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Background: First-line treatment with immunotherapy alone or in combination with antiangiogenic agents is a standard of care for advanced RCC. Many patients (pts) develop resistance to first-line treatment and effective second-line and beyond options are needed. The von Hippel-Lindau (VHL) gene is inactivated in approximately 90% of RCC cases, which results in the constitutive activation of hypoxia-inducible factor 2α (HIF-2α), a key oncogenic driver in RCC. The first-in-class HIF-2α inhibitor belzutifan has demonstrated promising antitumor activity with manageable safety in previously treated pts with advanced RCC. The cyclin-dependent kinase (CDK) pathway has also been implicated in RCC and is associated with poor clinical outcomes. In RCC cell lines, the CDK 4/6 inhibitor palbociclib inhibited cell growth. The addition of CDK 4/6 inhibition had synergistic antiproliferative effects with HIF-2α inhibition in HIF-2α-dependent VHL -/- RCC cell lines. Palbociclib could therefore potentially enhance the efficacy of belzutifan as combination therapy for previously treated pts with advanced RCC. Methods: The two-part, open-label, multicenter, phase 1/2 randomized LITESPARK-024 study (NCT05468697) is intended to establish the recommended phase 2 dose (RP2D) of belzutifan + palbociclib in combination with a modified toxicity probability interval design (Part 1), followed by a direct comparison of belzutifan monotherapy to the combination with respect to safety and efficacy in pts with advanced RCC (Part 2). Pts with histologically confirmed unresectable stage IV RCC with a clear cell component, whose disease progressed on or after having received at least 2 systemic treatments (both an anti-PD-1/PD-L1 monoclonal antibody and a VEGF receptor-targeted tyrosine kinase inhibitor, in sequence or in combination), have measurable disease per RECIST v1.1 by blinded independent central review, and have KPS score of ≥70% will be enrolled. Up to 30 pts will be enrolled into 3 dose groups in Part 1 and will receive belzutifan 120 mg once daily + palbociclib (75, 100, or 125 mg) daily for 21 consecutive days followed by 7 days off. In part 2, approximately 150 pts will be randomly assigned 2:1 to receive belzutifan 120 mg once daily + palbociclib RP2D (21 consecutive days/7 days off) or belzutifan 120 mg once daily. Pts will be stratified by IMDC risk (0 vs 1-2 vs 3-6) and sarcomatoid histology (yes vs no) at randomization in part 2. The primary end point for part 1 is to assess dose-limiting toxicities and adverse events to determine the RP2D of belzutifan + palbociclib. The primary end point for part 2 is ORR per RECIST v1.1 by investigator assessment. Secondary end points for part 2 are CBR, DOR, PFS, OS, and safety and tolerability. This abstract was accepted and previously presented at the 2023 ASCO Genitourinary Cancers Symposium. All rights reserved. Citation Format: David F. McDermott, Avivit Peer, Neeraj Agarwal, Michael B. Atkins, Jerry Cornell, Rodolfo F. Perini, Kenneth F. Grossmann, Howard Gurney. The randomized phase 1/2 LITESPARK-024 study of belzutifan with or without palbociclib in patients with advanced renal cell carcinoma (RCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT120.

We hypothesize that a significant number of patients do not respond to PD-1/L1 blockade because there are no pre-existing tumor antigen-specific T-cells, and this can be addressed by combination therapy with an oncolytic virus such as T-VEC. S1607 is a single arm Phase 2 study of T-VEC plus pembro in patients with advanced melanoma after PD-1/L1 inhibitor progression. The primary endpoint is ORR by modified RECIST (progression at the first follow-up disease assessment had to be confirmed). Secondary endpoints include durable response rate (response ≥ 6 months), ORR in injected, non-visceral non-injected, and visceral lesions, PFS, OS and toxicity. In Cohort A patients must have at least one measurable visceral lesion; in Cohort B patients must not have any visceral lesions. Each cohort had an independent accrual goal with a 2-stage design. All received intratumoral T-VEC and pembro 200mg IV every 21 days. Tumor biopsy and research blood are taken at baseline and on Day 28 (both injected and non-injected lesions). Tumor assessments are performed every 12 weeks for up to 2 years. 38 evaluable patients were enrolled. As of July 26, 2022, the median follow up was 28 months. Treatment was well tolerated, with 5/38 (13%) grade 3 AE (no grade 4/5) including injection site reactions, lymphocyte count decrease, and hypoxia. Cohort A was closed after stage I (n=11) with no confirmed responses. In Cohort B (n=27), there were 7 confirmed responses (26%; 2 CR, 5 PR; this rejected H0: ORR = 10%, p=0.01). Clinical outcomes are summarized in Table 1. Baseline tumor mutational burden from 17 patients in Cohort B were not different between responder vs non-responders (p=0.96). Translational study is ongoing for pharmacodynamic confirmation. T-VEC plus pembro in melanoma patients who have progressed on prior anti-PD1/L1 therapy has efficacy in the subset of melanoma patients who have non-visceral metastases. Table 1 Cohort A (Visceral) Cohort B(Non-Visceral) N (%; 95% CI) 11 27 Confirmed PR + CR 0 (0%; 0%-28%) 7 (26%; 11%-46%) Confirmed + Unconfirmed 1 (9%; 0%-41%) 9 (33%; 17%-54%) Durable response 0 (0%; 0%-28%) 4 (15%; 4%-34%) Median PFS in months 2.1 (0.7-5.5) 2.3 (1.9-6.2) INJECTED LESIONS 11 27 Confirmed PR + CR 0 (0%; 0%-28%) 6 (22%; 9%-42%) Confirmed + Unconfirmed, PR + CR 1 (9%; 0%-41%) 8 (30%; 14%-50%) NON-INJECTED, NON-VISCERAL LESIONS 8 19 Confirmed PR + CR 0 (0%; 0%-37%) 3 (16%; 3%-40%) Confirmed + Unconfirmed, PR + CR 0 (0%; 0%-37%) 5 (26%; 9%-51%) VISCERAL LESIONS 11 Confirmed PR + CR 0 (0%; 0%-28%) Confirmed + Unconfirmed, PR + CR 1 (9%; 0%-41%) ACQUIRED RESISTANCE 3 2 Confirmed PR + CR 0 (0%; 0%-71%) 2 (100%; 16%-100%) Confirmed + Unconfirmed, PR + CR 0 (0%; 0%-71%) 2 (100%; 16%-100%) Median PFS in months 2.1 (2.0-4.1) NR (8.0-∞) PRIMARY RESISTANCE 8 25 Confirmed PR + CR 0 (0%; 0%-37%) 5 (20%; 7%-41%) Confirmed + Unconfirmed, PR + CR 1 (13%; 0%-53%) 7 (28%; 12%-49%) Median PFS in months 1.8 (0.3-6.2) 2.1 (1.9-3.3) Citation Format: Siwen Hu-Lieskovan, James Moon, John Hyngstrom, Katie M. Campbell, Gino K. In, Theodore F. Logan, Kari L. Kendra, Ding M. Wang, Douglas B. Johnson, Gary C. Doolittle, Alan Tan, Ann W. Silk, Kenneth F. Grossmann, Christopher W. Ryan, Sapna P. Patel, Shay Bellasea, Michael C. Wu, John M. Kirkwood, Helen X. Chen, Antoni Ribas. Combination of talimogene laherparepvec (T-VEC) with pembrolizumab (pembro) in advanced melanoma patients following progression on a prior PD-1 inhibitor: SWOG S1607 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3275.

Background: Patients with advanced melanoma primarily refractory to single agent PD-1 blockade therapy have an option of receiving the CTLA-4 blocking antibody ipilimumab, but if ipilimumab should be given as a single agent or in combination with the anti-PD-1 nivolumab has not been established prospectively. Methods: Patients aged >18 with metastatic or unresectable melanoma without objective response to anti-PD-1 therapy given without CTLA-4 therapy were randomized 3:1 to receive either ipilimumab 3mg/kg + nivolumab 1mg/kg q3 wks x4 cycles followed by nivolumab 480mg q4wks (ipi/nivo) up to 2 years, or ipilimumab 3mg/kg q3weeks x4 cycles (ipi). Additional key eligibility criteria included ECOG Performance Statue (PS) 0-2, no active central nervous system metastases, autoimmune disease, or need for steroids at doses of >10 mg of prednisone or the equivalent. The primary endpoint was progression free survival (PFS). Disease assessments were performed every 12 weeks until progression. Secondary endpoints included overall survival (OS), objective response rate (ORR), and toxicity. All patients were to submit a fresh tumor biopsy and whole blood for correlative endpoints prior to cycle 1 and again at week 5. Results: 92 eligible patients were enrolled, 69 to ipi/nivo, 23 to ipi. Median age was 64 and 69 in the ipi/nivo and ipi arm respectively. 67% and 65% were male. 65% of patients in both arms had ECOG PS of 0. With a median follow up of 25.3 months, the hazard ratio (HR) for PFS was 0.63 (90% CI 0.41, 0.97) with a statistically significant 1-sided p-value of 0.04 favoring ipi/nivo. The 6-month PFS estimates were 34% (90% CI: 25%-44%) and 13% (4%-27%) for ipi/nivo and ipi respectively. ORR was 28% for ipi/nivo (95% CI 17%-40%) and 9% for ipi (95% CI: 3%-34%). With a median follow up of 24.4 months, 39/69 patients in the ipi/nivo arm and 12/23 patients in the ipi arm had died. 12-month OS was 63% (90% CI 52%-72%) in the ipi/nivo arm and 57% (38%-71%) months in the ipi arm. HR for OS was 0.94 (90% CI 0.54, 1.62) in favor of ipi/nivo with a p-value of 0.42. Adverse event rates were similar in both arms. One treatment related death was reported in the ipi/nivo arm due to disseminated intravascular coagulation and one treatment related death was reported in the ipi arm due to colonic perforation. Conclusions: This is the first prospective randomized study comparing ipi/nivo to ipi alone in patients with melanoma without response to anti-PD1 therapy. Ipi/nivo was associated with improved progression free survival as compared to ipi alone. The response rate of 28% to ipi/nivo as compared to 9% to ipi alone implies that patients who do not respond to PD-1 alone can be rescued with ipi/nivo. The toxicity of combination therapy was manageable. Ipi/nivo is an appropriate standard in patients with metastatic melanoma who do not respond to single-agent PD-1 therapy. ClinicalTrials.gov Identifier: NCT03033576 Funding: NIH/NCI grants: U10CA180888, U10CA180819, U10CA180821, U10CA180868; Other grants: SU2C-AACR-CT06-17 Citation Format: Ari M. Vanderwalde, James Moon, Kari Kendra, Nikhil I. Khushalani, Frances Collichio, Jeffrey A. Sosman, Alexandra Ikeguchi, Adrienne I. Victor, Thach-Giao Truong, Bartosz Chmielowski, David C. Portnoy, Michael C. Wu, Kenneth F. Grossmann, Antoni Ribas. S1616: Ipilimumab plus nivolumab versus ipilimumab alone in patients with metastatic or unresectable melanoma that did not respond to anti-PD-1 therapy [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 CT013.

Background: The CXCR4/CXCL12 pathway plays a central role in the trafficking of key immune cells in the tumor microenvironment (TME). X4P-001 is an oral, selective, allosteric CXCR4 inhibitor. We hypothesize that the disruption of CXCR4/CXCL12 signaling by X4P-001 will favor an improved response to checkpoint inhibitors by modulating the immune cell profile within the TME and increasing CD8+ T cell infiltration. A biomarker-driven phase 1b clinical study is being conducted in melanoma patients to test this hypothesis (NCT02823405). Materials and Methods: The primary objectives for the study are to evaluate the safety and tolerability of X4P-001 as a single agent and in combination with pembrolizumab in patients (pts) with metastatic melanoma, and to characterize the effects of X4P-001 alone and in combination with pembrolizumab on tumor immune cell infiltrates. Serial biopsies of cutaneous or subcutaneous melanoma lesions, peripheral blood mononuclear cells (PBMCs), and serum samples were collected pre-dose, after 3 weeks of X4P-001 treatment, and after 6 weeks of combination treatment. Biopsies were assessed by immunohistochemistry (IHC) and multiplexed immunofluorescence (mIF) for multiple markers, including CD3, CD8, FoxP3, PD-L1 and Granzyme B, and by NanoString® analysis for changes in gene expression. PBMCs were analyzed by flow cytometry for both lymphoid and myeloid cells. In addition, multiple serum markers will be assessed using the multi-analyte profile (MAP) platform. Results: As of September 15, 2017, 13 pts have been enrolled, and 11 have completed the study. The median age was 73 years (range 53-90). Of the evaluable pairs of biopsies, X4P-001 treatment alone increased CD8+ T cells, increased granzyme B signal, increased antigen-presenting machinery such as HLA-DR, and increased IFN-gamma gene expression signature scores in the TME. These biomarker responses were further enhanced when X4P-001 was combined with pembrolizumab. X4P-001 was well tolerated. AEs assessed as related to either X4P-001 or pembrolizumab at any time were diarrhea, maculopapular rash, fatigue, chills, and acute kidney injury. These data, along with additional biomarker measurements, will be presented. Conclusions: Evidence of enhanced immune cell infiltration and activation is observed in the TME with X4P-001 treatment alone. Increased IFN-gamma gene expression signature scores after single-agent X4P-001 treatment support the use of X4P-001 to increase the likelihood of a response when combined with anti-PD-1 therapy. X4P-001 as a single agent and in combination with pembrolizumab is generally safe and well tolerated. Further in-depth biomarker analysis is ongoing as enrollment nears completion. Citation Format: Robert H. Andtbacka, Robert H. Pierce, Jean S. Campbell, Melinda Yushak, Mohammed Milhem, Merrick Ross, Kenneth Grossmann, Kam Sprott, Eleni Tsiroyanni, Katie Niland, Lu Gan, Sudha Parasuraman, Yan Wang. X4P-001, an orally bioavailable CXCR4 antagonist, enhances immune cell infiltration and activation in the tumor microenvironment of melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 613.

Background: This phase II trial (CheckMate 069) demonstrated a statistically significant improvement in objective response rate (ORR) and progression-free survival (PFS) with the combination of NIVO+IPI vs. IPI alone in treatment-naïve patients (pts) with BRAF wild-type MEL (Postow et al. N Engl J Med 2015;372:2006). ORR was 61% for NIVO+IPI vs 11% for IPI alone (P Methods: Pts (N = 142) were randomized 2:1 (with stratification by BRAF mutation status) to receive either NIVO 1 mg/kg + IPI 3 mg/kg or IPI 3 mg/kg + placebo every 3 weeks x 4 doses, followed by NIVO 3 mg/kg or placebo, respectively, every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed ORR in pts with BRAF wild-type tumors. Secondary endpoints included PFS in pts with BRAF wild-type tumors, ORR in pts with BRAF V600 mutation-positive tumors, and safety. OS was an exploratory endpoint. The most recent database lock occurred in August of 2015, representing a minimum follow-up of 18 months. Results: In the current analysis, median PFS in BRAF wild-type pts had not yet been reached with the NIVO+IPI combination and was 4.3 months for IPI alone (hazard ratio [HR]: 0.34; 95% confidence interval [CI]: 0.20-0.57; P85% across organ categories). Conclusions: In this updated analysis, NIVO+IPI continued to show improved PFS vs. IPI alone, with an apparent plateau after 12 months in the combination group. At 18 months of follow-up, there was a trend toward higher OS rates in pts who received combination therapy. Further efficacy updates, including 2-year OS rates, will be presented according to BRAF mutation status and for all randomized pts. Citation Format: Michael Postow, Jason Chesney, Anna Pavlick, Caroline Robert, Kenneth Grossmann, David McDermott, Gerald Linette, Nicolas Meyer, Jeffrey Giguere, Sanjiv Agarwala, Montaser Shaheen, Marc Ernstoff, David Minor, April Salama, Matthew Taylor, Patrick Ott, Joel Jiang, Christine Horak, Paul Gagnier, Jedd Wolchok, F. Stephen Hodi. Initial report of overall survival rates from a randomized phase II trial evaluating the combination of nivolumab (NIVO) and ipilimumab (IPI) in patients with advanced melanoma (MEL). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT002.

Background: Adjuvant therapy for melanoma has centered on high dose interferon for now almost 20 years. Recently, the FDA approved ipilimumab dosed at 10 mg/kg (10/kg ipi) for use in high risk resected melanoma. Though these two treatment options are available they still have limits in terms of efficacy with approximately 1 year of relapse free survival benefit (HDI and 10/kg ipi) and a modest overall survival benefit (HDI). Toxicity remains an issue as well with both therapies. S1404 is a Phase III, open label trial which seeks to compare currently available FDA approved treatments to one year of pembrolizumab in patients at high risk of relapse and death after surgery. Study Design: 1,378 patients will be randomized 1:1 to an FDA approved standard therapy, or pembrolizumab. Stratification factors include PD-L1 staining status, clinical stage, and pre-randomization selected standard treatment option. Patients: Patients must be 18 or older, and have Stage IIIA (n2), IIIB, IIIC or IV (M1a, b and c) resected melanoma to be eligible. Exclusion factors include brain metastases, ocular primary, and auto-immune disease. Prior therapy is not allowed, but radiation as adjuvant treatment is considered an option available to patients prior to treatment. Current status: As of January 2016, 30 sites are registered and 5 patients are randomized. An amendment to include 10 mg/kg ipilimumab as a treatment option is under review and will likely be finalized by the time of the meeting. Support: NIH/NCI NCTN grants CA180888, CA180819, CA180818, CA180826, CA180858, CA180820, CA180844 Citation Format: Kenneth F. Grossmann, Vernon K. Sondak, Megan Othus, Ahmad Tarhini, Sapna Patel, John M. Kirkwood, Antoni Ribas, James Moon. A phase III randomized trial comparing FDA approved standard of care adjuvant therapy to one year of pembrolizumab in patients with high risk resected melanoma. SWOG 1404. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT125.

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Background: Blockade of the immune checkpoints PD-1 and CTLA-4 each results in improved overall survival in patients (pts) with metastatic melanoma using monotherapy. In a phase 1 dose-escalation study, dual inhibition of these pathways by nivolumab (NIVO) and ipilimumab (IPI) demonstrated encouraging antitumor activity. Methods: Treatment-naive pts with advanced melanoma were randomized (double-blind) 2:1 to IPI 3 mg/kg combined with either NIVO 1 mg/kg (NIVO+IPI combination group) or placebo (PBO; IPI alone group) every 3 weeks (Q3W) for 4 doses, followed by NIVO 3 mg/kg or PBO, respectively, Q2W until disease progression or unacceptable toxicity. Primary endpoint was investigator-assessed objective response rate (ORR) in BRAF wild-type (WT) pts. Secondary endpoints included progression-free survival (PFS), ORR in BRAF V600 mutation-positive (MT) pts, and safety. Results: In BRAF WT pts, ORR was 60% (43/72) in the NIVO+IPI group vs 11% (4/37) in the IPI group (P

Background: Disulfiram, when complexed with metal ions, is capable of inactivating key oncoproteins. It is thought to accomplish this via glutathionylation of sulfhydryl residues. In human experience thus far is limited. Despite recent advances in treatment including immunologic checkpoint blockade, and b-raf inhibition Stage IV melanoma remains a near-uniformly fatal disease. This study was designed to determine the response rate following treatment with disulfiram and chelated Zn in patients with stage IV melanoma with secondary endpoints of progression free survival, overall survival, pharmacodynamics and toxicity of the combination. Methods: Eligible patients had biopsy proven Stage IV melanoma. Patients with brain metastases were allowed provided the brain metastases were treated, and the patient was on stable doses of steroids. Disulfiram was dosed at 250 mg orally at bedtime, while chelated Zn was given thrice daily at 50 mg elemental Zn orally with each meal. A treatment cycle consisted of 28 days. Patients were scheduled for response evaluation after two cycles of therapy. Serum was sampled at baseline, and at 1 week from the start of therapy for pharmacodynamic analysis. Results: Enrollment for this study began 8/3/2010, with the final patient enrolling on 1/16/2013. In total, 12 patients were enrolled, with ten being evaluable for response for this interim futility analysis. 10 of the 12 patients were tested for b-raf mutation status, with three patients harboring a b-raf mutation. One patient experienced a partial response not meeting RECIST criteria with one target lesion decreasing 27% from baseline measurements. Average time on treatment for evaluable patients was 55 days (range 20-168). Progression free survival and overall survival of evaluable patients was 53 days and 203 days respectively. Overall safety data has shown this regimen to be well tolerated with only one Gr 3 or greater drug related adverse event recorded consisting of a confusional episode which resolved following discontinuation of study medication. Other Gr 1 and 2 toxicities have included fatigue, dysgeusia, nausea, vomiting, diarrhea, ataxia, renal insufficiency, and LFT elevations. Pharmacodynamic analysis is pending. Conclusions: Disulfiram dosed at 250 mg daily together with chelated Zn at doses of 50 mg three times daily is well tolerated in patients with advanced stage IV melanoma; the combination is capable of producing tumor shrinkage. The interim futility analysis endpoint of one responding patient was not met and the study will not expand to the full Phase II cohort of 29 patients. Future work with this combination may be warranted in other cancers given the favorable safety profile, and may also be considered in combination with other therapies actively in use for stage IV melanoma. Citation Format: Kenneth F. Grossmann, Moesis Terrazas, Hung T. Khong, Wallace Akerley, Ken Kosak, Ken Boucher, Thomas P. Kennedy, Paul J. Shami. Phase II study of disulfiram and chelated Zn for the treatment of disseminated metastatic melanoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-175. doi:10.1158/1538-7445.AM2013-LB-175

GSK2118436 is a potent and selective small-molecule inhibitor of BRAF kinase activity that is currently being developed for the treatment of BRAF mutation-positive tumors. This study evaluated the effect of a high-fat meal on the pharmacokinetics (PK) of a single 150 mg oral dose of GSK2118436 administered to patients with BRAF-mutant solid tumors. This was an open-label, randomized, two-period crossover study. In a cohort of 14 patients, GSK2118436 was administered under fasted state or with a high-fat meal, with a 1-week washout between periods. Blood samples were collected up to 96 hours post-dose to characterize the PK of GSK2118436 and its circulating metabolites. PK parameters were calculated by non-compartmental methods (WinNonlin 5.2). Geometric mean ratios (fed/fasted) for the point estimate and 90% CIs were calculated for Cmax and AUC0-α, and median difference (90% CI) was calculated for tmax using the Hodges-Lehmann non-parametric method. The absence of a food effect can be concluded if the 90% CIs are contained between 0.8 and 1.25 for Cmax and AUC0-α. Following administration of a high-fat meal, median Cmax concentrations were delayed by 3.7 h (90% CI: 2.4-5.0) compared with the fasted state. A high-fat meal decreased the exposure to GSK2118436, with geometric mean ratios (90% CI) for Cmax and AUC0-α of 0.49 (0.35-0.69) and 0.69 (0.57-0.85), respectively. Metabolite exposures were decreased to a similar extent. Based on the data generated in this study, it appears that there is a food effect for GSK2118436, as the 90% CI are not contained within the acceptable boundaries of 0.8 and 1.25. In clinical studies GSK2118436 has been administered on an empty stomach, and results from this study are consistent with these recommendations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3766. doi:1538-7445.AM2012-3766

Background: Disulfiram inhibits hepatic aldehyde dehydrogenase causing accumulation of acetaldehyde when alcohol is ingested and is used to treat alcohol addiction. When metal ions such as copper are combined with disulfiram, key oncoproteins are bound, and inactivated. Disulfiram and copper can inhibit tumor cell growth in cell culture, and xenograft models, and induce cell killing via apoptosis. Here we determined the safety and tolerability of disulfiram when administered together with copper gluconate in patients with advanced treatment-refractory solid tumors involving the liver. Methods: Four preselected oral doses of copper gluconate were tested (2, 4, 6, and 8 mg tid) in a standard “3+3” design. Disulfiram 250 mg was administered once daily. Patients were observed for DLTs, and pharmacodynamic studies were performed. Patients were required to refrain from alcohol consumption during the study. Results: As of November 15, 2010, 15 patients with treatment refractory solid tumors metastatic to the liver have been enrolled. The average number of prior treatments was 7 (range 1-16). Malignancies represented included pancreatic (2), breast (4), colon (1), prostate (1), lung (1), cutaneous melanoma (2), and ocular melanoma (2). Grade 3 toxicities included dehydration (1), hyperglycemia (1), constipation (1), LFT elevations (2) and troponin elevation (1) but these were felt to be more likely related to advanced malignancy or to causes other than the study drugs. Although hepatic toxicity is a potential side effect of disulfiram, the only Grade 3 LFT elevations that occurred on treatment were in patients with disease progression in the liver suggesting that these events were not drug related. There was one reported Grade 2 disulfiram reaction due to exposure to alcohol. Other Grade 1 and 2 toxicities included changes in mental status (6), headaches (2), and dizziness (3) though many of these events corresponded to progression of the underlying malignancy. No radiographic responses to treatment have been observed. Six patients progressed within 28 days of starting treatment. One patient with advanced colon cancer achieved disease stability for 125 days. The average duration on treatment was 37 days (range 1 – 125 days). Reasons for discontinuing treatment included functional decline (4), disease progression (10), and death (1). Two remaining slots are open on the 8 mg dose cohort. Analysis of S-glutathionylation of proteins in response to treatment is ongoing. Conclusions: Disulfiram dosed at 250 mg daily together with copper gluconate at doses of 6 mg three times daily is well tolerated in patients with advanced solid tumors involving the liver. No DLT has yet been observed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1308. doi:10.1158/1538-7445.AM2011-1308