improved median PFS from 3 (historical) to 4.5 months (m). Results: 29 of 43 planned pts have received therapy and the first 26 are included in this planned interim analysis. Baseline pt demographics are in the Table. Most frequently observed adverse events (any AE) included HTN (15%), diarrhea (35%), fatigue (65%) and HFS (91%). 19 pts (73%) had a grade 3 AE (12/19 were HFS). There were no grade 4 or 5 toxicities. 11/25 (44%) evaluable pts have radiographic stable disease. With a median f/u of 6.2 mo, interim PFS is 4.4m. Conclusions: Enrollment continues with manageable AEs, despite the overlapping toxicity of HFS. Planned interim PFS data appears promising in this refractory mCRC population. Molecular correlatives for predictors of response are being analyzed. Clinical trial information: NCT01471353. [Table: see text]

Abstract A26: Imprime PGG improves the efficacy of carboplatin, paclitaxel, and cetuximab chemoimmunotherapy of advanced non-small cell lung cancer (NSCLC).

Abstract Imprime PGG is a yeast-derived beta 1,3/1,6 glucan that primes innate immune cells to kill monoclonal antibody (MAb)-targeted cancer cells via a mechanism dependent on complement receptor 3 (CR3). In humans, naturally occurring anti-beta glucan antibodies are required for binding of Imprime PGG to CR3 on immune cells. A quantitative assay has been developed to measure these antibodies in serum; subjects with levels conducive to binding are considered “biomarker positive” (BM+) and others “biomarker negative” (BM-). In a Phase 2 study, stage IIIb or IV NSCLC subjects received cetuximab (250 mg/m2 following initial 400 mg/m2 loading dose) without (Control, N=30) or with Imprime PGG 4mg/kg (Imprime, N=60) on Days 1, 8 and 15 of each 3-week treatment cycle; all subjects also received carboplatin (AUC 6) plus paclitaxel (200 mg/m2) on Day 2 of each cycle for the first 4 to 6 cycles. Maintenance treatment with cetuximab alone or with Imprime was continued in subjects achieving radiographic stable disease or tumor responses (RECIST 1.0). In the efficacy population comprised of all treated subjects who had evaluable baseline and post-baseline scans, median overall survival was 11.2 mo in the control group (N=26), 10.2 mo in the entire Imprime group (N=46) (HR 1.06, p=0.85 vs. control), 16.5 mo in the BM+ Imprime group (N=15) (HR 0.63, p=0.26 vs. control) and 9.1 mo in the BM- Imprime group (N=31) (HR 1.35, p=0.35 vs. control). Three-year survival was 0% in the control group, 7% in the entire Imprime group, 17% in the BM+ Imprime group and 0% in the BM- Imprime group. The objective response rate (ORR, all partial responses) was 23% in the control group, 48% in the entire Imprime group (p= 0.048 vs. control), 67% in the BM+ Imprime group (p=0.009 vs. control) and 39% in the BM- Imprime group (p=0.26 vs. control). Among subjects with squamous cell histology, 6 of 6 BM+ Imprime subjects had responses compared with 3 of 10 control subjects (p=0.01). Grade 3/4 adverse events occurred in 25 of 29 control subjects (86%) and 46 of 59 Imprime subjects (78%). All adverse events were consistent with toxicities attributable to the cytotoxic drugs or cetuximab. In summary, the addition of Imprime PGG to chemoimmunotherapy with carboplatin, paclitaxel and cetuximab resulted in improved outcomes in BM+ subjects with respect to increased ORR and extended survival compared to control subjects and had a good safety profile. Citation Format: Michael Thomas, Parvis Sadjadian, Jens Kollmeier, Zhonglin Hao, Myra Patchen, Jamie Lowe, Paulette Mattson, Richard D. Huhn, Nandita Bose, Mary Antonysamy, Michele Gargano, Keith Gordon, Folker Schneller. Imprime PGG improves the efficacy of carboplatin, paclitaxel, and cetuximab chemoimmunotherapy of advanced non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr A26.

Phase I trial and pharmacokinetic (PK) study of satraplatin in children and young adults with refractory solid tumors including brain tumors.

2554 Background: Satraplatin is an orally bioavailable platinum analog. Based on pre-clinical activity (IC500.02-8 µg/ml) including activity in cisplatin resistant cell lines, and clinical activity without neuro-, nephro-, or ototoxicity in adults with refractory tumors, we developed a phase 1 trial to determine the toxicities, maximum tolerated dose (MTD), and PKs of satraplatin in children with refractory solid tumors. Methods: Satraplatin (10 and 50 mg capsules) was administered orally once daily on days 1 - 5 of a 28 day cycle to cohorts of 3-6 patients (pts) at 60 mg/m2/dose (DL 1) and 80 mg/m2/dose (DL 2). Plasma ultrafiltrate (PUF) platinum was measured using atomic absorption spectroscopy during cycle 1 for PK analysis. Results: 9 pts [5 male, 4 female, median age 17 years (range 8-19)] with malignant glioma (n=4), ependymoma (n=2), medulloblastoma (n=1), osteosarcoma (n=1), or hepatoblastoma (n=1) received 1-10+ cycles (median 2). The MTD was exceeded at DL 2 as 2/4 pts had dose limiting toxicities (DLT) of delayed and prolonged myelosuppression (grade 3 thrombocytopenia, n=1; grade 3-4 neutropenia, n=2). 0/5 pts at DL 1 had DLTs. Grade 1 ototoxicity was seen in 1 pt at cycle 10. Non-DLTs included myelosuppression, gastrointestinal toxicities, fatigue, headache, liver enzyme elevation, and electrolyte abnormalities. No objective responses were observed, but 1 pt with gliomatosis cerebri has had radiographic stable disease through cycle 10+. Satraplatin mean exposure (AUC) and peak concentration (Cmax) were similar at both dose levels [day 1 PUF AUC0-24h 1.22 ± 0.55 µg/ml*h at DL1 (n=3), 1.02 ± 0.45 µg/ml*h at DL2 (n=3); Cmax0.17 ± 0.08 µg/ml at DL 1 (n=3), 0.16 ± 0.05 µg/ml at DL 2 (n=3)]. Terminal half-life was 14 ± 6 h and apparent clearance was 76 ± 29 L/h (n=6). Conclusions: The MTD of oral satraplatin in children with solid tumors is 60 mg/m2/dose daily x 5 q28 days. The toxicity profile was similar to adults, and delayed myelosuppression was DLT. Satraplatin exposure appears higher in pediatric pts compared to adults (PUF AUC0-24h 0.25-0.47 µg/ml*h at 60-80 mg/m2/dose). DL 1 will be expanded to gain additional experience regarding toxicities and PKs in a broader age range. Clinical trial information: NCT01259479.

Phase II study of sorafenib and capecitabine (SorCape) in previously treated metastatic colorectal cancer (mCRC): NCT01471353.

489 Background: Sorafenib (Sor) is an oral multi-tyrosine kinase inhibitor (TKI) affecting tumor proliferation and angiogenesis through inhibition of the Ras/Raf/MEK/ERK, VEGF and PDGF pathways. Inhibition of the MEK/ERK pathway through Raf has been shown to resensitize tumor cells resistant to chemotherapy. A similar TKI, regorafenib, has recently demonstrated efficacy as monotherapy in advanced mCRC. Demonstrating activity of this class of compounds with standard cytotoxic therapy represents a clinical unmet need for patients (pts) with mCRC. Methods: Eligible pts had progressive mCRC after prior oxaliplatin and irinotecan, at least 1 measurable target lesion by RECIST, ECOG PS 0-1, and adequate organ function. Pts received Cape (1000mg/m2PO BID D1-14) and Sor (400mg PO BID max via dose escalation per cycle). Cycles were q21d with tumor assessments q9w. Endpoints included progression-free survival (PFS), objective and biochemical response rates, overall survival (OS), toxicity, and quality of life. Sample size was based on a 50% improved median PFS from 3 (historical) to 4.5 months (m). Results: 24 of 43 planned pts have received therapy. 19 were white and 17 male. Median age 61y (37-79). 14 (58%) were KRAS-mut. Median prior lines of therapy for mCRC was 3 (1-5). All but one had liver and/or lung metastases. Most frequently observed adverse events (AEs) included fatigue (29%), HTN (38%), and HFS (91%). 18 pts (75%) had a grade 3 AE (11/18 were HFS). There were no grade 4 or 5 toxicities. Preliminary PFS is 4.1m. 5/16 (31%) evaluable pts have radiographic stable disease. Conclusions: Enrollment continues with manageable AEs, despite the overlapping toxicity of HFS. Preliminary PFS data appears promising in this refractory mCRC population. Clinical trial information: NCT01471353.

A phase I study of erlotinib, bevacizumab, and external beam radiation therapy (RT) for patients with localized pancreatic carcinoma (PC).

281 Background: Localized PC is commonly managed with chemoradiotherapy, with or without surgical resection. The optimal combination of agents and doses is the subject of continued investigation. This phase I study examines the combination of two targeted radiosensitizing agents in combination with radiation therapy. Methods: Eligible patients had resectable, borderline resectable or locally advanced adenocarcinoma. Patients received RT (1.8 Gy qd to 50.4 Gy) concurrent with bevacizumab and erlotinib. Dose-level 1 was bevacizumab 10 mg/kg weeks 1, 3 and 5 and erlotinib 100 mg daily, RT days only. Drug doses were escalated depending on encountered toxicity. The primary endpoint was determination of the maximally tolerated dose of this combination. Secondary endpoints included toxicity and activity assessment. Results: Nine patients were enrolled in the phase I study. Maximal EUS/CT stage was T2N0 (n=1), T3N0 (n=1), T3N1 (n=2) or T4N0 (n=5). Of 3 patients in dose-level 1, two had radiographic stable disease (SD) and one partial response (PR). One pt underwent exploratory laparotomy and found to be unresectable, experiencing prolonged postoperative incisional healing. Three patients were then enrolled at dose-level 2 (bevacizumab 10 mg/kg, erlotinib 125 mg). Two had SD and one progressive disease (PD). One pt underwent exploratory laparotomy, aborted due to previously undetected hepatic metastases. Three patients were then enrolled at dose-level 3 (bevacizumab 10 mg/kg, erlotinib 150 mg). One pt had SD and two PR. One pt underwent distal pancreatectomy, experiencing postoperative pancreatic leak and abscess formation. All patients with elevated CA 19-9 at baseline had a decrease, with amedian decrease of 69% (R:13-93%). Dose-limiting toxicity (DLT) was not encountered at any dose-level. Primary non-dose limiting toxicities in all cohorts included NCI CTCAE v3.0 grade 1-2 nausea/vomiting, rash, diarrhea, fatigue, and anorexia. Conclusions: Concurrent chemoradiotherapy utilizing erlotinib and bevacizumab is reasonably well-tolerated. The recommended phase II dose is bevacizumab 10 mg/kg weeks 1, 3, and 5 and erlotinib 150 mg RT days only. Phase II accrual is underway. [Table: see text]

Phase I dose-escalation study of AGS-1C4D4, an anti-PSCA human antibody in castration-resistant prostate cancer (CRPC).

4669 Background: AGS-1C4D4 is a fully human MAb directed to PSCA, a cell surface antigen expressed on tumor cells in the majority of patients with prostate, pancreatic and bladder cancers. AGS-1C4D4 is produced in CHO cells and has an identical sequence to that of the hybridoma-derived AGS-PSCA. Preclinical studies confirmed comparability to AGS-PSCA in tumor inhibition tissue cross reactivity and PK. Due to differences in glycosylation and ADCC in vitro, a limited AGS-1C4D4 phase I trial was undertaken to explore potential differences in safety and PK. Methods: Thirteen patients with metastatic CRPC were treated. AGS-1C4D4 was administered by IV infusion Q3W for 4 doses at 6, 12, 24, and 48 mg/kg. Primary endpoints were safety and PK. Secondary endpoints included immunogenicity and anti-tumor activity. Disease assessments were performed Q12W. Patients with stable disease (SD) were eligible to receive extended treatment at the same dose and schedule. Results: Nine of 13 patients completed 4 doses. Toxicities were primarily grade 1-2. No deaths or grade 3-4 treatment-related events, acute infusion-related toxicities, or anti AGS-1C4D4 antibodies have been reported. PK was linear. Similarly to AGS-PSCA, serum concentrations of AGS-1C4D4 declined biphasically and the final elimination Ph was characterized by a slow clearance rate (CL) and a long terminal T1/2. Median CL values for the 4 dose levels ranged from 0.10 to 0.14 mL/h-kg; and T1/2 was from 2.2 to 2.9 weeks. The target trough serum antibody concentration of 200 mg/ml, based on xenograft models, was reached in most of the higher dose patients with available PK data and was maintained with subsequent dosing. SD was reported in 5 (38%) patients and all these received extended dosing with total treatment duration of up to 36 weeks (median 24, range 18-36). No PSA responses were observed. Conclusions: AGS-1C4D4 was well tolerated. PK indicated slow clearance and long T1/2 similar to AGS-PSCA. Radiographic SD was noted in 38% of the patients. Despite preclinical differences in ADCC in vitro, this phase I study confirmed similar safety and PK to the hybridroma-derived AGS-PSCA. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Agensys Astellas Pharma Agensys

Phase I Single-Dose Study of Intracavitary-Administered Iodine-131-TM-601 in Adults With Recurrent High-Grade Glioma

TM-601 binds to malignant brain tumor cells with high affinity and does not seem to bind to normal brain tissue. Preclinical studies suggest that iodine-131 (131I) -TM-601 may be an effective targeted therapy for the treatment of glioma. We evaluated the safety, biodistribution, and dosimetry of intracavitary-administered 131I-TM-601 in patients with recurrent glioma. Eighteen adult patients (17 with glioblastoma multiforme and one with anaplastic astrocytoma) with histologically documented recurrent glioma and a Karnofsky performance status of > or = 60% who were eligible for cytoreductive craniotomy were enrolled. An intracavitary catheter with subcutaneous reservoir was placed in the tumor cavity during surgery. Two weeks after surgery, patients received a single dose of 131I-TM-601 from one of three dosing panels (0.25, 0.50, or 1.0 mg of TM-601), each labeled with 10 mCi of 131I. Intracavitary administration was well tolerated, with no dose-limiting toxicities observed. 131I-TM-601 bound to the tumor periphery and demonstrated long-term retention at the tumor with minimal uptake in any other organ system. Nonbound peptide was eliminated from the body within 24 to 48 hours. Only minor adverse events were reported during the 22 days after administration. At day 180, four patients had radiographic stable disease, and one had a partial response. Two of these patients further improved and were without evidence of disease for more than 30 months. A single dose of 10 mCi 131I-TM-601 was well tolerated for 0.25 to 1.0 mg TM-601 and may have an antitumoral effect. Dosimetry and biodistribution from this first trial suggest that phase II studies of 131I-TM-601 are indicated.

A phase II study of nilutamide in men with prostate cancer following failure of flutamide or bicalutamide therapy

4669 Background: Determine PSA response, time to PSA progression and, in a subset with measurable disease at baseline, the objective response rate and time to radiographic progression in men with prostate cancer refractory to bicalutamide and/or flutamide therapy. Methods: Eligibility included histologically confirmed prostate cancer not amenable to curative therapy with either radiation or surgery and progressive disease demonstrated by radiographic or PSA criteria. Patients progressing on bicalutamide therapy must have undergone a 6-week anti-androgen withdrawal period while those progressing on flutamide were eligible following a 4-week withdrawal. All subjects received nilutamide, 150 mg/day orally, for a minimum of 8 weeks; patients were evaluable for PSA and radiographic response after 4 and 8 weeks, respectively. A baseline PSA, CXR, bone scan and abdominal/pelvic CT were obtained; re-evaluation included PSA every 4 weeks and repeat radiographic imaging for those with baselines abnormalities. A 50% PSA decline without radiographic progression was considered a partial response. CXR was repeated for any pulmonary symptoms. Results: To date, 13 men have been enrolled and 11 are evaluable. Median Gleason's score at diagnosis was 7 (range 6–9). Median number of prior therapies was 3 (range 1–5). Median baseline PSA was 16.7 ng/ml (range 4.9–151 ng/ml). 8 subjects had diffuse bone metastases and 3 had other radiographically measurable disease. Of these, 2 are not yet radiographically evaluable (on study < 8 weeks) and one has radiographic stable disease at 8 weeks. There have been no grade 3/4 toxicities; the most common grade 1/2 toxicities were constipation (2), sensory neuropathy (3), fatigue (3), and visual changes (2) involving transient change in color vision and sensitivity to light, respectively. Responses include 2 (18%) PR and 5 (45%) PD. Those progressing did so after 8 weeks of therapy and by PSA criteria only. Conclusions: Nilutamide is well tolerated and leads to PSA responses following bicalutamide or flutamide failure. Ongoing study will determine the response rate and duration of response for this third line hormonal approach. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Aventis

A phase II study of nilutamide in men with prostate cancer following failure of flutamide or bicalutamide therapy

4669 Background: Determine PSA response, time to PSA progression and, in a subset with measurable disease at baseline, the objective response rate and time to radiographic progression in men with prostate cancer refractory to bicalutamide and/or flutamide therapy. Methods: Eligibility included histologically confirmed prostate cancer not amenable to curative therapy with either radiation or surgery and progressive disease demonstrated by radiographic or PSA criteria. Patients progressing on bicalutamide therapy must have undergone a 6-week anti-androgen withdrawal period while those progressing on flutamide were eligible following a 4-week withdrawal. All subjects received nilutamide, 150 mg/day orally, for a minimum of 8 weeks; patients were evaluable for PSA and radiographic response after 4 and 8 weeks, respectively. A baseline PSA, CXR, bone scan and abdominal/pelvic CT were obtained; re-evaluation included PSA every 4 weeks and repeat radiographic imaging for those with baselines abnormalities. A 50% PSA decline without radiographic progression was considered a partial response. CXR was repeated for any pulmonary symptoms. Results: To date, 13 men have been enrolled and 11 are evaluable. Median Gleason's score at diagnosis was 7 (range 6–9). Median number of prior therapies was 3 (range 1–5). Median baseline PSA was 16.7 ng/ml (range 4.9–151 ng/ml). 8 subjects had diffuse bone metastases and 3 had other radiographically measurable disease. Of these, 2 are not yet radiographically evaluable (on study < 8 weeks) and one has radiographic stable disease at 8 weeks. There have been no grade 3/4 toxicities; the most common grade 1/2 toxicities were constipation (2), sensory neuropathy (3), fatigue (3), and visual changes (2) involving transient change in color vision and sensitivity to light, respectively. Responses include 2 (18%) PR and 5 (45%) PD. Those progressing did so after 8 weeks of therapy and by PSA criteria only. Conclusions: Nilutamide is well tolerated and leads to PSA responses following bicalutamide or flutamide failure. Ongoing study will determine the response rate and duration of response for this third line hormonal approach. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Aventis