PO BID Research Articles

A pilot study of the neoadjuvant use of vemurafenib plus cobimetinib in patients with BRAF-mutant melanoma with palpable lymph node metastases: Survival results.

9579 Background: Melanoma patients with palpable nodal metastases have a very poor prognosis with the majority recurring within the first 2-3 years post-resection with survival ranging from 20-50% at 5 years. We aimed to ascertain if patients with a BRAF V600 mutation that receive vemurafenib and cobimetinib before surgery (neoadjuvantly) have a higher probability of resectability, pathologic complete response (pCR), and a lower risk of local recurrence and a longer disease free survival (DFS), distant metastatic free survival (DMFS) and overall survival (OS). Methods: This was a single arm, prospective, multi centre phase II study in patients with histologically confirmed, BRAF V600 mutated Stage IIIB and IIIC melanoma (AJCC 7th Edition) with palpable nodal disease. Patients received vemurafenib 960mg PO BID and cobimetinib 60mg PO OD for 4 months prior to resection followed by 8 months of adjuvant therapy post-surgery. CTscans were performed at baseline and before resection and every 6 months for the first 3 years and yearly in year 4 and 5. Biopsies for correlative studies and diagnosis were performed at baseline prior to starting therapy. The primary outcomes were the proportion of patients achieving resectability, radiologic response as per RECIST and the proportion of patients achieving a pCR. Presented here are the LRFS, DMFS, DFS and OS. Results: Twenty-four patients were enrolled and received neoadjuvant vemurafenib and cobimetinib and 21 underwent resection. Following resection and pathological evaluation 12 (57%; 95% CI 34.02-78.18)) patients achieved a pCR, 8 (38%; 95% CI 18.11-61.56) had a partial pathologic response and 1 had no pathologic response. Of the 24 patients, 2 patients (8%) developed local recurrence, 6 patients (25%) developed distant metastasis, and 8 patients (33%) had either local or distant recurrences. 7 patients (29%) died due to metastatic disease. At 60 months, LRFS was 89.5% (76.7-100%), DMFS was 75.0% (59.5-94.5%), DFS was 85.7% (72.0-100%), and OS was 63.9% (95% CI 43.5-93.8). Among total 20 evaluable patients, 17 patients had CR/PR and 3 had PD/SD as best response. There was no significant difference between patients with CR/PR or SD/PD (log-rank p-value = 0.0548) with 48 month survival of 82.4% for CR/PR population compared to 33.3% with SD or PD. Conclusions: In this small phase II study, neoadjuvant vemurafenib and cobimetinib led to a higher LRFS, DMFS, DFS and OS of all resected patients with bulky nodal disease compared to historical survival rates. Clinical trial information: NCT02036086 .

The effect of megestrol acetate ± pterostilbene in endometrial cancer: A prospective, randomized, window-of-opportunity clinical trial.

5597 Background: Pterostilbene (3,5-dimethoxy-40-hydroxystilbene) is a potent oral antioxidant found naturally at highest concentrations in blueberries. Its anti-tumor effects in preclinical studies of various solid tumors include carcinogenesis, inflammation, reactive oxygen species (ROS) formation, and antiproliferative effects. In endometrial cancer (EC), in vitro and in vivo studies demonstrated a synergistic antiproliferative effect of pterostilbene (PT) in combination with megestrol acetate (MA). No clinical trials testing the potential therapeutic benefit of pterostilbene in cancer have been completed. Methods: We performed a prospective, window-of-opportunity, randomized phase 2 clinical trial (NCT03671811) in patients with EC. Eligible patients had to be surgical candidates for treatment with hysterectomy and not have received prior therapy. The primary objective was to determine the effect of MA plus PT versus standard treatment of MA alone on tumor proliferation as measured by the Ki-67 index during the preoperative window. Patients were randomized 1:1 to one of two arms: MA+PT PO BID versus MA PO BID, for 3 weeks. The Ki-67 index was measured via hot-spot and H-score methodology in the preoperative tumor and hysterectomy specimen by two blinded pathologists whose measurements were averaged. The net change between pre- and post-operative specimens was calculated for each patient and expressed as a percentage. Toxicity was assessed using CTCAE grading. Results: A total of 44 patients with EC of all histologies were recruited to the study and included in the toxicity analysis. Median age was 61.9 years. Baseline demographics were comparable between both arms. Median treatment duration was 21 days (14-56), similar in both arms. One G3 hypertension was encountered in the MA arm; one G3 thromboembolic event in the MA+PT arm. Of 35 patients with sufficient treatment duration (>10 days) and available pre-and post-treatment specimens, 29 patients with endometrioid histology were evaluated for the ki67 analysis: 14 in the MA arm and 15 in the MA+PT arm. The MA+PT group demonstrated a -41.1% change in Ki-67 index by Hot Spot Score compared to -27.5% in the MA-only group (p=0.17). A similar trend was observed for the Ki-67 index by H Score methodology (-41.6% vs -26.7%, MA+PT vs MA, p=0.17). Conclusions: The combination of MA + PT in preoperative treatment of endometrial adenocarcinoma is well tolerated. The addition of Pterostilbene demonstrates a trend towards decreased Ki-67 index in endometrioid EC patients. Molecular studies are pending to delineate biomarkers associated with response. Clinical trial information: NCT03671811 .

Mechanism-based peripheral blood biomarkers to evaluate anticancer effects of the plinabulin/docetaxel combination (plin/doc) vs. doc alone in second/third line EGFR wild-type (WT) NSCLC.

e21017 Background: Pretreatment neutrophil to lymphocyte (L) (NLR), platelet to L (PLR), and L to monocyte (LMR) levels are established prognostic biomarkers for advanced NSCLC. Plinabulin (Plin) is a well-tolerated, differentiated tubulin-binding agent being developed for neutropenia prevention as a monotherapy and in combination, and for improving the efficacy of anticancer agents. DUBLIN-3 (NCT02504489) was a randomized, single-blinded (pts only), active-controlled Ph3 study in 2nd/3rd line stage IIIB/IV, EGFR WT NSCLC with a measurable lung lesion (RECIST 1.1). Pts (N = 559) were randomized 1:1 to Plin/Doc or Doc (21-day (D) cycle (C)). Doc (75 mg/m2) on D1 and Plin (30 mg/m2) on D1/D8 were given by IV infusion with steroid premedication (8 mg PO BID x 3D). Differential WBCs and platelet counts were collected at baseline (pre-steroid), D1, and D8. We analyzed the posttreatment effects of Plin on NLR, PLR, and LMR. Methods: All evaluable Plin/Doc vs Doc pts were included. NLR/PLR/LMR ratios and their respective change from baseline (cNLR/cPLR/cLMR) were obtained from blood draws taken at predose, C1D8, and/or C2D8. For intra/inter-arm overall survival (OS) stratification, baseline median NLR (3.2), PLR (177), and LMR (3.5) values were selected as thresholds. By examining responders & long-term survivors in both arms, posttreatment NLR/LMR and cNLR/cLMR thresholds were established for C1D8 and C2D8. Finally, PFS/OS benefits were stratified to determine the statistical significances of Plin/Doc vs Doc. Results: In agreement with literature, baseline threshold levels for NLR = 3.2, PLR = 177, LMR = 3.5 were statistically significantly predictive of OS in both the Plin/Doc and Doc arms (p values ranging from 0.05 to 0.0001). Plin prevents Doc-induced neutropenia, and post-Doc neutrophil counts were higher on D8 with Plin/Doc vs Plin (p < 0.001). Despite Doc-induced myelosuppression, Plin/Doc responding pts maintained similar NLR/LMR values as baseline at C1D8 and C2D8. After a single Plin dose at C1D8, lower NLR (cutoff = 3.0; 1.2x median value of all pts) and higher LMR (cutoff = 4.5; median value of all pts) thresholds independently predicted PFS/OS benefits of Plin/Doc vs Doc. Further, a higher cNLR threshold (cutoff = 0.25) at C2D8, best predicted Plin/Doc vs Doc in PFS and OS (p < 0.0001 and p = 0.0035 respectively). Conclusions: Bone marrow suppression remains a common serious risk of classical/non-classical cancer drugs. Under these conditions, the addition of Plin offers rapid protection of GMP lineage cells which can be captured by simple blood cell counts. Incorporation of blood-based biomarkers may help enrich NSCLC pts with better sensitivity to Plin/Doc combination than Doc alone. Clinical trial information: NCT02504489 .

Phase II trial of BXCL701 and pembrolizumab in patients with metastatic pancreatic ductal adenocarcinoma (EXPEL-PANC).

TPS4194 Background: Pancreatic ductal adenocarcinoma (PDAC) has limited therapeutic options and is thought to be a “cold” tumor that does not respond to immunotherapy, due to a tumor microenvironment (TME) consisting of a desmoplastic stroma and poor T cell infiltrate. BXCL701 is an oral synthetic dipeptide that competitively inhibits dipeptidyl peptidases DPP4, DPP8, DPP9 and fibroblast activation protein (FAP). BXCL701 exerts antitumor activity via inhibition of DPP8/9, which is associated with induction of proinflammatory cytokines, as well as inhibition of FAP, which disrupts tumor-stromal interactions. Preclinical xenograft models demonstrate synergy between BXCL701 and an anti-PD-1 monoclonal antibody, reducing tumor growth and promoting an increase in intratumoral CD4+ and CD8+ T cells and NK cells. The combination of BXCL701 and pembrolizumab is already being studied in a phase II trial in patients with prostate cancer (NCT03910660) and a multi-cohort basket study (NCT04171219). Methods: This is a phase II trial of BXCL701 administered at 0.2 mg PO BID days 1-7 and 0.3 mg BID days 8-14 during cycle 1 (21 days) followed by 0.3 mg BID days 1-14 every 21 days in all subsequent cycles, given with pembrolizumab 200 mg IV every 21 days (all cycles). The primary objective is to determine the 18-week progression-free survival rate (PFS18weeks) in patients with metastatic PDAC treated in the second-line setting. We estimate that historical 2nd-line PFS18weeks is 30% or less; using a Simon’s two-stage (minimax) design, a type I error rate of 0.05 and power of 80% when the true response rate of 50%, we will need 19 patients in stage 1 and 20 in stage 2 (a total of 39). We plan to enroll 43 patients to account for a predicted 10% drop out of unevaluable patients. Eligible patients must have metastatic PDAC and disease progression or intolerance to only 1 line of therapy for metastatic disease, without exposure to prior immunotherapy. Patients must have measurable disease amenable to serial biopsies. Correlative pharmacodynamic studies include imaging mass cytometry to examine 34 markers of the PDAC TME in tissue biopsies, as well as blood-based analyses of KRAS circulating tumor DNA, circulating markers of fibrosis, and IL-6. Enrollment began in Q1 2023. Clinical trial information: NCT05558982 .

Preliminary translational immune and stromal correlates in a randomized phase II trial of pembrolizumab with or without defactinib for resectable pancreatic ductal adenocarcinoma (PDAC).

4024 Background: PDAC is an aggressive cancer and refractory to immunotherapy due to its immunosuppressive tumor microenvironment (TME). Focal adhesion kinase (FAK) is a master regulator of the TME and associated with TME immune suppression. Our current randomized phase II trial evaluates the use of pembrolizumab, a programmed cell death 1 (PD-1) immune checkpoint inhibitor, with or without defactinib, a FAK inhibitor (FAKi), as sequential neoadjuvant and adjuvant therapy in patients with high risk resectable PDAC. We hypothesize that the patients receiving pembrolizumab and defactinib treatment will exhibit a decrease in immunosuppressive fibroblasts and myeloid subtype populations, leading to increased CD8+ T-cell infiltration into the TME compared to patients receiving pembrolizumab alone. Methods: We performed quantitative analysis of multiplex immunohistochemistry (mIHC) using 40 biomarkers, evaluating immune and stromal cell types on 14 pre-treatment biopsies and post-treatment resections of PDAC patients enrolled in our platform neoadjuvant clinical trial (NCT03727880). All patients received 2 cycles of gemcitabine+nab-paclitaxel neoadjuvant chemotherapy and underwent a biopsy after completion of chemotherapy. Patients randomized to Arm A received 2 cycles of pembrolizumab 200 mg IV every 3 weeks and defactinib 400 mg PO BID, and those randomized to Arm B received pembrolizumab alone, followed by surgical resection. Image cytometry was used to quantify immune cell populations and colocalize biomarker expression in distinct cell types. Cell populations were compared using unpaired T-tests. Results: Lower FAP+ fibroblast density was significantly associated with higher CD8+ T-Cell infiltration in Arm A (p=0.002), but not in Arm B. Patients in Arm A demonstrated a 5.44-fold average increase in CD8+ T-cell percentage between pre-immunotherapy treatment and post-immunotherapy treatment specimens compared to a 2.01-fold increase in patients in Arm B (p=0.02, p=0.09, respectively). Only patients in Arm A showed a significant increase in M1 macrophage cell density (p=0.02) after treatment. Both arms increased in CXCR4+ cell percentage (p=0.011, p=0.06) following neoadjuvant immunotherapy; however, the increase in Arm A was less than in Arm B (0.72 and 0.84-fold, respectively). Conclusions: In this analysis, pembrolizumab combined with defactinib was associated with lower fibroblast infiltration, higher anti-tumor M1 macrophage expression and increased CD8+ T-cell infiltration into the TME, versus pembrolizumab alone. The increased expression of CXCR4 across both treatment arms may represent a resistance mechanism and supports CXCR4 as an additional TME target. These preliminary findings warrant continued research into FAK inhibition and immune checkpoint combinatorial strategies. Clinical trial information: NCT03727880 .

A phase 2 basket trial of ulixertinib (BVD-523) in combination with hydroxychloroquine in patients with advanced gastrointestinal malignancies harboring MAPK pathway mutations (BVD-523-HCQ).

TPS4174 Background: RAS-induced signaling through the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway plays an important role in the pathogenesis of many solid tumors. Ulixertinib (BVD-523) is a first-in-class and best-in-class small molecule inhibitor of ERK 1/2 that is currently being investigated in multiple cancer clinical trials, both as a single agent and as part of combination therapy. Preclinical studies have demonstrated that inhibition of the RAS/MAPK/ERK signaling cascade leads to upregulation of autophagy, a catabolic pathway that includes the lysosomal degradation of proteins to support cellular metabolism during times of cellular stress. Given cancer cells’ increased reliance on autophagy to enhance their survival in this context, this study seeks to evaluate the combination of ulixertinib with hydroxychloroquine, an antimalarial drug known to suppress autophagy, in patients with advanced gastrointestinal malignancies harboring mutations in genes involved in MAPK signaling. Methods: This is an open-label, multicenter, phase II basket study of ulixertinib in combination with hydroxychloroquine in patients with advanced GI malignancies harboring mutations in one of the following MAPK signaling-associated genes: KRAS, NRAS, HRAS, BRAF (non-V600), MEK1/2, or ERK1/2. The completed Phase 1 dose-escalation trial (NCT04145297) established the recommended Phase 2 dose which will be the doses used in this study; ulixertinib 450mg PO BID combined with hydroxychloroquine 600mg PO BID, both drugs administered daily in 28-day cycles, with tumor assessments after every 2 cycles. The trial has five baskets based on primary disease: cholangiocarcinoma, pancreatic adenocarcinoma, colorectal adenocarcinoma, esophageal adenocarcinoma, and gastric adenocarcinoma. A Simon two-stage design will be employed within each of the 5 disease-specific baskets noted above, with the first stage of enrollment consisting of n=13 patients/ basket. To be considered evaluable, a patient must complete at least one cycle of therapy and receive at least 75% of the prescribed dose during that first cycle. If ≥ 4 patients in a specific basket achieve a response (complete or partial), that basket will then open to Stage 2 with enrollment of an additional 30 patients. Primary study endpoints will include safety/toxicity as well as ORR by RECIST 1.1. The secondary endpoint for efficacy is progression-free survival. Exploratory endpoints include pharmacokinetics of both ulixertinib and hydroxychloroquine, as well as predictive biomarkers from blood and tumor tissue-based samples. At the time of abstract submission, 26 of the planned 65 patients in Stage 1 had been enrolled. Clinical trial information: NCT05221320 .

Interim analyses (IA) of the giredestrant (G), G + abemaciclib (A), and G + ribociclib (R) arms in MORPHEUS Breast Cancer (BC): A phase I/II study of G treatment (tx) combinations in patients (pts) with estrogen receptor-positive, HER2-negative locally advanced/metastatic BC (ER+, HER2– LA/mBC).

1061 Background: Limitations of current approved endocrine therapies (ETs), a mainstay tx for ER+ BC, include incomplete ER signaling inhibition. Novel ETs, such as selective estrogen receptor antagonists and degraders (SERDs), may help overcome this. G, a potent, nonsteroidal, oral (PO) SERD, is well tolerated and has shown robust ER occupancy and encouraging antitumor activity as monotherapy and in combination with the cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) palbociclib (P). MORPHEUS BC (NCT04802759) is evaluating the safety and efficacy of G tx combinations in ER+, HER2– LA/mBC. We present results from the 16-week IA of G and G + CDK4/6i (A or R). Methods: Eligible pts had disease progression on 1–2 lines of ET (including a CDK4/6i) for LA/mBC. Pts were randomized 1:6 (planned n = 15 per arm) to receive G (30 mg PO QD; control arm), G + A (150 mg PO BID), or sequentially, G + R (600 mg PO QD) until disease progression/unacceptable toxicity. The study was not designed to make explicit power and type I error considerations for a hypothesis test. Primary endpoints were safety and objective response rate; other endpoints included progression-free survival, overall survival, clinical benefit rate, disease control rate (DCR), duration of response, and pharmacokinetics. Genetic alterations were defined using baseline circulating tumor DNA. Results: As of Feb 4, 2022, 15 pts were enrolled in the G + A arm; 73% received one prior line of tx in the LA/mBC setting; 27% received prior fulvestrant; 73% had liver metastases at baseline (BL). As of Sept 22, 2022, 11 and 16 (of whom 14 were evaluable) pts were enrolled in the G and G + R arms, respectively; 64%/86% received one prior line of tx in the LA/mBC setting; 73%/36% received prior fulvestrant; 73%/57% had liver metastases at BL. Three pts had a partial response (PR; G + A, n = 1; G + R, n = 2); 19 had stable disease (G, n = 5; G + A, n = 7; G + R, n = 7). DCRs were 36% (G), 40% (G + A), and 50% (G + R). Safety is shown. Conclusions: G combined with a CDK4/6i (A or R) was well tolerated, with no unexpected safety signals. Three PRs were seen in this heavily pretreated population of pts with disease progression post-CDK4/6i tx. This study provides the first data supporting the combinability of G with the CDK4/6is A and R, in addition to P as seen in prior studies. G can therefore be combined with all three approved CDK4/6is. Clinical trial information: NCT04802759 . [Table: see text]

Abstract ND05: The discovery and characterization of CFT1946: A potent, selective, and orally bioavailable degrader of mutant BRAF for the treatment of BRAF-driven cancers

Abstract The BRAF kinase plays a critical role in the MAPK signaling pathway and is mutated in ~8% of all human cancers including melanoma (~60%), thyroid (~60%), and lung adenocarcinoma (~10%). The most common mutation in BRAF is V600E (Class I), which is found in >70% in these cancers. Despite the clinical success of approved small molecule inhibitors of BRAF V600E (vemurafenib, dabrafenib and encorafenib), this remains an area of unmet medical need because nearly all patients progress, due to either primary or acquired resistance. A bifunctional degradation activating compound (or BiDACTM degrader) may address the liabilities of approved drugs by overcoming, or preventing the emergence of, resistance to BRAF inhibitors. Here we describe CFT1946, an orally bioavailable cereblon-based BiDAC degrader of BRAF V600 mutant proteins, and provide an overview of the medicinal chemistry path leading to its discovery. CFT1946 degrades BRAF V600 mutant proteins, while maintaining exquisite selectivity against the proteome, sparing wild type BRAF (BRAF-WT), ARAF, and CRAF. In A375 cells, CFT1946 potently degraded BRAF V600E and inhibited ERK phosphorylation and cell growth while having no effect in the mutant KRAS, BRAF-WT driven cell line HCT116. In the A375 xenograft model, oral delivery of CFT1946 at 10 mg/kg PO BID resulted in deeper and more durable tumor regression compared to a clinically relevant dose of encorafenib. Further evaluation of CFT1946 in an engineered, clinically relevant BRAFi-resistant A375 cell line (endogenous BRAF V600E + engineered expression of NRAS Q61K) demonstrated that CFT1946 both degraded BRAF V600E and caused a loss of viability in these cells, while treatment with encorafenib had no effect. In xenografts derived from this BRAFi-resistant cell line, oral dosing of CFT1946 as a single agent led to tumor growth inhibition, while treatment with a clinically relevant dose of encorafenib had no effect on tumor growth. Furthermore, dosing CFT1946 in combination with the MEK inhibitor, trametinib, resulted in significant tumor regression, whereas combining encorafenib with the same dose of trametinib had no effect. The medicinal chemistry campaign resulting in CFT1946 focused on the improvement of in vivo pharmacokinetics and rational linker design to achieve high oral bioavailability in a beyond Rule of 5 heterobifunctional degrader. The preclinical data presented herein support the planned Phase 1/2 clinical trial of CFT1946 for the treatment of BRAF-V600 mutant solid tumors. Citation Format: Yanke Liang, Mathew E. Sowa, Katrina L. Jackson, Jeffrey R. Simard, Bridget Kreger, Ping Li, Laura Poling, Joelle Baddour, Andrew Good, Hongwei Huang, Scott Eron, Christopher G. Nasveschuk, Robert Yu, Mark Fitzgerald, Victoria Garza, Morgan W. O’Shea, Gesine Veits, Jeremy L. Yap, Moses Moustakim, Ashley Hart, Roman V. Agafonov, Grace Sarkissian, Joe S. Patel, Richard Deibler, Kyle S. Cole, David Cocozziello, Fazlur Rahman, Andrew J. Phillips, Elizabeth Norton, Adam S. Crystal, Roy M. Pollock, Stewart L. Fisher. The discovery and characterization of CFT1946: A potent, selective, and orally bioavailable degrader of mutant BRAF for the treatment of BRAF-driven cancers [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 ND05.

Randomized Placebo-Controlled Trial to Evaluate Effects of Eplerenone on Myocardial Perfusion and Function Among Persons With Human Immunodeficiency Virus (HIV)-Results From the MIRACLE HIV Study.

Increased renin angiotensin aldosterone system (RAAS) activity may contribute to excess cardiovascular disease in people with HIV (PWH). We investigated how RAAS blockade may improve myocardial perfusion, injury, and function among well-treated PWH. Forty PWH, on stable ART, without known heart disease were randomized to eplerenone 50 mg PO BID (n = 20) or identical placebo (n = 20) for 12 months. The primary endpoints were (1) myocardial perfusion assessed by coronary flow reserve (CFR) on cardiac PET or stress myocardial blood flow (sMBF) on cardiac MRI or (2) myocardial inflammation by extracellular mass index (ECMi) on cardiac MRI. Beneficial effects on myocardial perfusion were seen for sMBF by cardiac MRI (mean [SD]: 0.09 [0.56] vs -0.53 [0.68] mL/min/g; P = .03) but not CFR by cardiac PET (0.01 [0.64] vs -0.07 [0.48]; P = .72, eplerenone vs placebo). Eplerenone improved parameters of myocardial function on cardiac MRI including left ventricular end diastolic volume (-13 [28] vs 10 [26] mL; P = .03) and global circumferential strain (GCS; median [interquartile range 25th-75th]: -1.3% [-2.9%-1.0%] vs 2.3% [-0.4%-4.1%]; P = .03), eplerenone versus placebo respectively. On cardiac MRI, improvement in sMBF related to improvement in global circumferential strain (ρ = -0.65, P = .057) among those treated with eplerenone. Selecting for those with impaired myocardial perfusion (CFR <2.5 and/or sMBF <1.8), there was a treatment effect of eplerenone versus placebo to improve CFR (0.28 [0.27] vs -0.05 [0.36]; P = .04). Eplerenone prevented a small increase in troponin (0.00 [-0.13-0.00] vs 0.00 [0.00-0.74] ng/L; P = .03) without effects on ECMi (0.9 [-2.3-4.3] vs -0.7 [-2.2--0.1] g/m2; P = .38). CD4+ T-cell count (127 [-38-286] vs -6 [-168-53] cells/μL; P = .02) increased in the eplerenone- versus placebo-treated groups. RAAS blockade with eplerenone benefitted key indices and prevented worsening of myocardial perfusion, injury, and function among PWH with subclinical cardiac disease when compared with placebo. NCT02740179 (https://clinicaltrials.gov/ct2/show/NCT02740179?term=NCT02740179&draw=2&rank=1).

(037) Hypersexuality with the Use of Selective Serotonin Receptor Inhibitors

Abstract Introduction We present two cases of hypersexuality in perimenopausal women evaluated, diagnosed, and being managed at this time for what seems to be a sexual dysfunction recently described as a consequence of the use of a combination of 2 kinds of medications: Bupropion, a Norepinephrine Dopamine Reuptake Inhibitor (NDRI), and Sertraline/Fluoxetine, a Selective Serotonin Receptor Inhibitor (SSRI), used as an anti-depressant and anxiolytics for psychiatric conditions. Both cases arrived at our centers referred by their primary care physicians or a psychiatrist for sexual therapy and sexological evaluation. Objective To show a new sexual dysfunction related to the use of SSRI medications. Methods The analysis of 2 cases of a new described sexual dysfunction related with the use of SSRI medications: Bupropion at 150 mg PO bid, and Fluoxetine at 125 mg PO qd. Results The first case, one week after the initiation of Fluoxetine, having been taking Bupropion for months, started to develop uncontrolled need for sex, having sex with multiple men, in addition to her husband. Her husband accepted to have sexual relationships in trios, a situation that lasted for several months. However, after 4-6 weeks, she started to look for additional partners other than her husband. He left. She arrived with extreme anxiety during her first visit. Neither her, nor the psychiatrist understood why this was happening. At that moment, she was having sex with several men on a daily basis. She wanted to preserve her marriage but her sexual compulsion was an impediment. The second patient decided to be unfaithful to her husband of 10 years. In this case, she decided to have hidden sexual relations with several men at the same time with just one. She was also undergoing psychiatric treatment with both medications, Fluoxetine and Bupropion. There was a temporal correlation between the initiation of Fluoxetine and the appearance of the sexual dysfunction. We suspended both medications and around 10 days after this therapeutic step, there was a frank decline in the compulsive sexual behavior. However, due to depression and anxiety symptoms, the psychiatrist decided to restart only Bupropion without the Fluoxetine that was the medication with which the appearance of symptoms have been related. Now, she is okay. Conclusions We describe the possible pharmacological mechanisms involved in the pathophysiology of this disorder and the way in which we have managed the two cases up to now. This condition needs to be differentiated from the hyperactive sexual arousal disorder, previously described in the sexological literature and we need to determine if this is a variant of that kind of syndrome. We have never encountered this kind of reaction before and have only found one publication describing a similar case. Disclosure No

Is Thalamic DBS Synergistic With VNS in Drug Resistant Genetic Generalized Epilepsy? (P5-1.001)

<h3>Objective:</h3> To report prolonged seizure freedom and improved quality of life after combining anterior nucleus of the thalamus deep brain stimulation (ANT-DBS) with vagus nerve stimulation (VNS) in a patient with drug resistant genetic generalized epilepsy (GGE). <h3>Background:</h3> Neuromodulation remains at forefront of management in patients with drug-resistant epilepsies though efficacy has been palliative and FDA approved in focal epilepsies. While polytherapy with anti-seizure medications (ASMs) is common, dual neuromodulation has received limited attention. <h3>Design/Methods:</h3> A 32-year-old female patient with drug resistant GGE who failed 10 antiseizure medications underwent video-EEG monitoring. EEG revealed 3–3.5 Hz generalized polyspike-and-wave discharges and generalized paroxysmal fast activity in brief run lasting less than 3 seconds increased during sleep. Seizures were not recorded. VNS model 106 Aspire SR was implanted at age 23 achieving parameters of 1.5 mA, 25 Hz, 250 μs, 14 sec on, 1.1 min off. Despite improvement with seizure reduction, ongoing monthly convulsions resulted in recurrent injuries. The patient subsequently underwent bilateral ANT-DBS placement with inferior most contacts on both sides well-positioned at the junction of the mammillothalamic tracts for monopolar stimulation at 5 V, 145 Hz, and 90 μs. <h3>Results:</h3> Neuro- “modulation” was observed in our patient with VNS following implantation of ANT-DBS by gradual reduction diminishing seizure frequency, intensity, and duration to ultimately become seizure-free for 21 months. Stable doses of Onfi 20 mg po bid and Keppra 1500 mg po bid were continued. After combining ANT-DBS with her incomplete VNS response she married, became employed, and was able to retain driving privileges and lead an independent lifestyle. <h3>Conclusions:</h3> Identifying a subset of patients with GGE responsive to polyneuromodulation promises personalized therapy for those with life-altering effects from generalized seizures. We speculate that the thalamic network connectivity may be modulated by dual ANT-DBS and VNS, leading to targeted neurobiological therapy in some patients with GGE. <b>Disclosure:</b> Dr. Khan has nothing to disclose. Erik Middlebrooks has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Varian Medical Systems Inc. Erik Middlebrooks has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Boston Scientific Corp. The institution of Erik Middlebrooks has received research support from Varian Medical Systems Inc. Dr. Freund has nothing to disclose. Sanjeet S. Grewal, MD has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Medtronic. Dr. Tatum has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Bioserenity. Dr. Tatum has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. Dr. Tatum has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Defense Law Firm on behalf of a patient with epilepsy with funds donated to the Epilepsy Foundation of America. The institution of Dr. Tatum has received research support from Esai. The institution of Dr. Tatum has received research support from Mayo Clinic. The institution of Dr. Tatum has received research support from Liva Nova. The institution of Dr. Tatum has received research support from Engage Pharmaceuticals. The institution of Dr. Tatum has received research support from Xenon. Dr. Tatum has received publishing royalties from a publication relating to health care. Dr. Tatum has received publishing royalties from a publication relating to health care.

Results from 96 Weeks Open-Label Extension of a Phase 2 Trial of Losmapimod in Subjects with FSHD: ReDUX4 (S48.008)

<h3>Objective:</h3> Evaluate the 96-week results from the open-label extension of a Phase 2 trial of losmapimod in subjects with FSHD. <h3>Background:</h3> Facioscapulohumeral muscular dystrophy (FSHD) is a relentless, variably progressive disease leading to accumulation of disability. Fulcrum is developing losmapimod, a small molecule p38 α/β MAPK inhibitor, to treat FSHD. <h3>Design/Methods:</h3> ReDUX4 is a 48-week, placebo-controlled study assessing 80 subjects, 18–65 years old with genetically confirmed FSHD1, Ricci score 2–4, randomized 1:1 to receive 15 mg losmapimod or placebo (PO BID), followed by an Open-Label Extension (OLE) with all participants receiving losmapimod. <h3>Results:</h3> Seventy-six of 77 (99%) participants entered the OLE after 48 weeks, and 74 (97%) were enrolled at Week 96. For participants continuing to receive losmapimod (LOS/LOS), durability of treatment response was observed at 96 weeks, by assessing upper extremity function with Reachable Workspace (RWS). Placebo participants who converted to losmapimod (PBO/LOS) at Week 48 demonstrated trends of slowing or stopping disease progression based on RWS. Annualized total (Q1–5) relative surface area (RSA) in the dominant arm with weights demonstrated stability in the LOS/LOS group during the 2^nd year of dosing compared to the first (0.18%/yr vs −0.77%/yr, respectively) and improvement in PBO/LOS (4.07% vs −9.96%). Mean change in RSA from Week 48 to Week 96 was 0.0 for LOS/LOS and 0.02 for PBO/LOS with similar findings in the non-dominant arm in both groups and without weight. No related serious adverse events or discontinuations due to adverse events were reported in 96 weeks of dosing. Most commonly reported adverse events were fall (22.4%), headache (14.5%), arthralgia (7.9%), and back pain (7.9%). <h3>Conclusions:</h3> Losmapimod slowed disease progression and demonstrated maintenance of effect for through a 96-week period, with no new safety findings. <b>Disclosure:</b> Dr. Wang has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for AskBio. Dr. Wang has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Fulcrum Therapeutics. Dr. Wang has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Dr. Wang has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Mitsubishi Tanabe. Dr. Wang has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Argenx. Dr. Wang has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Avidity. Dr. Wang has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Scholar Rock. The institution of Dr. Wang has received research support from National Institute of Health. Dr. Wang has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant with US Government. Dr. Han has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Fulcrum. Dr. Han has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi. The institution of Dr. Han has received research support from Fulcrum. Dr. Shoskes has received personal compensation for serving as an employee of Fulcrum Therapeutics. An immediate family member of Dr. Shoskes has received personal compensation for serving as an employee of Exact Science. Dr. Jiang has received personal compensation for serving as an employee of Fulcrum Therapeutics. Dr. Tawil has received personal compensation in the range of $500-$4,999 for serving as a Consultant for DYNE Therapeutics. Dr. Tawil has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Arrowhead Pharma. Dr. Tawil has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Fulcrum Therapeutics. Dr. Tawil has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Acceleron Pharma. Dr. Tawil has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for MT Pharma. Dr. Tawil has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche Pharma. Dr. Tawil has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for miRecule. The institution of Dr. Tawil has received research support from Friends of FSH Research. The institution of Dr. Tawil has received research support from FSH Society. The institution of Dr. Tawil has received research support from NIH. The institution of Dr. Tawil has received research support from Fulcrum. Dr. Tawil has received intellectual property interests from a discovery or technology relating to health care. Dr. Tawil has received publishing royalties from a publication relating to health care.

Safety and Tolerability of Losmapimod for the Treatment of FSHD (P3-8.001)

<h3>Objective:</h3> Evaluate the safety and tolerability of losmapimod in the treatment for FSHD. <h3>Background:</h3> FSHD is a relentless, variably progressive disease leading to accumulation of disability over decades. Fulcrum has assessed losmapimod, a small molecule p38 α/β MAPK inhibitor, in FSHD in one completed Phase 1 study (FIS-001-2018) and two ongoing Phase 2 studies in the open-label extension period (FIS-001-2019 and FIS 002-2019). <h3>Design/Methods:</h3> Subjects aged 18–65 years with genetically confirmed FSHD1, Clinical Severity Score 2–4, and MRI-eligible muscles for biopsy were exposed to losmapimod 7.5 or 15 mg BID PO for 14 days and up to 76 weeks. In study FIS 001-2018, 6 subjects were exposed to 7.5 mg and 11 subjects to 15 mg twice daily dosing for 14 consecutive days. In studies FIS-001-2019 and FIS-002-2019, 14 and 77 subjects respectively, received at least one dose of losmapimod 15 mg twice daily for up to 76 weeks. <h3>Results:</h3> A total of 108 subjects with FSHD1 have been exposed to losmapimod, with ~131 patient-years of exposure. Fifty-seven subjects were exposed to losmapimod for 12 to 18 months, and 30 were exposed for over 18 months. Most adverse events (AEs) observed during the studies were considered mild to moderate in severity. Most common AEs were alanine aminotransferase increase, headache, dizziness, dry skin, eczema and gastrointestinal disorders. The majority of AEs resolved with continued dosing. Dosing has been paused for 14 days in four subjects (3 in FIS 001-2019 and 1 in FIS-002-2019) subjects due to COVID-19 infection. No drug-related SAEs, deaths, discontinuations due to AEs, or clinically significant changes in vital signs, clinical laboratory results, or ECG parameters were reported. <h3>Conclusions:</h3> Losmapimod administered up to 15 mg BID in &gt;100 subjects with FSHD1 for up to 76 weeks has been generally well-tolerated; the benefit-risk profile of losmapimod for the treatment of FSHD remains favorable. <b>Disclosure:</b> Dr. Ramana has nothing to disclose. Dr. Shoskes has received personal compensation for serving as an employee of Fulcrum Therapeutics. An immediate family member of Dr. Shoskes has received personal compensation for serving as an employee of Exact Science.

Abstract CT158: BrUOG360: A phase Ib/II study of copanlisib combined with rucaparib in patients with metastatic castration-resistant prostate cancer (mCRPC)

Abstract Background: Molecular alterations in genes regulating homologous recombination (HR) confer sensitivity of mCRPC to poly ADP-ribose polymerase inhibitors (PARPi). Increased activation of thePI3K-AKT-mTOR pathway in mCRPC contributes to tumor progression and represents an important therapeutic target. Preclinical studies have shown that PI3K inhibitors (PI3Ki) impair HR and sensitize cancer cells to PARPi even in the absence of HR gene mutations. We hypothesize that dual PI3K and PARP inhibition may improve clinical outcomes of mCRPC. We describe preliminary results of a phase Ib/II study investigating safety of the combination of copanlisib (pan-class I PI3Ki) and rucaparib (PARP-1, -2 and -3 inhibitor). Methods: Enrollment criteria included progressive mCRPC, prior androgen inhibitors (abiraterone, enzalutamide, and/or apalutamide); prior taxane chemotherapy was allowed. HR defects (HRD) was not required for the phase Ib but was an inclusion criterion for the Phase II component of the trial. The phase I followed a standard 3+3 escalation design. Dose level (DL) 1 consisted of rucaparib 400 mg PO BID continuously and copanlisib 45 mg IV days 1, 8 and 15 every 28 days; in DL -1 the copanlisib was reduced to 45 mg days 1 and 15 only. Adverse events (AE) were graded by CTCAE v5.0. The primary aim of the phase I was to establish the MTD and the recommended phase II dose (RP2D) of copanlisib in combination with rucaparib. Results: Thirteen patients were enrolled with a median age of 64 (55-78) and a median baseline PSA of 11.7 ng/mL (0.015-1939.2). Nine patients (69%) received prior chemotherapy (docetaxel [6], cabazitaxel [3]). Seven patients had HRD (54%) BRCA1 (1), BRCA2 (4), CDK12 (1), and FANCA (1). Treatment-related AEs included grade 2 (G2) leukopenia (46%), G2/G3 anemia (31%), G2/G3 rash (31%). Two dose-limiting toxicities (DLTs) were observed in 5 patients treated in DL 1: G3 rash and G3 AST/ALT elevation attributed to both drugs. Six patients were treated at DL -1 without DLTs; this was identified as the RP2D. Two additional patients have been treated at this dose in Phase II of the study. By RECIST 1.1 criteria, one patient (8%) achieved a partial response (BRCA1 mutation) and three (23%) achieved stable disease resulting in a clinical benefit rate of 30.7%. Median duration of treatment was 12 weeks. One patient harboring a PALB2 VUS mutation remained on treatment for 21.7 months. Of 13 evaluable patients, there were 2 confirmed PSA responses (15%) (one patient without an HRD and one with a BRCA1 mutation). Conclusions: The combination of rucaparib and copanlisib is well tolerated. The RP2D was rucaparib 400mg BID with copanlisib 45mg (D1, D15; 28-day cycle) with signal of efficacy in patients with and without HRD. Clinical trial information: NCT04253262. Citation Format: Matthew J. Hadfield, Andre De Souza, Dragan Golijanin, Roxanne Wood, Adam Olszewski, Sheldon L. Holder, Wafik S. El-Deiry, Rahul Aggarwal, Anthony Mega, Benedito A. Carneiro. BrUOG360: A phase Ib/II study of copanlisib combined with rucaparib in patients with metastatic castration-resistant prostate cancer (mCRPC) [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 CT158.

Abstract CT078: First-line treatment with sintilimab (sin) vs placebo in combination with chemotherapy (chemo) in patients (pts) with unresectable gastric or gastroesophageal junction (G/GEJ) cancer: Final overall survival (OS) results from the randomized, phase III ORIENT-16 trial

Abstract Background: The phase III ORIENT-16 trial evaluated sin (a PD-1 inhibitor) versus placebo plus chemo as first-line (1L) treatment in pts with advanced G/GEJ adenocarcinoma. Sin+chemo previously showed a significant improvement in OS vs chemo in pts with PD-L1 combined positive score (CPS) ≥5 (HR 0.660; 95% CI 0.505-0.864; P=0.0023) and in all pts (HR 0.766; 95% CI 0.626-0.936; P=0.0090), with a median follow-up of 18.8 months (m) at interim analysis (Xu, et al. Ann Oncol 2021). Here we report the results from the final analysis (NCT03745170). Methods: This double-blind, phase III trial enrolled 650 pts ≥18 years of age with untreated, unresectable, locally advanced, or metastatic G/GEJ adenocarcinoma, regardless of PD-L1 expression. Pts were randomized 1:1 to receive sin (3 mg/kg in pts weighing &amp;lt;60 kg or 200 mg in pts weighing ≥60 kg, IV Q3W) or placebo plus chemo (oxaliplatin 130 mg/m2 IV Q3W for up to 6 cycles, capecitabine 1000 mg/m2 PO Bid d1-14 Q3W) for 24 months. The primary endpoints were OS in pts with CPS ≥5 and all randomized pts. The data cutoff date for the final analysis was Sep 2, 2022. Results: With a median follow-up of 33.9 m, sin+chemo continued to show OS benefit over chemo in all pts (15.2 vs 12.3 m; HR 0.681 [95% CI: 0.571, 0.812]; P&amp;lt;0.0001); estimated OS rates at 24 and 36 m for sin+chemo vs chemo were 37.6% vs 20.6% and 26.0% vs 10.7%, respectively. OS benefits with sin+chemo vs chemo across subgroups were generally consistent with the previous report. The updated PFS was superior with sin+chemo vs chemo (HR 0.638, 95% CI 0.530-0.768; P&amp;lt;0.0001). The updated confirmed ORR per RECIST v1.1 was 58.2% vs 48.8% in all pts with measurable disease at baseline, with a median DoR of 9.9 vs 7.0 m, respectively; 47.8% of responders in sin+chemo group and 25.9% of responders in chemo group had DoR ≥12 m. In pts with CPS ≥5, significant OS benefit (median OS 19.2 vs 12.9 m; HR 0.587 [95% CI: 0.467, 0.738]; P&amp;lt;0.0001) and superior PFS (HR 0.621, 95% CI 0.490-0.787; P&amp;lt;0.0001) with sin+chemo over chemo remained. A delayed numerical OS improvement was observed for subgroup pts with CPS &amp;lt;5. No new or unexpected safety signals were identified. Conclusion: The previously reported significant OS benefit with sin+chemo vs chemo was more evident in CPS ≥5 pts and in all pts with 15 m of additional follow-up, further confirming sin+chemo as a standard of care for 1L treatment of G/GEJ adenocarcinoma. Citation Format: Jianming Xu, Haiping Jiang, Yueyin Pan, Kangsheng Gu, Shundong Cang, Lei Han, Yongqian Shu, Jiayi Li, Junhui Zhao, Hongming Pan, Suxia Luo, Yanru Qin, Qunyi Guo, Yuxian Bai, Yang Ling, Yingmei Guo, Yuling Chen, Yan Wang, Hui Zhou. First-line treatment with sintilimab (sin) vs placebo in combination with chemotherapy (chemo) in patients (pts) with unresectable gastric or gastroesophageal junction (G/GEJ) cancer: Final overall survival (OS) results from the randomized, phase III ORIENT-16 trial [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 CT078.

Safety and efficacy of GEMOX plus donafenib and tislelizumab as first-line therapy for advanced epithelial malignant biliary tract cancer.

This study was aimed to evaluate the safety and the efficacy of gemcitabine and oxaliplatin (GEMOX) combined with donafenib plus tislelizumab as the first-line treatment for patients with unresectable biliary tract cancer (BTC). This is a prospective single-center exploratory study. Eligible patients (Stage III/IV BTC, at least one measurable disease according to RECIST v1.1, etc.) received gemcitabine 1000 mg/m2 IV Q3W, oxaliplatin 100 mg/m2 IV Q3W, donafenib 200 mg PO BID, and tislelizumab 200 mg IV Q3W until disease progression, unacceptable toxicity, or withdrawal of consent whichever occurred first. The primary endpoint was safety and secondary endpoints included disease control rate (DCR), objective response rate (ORR), conversion rate, and overall survival (OS). A total of 13 patients were enrolled. The median follow-up time was 420 days (range 345-487). The median duration of treatment was four cycles (range 1-15). The incidence of ≥Grade 3 treatment-related adverse events (TRAEs) was 53.8% and no Grade 5 TRAE. The most frequent Grade 3-4 TRAEs were rash (4/13, 30.8%), platelet count decreased (2/13, 15.4%), and fatigue (2/13, 15.4%). Tumor response was assessed in eight evaluable patients; ORR was 25.0% (95% CI, 3.2%-65.1%) and DCR 87.5% (95% CI, 47.3%-99.7%). The median PFS was 4.8 months (95% CI, 1.25-NE). Three Stage III patients underwent subsequent surgery with a conversion rate of 23.1%. The median OS was not estimable. GEMOX combined with donafenib plus tislelizumab as the first-line therapy for unresectable BTC showed manageable toxicity and encouraging efficacy especially in terms of promising conversion rate in Stage III patients.

Abstract 475: Preclinical development of ABM-168, a novel MEK Inhibitor to treat cancer with brain tumors

Abstract The Mitogen-Activated Extracellular Signal-Regulated Kinase (MEK) is a critical member of the MAPK signaling pathway family. In cancer cells, the abnormality in MAPK pathway associates with the mutation occurred in the upstream KARS or BRAF. Blockage of the pathway with MEK1/2 inhibitors result in inhibiting cell proliferation and inducing apoptosis. It hence has the potential for clinical benefits for treating cancers with RAS/RAF dysfunctions.ABM-168 is a novel small molecule, allosteric, highly selective MEK inhibitor with high water solubility, cell permeability and brain penetration. We have demonstrated its anti-cancer efficacy in vitro in multiple cancer cell lines, and in vivo in several xenograft, subcutaneous, intracardiac and intracranial, animal models. In-vitro data showed the similar on-target enzyme activity of ABM-168 to marketed MEK inhibitors, as well as high anti-proliferation activities (IC50 &amp;lt;30nM) in multiple cancer cell lines with BRAF or RAS or NF1 mutation like A375, Colo-829, HT-29, MiaPaca-2, LN-229 etc. In vivo pharmacology studies demonstrated that ABM-168 had good potencies of tumor growth inhibitions with oral dose alone or combo with other drugs or compounds in multiple xenograft cancer models: In an A375-luc intracardiac melanoma metastatic model, ABM-168 at 2 mg/kg PO BID demonstrated an antitumor activity comparable to ABM-1310 (A highly BBB-permeable BRAF inhibitor developed by ABM Therapeutics) at different dose levels and frequencies. On Day 28, the BLI% decreased 95.5%, 93.2%, 99.44% and 99.7% for ABM-168 (2 mg/kg), ABM-1310 at 1 mg/kg PO QD, 5 mg/kg PO QD and 2.5 mg/kg PO BID, respectively. In a LN229 glioblastoma orthotopic model in BALB/c nude mice, ABM-168 at 5-10 mg/kg PO QD showed a significant activity, the BLI (%) decreased in the brain 68 % on Day 49. These results indicate that the BBB-permeable ABM-168 may be efficacious as a single agent or combo with ABM-1310 to treat BRAF-mutant, advanced cancers with or without brain metastases or primary CNS tumors with an abnormal up-regulated MAPK signal. Non-clinical pharmacokinetics studies also showed that ABM-168 had a favorable ADME profile both in vitro and in vivo, and good brain penetration in animals. Single-dose, seven-day repeat dose non-GLP studies and four-week GLP toxicity studies in SD rats and beagle dogs were all completed. Based on these supportive preclinical study results, the IND of ABM-168 was submitted in 2022 Q3 to investigate its safety in human, which will be followed by further clinic development as a single agent, or in combination with other molecules to treat advanced cancers resulted from the abnormal MAPK signal pathway, particularly with brain tumors. Citation Format: Chen Chen, Charles Huang, Min Xu, YouQin Chen, Lanjiao Zhao, Yang Chen, Yong Hu. Preclinical development of ABM-168, a novel MEK Inhibitor to treat cancer with brain tumors [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 475.

Abstract 3425: The discovery and characterization of CFT1946: A potent, selective, and orally bioavailable degrader of mutant BRAF for the treatment of BRAF-driven cancers

Abstract The BRAF kinase plays a critical role in the MAPK signaling pathway and is mutated in ~8% of all human cancers including melanoma (~60%), thyroid (~60%), and lung adenocarcinoma (~10%). The most common mutation in BRAF is V600E (Class I), which is found in &amp;gt;70% in these cancers. Despite the clinical success of approved small molecule inhibitors of BRAF V600E (vemurafenib, dabrafenib and encorafenib), this remains an area of unmet medical need because nearly all patients progress, due to either primary or acquired resistance. A bifunctional degradation activating compound (or BiDACTM degrader) may address the liabilities of approved drugs by overcoming, or preventing the emergence of, resistance to BRAF inhibitors. Here we describe CFT1946, an orally bioavailable cereblon-based BiDAC degrader of BRAF V600 mutant proteins, and provide an overview of the medicinal chemistry path leading to its discovery. CFT1946 degrades BRAF V600 mutant proteins, while maintaining exquisite selectivity against the proteome, sparing wild type BRAF (BRAF-WT), ARAF, and CRAF. In A375 cells, CFT1946 potently degraded BRAF V600E and inhibited ERK phosphorylation and cell growth while having no effect in the mutant KRAS, BRAF-WT driven cell line HCT116. In the A375 xenograft model, oral delivery of CFT1946 at 10 mg/kg PO BID resulted in deeper and more durable tumor regression compared to a clinically relevant dose of encorafenib. Further evaluation of CFT1946 in an engineered, clinically relevant BRAFi-resistant A375 cell line (endogenous BRAF V600E + engineered expression of NRAS Q61K) demonstrated that CFT1946 both degraded BRAF V600E and caused a loss of viability in these cells, while treatment with encorafenib had no effect. In xenografts derived from this BRAFi-resistant cell line, oral dosing of CFT1946 as a single agent led to tumor growth inhibition, while treatment with a clinically relevant dose of encorafenib had no effect on tumor growth. Furthermore, dosing CFT1946 in combination with the MEK inhibitor, trametinib, resulted in significant tumor regression, whereas combining encorafenib with the same dose of trametinib had no effect. The medicinal chemistry campaign resulting in CFT1946 focused on the improvement of in vivo pharmacokinetics and rational linker design to achieve high oral bioavailability in a beyond Rule of 5 heterobifunctional degrader. The preclinical data presented herein support the planned Phase 1/2 clinical trial of CFT1946 for the treatment of BRAF-V600 mutant solid tumors. Citation Format: Yanke Liang, Mathew E. Sowa, Katrina L. Jackson, Jeffrey R. Simard, Bridget Kreger, Ping Li, Laura Poling, Joelle Baddour, Andrew Good, Hongwei Huang, Scott Eron, Christopher G. Nasveschuk, Robert Yu, Mark Fitzgerald, Victoria Garza, Morgan W. O’Shea, Gesine Veits, Jeremy Y. Yap, Moses Moustakim, Ashley Hart, Roman V. Agafonov, Grace Sarkissian, Joe S. Patel, Richard Deibler, Kyle S. Cole, David Cocozziello, Fazlur Rahman, Andrew J. Phillips, Elizabeth Norton, Adam S. Crystal, Roy M. Pollock, Stewart L. Fisher. The discovery and characterization of CFT1946: A potent, selective, and orally bioavailable degrader of mutant BRAF for the treatment of BRAF-driven cancers [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 3425.

Abstract OT3-05-01: Adaptive Multi-Drug Treatment of Evolving Cancers (AMTEC): A Phase II, Open-Label, Study of Olaparib in Combination with either Durvalumab, Selumetinib or Capivasertib, or Ceralasertib Monotherapy in Patients with Metastatic TNBC

Abstract BACKGROUND PARP inhibitors (PARPi) afford a rational therapeutic strategy in metastatic TNBC (mTNBC) due to the high incidence of dysregulated DNA damage repair mechanisms and high-level genomic instability that resemble tumors originating in germline BRCA-mutated carriers. However, PARPi monotherapy has limited efficacy in BRCA wild-type mTNBC; in BRCA mutant disease following initial response, compensatory mechanisms inevitably restore replication fork protection. AMTEC leverages pre- and on-therapy biopsies from a 4-week PARPi monotherapy run-in period for personalized biomarker-driven patient selection to interdict adaptive resistance to the PARPi. Data from our pilot study (NCT03544125) and from Arm 1 of AMTEC (olaparib + durvalumab) identified PI3K-AKT, RAS-MEK, and ATR/CHK1/WEE1 as targetable pathways contributing to PARPi adaptive resistance in individual participants. Clinically validated assays (DNA, RNA, and protein) enable the identification of cellular mechanisms of PARPi sensitivity and resistance in individual patients and further reveal combined drug treatments that could prevent emergence of PARPi resistance. METHODS AMTEC is a non-comparative, multi-arm, open-label, phase II study to assess the efficacy of combining olaparib (ola) with durvalumab (dur), or MEKi, selumetinib (sel), or AKTi, capivasertib (cap), or monotherapy with ATRi, ceralasertib, (cer mono) in mTNBC patients. Participants with biopsy proven mTNBC (ER&amp;lt; 10%, PR&amp;lt; 10%, and HER-2 non-amplified), AR&amp;lt; 80% are eligible. - Participants undergo a pre-treatment biopsy, then start a 28-day induction with ola (300 mg PO BID, D1-28). On C1D14, patients undergo a repeat, on-treatment biopsy. Clinically validated assays (DNA, RNA, protein) from both biopsies inform patient assignment to a specific ola combination arm starting on C2D1: - Arm 1 tumor immune activated: ola + dur (1500 mg IV Q4W) - Arm 2 RAS-MEK-ERK pathway activation: ola + sel (BSA-based BID D1-28) - Arm 3 PI3K-AKT pathway activation: ola + cap (400 mg PO BID, 4 days on/3 days off) - Arm 4: If not eligible for Arms 1-3 (per biomarker selection criteria): Cer mono (240 mg PO BID D1-14) Endpoints: The primary endpoint is objective response rate (ORR per RECIST 1.1). Secondary endpoints include safety and toxicity, clinical benefit rate, duration of response, and survival. Statistical Methods: - Arm 1 will enroll 28 patients to detect an ORR difference of 20% (H0: π = 0.15 and Ha: π =0.35). Arm 1 will continue on to stage 2 if ORR ≥3 of the first 15 patients. The null hypothesis for Arm 1 is rejected if ≥ 7/28 patient achieve a response. - Arms 2, 3, and 4, will each enroll 22 patients to detect an ORR difference of 25% (H0: π = 0.15 and Ha: π =0.40). Arms 2, 3, and 4 will each continue on to stage 2 if ORR ≥2 of first 11 patients in each arm, respectively. The null hypothesis for Arm 2, 3, and 4 is rejected if ≥ 7/22 patients achieve a response in each arm, respectively. For arms 2 and 3, if there are ≥5/11 responses, the trial will open a biomarker negative expansion cohort for each arm (N = 19 patients/arm). ENROLLMENT The study was activated on 1/7/2019. Arm 1 met pre-specified interim analysis criteria in 12/2020, and accrual to stage 2 began in 1/2021. Arms 2, 3, and 4 start enrolling in Q4 of 2022. Up to 132 patients will be enrolled. Clinical trial information: NCT03801369 Contact information: For more information or to refer a patient, email hobbev@ohsu.edu Citation Format: Evthokia Hobbs, Gordon Mills, Jeong Lim, Marlana Klinger, Kiara Siex, Sidney Huszti, Annie Yang, Danielle Galipeau, Christina Zheng, Lauren Murray, Becky Goodford, Nicholas Marter-Sanders, Anastasiya Olson, Jayne Stommel, Brett Johnson, Jamie Keck, Ben Kong, Allison Solanki, Shaun Goodyear, Christopher Corless, Joe Gray, Mitri Zahi. Adaptive Multi-Drug Treatment of Evolving Cancers (AMTEC): A Phase II, Open-Label, Study of Olaparib in Combination with either Durvalumab, Selumetinib or Capivasertib, or Ceralasertib Monotherapy in Patients with Metastatic TNBC [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-05-01.

Abstract OT3-11-02: SOLTI-1910: Predicting olaparib sensitivity in patients with unresectable locally advanced/metastatic HER2-negative breast cancer with BRCA1/2, PALB2, RAD51C/D mutations or HRD by the RAD51 test: RADIOLA TRIAL

Abstract Background The OlympiAD trial evaluated the PARP inhibitor (PARPi) olaparib versus a non-platinum standard chemotherapy in HER2-negative metastatic breast cancer (MBC) patients with a germline BRCA1/2 (gBRCA) mutation. Olaparib resulted in improved progression-free survival (PFS) and doubled the response rate vs chemotherapy. Nevertheless, the response rate to PARPi is 60% in the gBRCA1/2 population with MBC (current approval), suggesting a limited positive predictive value of gBRCA1/2 status. Moreover, patients with other relevant Homologous Recombination Repair defects (HRD) such as PALB2 or RAD51C/D mutation carriers, or HRD epigenetic silencing, are not captured with a gBRCA analysis. We have previoulsy shown that the functional HRD biomarker RAD51, tested in FFPE tumor samples using an optimized immunofluorescence-based assay, is associated with platinum response in early TNBC and PARPi response in preclinical BC models. We hypothesize that the RAD51 test would help to expand the clinical benefit of PARPi by predicting response to olaparib in MBC with germline/somatic BRCA1/2, PALB2 or RAD51C/D mutation and beyond. Study design RADIOLA is an open-label, single-arm, multicentre phase II study evaluating treatment with olaparib in male or female ≥18 years patients with HER2-negative MBC with ≤ two prior chemotherapy lines in two cohorts: cohort 1 (N=41) with known germline/somatic BRCA1/2, PALB2 or RAD51C/D mutation; cohort 2 (N=25) with functional HRD, namely RAD51-low score (≤10%), in wild-type/unknown mutation status at study entry. All patients will receive olaparib 300mg po BID until progression or unacceptable toxicity. Primary objective will assess, in terms of overall response rate (ORR), the capacity of the RAD51 score to predict olaparib efficacy in cohort 1. Secondary objectives include PFS, clinical benefit rate, duration of response, safety in both cohorts and ORR in cohort 2. Recruitment Recruitment (11 sites) started in March 2022. As of July 2022, 7 patients have been enrolled in Spain. Funding This study is financially supported by AstraZeneca. Citation Format: Judith Balmaña, Tomás Pascual, Alba Llop-Guevara, Pablo Tolosa, Isabel Blancas, Maria-Eva Perez-Lopez, Barbara Adamo, Iris Teruel, Jose Ponce, Marta Gonzalez, Gemma Viñas, Laura Lema, Francisco Javier Salvador, Mª Teresa Martinez, Alejandra Espinosa, Aleix Prat, Violeta Serra. SOLTI-1910: Predicting olaparib sensitivity in patients with unresectable locally advanced/metastatic HER2-negative breast cancer with BRCA1/2, PALB2, RAD51C/D mutations or HRD by the RAD51 test: RADIOLA TRIAL [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-11-02.