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3000 Background: Targeting cytosolic nucleic acid sensing pathways and the Type I interferon (IFN) response is an emerging therapeutic strategy in oncology. PARP7 is a member of the monoPARP class of enzymes and a newly identified negative regulator of nucleic acid sensing in tumor cells. PARP7 expression is increased by cellular stress and aromatic hydrocarbons, and the PARP7 gene is amplified in multiple cancers. RBN-2397 is a potent, selective inhibitor of PARP7. In preclinical models, RBN-2397 restored Type I IFN signaling in tumors, caused complete tumor regressions, and induced adaptive immunity. Methods: Patients (pts) with advanced solid tumors were treated with RBN-2397 on either a continuous or 14-of-21-day intermittent schedule using a 3+3 dose escalation design. Primary objective: establish MTD and/or RP2D. Secondary obj.: safety, activity, PK of unmicronized/micronized tablets. Exploratory obj.: Pd. Results: As of 4 January 2021, 47 pts were treated: 25 pts in the intermittent schedule (25 to 500 mg BID) and 22 patients in the continuous schedule (100 to 400 mg BID). The most frequent RBN-2397-related AEs (all grades) were dysgeusia (26%), decreased appetite (13%), fatigue (11%), and diarrhea (11%). Gr 3/4 RBN-2397-related AEs all occurred in 7 pts (15%) at doses ≥ 200 mg: diarrhea (2 pts, 4%), increased ALT, AST, and bilirubin (1 pt, 2%), and fatigue, anemia, neutropenia, and thrombocytopenia in 1 pt (2%) each. The 2 DLTs were Gr 3 febrile neutropenia (400 mg continuous schedule) and Gr 4 increase in ALT/AST (500 mg intermittent schedule). Plasma exposures generally increased dose dependently with the majority at or above the projected efficacious range based on animal studies. All evaluable baseline tumor biopsies showed evidence of PARP7 expression as measured by mRNA in situ hybridization (n = 11; Median tumor H score: 128). In 5 evaluable tumor biopsy pairs, increases in interferon-stimulated gene expression were observed post RBN-2397, consistent with activation of Type I IFN. CXCL10 mRNA increased in all evaluable on-treatment biopsies (1.5 to 8-fold). Several on-treatment biopsies showed enrichment for immune response gene sets that was accompanied by an increase in CD8+ T cells and Granzyme B expression, evidence for induction of an adaptive immune response post RBN-2397. This increase in immune response related genes and CD8+ T cells was observed in a pt with metastatic squamous NSCLC who has been on study for 16+ months. 1 pt with HR+, HER2- breast cancer achieved a confirmed PR at 100 mg and 8 pts had SD for ≥18 weeks (RECIST 1.1). Conclusions: To date, RBN-2397 is well tolerated and demonstrates dose dependent increases in plasma exposures, evidence of target inhibition, and preliminary signs of clinical activity. Determination of MTD/RP2D is imminent and study expansion is planned to evaluate safety and efficacy in squamous NSCLC, HNSCC, HR+ breast cancer, and PARP7 amplified tumors. Clinical trial information: NCT04053673.

e15656 Background: FN1501 inhibits various tyrosine kinases as CDK4/6, KIT, PDGFR, ALK and RET proteins, particularly potent on FLT3 and EGFR2. A Ph1 FIH trial for patients (pts) with solid tumors and Acute Myeloid Leukemia (AML) is on-going1. Preclinical data showed that FN1501 inhibits the phosphorylation of FLT3 and its downstream kinase STAT5 in human acute leukemia cell lines, arrests the cell cycle inducing apoptosis and inhibits growth and proliferation of leukemia cells. It has anti-proliferation activity against other leukemia cell lines bearing FLT3 mutations, and lymphoma cell lines2, 3. Methods: 26 pts with advanced solid tumors or AML enrolled in the escalation phase and received IV FN1501 on days 1, 3, 5, 8, 10 and 12 on 21-day cycles. Primary objectives are safety and MTD, secondary objectives include preliminary activity, PK and PD. Plasma PK were assessed at different timepoints pre and post dose in C1 and C2. Results: As of 6FEB20, 26 pts have been treated in 7 ascending doses of 2.5mg, 5mg, 10mg, 15mg, 22.5mg, 30mg and 40mg. A 54 mg dose cohort is on-going. No DLTs, no SAEs or deaths associated to FN1501 have been reported. 12 pts (46%) had one grade 3 or higher TEAE and 7 pts (27%) had dose interruptions due to a TEAE. Administration of FN1501 to pts with metastatic solid tumors has resulted in anti-tumor activity. 9 pts had durable stable disease across 4 doses in renal, endometrial, ovarian, gastric, appendix and thymic malignancies. One pt with serous endometrial carcinoma achieved a cPR after 2 cycles at 40mg with a 47% tumor size reduction (target lesions). As of 26Oct19 preliminary PK data showed a t1/2 of approximately 12.7-19.0 hours post-dose. Mean Cmax and AUC increased proportionally with dose and Clearance is consistent among all doses. Conclusions: This on-going Ph1trial of FN1501 is providing evidence of dose or exposure effects as a single agent in patients with solid tumors. Since FN1501 targets multiple kinases on addition to FLT3, antitumor activity beyond AML is also being observed, suggesting that the potent inhibitory effects of other tyrosine kinases, including EGFR2 may be playing a role in the regulation of cellular functions, cell growth, differentiation and angiogenesis effects. FN1501 has been well tolerated and AEs are manageable. Genomic alterations investigations are underway to identify candidate biomarkers useful for predicting sensitivity to the multiple FN1501 tyrosine kinases. Further development of FN1501 is warranted. Clinical trial information: NCT03690154.

TPS3150 Background: Receptor tyrosine kinases (RTK), a group of transmembrane proteins, are responsible for growth factor signaling transduction in normal cellular functions. Abnormal RTK functions are associated with human tumorigenesis. FMS-like tyrosine kinase 3 (FLT3) belongs to the type III receptor tyrosine kinase family and plays a well-established role in normal growth and differentiation of hematopoietic precursor cells. FLT3 mutations have been reported to occur in approximately 30% newly diagnosed AML patients. The internal tandem duplications mutation (FLT3/ITD) is the major mutation and correlated with more aggressive progress and poor prognosis. FN-1501 is an inhibitor of various tyrosine kinases such as cyclin-dependent kinase 4/6(CDK4/6), platelet-derived growth factor receptor (PDGFR), KIT protein, anaplastic lymphoma kinase (ALK) and RET protein, particularly potent on FLT3. The preclinical data generated from biochemical, cell based and animal in vivo studies suggest that FN-1501 as a single agent could offer cancer patients clinical benefit by inhibiting multiple tyrosine kinases including FLT3, PDGFR, KIT, ALK, and RET. Methods: This is a Phase1, open label, multicenter, dose-escalation study that will evaluate the safety, pharmacokinetics (PK), and preliminary efficacy of FN-1501 in up to 33 cancer patients with solid tumors. There is a dose escalation phase that will be followed by an expansion cohort. The dose escalation phase utilizes a standard “3 + 3” design where doses of FN-1501 will be escalated up to the Maximum-Tolerated Dose (MTD) or until the Recommended Phase 2 dose (RP2D) is identified. Once the MTD or RP2D dose is identified, an expansion cohort including patients with hematologic malignancies will be enrolled to further evaluate the safety and efficacy of FN-1501. Key exploratory analyses will include an evaluation of safety and efficacy and levels of expression and/or amplification of FLT3 mutations. As of February 8, 2019, cohorts 1 and 2 have been completed without a dose limiting toxicity (DLT). A total of 11 patients have been treated. Enrollment to cohort 3 is on-going. Clinical trial information: NCT03690154.

TPS870 Background: Approximately 96% of CRCs have an MSS phenotype, which results in more immunologically quiescent tumors for which immunotherapies are largely ineffective (Lee et al. 2015; Overman et al. 2016). Pts with MSS CRC and activating RAS mutation (35%–45% of CRCs) have treatment options limited still further because anti-EGFR monoclonal antibodies (eg, cetuximab) are ineffective owing to dominant activation of RAS in the MAPK pathway (Douillard et al. 2014). However, preclinical and preliminary clinical data suggest that MAPK pathway inhibition enhances antigen presentation and T-cell cytotoxicity to positively modulate the efficacy of checkpoint inhibitors (Brea et al. 2016; Bendell et al. 2014). The main objective of this open-label multicenter phase 1b/2 study is to evaluate whether the potential positive modulation of NIVO or NIVO plus IPI, when combined with BINI, translates into clinically meaningful overall response in pts with MSS mCRC and RAS mutation. Methods: The study will enroll ~90 previously treated pts (1 or 2 prior regimens), ~42 in phase 1b and ~48 in phase 2. The primary objective of phase 1b will be to determine the recommended phase 2 dose (RP2D) of BINI in combination with NIVO ± IPI. Dose finding in the doublet arm will begin with BINI 45 mg BID + NIVO 480 mg Q4W; the triplet arm will begin with the BINI RP2D from the doublet arm + NIVO 480 mg Q4W + IPI 1 mg/kg Q8W. In phase 2, pts will be randomized 1:1 to doublet or triplet arms, incorporating the BINI RP2Ds found in phase 1b; treatment will continue in 28-day cycles until disease progression, unacceptable toxicity, withdrawal of consent, initiation of subsequent anticancer therapy, loss to follow-up, or death. The primary objective for phase 2 will be to assess response by RECIST version 1.1. The study will also characterize safety and PK. CT.gov Identifier: Clinical trial information: NCT03271047.

Purpose Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) blockade with tremelimumab (CP-675,206), a fully human anti-CTLA4 monoclonal antibody, was tolerated and demonstrated antitumor activity in a single dose, dose-escalation phase I trial in patients with solid tumors. This phase I/II trial was conducted to examine safety of multiple doses of tremelimumab, to further assess efficacy, and to identify an appropriate dosing regimen for further development. Patients and Methods Twenty-eight patients with metastatic melanoma received monthly intravenous infusions of tremelimumab at 3, 6, or 10 mg/kg for up to 1 year to determine recommended monthly phase II dose. During phase II, 89 patients received tremelimumab 10 mg/kg once every month or 15 mg/kg every 3 months. Results No dose-limiting toxicity was observed in phase I once every month dosing. In phase II, 8 (10%) of 84 response-assessable patients attained objective antitumor responses; best overall objective response was one complete response and three partial responses in each dosing regimen. Most responses were durable (range, 3 to 30+ months). Most frequent treatment-related adverse events (AEs) were diarrhea, rash, and pruritus. Frequency of grade 3/4 AEs was 13% in the 15 mg/kg every 3 months arm and 27% in the 10 mg/kg once every month. Serious AEs were also less frequent in the 15 mg/kg once every 3 months cohort (9% v 23% in 10 mg/kg arm). Conclusion Multiple infusions of tremelimumab were generally tolerable and demonstrated single-agent antitumor activity. Both phase II regimens generated durable tumor responses. Based on its more favorable safety profile, 15 mg/kg every 3 months was selected for further clinical testing.

9519 Background: Simultaneous inhibition of MEK and CDK4/6 may suppress MAPK pathway activation and cell-cycle checkpoint dysregulation in NRAS-mutant melanoma, resulting in enhanced antitumor activity. Phase 1b data are reported. Methods: The phase 1b primary objective was to determine maximum tolerated dose (MTD)/RP2D. A 28-d cycle of oral ribociclib (RIBO) once daily (QD) for 21 d + oral binimetinib (BINI) twice daily (BID) for 28 d, and a 21-d cycle of RIBO QD + BINI BID, both for 14 d per cycle, were evaluated. Secondary objectives were to evaluate efficacy, safety and pharmacodynamics. Results: Based on dose escalation (van Herpen, ESMO 2015), MTD was 600mg RIBO/45mg BINI for the 21-d and 200/45 for the 28-d regimens. Due to promising activity, the 28-d cycle was selected as RP2D(unconfirmed partial response [PR] with limited follow-up occurred in 35% of pts). This finding was supported by comparable and manageable safety and the Bayesian logistic regression model.As of Jan 2017, the RP2D was received by 16 pts in phase 1b (ECOG PS 0/1/2, 63%/31%/6%; elevated lactate dehydrogenase, 44%; stage IVM1c disease, 50%; prior ipilimumab [ipi], 44%; prior anti–programmed death [PD]-1/PD-L1, 31%). Median (range) exposure was 4 (0–13) mo. Common adverse events (AEs) were increased blood creatine phosphokinase, elevated AST, peripheral edema, acneiform dermatitis, diarrhea and fatigue. Common grade 3/4 AEs were elevated AST and ALT (19%/6%), nausea (19%/0%), rash (19%/0%), vomiting (6%/6%) and neutropenia (12%/0%). Confirmed PR (cPR) occurred in 4 pts (25%; time to response, 48–168 d), stable disease in 7 pts (44%), disease progression in 3 pts (19%); 2 pts (12%) were not evaluable. Among cPR pts, 3 had prior ipi and/or anti–PD-1/PD-L1. Median progression-free survival (mPFS) was 6.7 (95% CI, 3.5–9.2) mo. Sequence analysis of synchronous non- RAS genetic alterations will be presented. Conclusions: Combined RIBO/BINI at the selected RP2D had a manageable safety profile and favorable efficacy (based on mPFS) for NRAS-mutant melanoma in phase 1b. Based on these promising data, the phase 2 expansion is underway to assess antitumor activity at the RP2D. Clinical trial information: NCT01781572.

9500Background: NRAS mutation in melanoma occurs in ~20% of patients (pts). There are no specific therapies for NRAS melanoma. Despite emergence of immunotherapies (ITs) as effective treatments in ...

TPS2609 Background: Signaling hyperactivation secondary to MAPK pathway aberrations are common. RAF kinases play key roles in the RAS/RAF/MEK/ERK signaling cascade, representing potentially valid t...

2547 Background: MLN2480 is an investigational pan-RAF kinase inhibitor. In vivo, MLN2480 showed antitumor activity in melanoma, colon, lung, and pancreatic cancer xenograft models. This first-in-human study aimed to evaluate the safety of MLN2480, determine the MTD/recommended phase 2 dose (RP2D), and evaluate pharmacokinetics (PK) and preliminary efficacy. Methods: Pts aged ≥18 yrs with advanced solid tumors who had failed/were not candidates for standard therapy received oral MLN2480 every other day (Q2D) in 22-d cycles, with dose escalation (3+3 design) based on DLTs in cycle 1. AEs were graded per NCI-CTCAE v4.03. Blood samples for plasma PK assessment were taken pre-dose and at multiple times post-dose, d 1 and 21, cycle 1. Results: 24 pts (10 male, median age 64.5 yrs [range 37–83]) have been treated at 20, 40, 80, 135, 200, and 280 mg (n=4, 3, 3, 3, 4, and 7), respectively. The most common tumors included colorectal cancer in 11 pts and non-small-cell lung cancer in 2 pts. Pts received a median of 2 (range 1–6) cycles. 2 pts treated at 280 mg had DLTs: grade 3 macular rash and grade 3 periorbital edema. 20 pts had drug-related AEs, including fatigue 46%, arthralgia 25%, maculopapular rash 21%, and myalgia 17%. 4 pts had drug-related grade ≥3 AEs, which included the 2 DLTs listed above, anemia, dyspnea, and fatigue. No keratocanthomas/ squamous cutaneous carcinomas have been seen to date. 4 pts discontinued due to AEs. There were 3 on-study deaths (1 treatment-related per investigator; dyspnea and respiratory failure). At 20–200 mg MLN2480 PK data (13 pts) exhibited rapid absorption (median Tmax 2 hr), low fluctuation at steady state (mean peak to trough ratio 2.1), and mean accumulation half-life of 67 hr. Overall mean accumulation was 2.6-fold following repeated Q2D dosing for 21 d. Steady-state (d 21) exposures increased in an approximately dose-proportional manner over 20–200 mg range. No pts had an objective response to date; no pts with BRAF mutation enrolled to date. Conclusions: In this first-in-human study (n=24), the safety profile of MLN2480 up to 200 mg Q2D was acceptable. Accrual continues at 200 mg to confirm the MTD. Melanoma expansion cohorts are planned at the RP2D using a Q2D 28-d cycle. Clinical trial information: NCT01425008.

TPS145 Background: The Ras/Raf/MEK/ERK cascade is frequently activated in human cancers; MEK inhibition is an attractive therapeutic target for preventing tumor growth and angiogenesis. The investi...

8032 Background: Ticilimumab therapy has demonstrated anti-tumor activity in pts with metastatic melanoma. Its indirect, immune-mediated antitumor effects pose unique challenges for dose/regimen selection. Methods: It was our original intention to select the clinical dose/regimen of ticilimumab based on (1) clinical safety and tolerability and (2) attainment of target plasma concentrations derived from pre-clinical work using an ex vivo assay of ticilimumab-induced enhancement of cytotoxic T-cell function. Because numerous pts with metastatic melanoma experienced clinical benefit (i.e., durable objective responses [OR] and/or long-term survival) in early clinical trials of ticilimumab, we are using (1) safety and tolerability and (2) clinical benefit to guide dose/regimen selection. Data for evaluating these criteria come from a single-dose Phase 1 trial (0.01, 0.1, 1, 3, 6, 10 and 15 mg/kg) and an ongoing multiple-dose Phase 1/2 trial in pts with melanoma (Phase 1 portion: 3, 6 and 10 mg/kg Q1M; Phase 2 portion: 10 mg/kg Q1M and 15 mg/kg Q3M). Results: In the single-dose Phase 1 trial, 10 mg/kg was the Protocol-defined MTD but a high rate of clinical benefit was seen in the 15 mg/kg dose cohort (6/6 pts). Because the DLTs seen at 15 mg/kg (Gr 3 diarrhea, Gr 3 rash) were moderate and resolved completely within 3 months of dosing, 15 mg/kg Q3M was proposed as a safe and tolerable dose and is being studied in the Phase 2 portion of the multiple-dose Phase 1/2 trial. The Phase 1 portion of the multiple-dose Phase 1/2 trial revealed that 10 mg/kg is safe and tolerable with monthly dosing so 10 mg/kg Q1M is also being studied in the Phase 2 portion of the trial. At the end of the Simon Optimum-defined Stage 1 of the Phase 2 portion of the ongoing trial, the OR rate (3/18 pts) is the same for both dosing regimens. However, with 15 mg/kg Q3M, Gr 3/4 adverse events were less frequent (6% versus 34%). Conclusions: 15 mg/kg Q3M is proposed as the clinical dose/regimen for ticilimumab in metastatic melanoma. This dose/regimen appears to have anti-tumor activity approximately equal to 10 mg/kg Q1M but it appears to have a superior safety profile. [Table: see text]

8033 Background: We previously defined the magnitude of the minimum statistically significant change in value for the MHC tetramer and ELISPOT assays (Comin-Anduix, Clin Cancer Res 2006). We used those reference change values (RCV) to determine if the administration of ticilimumab to patients with melanoma expands the circulating populations of tumor antigen-specific T cells. Methods: HLA-A2.1+ pts with sIIIc or IV melanoma and baseline circulating MART-1-specific T cells above the low limit of detection by tetramer assay (LLD, 0.03% of CD8+ T cells) received ticilimumab at 10 mg/kg monthly. Two 40 ml blood samples were collected at baseline, and one at 1 and 2 weeks after each dose for 4 cycles. Primary endpoint was immune response for MART-1 by tetramer assay, for which the RCV is 80% (expressed as percent change from baseline). Results: Of 15 pts (2 sIIIc, 5 sIVa, 2 sIVb, 6 sIVc), 1 was not treated and 2 received only 1 dose due to rapid progression. The 12 remaining pts received 2–11 doses. Clinical immunologic response to ticilimumab was evidenced by immune-related toxicity (G3 diarrhea in 2 pts, G2 hypophysitis in 1 pt, G3 hepatitis in 2 pts) and by anti-tumor activity: CR in 1 pt (15+ mo), PR in 2 pts (9+, 8 mo), and SD in 3 pts (11, 8+ and 4 mo); the rest had PD at 4 mo or less. A mean of 2 baseline and 7 follow up (range 5–9) time points were tested by tetramer and ELISPOT assays. 4 pts had an increase in MART-1-specific T cells beyond the RCV on 1 or more occasions, but no pt had a consistent pattern of change over time. Indeed, there was no consistent pattern of change in any pt in circulating T cells specific for MART-1, gp100, tyrosinase, EBV, or CMV by tetramer or by ELISPOT assay. One pt had accessible regressing lesions which on biopsy showed heavy infiltration by CD8+/Granzyme B+ CTL and a 10-fold enrichment of gp100-specific T cells compared to his peripheral blood. Conclusion: Ticilimumab administered monthly induces immune-related phenomena and tumor responses in patients with melanoma without a demonstrable expansion of circulating melanoma antigen-specific T cells. Evaluation of melanoma antigen-specific T cells within the tumor may be a better way to study the mechanism of antitumor activity of CTLA4 blocking mAb. [Table: see text]

8036 Background: Clinical studies examining anti-CTLA4 monoclonal antibodies (mAb) provide evidence of the biologic and clinical activity of this class of agents. Two Phase 1 studies with ticilimumab, a fully human anti-CTLA4 mAb, have been reported previously. In both studies, objective responses (OR) were seen in some patients (pts) with melanoma. In addition, we observed highly favorable outcomes among several pts who did not experience objective responses. This may indicate a positive impact of ticilimumab on melanoma in these pts, not well reflected by traditional response criteria. Long-term follow-up data on survival for pts enrolled in these Phase 1 studies is now reported. Methods: We studied the safety, pharmacokinetics, immunostimulatory activity, and clinical activity of ticilimumab in 53 pts with solid malignancies. Ticilimumab was administered, as a single agent, at single dose levels ranging from 0.01 to 15 mg/kg and at multiple dose levels ranging from 3 to 15 mg/kg. The dosing regimens included either a single dose, multiple doses given q3 months, or multiple doses given q1 month. Results: The two studies included 43 pts with measurable melanoma. Ticilimumab proved safe and overall was well tolerated (Ribas et al. ProcASCO 2005, and JCO Dec2005). Of the 43 pts with measurable melanoma, 18 were alive at >12 months (range: 13 - 42+) after initial treatment with ticilimumab. This includes 5 pts with an OR who continue on ticilimumab, either on-study or as part of a single IND, and 13 pts without an objective response. Among the pts who did not experience an OR, 5 had surgical resection of metastatic lesions and remain relapse free, and 8 are alive with disease. Conclusions: In pts with melanoma treated with ticilimumab, long-term survival has been achieved by all 5 pts who experienced an OR and in 13 pts who did not experience an OR. These findings suggest that lack of objective response is a poor predictor of long-term survival following ticilimumab therapy. [Table: see text]

7505 Background: T-regulatory (T-reg) cells are CD3+CD4+CD25+ and produce IL-10. Engagement of CTLA-4 on activated T cells with CD80/CD86 on APC diminishes T-cell activation and proliferation via i...

7524 Background: CP-675,206 had a manageable safety profile and antitumor activity in a prior Single-Dose phase I trial (Camacho et al. ProcASCO 2004). The safety, tolerability and recommended phase II dose of Monthly CP-675,206 was assessed in this study. Methods: Eligibility: stage IIIc-IV melanoma, measurable disease, ECOG 0–1, no active brain metastasis. 3 dose levels were sequentially tested. Results: 14 pts (9 M, 5 F) mean age 55 (range 42–67) were enrolled (3 at 3.0 mg/kg, 3 at 6.0 mg/kg, 8 at 10.0 mg/kg). 57% had stage IVc. All pts at 3 and 6 mg/kg received 2 doses, at 10 mg/kg received a median of 4.5 (range 2–8) monthly doses for a total of 51 doses administered. No G4 treatment-related toxicities were observed. G3 diarrhea in 1 pt at 3 mg/kg, none at 6 mg/kg, 2 pts at 10 mg/kg. G2 treatment-related adverse events included 4 dermatitis, and 1 each of diarrhea, pruritus, hypothyroidism, urticaria, and myalgias. Preliminary PK analysis suggests little accumulation of CP-675,206 with multiple dosin...