Coté, Gregory M.

TPS11592 Background: Epithelioid hemangioendothelioma (EHE) is an ultra-rare vascular sarcoma with about 120 cases diagnosed in the US per year. Although it is commonly considered an indolent disease, in its aggressive form clinical outcomes are poor. Molecularly, EHE is characterized by the presence of oncogenic fusions with HIPPO pathway effectors TAZ or YAP; TAZ-CAMTA1 or YAP-TFE3. YAP/TAZ are modulators of mTORC1 in preclinical models, suggesting that mTOR inhibition may be an effective treatment mechanism for EHE. Nab-sirolimus is albumin bound sirolimus, which achieves higher intratumoral accumulation compared to oral sirolimus and has demonstrated increased antitumor activity in preclinical cancer models compared to the oral mTOR inhibitors sirolimus and everolimus. This is an open label, multi-center, single arm, phase II clinical trial with a two-stage design, testing nab-sirolimus for progressing or symptomatic EHE. The primary objective is to determine ORR of nab-sirolimus in patients with EHE who require systemic treatment. We hypothesize that nab-sirolimus will have significant clinical efficacy for EHE as measured by the primary endpoint of objective response rate, as well as by secondary outcomes including progression free survival benefit over historical controls and by improvement in patient reported outcomes (PROs). If positive, this trial could lead to a new standard of care for treating EHE. Methods: This is a single arm, multi-center, phase 2 study with a two-stage design. Key inclusion criteria include histologically or cytologically confirmed EHE that is either progressing or clinically symptomatic, not a candidate for curative intent surgery, and requires systemic therapy in the opinion of the investigator, radiographically evaluable disease by RECIST v1.1, age ≥18 years, ECOG performance status ≤ 2, and adequate end organ function. With a Simon two-stage optimal design with one sided alpha 0.10, power 90%, assuming a historical control ORR 5% to detect an ORR of 20% (alternative hypothesis), 12 patients will be included in the first stage. If there is ≥ 1 response, an additional 25 patients will be enrolled to a total of 37 patients. ≥ 4 responses are needed for a significant result. The total planned accrual is 41 patients to account for unevaluable patients who may be enrolled, 10% above the required evaluable patients. Planned post hoc subgroup analyses will include outcomes by fusion type and presence of serosal effusions at the time of study enrollment. The trial is registered at clinicaltrials.gov NCT07104331. Clinical trial information: NCT07104331 .

Abstract Background To determine if dose escalation improves outcomes for chondrosarcomas (CHS) of the base of the skull (BOS) and the cervical spine (CS). Methods A prospective, randomized, dose-escalation trial was designed for patients with CHS of the BOS and CS. Patients were randomly assigned to 70 Gy (RBE) or 76 Gy (RBE). The primary endpoint was local failure (LF). Secondary endpoints included overall survival (OS), cancer-specific survival (CSS), progression-free survival (PFS), and treatment-related toxicities. Results Between 1987 and 2007, 105 patients were randomized, median follow-up was 29.2 years (IQR, 26.7-32.4). Forty-six patients were assigned to 70 Gy (RBE) and 59 were assigned to 76 Gy (RBE). LF at 5-, 10-, and 20 years were 7%, 9%, and 11% for 70 Gy (RBE), and 10%, 15%, and 19% for 76 Gy (RBE) (P = .16). Like LF rates, there was no benefit in dose escalation for OS (P = .28) and CSS (P = .22). Progression-free survival at 5-, 10-, and 20 years was 93%, 89%, and 77% for the low-dose group and 83%, 71%, and 59% for the high-dose group (P = .069). Late RT injury ≥ grade 3 was reported in a total of 19 (18%) patients across both dose levels, with 11% in the low-dose group and 24% in the high-dose group (P = .13). Conclusions This is the first and largest trial of patients with grade I/II BOS and CS CHS evaluating dose escalation for tumor control. Proton-based RT is effective and safe for these tumors, but there is no apparent benefit in dose escalation. Clinical Trial Information NCT00592748.

AbstractBackgroundThis was a single‐arm, phase 2 clinical trial of Bavarian Nordic (BN)‐Brachyury vaccine plus radiotherapy (RT) designed to determine the objective response rate (ORR), progression‐free survival (PFS), and safety of the combination in chordoma.MethodsA total of 29 adult patients with advanced chordoma were treated with two subcutaneous priming vaccine doses of modified vaccinia Ankara‐Bavarian Nordic (MVA‐BN)‐Brachyury and one vaccine dose of fowlpox virus (FPV)‐Brachyury before RT. After RT, booster vaccinations were given with FPV‐Brachyury every 4 weeks for 4 doses, then every 12 weeks (week 110). A minimum RT dose of >8 Gy in one fraction for each target was required. Response was evaluated by modified Response Evaluation Criteria in Solid Tumors 1.1 (mRECIST), where only radiated lesions were considered targets, and by standard RECIST 1.1 in a subset of patients.ResultsTwo of 26 evaluable patients experienced durable partial response (PR) (ORR of 7.7%; 90% confidence interval [CI], 2.6–20.8]) by mRECIST 1.1. A total of 21 patients (80.8%; 90% CI, 65.4–90.3) had stable disease, and three patients (11.5%; 90% CI, 4.7–25.6) had progressive disease as best response per mRECIST 1.1. Median PFS was not reached during the study.ConclusionsThis trial confirms the safety of BN‐Brachyury and RT. Although the study did not meet the predefined study goal of four responses in 29 patients, we did observe two PRs and a PFS of greater than 2 years. For a vaccine‐based study in chordoma, an ultra‐rare disease where response rates are low, a randomized study or novel trial designs may be required to confirm activity.

PURPOSE Uterine leiomyosarcoma (uLMS) is an aggressive subtype of soft-tissue sarcoma with frequent metastatic relapse after curative surgery. Chemotherapy provides limited benefit for advanced disease. Multiomics profiling studies have identified homologous recombination deficiency in uLMS. In preclinical studies where olaparib and temozolomide provided modest activity, the combination was highly effective for inhibiting uLMS tumor growth. PATIENTS AND METHODS NCI Protocol 10250 is a single-arm, open-label, multicenter, phase II study evaluating olaparib and temozolomide in advanced uLMS. Patients with progression on ≥1 prior line received temozolomide 75 mg/m2 orally once daily with olaparib 200 mg orally twice a day both on days 1-7 in 21-day cycles. The primary end point was the best objective response rate (ORR) within 6 months. A one-stage binomial design was used. If ≥5 of 22 responded, the treatment would be considered promising (93% power; α = .06). All patients underwent paired biopsies that were evaluated with whole-exome sequencing (WES)/RNAseq and a RAD51 foci formation assay. RESULTS Twenty-two patients were evaluable. The median age was 55 years, and 59% had received three or more prior lines. Best ORR within 6 months was 23% (5 of 22). The overall ORR was 27% (6 of 22). The median progression-free survival (mPFS) was 6.9 months (95% CI, 5.4 months to not estimable). Hematologic toxicity was common (grade 3/4 neutropenia: 75%; thrombocytopenia: 32%) but manageable with dose modification. Five of 16 (31%) of tumors contained a deleterious homologous recombination gene alteration by WES, and 9 of 18 (50%) were homologous recombination-deficient by the RAD51 assay. In an exploratory analysis, mPFS was prolonged for patients with homologous recombination-deficient versus homologous recombination-proficient tumors (11.2 v 5.4 months, P = .05) by RAD51. CONCLUSION Olaparib and temozolomide met the prespecified primary end point and provided meaningful clinical benefit in patients with advanced, pretreated uLMS.

11507 Background: Single agent or combination chemotherapy, typically Dox- or gemcitabine-based, are standard 1st- and 2nd-line therapies in patients (pts) with metastatic LMS; however, objective response rates (ORR), progression-free, and overall survival (PFS/OS) remain inadequate. Lurbi (PharmaMar S.A. / Jazz Pharmaceuticals) binds to DNA inhibiting transcription and inducing double strand breaks leading to apoptosis and delaying S/G2 progression. In a prior pilot study, we showed Lurbi+Dox is well-tolerated, with signs of activity, particularly in LMS. We designed this phase 1b to optimize dosing to lead into a randomized (1:1) phase 2 trial of Dox+/-Lurbi in anthracycline-naïve LMS. Herein we provide updated efficacy and tolerability data for this Phase 1b cohort. Methods: Pts > 18 yrs with locally advanced/metastatic, unresectable non-GIST STS (Phase 1b only) w/o prior anthracycline or Lurbi/trabectedin, ECOG PS < 3, RECIST 1.1 measurable, and normal organ function were eligible. The phase 1b followed a 3+3 design. Dosing included fixed Lurbi (3.2 mg/m2 d1) with two Dox dose levels (DL; DL1: 25 mg/m2 d1; DL2 25 mg/m2 d1+8). All pts received GCSF prophylaxis. Tumor assessments were every 2 cycles. DL1 was chosen as RP2D and the phase 2 trial began accrual in Aug 2022 aiming to enroll 50 LMS pts randomized 1:1 (stratified by uterine LMS [uLMS]] v. other LMS) with PFS as primary endpoint. Pts progressing on Dox are allowed to cross to Lurbi monotherapy. Results: 10 patients were enrolled in Phase 1b. Histologies included 5 LMS (4 uLMS) and 1 each of myxofibrosarcoma (myxFS), undifferentiated pleomorphic sarcoma (UPS), dedifferentiated liposarcoma (DDLPS), endometrial stromal sarcoma (ESS), and solitary fibrous tumor (SFT). With a median follow-up of 344 days, 5/10 pts remain on treatment with median PFS of 357 days (95%CI 175-ND). 6 pts demonstrated partial response (PR; 5 confirmed), 3 with stable disease (SD), and 1 with progressive disease (PD, Table). Median time to PR was 81 days (range 46-207). Duration of response was over 132 days in all responders with 3 still on treatment. Treatment-related AEs were typical for Dox/Lurbi, including nausea, fatigue, and reversible LFT elevations/cytopenias. Updated safety and response data will be provided at the time of the meeting. Conclusions: Lurbi+Dox is well-tolerated with efficacy in STS including 6/10 pts achieving PR, 9/10 pts staying on treatment for >120d, and 6/10 pts >200d. The randomized phase 2 study is currently enrolling. Clinical trial information: NCT05099666 . [Table: see text]

Abstract Introduction: ATRi and PARPi combinations kill tumor cells via synergistic modulation of complementary DDR pathways but clinical utility is limited by overlapping toxicities. A genome-wide CRISPR-Cas9 screen identified DDR alterations that sensitize tumors to the ATRi camonsertib (cam) plus PARPi. Based on preclinical models, tolerability and efficacy of cam plus PARPi given intermittently at low doses in pts with solid tumors with DDR alterations, including BRCA-mutated PARPi-resistant cancers, was evaluated. Methods: Pts (≥ 18 yrs) with relapsed/refractory (r/r) solid tumors with DDR alterations were treated with cam plus talazoparib (tala), niraparib (nira), or olaparib (ola) in 2 phase I trials (NCT04497116, NCT04972110). An adaptive BOIN design was used to optimize dose/schedule. Endpoints were safety, recommended phase II dose (RP2D), pharmacokinetics (PK), response (RECIST v1.1 [confirmed/unconfirmed], CA 125, or PSA), clinical benefit rate (CBR; RECIST/tumor marker response or treatment duration ≥ 16 wk), and ctDNA molecular response rate (MRR; best reduction in mean variant allele frequency [mVAF] ≥ 50%). Results: As of Nov 2022, 99 pts were enrolled (61 with ≥ 3 prior lines of therapy, 36 PARPi-pretreated); 43, 27, 29 pts in tala, nira, and ola combinations, respectively. Tumors included ovarian (n=20), prostate (n=13), breast (n=17), bile duct (n=3); most common genotypes were ATM (n=26), BRCA1 (n=19), and BRCA2 (n=33). Grade 3+ toxicities included reversible myelosuppression (neutropenia, anemia, and thrombocytopenia in 35%, 28%, and 14% of pts overall; 33%, 16%, and 11% at preliminary RP2Ds), fatigue (3%), and alkaline phosphatase increase (2%). Two pts discontinued treatment due to drug-related toxicity. Forty pts remain on therapy, up to 63 wks. Preliminary RP2Ds: cam 80 mg QD (d 5-7) + tala 0.25 mg QD, 1 wk on/1 wk off; cam 80 mg QD + nira 100 mg QD, 2 d on/5 d off; cam 50 mg QD + ola 100 mg BID, 3 d on/4 d off. As of abstract submission, response rate was 13% in 85 evaluable pts; CBR was 49%. Responders included pts with ovarian (n=6), bile duct (n=2), and breast, pancreatic, and carcinoma of unknown primary (n=1 each) cancers harboring alterations in BRCA1/2 (n=9), IDH1 (n=1), and ATM (n=1). Of 30 evaluable PARPi-pretreated pts, response rate was 23% and CBR was 52%. MRR was 64% (14/22 evaluable); change in mVAF correlated with a change in target lesion size (r=0.63, P=0.001). PK of each drug in the combination was consistent with respective monotherapy PK. Conclusion: Combination of cam plus PARPi at low doses on intermittent schedules was generally well-tolerated with clinical activity in DDR-aberrant tumors, including those pretreated with PARPi. RP2D optimization and translational correlative studies are ongoing. Citation Format: Timothy A. Yap, Siddhartha Yadav, Benjamin Herzberg, Benedito A. Carneiro, Elisa Fontana, Martin Højgaard, Michael J. Pishvaian, Ruth Plummer, Theresa L. Werner, Vaibhav Sahai, Stephanie Lheureux, Elizabeth K. Lee, Niharika B. Mettu, Gregory M. Cote, Joseph D. Schonhoft, Victoria Rimkunas, Ian M. Silverman, Marisa Wainszelbaum, Gerson Peltz, Adrian J. Fretland, Kezhen Fei, Danielle Ulanet, Insil Kim, Maria Koehler, Ezra Rosen, Michael Cecchini. Safety and efficacy of three PARP inhibitors (PARPi) combined with the ataxia telangiectasia- and Rad3-related kinase inhibitor (ATRi) camonsertib in patients (pts) with solid tumors harboring DNA damage response (DDR) alterations [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 CT018.

TPS11592 Background: Single agent or combination chemotherapy regimens, typically including doxorubicin or gemcitabine, represent standard of care options for first- and second-line therapy in patients (pts) with metastatic LMS. However, response rates (ORR) and progression-free (PFS)/overall survival (OS) remain poor. Lurbinectedin (PharmaMar S.A. and Jazz Pharmaceuticals) uniquely binds DNA, inducing DNA double strand breaks leading to apoptosis and delaying progression through phase S/G2 of the cell cycle. Lurbinectedin is a novel structural analog of trabectedin with improved toxicity profile, potency, and pharmacokinetics. In a prior pilot study, we showed that the combination of lurbinectedin and doxorubicin (L+D) was safe, with early signs of clinical activity, particularly in LMS. Thus, we designed this investigator-initiated/investigator-sponsored phase 1b lead-in to optimize doses of L+D, to be followed by a randomized (1:1) phase 2 study of L+D versus doxorubicin monotherapy in anthracycline-naïve LMS. Methods: Pts age > 18 years with locally advanced or metastatic, unresectable LMS (non-GIST soft-tissue sarcoma histologies allowed in Phase 1b), without prior anthracycline or lurbinectedin/trabectedin, ECOG PS < 3, measurable disease by RECIST 1.1, and normal organ function, are eligible. Phase 1b dosing will include a fixed dose of lurbinectedin and two dose levels of doxorubicin. The Phase 1b lead-in follows a standard 3+3 design where dose escalation will occur if 0/3 or 1/6 patients experience a dose-limiting toxicity (DLT). Tumor assessments are conducted every two cycles. Once the recommended phase 2 dose (RP2D) is confirmed, Phase 2 will be initiated. Fifty pts will be randomized 1:1 including doxorubicin +/- lurbinectedin. Randomization will be stratified by uterine v. non-uterine origin of LMS. Pts progressing on single agent doxorubicin will be allowed to cross over to lurbinectedin monotherapy. The Phase 2 primary endpoint is PFS. Secondary endpoints include disease control rate, ORR, OS, PFS2 (for doxorubicin monotherapy patients who cross to lurbinectedin monotherapy). Archival tumor, germline DNA, and ctDNA will be collected for correlative studies exploring genomic markers of sensitivity/resistance. We will provide respective point estimate along with 90% confidence interval for each of the arms. Log-rank test will be performed to test the difference in survival (both PFS and OS) between groups. Regression analyses of survival data will be based on the Cox proportional hazards model. The first pt in dose-level 1 of the Phase 1b lead-in was enrolled in February 2022. Clinical trial information: NCT05099666.

11509 Background: uLMS is an aggressive sarcoma subtype of smooth muscle origin. Chemotherapy provides limited benefit for advanced disease. 18-25% of uLMS harbor deleterious alterations in homologous recombination (HR) DNA repair genes. uLMS exhibits high levels of replicative stress. These findings prompted a phase 2 study of O+T in pretreated uLMS where O+T demonstrated activity: ORR 27%, mPFS 6.9 mos (Ingham M. et. al. ASCO 2021: #11506) Methods: NCI protocol #10250 is a single-arm, multicenter, phase 2 trial evaluating O+T in advanced uLMS pts with progression on ≥1 prior line. Pre-treatment (Pre) and on-treatment (On) biopsies were collected from 22 pts. In prespecified analysis, we evaluated for a relationship between clinical outcomes and HR gene alterations by whole exome sequencing (WES), SLFN11/MGMT expression by RNAseq, and RAD51 foci formation (functional assay). HRD scores were calculated from WES using scarHRD. Gene expression was evaluated using a Spearman rank-order correlation analysis to identify genes associated with PFS (p < 0.01) and overexpressed in sensitive (S: PFS > 240d) or resistant (R: PFS < 240d) pts. Gene set enrichment analysis (GSEA) was performed (q = FDR-adjusted p value). Pts with available results: WES/RNAseq (16), Pre HRD score (13), Pre RAD51 foci (12). Results: 31% (5/16) pts had a mutation (Mut) or homozygous deletion (Hd) in the HR panel: ATRX Mut (2), ATR Mut, PALB2 Hd, RAD51B Hd. Pts with PALB2 and RAD51B Hd had longest PFS on study. Recurrent alterations also occurred in TP53 (56%) and RB1 (19%). Median HRD score in Pre samples was 51 (range 36-66) and 10/13 had HRD scores ≥ 42. Pre and On SLFN11 and MGMT RNA expression were not correlated with ORR/PFS. 6/13 Pre samples were HR-deficient by the RAD51 foci assay. Of pts with PFS ≥ 200d, 4/6 were HR-deficient. In Pre samples, 81 genes were overexpressed in S pts and 73 in R pts. In On samples, 146 genes were overexpressed in S pts and 127 in R pts. In On samples, GSEA identified the epithelial-mesenchymal transition enriched in S pts (q = 3.38e-7) and cell cycle pathways (E2F targets, G2M checkpoint) in R pts (q = 7.43e-4). Only 2 genes, CXCL10 and PCDH15, were differentially expressed between paired Pre and On samples (both increased in On). Gene expression signatures for replicative stress showed borderline association with worse PFS. Conclusions: Most uLMS tumors exhibit HR defects as measured by HRD scores. A subset of pts with greater benefit from O+T were identified by WES for HR genes and the RAD51 assay. There was no correlation between SLFN11 and MGMT expression and outcomes. GSEA identified pathways differentially expressed in S and R pts in On samples. O+T induced CXCL10 which has been associated with T-cell trafficking to tumors. A randomized phase 3 trial of O+T versus investigator’s choice is planned. These results provide insight into which pts may benefit most from this novel drug combination. Clinical trial information: NCT03880019.

11550 Background: RPS often have local recurrence (LR) after surgery. Preoperative radiation (RT) to 50.4 Gy can reduce LR risk but is not uniformly effective, especially after (+) margin resections. Therefore, we conducted a multi-institutional, prospective Phase II study to assess efficacy and tolerability of preop IMPT with selective dose escalation to 63 GyRBE to the posterior RPS margin (clinical target volume [CTV] 2) at high risk for (+) margins to further reduce the risk of LR. This dose was tolerable in a prior phase I study (DeLaney T et al, 2017, PMID:28740917). Methods: Primary RPS patients (pts) >18 years received preop IMPT, 50.4 GyRBE in 28 fractions (fx) of 1.8 GyRBE to CTV1 (tumor plus adjacent tissue at risk of subclinical disease) with SIB to CTV2 to 63.0 GyRBE in 28 fx of 2.25 GyRBE. Pts with high-grade tumors could get chemotherapy(CTX) prior to IMPT. To avoid treatment delay, 11 fx of IMRT x-rays could be substituted for IMPT. Pts had restaging and surgery 4-8 weeks after IMPT. Primary study endpoint was local tumor control. Secondary endpoints included clinical and pathologic response, surgical margin status, and disease-free and overall survival. Results: We accrued 60 pts from January 2016 to February 2021. Histology: 35 liposarcoma(LPS) (19 dediff and 16 well diff), 22 leiomyosarcoma(LMS), and 3 undifferentiated pleomorphic sarcoma. IMPT was delivered per protocol in all pts. 51 pts have had surgery, 5 are awaiting surgery, and 4 had no surgery due to metastases(DM) on preop imaging. 22 pts had (+) margins. 2 pts had > 75% necrosis. With 23-month median (range 1-52 months) follow-up after start of RT, there were two LRs. A dediff LPS pt had a well diff LPS LR 26 months postop, resected, and is disease-free. A renal vein/IVC LMS pt treated with CTX and IMPT had LR and DM 4 months postop and died from disease. Surgical Clavien-Dindo morbidity scores: 0(21), 1(9), 2(8), 3a (4), 3b(4), 4a(2), 4(b)1, 5(2); the periop deaths were from sepsis(pneumonia) and duodenal ulcer. The grade 3-4 periop morbidity included abscess(3), treated by catheter(2) or operative(1) drainage, prolonged hospital stays (2 pts with IVC LMS), small bowel obstruction (1), and late sigmoid colon anastomotic failure (1). Readmissions for lymphopenia(1), pneumoperitoneum (1), and volume overload (1). One late neuropathy was seen in a Type II diabetic pt with transient postop weakness after femoral nerve dissection who later had significant lower extremity weakness 3.75 years postop. Study was amended to reduce IMPT dose in diabetic pts. Conclusions: Preoperative IMPT with selective dose escalation to 63 GyRBE to the high risk posterior RPS margin is feasible. Early local control results with this approach appear promising. Some peri-operative morbidity was noted but appears to be in the expected range for RPS resections. Clinical trial information: NCT01659203.

11506 Background: Uterine leiomyosarcoma (uLMS) is an aggressive sarcoma subtype with frequent metastatic relapse. After failure of front-line chemotherapy, remaining options provide limited benefit (trabectedin: ORR 11%, mPFS 4.0 mos; pazopanib: ORR 11%, median PFS 2.9 mos; dacarbazine: ORR 9%, mPFS 1.5 mos). Recent molecular studies suggest uLMS harbors characteristic defects in the homologous recombination (HR) DNA repair pathway, including somatic biallelic BRCA2 deletion in 10%, implicating potential sensitivity to PARP-inhibitor based treatment approaches. In preclinical uLMS models in which temozolomide (T, an oral equivalent to dacarbazine) or the PARP inhibitor olaparib (O) showed limited single agent activity, the combination of T + O was highly effective in inhibiting uLMS tumor growth and promoting apoptosis. Methods: NCI protocol #10250 is a single-arm, open-label, multi-center phase II study evaluating T + O in advanced uLMS. Pts had progression on ≥ 1 prior line and ECOG PS ≤ 2. Pts received T 75 mg/m2 PO daily + O 200 mg PO BID days 1-7 in 21-day cycles. Primary endpoint was ORR. A one-stage binomial design was used. If ≥ 5/22 responded, the treatment was considered promising (95% power; α = 0.06). All pts underwent paired tumor biopsies. Correlative assays to evaluate for HR deficiency (whole exome sequencing/RNAseq, RAD51 foci formation) and for intrinsic PARP inhibitor resistance (SLFN11 expression) will be correlated with response. Results: 22 patients were evaluable (median age 55, median prior treatment lines 3). Median follow-up was 10.8 mos. Primary endpoint, ORR within 6 mos of initiating treatment, was 23% (5/22). Overall ORR was 27% (6/22). Median PFS was 6.9 mos (95% CI: 5.4 mos – not estimable (NE)). Median duration of response (DOR) was 12.0 mos (95% CI: 9.5 mos – NE). Hematologic toxicity was common (grade 3/4 neutropenia, 77%; thrombocytopenia 32%) but manageable with dose modification. Correlative assays are ongoing with plans to present at the meeting. An immunohistochemical assay for RAD51 foci has been adapted for uLMS samples and clearly distinguishes BRCA2- deleted and wild-type tumors. Conclusions: NCI 10250 met the prespecified primary efficacy endpoint of ORR in a population of patients with heavily pre-treated uLMS. Responses are durable (median DOR 12 mos). Correlative assays are being completed to evaluate whether uLMS tumors with HR deficiency or with preserved SLFN11 expression are most sensitive to T + O and may underlie durable responses. A randomized study of the combination is planned. Clinical trial information: NCT03880019.