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Supplementary Table 1 and 2 - PDF file 42K, Supplemental Table 1. Phospho-mTOR and Rictor immunoreactivity in CCCs and SACs. Supplemental Table 2. Effects of AZD8055 or RAD001 on cell cycle progression

Supplemental Table S1. Patient disposition Supplemental Table S2. M30 and M65 for cohorts with greatest number of patients Supplemental Table S3. m65 fragment for cohort 1-3 Supplemental Table S4. caspase measurements

Supplementary Figure 1 - PDF file 46K, Establishment of RAD001-resistant variant cell lines

The goal of this study was to examine the role of mTOR complex 2 (mTORC2) as a therapeutic target in ovarian clear cell carcinoma (CCC), which is regarded as an aggressive, chemoresistant histologic subtype. Using tissue microarrays of 98 primary ovarian cancers [52 CCCs and 46 serous adenocarcinomas (SAC)], activation of mTORC2 was assessed by immunohistochemistry. Then, the growth-inhibitory effect of mTORC2-targeting therapy, as well as the role of mTORC2 signaling as a mechanism for acquired resistance to the mTOR complex 1 (mTORC1) inhibitor RAD001 in ovarian CCC, were examined using two pairs of RAD001-sensitive parental (RMG2 and HAC2) and RAD001-resistant CCC cell lines (RMG2-RR and HAC2-RR). mTORC2 was more frequently activated in CCCs than in SACs (71.2% vs. 45.7%). Simultaneous inhibition of mTORC1 and mTORC2 by AZD8055 markedly inhibited the proliferation of both RAD001-sensitive and -resistant cells in vitro. Treatment with RAD001 induced mTORC2-mediated AKT activation in RAD001-sensitive CCC cells. Moreover, increased activation of mTORC2–AKT signaling was observed in RAD001-resistant CCC cells compared with the respective parental cells. Inhibition of mTORC2 during RAD001 treatment enhanced the antitumor effect of RAD001 and prevented CCC cells from acquiring resistance to RAD001. In conclusion, mTORC2 is frequently activated, and can be a promising therapeutic target, in ovarian CCCs. Moreover, mTORC2-targeted therapy may be efficacious in a first-line setting as well as for second-line treatment of recurrent disease developing after RAD001-treatment. Mol Cancer Ther; 12(7); 1367–77. ©2013 AACR.

Figure S6 shows the association of circulating cytokine levels with objective clinical response.

Purpose:A phase I clinical trial (GOG-9929) examined the safety and efficacy of adjuvant immune-modulation therapy with the checkpoint inhibitor ipilimumab [anti–CTL antigen-4 (anti–CTLA-4)] following chemoradiation therapy (CRT) for newly diagnosed node-positive human papillomavirus (HPV)-related cervical cancer. To better understand the mechanism of action and to identify predictive biomarkers, immunologic and viral correlates were assessed before, during, and after treatment.Patients and Methods:Twenty-one patients who received CRT and ≥2 doses of ipilimumab and 5 patients who received CRT only were evaluable for translational endpoints. Circulating T-cell subsets were evaluated by multiparameter flow cytometry. Cytokines were evaluated by multiplex ELISA. HPV-specific T cells were evaluated in a subset of patients by IFNγ ELISpot.Results:Expression of the activation markers ICOS and PD-1 significantly increased on T-cell subsets following CRT and were sustained or increased following ipilimumab treatment. Combined CRT/ipilimumab treatment resulted in a significant expansion of both central and effector memory T-cell populations. Genotype-specific E6/E7-specific T-cell responses increased post-CRT in 1 of 8 HPV16+ patients and in 2 of 3 HPV18+ patients. Elevation in levels of tumor-promoting circulating cytokines (TNFα, IL6, IL8) post-CRT was significantly associated with worse progression-free survival.Conclusions:Our data indicate that CRT alone and combined with ipilimumab immunotherapy show immune-modulating activity in women with locally advanced cervical cancer and may be a promising therapeutic option for the enhancement of antitumor immune cell function after primary CRT for this population at high risk for recurrence and metastasis. Several key immune biomarkers were identified that were associated with clinical response.

Objective To evaluate how women with epithelial ovarian cancer (EOC), dichotomized by BRCA status, tolerate intravenous (IV) or intraperitoneal (IP) chemotherapy given with veliparib and bevacizumab (bev) on a GOG phase I study (GOG 9923, NCT00989651). Methods This is an unplanned, post hoc analysis of an IRB approved, multi-institutional, prospective study (GOG 9923). Clinical characteristics and toxicity data based on BRCA status were evaluated and descriptive statistics were used to summarize baseline patient characteristics and toxicities. The Kaplan Meier method was used to generate survival estimates. Results Four hundred twenty-four patients were evaluable. Patients were treated with IV carboplatin, paclitaxel, and bev every 21 days (regimen 1), weekly IV paclitaxel with carboplatin and bev (regimen 2) or IV paclitaxel and bev with IP cisplatin (regimen 3). Bev was continued as maintenance in all arms. Within each of these regimens, veliparib was given either twice daily for the entirety of each cycle (continuous) or on days −2 to 5 (intermittent). Ten percent of patients treated on regimen 1, 12% on regimen 2, and 19.8% on regimen 3 had BRCA-associated tumors. Patients with BRCA-associated tumors, when compared to wild type, experienced similar rates of anemia, febrile neutropenia (, abdominal pain, colonic perforation, nausea, vomiting, and peripheral sensory neuropathy. Median progression free survival (PFS) was not significantly different between BRCA-associated and wild type cancers (HR 0.96, CI 0.65–1.42), though this study's primary aim was not to evaluate outcomes. Conclusions Germline BRCA mutations positively affect chemosensitivity in EOC, but whether differences in toxicities among BRCA-associated and BRCA wild type tumors existed was previously not reported. In this population with newly diagnosed ovarian cancer no differences in reported toxicity between the two groups was observed.

Background: EP0057 (formerly CRLX101) is an investigational nanoparticle-drug conjugate (NDC) of a cyclodextrin-based polymer backbone plus camptothecin, a topoisomerase-1 inhibitor. Prior studies showed efficacy in recurrent or persistent, epithelial ovarian, fallopian tube or primary peritoneal cancer (EOC). Methods: This phase Ib/2 trial assessed safety and efficacy of EP0057 Q2W plus weekly paclitaxel in patients with EOC. The recommended phase 2 dose (RP2D) was identified using a 3+3 design. The single-arm phase 2 assessed overall response (ORR) per RECIST 1.1 in patients previously treated with bevacizumab. Secondary objectives included progression free survival (PFS) and duration of response. Results: The RP2D was established as 15 mg/m2 EP0057 Q2W plus 80 mg/m2 paclitaxel administered 3 weeks on/1 week off. Nine patients enrolled on phase 1b, with no DLTs; 21 additional patients enrolled on phase 2. All completed > 1 cycle. Median age was 62 (44-76) years, 57% ≥3 prior therapies. For the primary analysis, 6/19 patients with prior bevacizumab had confirmed responses (ORR=31.6% (95% CI: 15.4% to 54.0%)) including one complete response (CR). Median PFS was 5.4 months. Most common grade 3/4 adverse events attributed to treatment were decreased neutrophil count (13, 43%) and anemia (3, 10%). Conclusions: Although the observed ORR was not statistically better than the historical control rate, EP0057 remains an interesting option for treatment of recurrent EOC. EP0057 exhibits high plasma drug retention, slow clearance, and controlled slow release of CPT from the polymer when administered alone and with paclitaxel. (NCT02389985) 242 words

Purpose: A phase I clinical trial (GOG-9929) examined the safety and efficacy of adjuvant immune-modulation therapy with the checkpoint inhibitor ipilimumab [anti–CTL antigen-4 (anti–CTLA-4)] following chemoradiation therapy (CRT) for newly diagnosed node-positive human papillomavirus (HPV)-related cervical cancer. To better understand the mechanism of action and to identify predictive biomarkers, immunologic and viral correlates were assessed before, during, and after treatment. Patients and Methods: Twenty-one patients who received CRT and ≥2 doses of ipilimumab and 5 patients who received CRT only were evaluable for translational endpoints. Circulating T-cell subsets were evaluated by multiparameter flow cytometry. Cytokines were evaluated by multiplex ELISA. HPV-specific T cells were evaluated in a subset of patients by IFNγ ELISpot. Results: Expression of the activation markers ICOS and PD-1 significantly increased on T-cell subsets following CRT and were sustained or increased following ipilimumab treatment. Combined CRT/ipilimumab treatment resulted in a significant expansion of both central and effector memory T-cell populations. Genotype-specific E6/E7-specific T-cell responses increased post-CRT in 1 of 8 HPV16+ patients and in 2 of 3 HPV18+ patients. Elevation in levels of tumor-promoting circulating cytokines (TNFα, IL6, IL8) post-CRT was significantly associated with worse progression-free survival. Conclusions: Our data indicate that CRT alone and combined with ipilimumab immunotherapy show immune-modulating activity in women with locally advanced cervical cancer and may be a promising therapeutic option for the enhancement of antitumor immune cell function after primary CRT for this population at high risk for recurrence and metastasis. Several key immune biomarkers were identified that were associated with clinical response.

Summary Background High-grade serous ovarian cancers show increased replication stress, rendering cells vulnerable to ATR inhibition because of near universal loss of the G1/S checkpoint (through deleterious TP53 mutations), premature S phase entry (due to CCNE1 amplification, RB1 loss, or CDKN2A mRNA downregulation), alterations of homologous recombination repair genes, and expression of oncogenic drivers (through MYC amplification and other mechanisms). We hypothesised that the combination of the selective ATR inhibitor, berzosertib, and gemcitabine could show acceptable toxicity and superior efficacy to gemcitabine alone in high-grade serous ovarian cancer. Methods In this multicentre, open-label, randomised, phase 2 study, 11 different centres in the US Experimental Therapeutics Clinical Trials Network enrolled women (aged ≥18 years) with recurrent, platinum-resistant high-grade serous ovarian cancer (determined histologically) and Eastern Cooperative Oncology Group performance status of 0 or 1, who had unlimited previous lines of cytotoxic therapy in the platinum-sensitive setting but no more than one line of cytotoxic therapy in the platinum-resistant setting. Eligible patients were randomly assigned (1:1) to receive intravenous gemcitabine (1000 mg/m2) on day 1 and day 8, or gemcitabine plus intravenous berzosertib (210 mg/m2) on day 2 and day 9 of a 21-day cycle until disease progression or intolerable toxicity. Randomisation was done centrally using the Theradex Interactive Web Response System, stratified by platinum-free interval, and with a permuted block size of six. Following central randomisation, patients and investigators were not masked to treatment assignment. The primary endpoint was investigator-assessed progression-free survival, and analyses included all patients who received at least one dose of the study drugs. The study is registered with ClinicalTrials.gov , NCT02595892 , and is active but closed to enrolment. Findings Between Feb 14, 2017, and Sept 7, 2018, 88 patients were assessed for eligibility, of whom 70 were randomly assigned to treatment with gemcitabine alone (36 patients) or gemcitabine plus berzosertib (34 patients). At the data cutoff date (Feb 21, 2020), the median follow-up was 53·2 weeks (25·6–81·8) in the gemcitabine plus berzosertib group and 43·0 weeks (IQR 23·2–69·1) in the gemcitabine alone group. Median progression-free survival was 22·9 weeks (17·9–72·0) for gemcitabine plus berzosertib and 14·7 weeks (90% CI 9·7–36·7) for gemcitabine alone (hazard ratio 0·57, 90% CI 0·33–0·98; one-sided log-rank test p=0·044). The most common treatment-related grade 3 or 4 adverse events were decreased neutrophil count (14 [39%] of 36 patients in the gemcitabine alone group vs 16 [47%] of 34 patients in the gemcitabine plus berzosertib group) and decreased platelet count (two [6%] vs eight [24%]). Serious adverse events were observed in ten (28%) patients in the gemcitabine alone group and nine (26%) patients in the gemcitabine plus berzosertib group. There was one treatment-related death in the gemcitabine alone group due to sepsis and one treatment-related death in the gemcitabine plus berzosertib group due to pneumonitis. Interpretation To our knowledge, this is the first randomised study of an ATR inhibitor in any tumour type. This study shows a benefit of adding berzosertib to gemcitabine in platinum-resistant high-grade serous ovarian cancer. This combination warrants further investigation in this setting. Funding US National Cancer Institute.

BackgroundThe selective TRK inhibitor larotrectinib was approved for paediatric and adult patients with advanced TRK fusion-positive solid tumours based on a primary analysis set of 55 patients. The aim of our analysis was to explore the efficacy and long-term safety of larotrectinib in a larger population of patients with TRK fusion-positive solid tumours.MethodsPatients were enrolled and treated in a phase 1 adult, a phase 1/2 paediatric, or a phase 2 adolescent and adult trial. Some eligibility criteria differed between these studies. For this pooled analysis, eligible patients were aged 1 month or older, with a locally advanced or metastatic non-CNS primary, TRK fusion-positive solid tumour, who had received standard therapy previously if available. This analysis set includes the 55 patients on which approval of larotrectinib was based. Larotrectinib was administered orally (capsule or liquid formulation), on a continuous 28-day schedule, to adults mostly at a dose of 100 mg twice daily, and to paediatric patients mostly at a dose of 100 mg/m2 (maximum of 100 mg) twice daily. The primary endpoint was objective response as assessed by local investigators in an intention-to-treat analysis. Contributing trials are registered with ClinicalTrials.gov, NCT02122913 (active not recruiting), NCT02637687 (recruiting), and NCT02576431 (recruiting).FindingsBetween May 1, 2014, and Feb 19, 2019, 159 patients with TRK fusion-positive cancer were enrolled and treated with larotrectinib. Ages ranged from less than 1 month to 84 years. The proportion of patients with an objective response according to investigator assessment was 121 (79%, 95% CI 72-85) of 153 evaluable patients, with 24 (16%) having complete responses. In a safety population of 260 patients treated regardless of TRK fusion status, the most common grade 3 or 4 larotrectinib-related adverse events were increased alanine aminotransferase (eight [3%] of 260 patients), anaemia (six, 2%), and decreased neutrophil count (five [2%]). The most common larotrectinib-related serious adverse events were increased alanine aminotransferase (two [

BackgroundThere is a lack of data exploring the use and optimal timing of immunotherapy and chemoradiation therapy (CRT) in node-positive cervical cancer. Further translational research into mechanisms of response and resistance to immunotherapy in advanced cervical cancer is warranted.Primary Objective(s)To determine if sequencing of atezolizumab and CRT result in differential immune activation, as determined by clonal expansion of T cell receptor beta (TCRB) repertoires in peripheral blood on day 21.Study HypothesisThere is a difference for clonal expansion of T cell receptor beta repertoires in the peripheral blood at day 21 between the priming and concurrent atezolizumab and CRT in Arm A vs the concurrent atezolizumab and CRT in Arm B.Trial DesignLocally advanced cervical cancer patients with lymph node-positive disease will be randomized on this open-label, randomized trial with two experimental arms. Arm A will get one dose of atezolizumab prior to cisplatin CRT, and then two subsequent doses of atezolizumab during the CRT, and Arm B will get three doses during CRT. Patients will be followed for 2 years to assess outcomes.Major Inclusion/Exclusion CriteriaPatients must have histologically confirmed, newly diagnosed advanced cervical cancer (squamous cell carcinoma, adenocarcinoma, and adenosquamous cell carcinoma): FIGO 2009 clinical stages IB2/IIA with positive para-aortic nodes, or FIGO 2009 clinical stages IIB/IIIB/IVA with positive pelvic or para-aortic lymph nodes. Exclusion criteria include those who had a prior hysterectomy or lymph node dissection.Primary Endpoint(s)Clonal expansion of TCRB) repertoires in peripheral blood on day 21.Sample SizeThe sample size will be 40 patients.Estimated Dates for Completing Accrual and Presenting ResultsWe estimate accrual to finish by the summer of 2020 with presentation of results to follow in 2021.Trial RegistrationNCT03738228.

2643 Background: The B- and T-lymphocyte attenuator (BTLA) is an inhibitory receptor expressed on B, T and NK cells. Icatolimab (TAB004 or JS004) is a humanized IgG4 monoclonal antibody (mAb) with a hinge mutation (S228P) that binds BTLA and blocks its interaction with its ligand HVEM. In preclinical studies, icatolimab monotherapy suppressed tumor growth in murine tumor models using human BTLA knock-in mice. In this first-in-human dose-escalation study, we report the preliminary safety and efficacy of icatolimab as a single agent in patients with advanced solid tumors. Methods: Eligible patients with advance solid tumors refractory to standard therapies were enrolled in this study. Icatolimab was administered at escalating doses of 0.3, 1, 3 and 10 mg/kg intravenously Q3W and followed by dose expansion in 3 and 10 mg/kg cohorts until disease progression or intolerable toxicity. Dose-limiting toxicity (DLT) was evaluated by a safety monitoring committee. Study objectives included safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity. Results: A total of 25 patients with solid tumor were enrolled in the Part A of this phase I study (NCT04137900). The median age was 62 (range 32-85) years with 16 (64%) male patients. Patients were heavily pretreated with a median of 4 prior lines of therapy. Fifteen (60%) patients received and progressed upon prior anti-PD-1/L1 therapy. By the data cutoff date of December 31, 2021, the median follow-up was 32 weeks. No DLT was observed. 24 (96%) patients experienced treatment emergent adverse event (TEAEs), with 7 (28%) experienced grade 3 TEAEs. No grade 4 or 5 TEAE occurred. The incidence or severity of AE was not associated with the dose. The most common TEAEs were fatigue (32%), abdominal pain (20%), diarrhea (16%), arthralgia (16%), aspartate aminotransferase increased (16%), constipation (16%), and contusion (16%). One (4%) TEAE led to discontinuation of study drug. Four (16%) patients experienced immune related AE. Among 19 evaluable patients by the cutoff date, 1 confirmed PR (melanoma) and 6 SD were observed as assessed by the investigator per RECIST v1.1. The response was still ongoing over 12 months in the melanoma patient who had progressed upon prior nivolumab and BRAF/MEK inhibitors treatments. BTLA receptor was fully occupied in the 3 and 10 mg/kg cohorts. The mean elimination half-life of icatolimab was 7.5 to 19.2 days in four dose cohorts. Biomarker analysis indicated co-expression of HVEM and CD8 was associated with favorable response. Conclusions: Icatolimab monotherapy were well tolerated in all doses evaluated and showed preliminary clinical efficacy as a monotherapy. Icatolimab in combination with toripalimab (anti-PD-1) for the treatment of patients with advanced solid tumors is currently ongoing. Clinical trial information: NCT04137900.

TPS5622 Background: STRO-002 is a novel FolRα targeting ADC, generated using cell-free antibody production and site-specific conjugation technology. STRO-002 demonstrates potent in vitro cytotoxicity in EOC cell lines and anti-tumor activity in xenograft models, including induction of immunogenic cell death. STRO-002 is currently being studied as a single agent in ovarian and endometrial cancer (Phase 1 Study STRO-002-GM1; NCT03748186). Preliminary efficacy data in relapsed/progressive platinum resistant EOC compared favorably to standard chemotherapy (Naumann W., et al, ASCO 2021). Pre-clinical models tested with STRO-002/bevacizumab combinations demonstrated additive anti-tumor activity compared to monotherapy. This study is a first in human study of STRO-002 plus bevacizumab in patients with advanced ovarian cancer that have progressed on standard therapy. Methods: STRO-002-GM2 is a Phase 1, open-label, multicenter, dose escalation study with a standard 3+3 design with a 21-day dose-limiting toxicity (DLT) assessment period followed by dose expansion. The study will assess safety, establish recommended phase 2 dose (RP2D), and preliminary efficacy of STRO-002/bevacizumab combination in patients with recurrent high-grade EOC. Bevacizumab will be administered at the labeled dose of 15 mg/kg given with STRO-002 starting at 3.5 mg/kg, both administered IV q 3 weeks. Planned dose escalation doses of STRO-002 include 3.5, 4.3, and 5.2 mg/kg and will continue until MTD/MAD is reached. Additional intermediate dose level cohorts may be added for RP2D optimization. Once a cohort is cleared per dose escalation rules, up to 10 additional subjects may be enrolled and treated at that cleared dose level in order to obtain additional safety and efficacy data for RP2D determination and ungating of the expansion stage. Dose expansion will enroll approximately 40 patients treated at the RP2D. The patient population is relapsed high-grade EOC with up to 4 prior regimens. Subjects with primary platinum refractory disease will be enrolled in dose escalation only. Key inclusion criteria include: measurable disease, adequate bone marrow and renal function. Key exclusion criteria include: contraindication to receive bevacizumab and prior treatment with a FolRα ADC or ADC containing a tubulin inhibitor. Efficacy evaluation is per RECIST v1.1. Tumor tissue (archival or fresh biopsy) is required. Study oversight includes a Safety Evaluation Team. Samples will be collected to assess the PK and immunogenicity. No formal statistical hypothesis testing will be conducted in this study. This study is currently open for enrollment in the U.S. Clinical trial information: NCT05200364.

Introduction STRO-002 is a novel FRα-targeting ADC that delivers SC209, a potent tubulin-targeting hemiasterlin cytotoxin-warhead. Methods All patients in the ongoing dose escalation study (NCT03748186) had platinum resistant/refractory OC without selection for FRα expression. STRO-002 is given IV on Day 1 of each 21-day cycle. Results 38 patients have been dosed at 9 dose levels (0.5 to 6.4 mg/kg). Median number of cycles given is 3 (1–18). Median age is 61 (48–79). Median prior therapies - 5 (2–10). Clinically active doses (≥ 2.9 mg/kg) have been administered to 33 patients. 21/33 (64%) remain on treatment. Partial response was seen in 5 of 29 evaluable patients (17%) with 2 confirmed on second scan. 9 pts have confirmed SD for a clinical benefit rate of 48% (14/29). CA125 reduction of >50% was seen in 14/22 (64%) evaluable patients per GCIG. Clinical activity appears to be durable with 36% and 24% on study >16 and >24 weeks, respectively. 88% of AEs are grade 1 or 2. Grade 3–4 neutropenia, an expected and reversible effect of STRO-002 occurred in 15/38 (39%). DLTs reported – grade 3 neuropathy (6.0 mg/kg) and grade 3 bone pain (6.4 mg/kg). Conclusions STRO-002 is a novel FRα-targeting ADC with a promising emerging safety and efficacy profile and preliminary clinical benefit/disease control rate of 48% in patients with relapsed/refractory OC treated at ≥ 2.9 mg/kg. No ocular toxicity signals have been observed, suggesting potential differentiation from other FRα-targeting investigational therapies. Expansion cohorts in less heavily pre-treated patients are planned for 4Q20.

Neurotrophic tyrosine receptor kinase (NTRK) gene fusions lead to chimeric tropomyosin receptor kinase (TRK) fusion proteins, which act as primary oncogenic drivers in diverse tumor types in adults and children. Larotrectinib, a highly selective and central nervous system-active TRK inhibitor, has shown high objective response rates, durable disease control, and a favorable safety profile in patients with TRK fusion cancer. The impact of larotrectinib on health-related quality of life (HRQoL) was evaluated in adult and pediatric patients in two phase I/II clinical trials (NAVIGATE; NCT02576431 and SCOUT; NCT02637687). Patients completed HRQoL questionnaires (EORTC QLQ-C30, EQ-5D-5L, and PedsQL) at baseline and at planned treatment cycle visits. Changes in questionnaire scores were evaluated over time, and by tumor type and treatment response. Questionnaires from 40 adult and 17 pediatric (2-19 years of age) patients receiving larotrectinib were completed at baseline and at least one post-baseline timepoint. Meaningful within-patient HRQoL improvements occurred at one or more timepoints in 60% of adults and 76% of pediatric patients. Sustained improvements in EORTC QLQ-C30 and PedsQL scores were rapid, occurring within 2 months of treatment initiation in 68% and 71% of patients, respectively. Improvements were observed regardless of tumor type and appeared to correlate with clinical efficacy. The rapid within-patient HRQoL improvements in adult and pediatric patients with TRK fusion cancer are consistent with the clinical profile of larotrectinib. Our results provide valuable information for use of this agent in this patient population. A plain language summary of this article is available in the supplementary appendix.

Objective The study's purpose was to assess safety and efficacy of escalating doses of weekly GEN-1 with pegylated liposomal doxorubicin (PLD) in patients with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancers (EOC). Methods Patients had persistent or recurrent platinum-resistant EOC. The trial was a standard 3+3 phase I dose escalation design with patients receiving intravenous PLD 40mg/m 2 (dose level 1 and 2) or 50mg/m 2 (dose level 3) every 28days and intraperitoneal GEN-1 at 24mg/m 2 (dose level 1) or 36mg/m 2 (dose level 2 and 3) on days 1, 8, 15, and 22 of a 28day cycle. Cycles were repeated every 28days until disease progression. Patients were monitored for toxicity, clinical efficacy, and evidence of systemic and intraperitoneal immunologic effect. Results Sixteen evaluable patients received a median of 4cycles (range 1–8). No dose limiting toxicities were found. The adverse side effects were 4 grade 3 anemia, 2 grade 3 abdominal pain, 7 grade 3 neutropenia, and 2 grade 4 neutropenia. A clinical benefit of 57.1% (PR=21.4%; SD=35.7%) was found in the 14 patients with measurable disease. The highest number of partial responses (28.6%) and stable disease (57.1%) were found at dose level 3. The maximum tolerated dose was not reached. Increases in IL-12, IFN-γ, and TNF-α levels were found in peritoneal fluid following GEN-1 treatment. Conclusions GEN-1 in combination with PLD has encouraging clinical benefit and biological activity in recurrent or persistent EOC and warrants further investigation with escalating doses of GEN-1.

Importance Despite standard chemoradiotherapy (CRT), most women with lymph node (LN)–positive cervical cancer experience disease recurrence. Immunotherapy is being investigated in the up-front treatment setting. Objectives To assess the safety of sequential immunotherapy after CRT and to investigate human papillomavirus (HPV) genotype and HLA allele status on survival and programmed cell death 1 (PD-1) expression before and after CRT and sequential immunotherapy. Design, Setting, and Participants This prospective phase 1 trial conducted in 29 Gynecology Oncology Cooperative Group member institutions enrolled participants from December 18, 2012, to August 31, 2016, with a 14.8-month median follow-up and translational end points. Thirty-four women with International Federation of Gynecology and Obstetrics stage IB2 to IVA cervical cancer with positive pelvic LNs, para-aortic LNs, or both were enrolled; 13 did not receive ipilimumab and were excluded from the analysis. Data were analyzed from January 21 to April 4, 2018. Interventions Treatment consisted of 6 weekly doses of cisplatin, 40 mg/m2, concurrent with radiotherapy. After completion of chemotherapy, sequential ipilimumab was given every 21 days for 4 doses. Two dosage levels of ipilimumab, 3 mg/kg and 10 mg/kg, were studied to identify the maximum tolerated dose. Main Outcomes and Measures The primary end point was safety, and the secondary end points were overall survival and progression-free survival. Exploratory end points included HPV genotype, HLA allele status, and PD-1 expression measured in peripheral blood. Results The median age of the 32 participants included in the intent-to-treat analysis was 50 (range, 26-61) years, and 22 patients (69%) were white. Of the 21 patients who received ipilimumab, all had positive pelvic LN, and 6 (29%) had positive para-aortic LNs. All patients completed CRT, and of the 21 patients who received at least 2 cycles of ipilimumab, 18 (86%) completed 4 cycles of ipilimumab, and 3 (14%) completed 2 cycles. The maximum tolerated dose was 10 mg/kg. Two of the 21 patients (9.5%) who received ipilimumab had self-limiting grade 3 toxic effects (lipase increase; dermatitis). The 12-month overall survival was 90%, and progression-free survival was 81%. Human papillomavirus genotype and HLA subtype were not associated with progression-free survival or overall survival. T cells expressing PD-1 increased after CRT, and levels were sustained with ipilimumab. Conclusions and Relevance This study’s findings suggest that the use of immunotherapy after CRT for curative-intent treatment of patients with cervical cancer is tolerable and effective. The results indicated that PD-1 was upregulated after CRT and sustained with sequential ipilimumab therapy. These immune findings may help guide future therapies to harness the activated T-cell phenotype in patients with node-positive cervical cancer.

Importance Multiple immunostimulatory agonist antibodies have been clinically tested in solid tumors to evaluate the role of targeting glucocorticoid-induced tumor necrosis factor (TNF) receptor–related protein in anticancer treatments. Objective To evaluate the safety and activity of the fully human glucocorticoid-induced TNF receptor–related protein agonist IgG1 monoclonal antibody BMS-986156 with or without nivolumab in patients with advanced solid tumors. Design, Setting, and Participants This global, open-label, phase 1/2a study of BMS-986156 with or without nivolumab enrolled 292 patients 18 years or older with advanced solid tumors and an Eastern Cooperative Oncology Group performance status of 1 or less. Prior checkpoint inhibitor therapy was allowed. Monotherapy and combination dose-escalation cohorts ran concurrently to guide expansion doses beginning October 16, 2015; the study is ongoing. Interventions The protein agonist BMS-986156 was administered intravenously at a dose of 10, 30, 100, 240, or 800 mg every 2 weeks as monotherapy, and in the combination group 30, 100, 240, or 800 mg plus 240 mg of nivolumab every 2 weeks; same-dose cohorts were pooled for analysis. One cohort also received 480 mg of BMS-986156 plus 480 mg of nivolumab every 4 weeks. Main Outcomes and Measures The primary end points were safety, tolerability, and dose-limiting toxic effects. Additional end points included antitumor activity per Response Evaluation Criteria in Solid Tumors, version 1.1, and exploratory biomarker analyses. Results With a follow-up range of 1.4 to 101.7 weeks (follow-up ongoing), 34 patients (16 women and 18 men; median age, 56.6 years [range, 28-75 years]) received monotherapy (4 patients completed initial treatment), and 258 patients (140 women and 118 men; median age, 60 years [range, 21-87 years]) received combination therapy (65 patients completed initial treatment). No grade 3 to 5 treatment-related adverse events occurred with BMS-986156 monotherapy; grade 3 to 4 treatment-related adverse events occurred in 24 patients (9.3%) receiving BMS-986156 plus nivolumab, with no grade 5 treatment-related adverse events. One dose-limiting toxic effect (grade 4 elevated creatine phosphokinase levels) occurred in a patient receiving 800 mg of BMS-986156 plus 240 mg of nivolumab every 2 weeks; BMS-986156 with or without nivolumab exhibited linear pharmacokinetics with dose-related increase after a single dose. Peripheral T-cell and natural killer–cell proliferation increased after administration of BMS-986156 with or without nivolumab. No consistent and significant modulation of intratumoral CD8+T cells and FoxP3+regulatory T cells was observed. No responses were seen with BMS-986156 alone; objective response rates ranged from 0% to 11.1% (1 of 9) across combination therapy cohorts, with a few responses observed in patients previously treated with anti–programmed death receptor (ligand) 1 therapy. Conclusions and Relevance Based on this cohort, BMS-986156 appears to have had a manageable safety profile, and BMS-986156 plus nivolumab demonstrated safety and efficacy comparable to historical data reported for nivolumab monotherapy. Trial Registration ClinicalTrials.gov identifier:NCT02598960

BACKGROUND: Improvements in disease free survival for epithelial ovarian, peritoneal or fallopian tube cancer (EOC) will only come with improved primary therapy. Incorporation of poly-ADP-ribose inhibitors (PARPi) in the frontline setting may represent one strategy. This study sought to determine the maximum tolerated and feasible doses of the PARPi veliparib in combination with chemotherapy for EOC. METHODS: A phase I, 3+3 dose escalation evaluated dose-limiting toxicities (DLTs) in cycles 1–2. Once

5550 Background: STRO-002-GM1 is a Phase 1, open-label study in patients (pts) with advanced, platinum resistant or refractory EOC. STRO-002 is a novel FRα-targeting ADC with a precise DAR of 4 using site-specific conjugation technology to circumvent limitations of current ADCs. STRO-002 induces immunogenic cell death and contains the tubulin-targeting 3-aminophenyl hemiasterlin warhead SC209, a potent cytotoxin that is a weak substrate for P-gp. Methods: STRO-002 is given IV on Day 1 of each 21-day cycle until disease progression. Ocular exams are performed at baseline and every other cycle. Prophylactic corticosteroid eyedrops are not administered. FRα expression was not required for eligibility and retrospective analysis of FRα expression in archival tumor tissue is ongoing. Results: Enrollment has been completed with 39 pts treated at 9 dose levels (0.5 to 6.4 mg/kg). Data cut-off is Jan 30, 2021. Median age was 61 years (range 48-79). Median number of prior systemic therapies was 6 (range 2-11). 86% of treatment emergent adverse events (AEs) were Grade 1-2. The most common treatment related Grade 3 and 4 AEs were reversible neutrophil count decreased (36%) and neutropenia (33%), Grade 3 arthralgia (12.8%) and neuropathy (7.7%). Two pts developed neutropenic fever that resolved with antibiotic therapy. 34 pts were treated at clinically active doses (≥ 2.9 mg/kg) and 31/34 are evaluable for RECIST 1.1 response. Objective responses were seen in 10/31 pts - 1 CR, 4 confirmed PR, and 5 unconfirmed PR (imaging studies under review in 1 pt with uPR). Disease control rate (CR+PR+SD) is 74% at ≥ 12 weeks and 61% at ≥ 16 weeks. 5 pts remain on treatment with 3 ongoing at > 74 weeks. FRα-expression results are available in 14 pts treated at ≥ 2.9 mg/kg with 50% low, 21% medium and 29% high FRα-expressing tumors per PS2+ scoring algorithm. 12/13 pts with H-scores of ≥ 105 achieved disease control with PR or SD. Maximum plasma concentrations of STRO-002 were achieved at the end of the 1 hour infusion and exposure increased in an apparent dose proportionate/linear manner. Conclusions: STRO-002 is a novel FRα-targeting ADC with an encouraging emerging safety and efficacy profile in heavily pretreated relapsed/refractory EOC. No ocular toxicity signals have been observed. Durable responses and anti-tumor activity have been demonstrated across a broad range of FRα expression levels in evaluable pts treated at ≥ 2.9 mg/kg. 48% (15/31) of pts were on treatment without disease progression for ≥ 24 weeks and 13% (4/31) remain on treatment for over a year, suggesting that STRO-002 is well tolerated in long-term responding patients. A randomized expansion cohort comparing STRO-002 at 4.3 mg/kg vs 5.2 mg/kg dose levels in less heavily pretreated EOC pts is ongoing. Clinical trial information: NCT03748186.

Objective: Brain Metastasis (BM) from primary gynecologic cancers is a rare entity. The advances and successes in the treatment of primary gynecologic malignancies, have led to prolonged survival and, a higher incidence of BM. This study aims to report the experience at our institution in managing these patients, and provide possible data points that may be essential to note as prognostic factors, and see if our findings are consistent with the literature in this subject. We also aim to provide a brief literature review of patients with gynecologic cancers and BM. Methods: This is a small single institution retrospective study of 23 patients with a gynecologic malignancy and BM, identified between the years 2007-2015. Data were collected on variables including patient demographics, disease and treatment. Results: The median overall survival from the primary diagnosis was 28 months. Median time from diagnosis of BM to death was 9 months. Conclusion: The outcomes in our study are similar to what is stated in the current literature with regard to BM from gynecologic malignancies. Our literature search also revealed that the molecular analysis and treatment of the primary tumor remain important to prevent BMs. The tendency of tumors to metastasize varies for one tumor type to another for the same type of tumor. The tendency to develop BM may not only depend on risk factors such as stage, grade, and histology, but also on the genetic profile of the primary tumor. The study suggests that multimodal treatment of BM has better outcomes in managing BM from gynecologic cancers.

RGX-104, a first-in-class small-molecule LXR agonist modulates innate immunity and cancer progression via transcriptional activation of ApoE. ApoE protein suppresses tumor cell invasion and angiogenesis, and also depletes circulating and tumoral myeloid derived suppressor cells (MDSC), leading to T cell activation.A multivariate approach was used to address pharmacokinetic (PK) and pharmacodynamic relationships of RGX-104 in a phase 1 dose escalation study in patients with relapsed/refractory solid tumors. The study entailed multiple escalation arms with RGX-104 as monotherapy and in combination with nivolumab, ipilimumab, or docetaxel. Various markers including intratumoral ApoE and its receptor LRP1 in biopsy specimens, gene expression of LXR-targets in whole blood, serum markers including cytokines and lipids, as well as immune cell types such as MDSC, CD8 T-cells, and neutrophils in peripheral blood from patients were monitored at several time points. PK metrics were tracked to assess dose response relationships. Clinical outcomes such as objective response, time to disease progression, and duration on therapy were used for exploratory correlative analyses. A generally dose dependent increase in steady state exposure to RGX-104 was observed among all cohorts; the lowest efficacious exposure among patients with partial response was ~14,000 ng*h/mL. Treatment with RGX-104 at doses ranging from 120 mg BID to 240 mg BID induced expression of LXR targets, ApoE [2.7X (p=0.008) to 7.1X (p=0.007)] and ABCA1 [ 6.3X (p=1.20E-03) to 7X (p=8.1E-04] over baseline in a generally dose-dependent manner as assessed in whole blood. Similarly, MDSC depletion, ranging from 70%-90% relative to baseline, was observed in patients treated with RGX-104 along with concomitant CD8 T-cell activation; similar effects were noted in patients in combination cohorts. A model to explore dose dependency of change in immune cell types suggested that baseline levels of MDSC were most predictive of the magnitude of MDSC reduction after treatment, and that favorable clinical outcomes correlate with the extent of MDSC reduction and T cell activation. Low baseline levels of tumoral ApoE were associated with greater clinical benefit, with almost all patients with stable disease or partial response exhibiting ApoE tumor positive score of ≤20%; these patients also exhibited low/negative PD-L1 ( Citation Format: Monica Mita, Alan Mita, Erika Hamilton, Gerald S. Falchook, Michael Postow, Bartosz Chmielowski, Russell J. Schilder, James Strauss, Emerson Lim, Shubham Pant, Angela Jain, Oliver Rixe, Rebecca Redman, Kevin B. Kim, Tomislav Dragovich, R. Donald Harvey, Igor Puzanov, Nimisha Schneider, Renee Deehan, Tobi Guennel, Joe Lin, Sohail Tavazoie, Roger Waltzman, Eric Rowinsky, Michael Szarek, Subhasree Sridhar, Robert Busby, Narayan Lebaka, Celia Andreu, Isabel Kurth, David Darst, Masoud Tavazoie, Syed Raza, Robert Wasserman, Foster C. Gonsalves. Correlative analysis of pharmacokinetics and pharmacodynamics of RGX-104, a first-in-class Liver-X-Receptor (LXR) agonist, and clinical outcomes in patients with advanced solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-133.

Background: RGX-104 is a small-molecule LXR agonist that modulates innate immunity via transcriptional activation of the ApoE gene. Binding of ApoE to its receptor LRP8 robustly inhibits angiogenesis and depletes myeloid derived suppressor cells (MDSC), thereby activating cytotoxic T-lymphocytes. MDSCs are associated with resistance to both checkpoint inhibitors (CPI) and chemotherapy, providing a rationale for combination therapy with RGX-104. We previously reported results of the RGX-104 monotherapy dose escalation for which 26 patients with refractory solid tumors were treated in 5 dose cohorts. On-target AEs included hyperlipidemia and neutropenia. Flow-cytometry demonstrated MDSC depletion with associated T cell activation, which correlated with clinical benefit. A 40% disease control rate (DCR; SD+PR) was observed with a confirmed partial response (PR) by irRC (>79% reduction in index lesions) in a patient with platinum-refractory small cell lung cancer (SCLC). Methods: Here, we present the safety, biomarker and efficacy results of the docetaxel combination arm of the RGX-104 trial. Cohort 1- RGX-104 80 mg BID, and docetaxel at 35 mg/m2 days 1, 8, and 15 of a 28-day cycle; Cohort 2- RGX-104 80 mg BID, 5 days-on/2 days-off (5/2), and docetaxel at 28 mg/m2 on above schedule. Cohort 3- RGX-104 100 mg BID (5/2), and docetaxel as per cohort 2. Results: As of February 7, 2020, 11 patients with refractory solid tumors have been treated in 3 dose escalation cohorts with RGX-104 plus docetaxel. AEs were consistent with the individual toxicity profiles of docetaxel and RGX-104, with neutropenia being the most common AE and dose-limiting in cohort 1. The 5/2 dosing regimen in cohorts 2 and 3 resulted in significantly fewer episodes of neutropenia and no DLTs, while maintaining pharmacodynamic effects including >50% sustained MDSC depletion. A 66% DCR was observed in 9 evaluable patients including 2 patients in cohort 2 with PRs, a CPI-refractory SCCHN patient and a CPI-refractory melanoma patient, who remains on treatment at 36 weeks. A patient with melanoma in Cohort 3 had an initial assessment of SD and continues on study at 14 weeks. Clinical responses were associated with increases in T cell activation markers exceeding that generally observed with RGX-104 alone (up to a 5-fold increase in total CD8 T cells, a 7-fold increase in LAG-3+ CD8 T cells, and a 75-fold induction of serum IFNγ). Conclusion: The safety profile and marked pharmacodynamic and clinical activity of the RGX-104/docetaxel combination in CPI-refractory patients supports further development of this regimen. Consequently, the RGX-104/docetaxel regimen will be evaluated in a Phase 1b/2 expansion cohort in patients with relapsed/refractory ES-SCLC/high grade-neuroendocrine tumors. Citation Format: Emerson Lim, Erika P. Hamilton, Rebecca Redman, Michael A. Postow, Russell J. Schilder, Monica M. Mita, Alain C. Mita, Bartosz Chmielowski, James Strauss, Angela Jain, Shubham Pant, Olivier Rixe, Tomislav Dragovich, R. Donald Harvey, Igor Puzanov, Kevin B. Kim, Eric K. Rowinsky, Michael Szarek, Foster Gonsalves, Isabel Kurth, Celia Andreu, Robert W. Busby, David Darst, Masoud Tavazoie, Syed Raza, Narayan Lebaka16, Robert Wasserman, Gerald Falchook. RGX-104, a first-in-class immunotherapy targeting the liver-X receptor (LXR): Initial results from the phase 1b RGX-104 plus docetaxel combination dose escalation cohorts [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT146.

IMPORTANCE: There is an unmet medical need for the treatment of recurrent ovarian cancer, and new approaches are needed to improve progression-free survival (PFS) and overall survival. OBJECTIVE: This phase 1/2 study evaluated the activity of alisertib in combination with weekly paclitaxel in patients with breast (phase 1) and ovarian cancer (phase 1 and phase 2). DESIGN, SETTING, AND PARTICIPANTS: An open-label phase 1 and randomized phase 2 clinical trial conducted from April 16, 2010, for phase 1 and March 28, 2012, to August 12, 2013, for phase 2 was conducted at 33 sites (United States, France, and Poland). Data are reported from a cutoff date of August 12, 2014, with a median duration of follow-up of 7.2 months in the alisertib plus paclitaxel arm and 4.6 months in the paclitaxel arm. A total of 191 women with advanced breast (phase 1 only) or recurrent ovarian cancer were enrolled, including 142 patients randomized to alisertib plus paclitaxel (n = 73) or paclitaxel alone (n = 69) in the phase 2 study. INTERVENTIONS: Patients were randomized 1:1 stratified by platinum-free interval (refractory, 0-6 months, 6-12 months) and prior weekly taxane treatment (yes, no) to receive alisertib 40 mg twice per day orally and 3 days on and 4 days off for 3 weeks, plus paclitaxel (60 mg/m(2) intravenously, days 1, 8, and 15), or weekly paclitaxel 80 mg/m(2) intravenously in 28-day cycles. MAIN OUTCOMES AND MEASURES: Primary endpoint was PFS; primary efficacy analysis and safety analysis used modified intention to treat (mITT) population (all randomized patients who received ≥1 dose of study drug). RESULTS: The median age for the 191 patients enrolled in phase 1 was 59 (range, 29-75) years. The median age for the 142 patients enrolled in phase 2 was 63 (range, 30-81) years for patients receiving alisertib plus paclitaxel and 61 (range, 41-81) years for patients receiving paclitaxel. At data cutoff, 107 (75%) patients had a documented PFS event; 52 (71%) in the alisertib plus paclitaxel arm, and 55 (80%) in the paclitaxel arm. Median PFS was 6.7 months with alisertib plus paclitaxel vs 4.7 months with paclitaxel (HR, 0.75; 80% CI, 0.58-0.96; P = .14; 2-sided P value cutoff = .20 to be considered worthy of further investigation). Drug-related grade 3 or higher adverse events were reported in 63 (86%) vs 14 (20%) patients in the alisertib plus paclitaxel and paclitaxel arms, including 56 (77%) vs 7 (10%) neutropenia, 18 (25%) vs 0 stomatitis, and 10 (14%) vs 2 (3%) anemia; 54 (74%) vs 17 (25%) had adverse events leading to dose reductions. Two patients died during the study (1 in each arm); neither death was considered related to study drug. CONCLUSIONS AND RELEVANCE: The primary endpoint, PFS, significantly favored alisertib plus paclitaxel over paclitaxel alone. Further investigation is warranted. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01091428

Endometrial cancer is the most common gynecologic malignancy in developed countries. Its increasing incidence is thought to be related in part to the rise of metabolic syndrome, which has been shown to be a risk factor for the development of hyperestrogenic and hyperinsulinemic states. This has consequently lead to an increase in other hormone-responsive cancers as well e.g., breast and ovarian cancer. The correlation between obesity, hyperglycemia, and endometrial cancer has highlighted the important role of metabolism in cancer establishment and persistence. Tumor-mediated reprogramming of the microenvironment and macroenvironment can range from induction of cytokines and growth factors to stimulation of surrounding stromal cells to produce energy-rich catabolites, fueling the growth, and survival of cancer cells. Such mechanisms raise the prospect of the metabolic microenvironment itself as a viable target for treatment of malignancies. Metformin is a biguanide drug that is a first-line treatment for type 2 diabetes that has beneficial effects on various markers of the metabolic syndrome. Many studies suggest that metformin shows potential as an adjuvant treatment for uterine and other cancers. Here, we review the evidence for metformin as a treatment for cancers of the endometrium. We discuss the available clinical data and the molecular mechanisms by which it may exert its effects, with a focus on how it may alter the tumor microenvironment. The pleiotropic effects of metformin on cellular energy production and usage as well as intercellular and hormone-based interactions make it a promising candidate for reprogramming of the cancer ecosystem. This, along with other treatments aimed at targeting tumor metabolic pathways, may lead to novel treatment strategies for endometrial cancer.

Background Alisertib (MLN8237) is an investigational, oral, selective Aurora A kinase inhibitor. Aurora A contains two functional single nucleotide polymorphisms (SNPs; codon 31 [F/I] and codon 57 [V/I]) that lead to functional changes. This study investigated the prognostic and predictive significance of these SNPs. Methods This study evaluated associations between Aurora A SNPs and overall survival (OS) in The Cancer Genome Atlas (TCGA) database. The Aurora A SNPs were also evaluated as predictive biomarkers for clinical outcomes to alisertib in two phase 2 studies (NCT01045421 and NCT01091428). Aurora A SNP genotyping was obtained from 85 patients with advanced solid tumors receiving single-agent alisertib and 122 patients with advanced recurrent ovarian cancer treated with alisertib plus weekly paclitaxel (n = 62) or paclitaxel alone (n = 60). Whole blood was collected prior to treatment and genotypes were analyzed by PCR. Findings TCGA data suggested prognostic significance for codon 57 SNP; solid tumor patients with VV and VI alleles had significantly reduced OS versus those with II alleles (HR 1.9 [VI] and 1.8 [VV]; p, Highlights • Aurora A contains two single nucleotide polymorphisms (SNPs) at codons 31 and 57 that lead to functional amino acid changes • We evaluated the potential prognostic and predictive value of these SNPs and revealed the SNP at codon 57 may predict disease outcome and response to Alisertib in patients with solid tumors Alisertib, an investigational Aurora A kinase inhibitor, was evaluated in clinical trials and showed clinically meaningful benefit in patients with solid tumors. Two coding region single nucleotide polymorphisms (SNPs) in the Aurora A gene have been reported to be associated with functional changes of the protien. Here we assessed the prognostic and predictive value of Aurora A SNPs in a range of solid tumors. The results suggest that codon 57 SNP may predict disease outcome and response to alisertib in patients. These findings warrant further investigation and may ultimately provide a patient selection strategy for alisertib in certain cancers.

Purpose Intraperitoneal (IP) therapy improves survival compared to intravenous (IV) treatment for women with newly diagnosed, optimally cytoreduced, ovarian cancer. However, the role of IP therapy in recurrent disease is unknown. Preclinical data demonstrated IP administration of the proteasome inhibitor, bortezomib prior to IP carboplatin increased tumor platinum accumulation resulting in synergistic cytotoxicity. We conducted this phase I trial of IP bortezomib and carboplatin in women with recurrent disease. Methods Women with recurrent ovarian cancer were treated with escalating doses of IP bortezomib - in combination with IP carboplatin (AUC 4 or 5) every 21days for 6cycles. Pharmacokinetics of both agents were evaluated in cycle 1. Results Thirty-three women participated; 32 were evaluable for safety. Two patients experienced dose-limiting toxicity (DLT) at the first dose level (carboplatin AUC 5, bortezomib 0.5mg/m 2 ), prompting carboplatin reduction to AUC 4 for subsequent dose levels. With carboplatin dose fixed at AUC 4, bortezomib was escalated from 0.5 to 2.5mg/m 2 without DLT. Grade 3/4 related toxicities included abdominal pain, nausea, vomiting, and diarrhea which were infrequent. The overall response rate in patients with measurable disease (n=21) was 19% (1 complete, 3 partial). C max and AUC in peritoneal fluid and plasma increased linearly with dose, with a favorable exposure ratio of the peritoneal cavity relative to peripheral blood plasma. Conclusion IP administration of this novel combination was feasible and showed promising activity in this phase I trial of heavily pre-treated women with ovarian cancer. Further evaluation of this IP combination should be conducted.

The last decade has seen advances in knowledge about cancer cell function at the molecular level, the importance of the tumor cell microenvironment, and the advent of novel-targeted therapeutics that have improved outcomes for women with ovarian cancer (OC). In spite of this activity, most women will still succumb to their disease. Novel agents that are becoming available attempt to control disease by more specific targeting of cancer cells than traditional cytotoxic chemotherapeutics, bringing hope of more effective and less toxic treatments that have been developed based on growing knowledge about factors within tumor cells and their microenvironments. This chapter highlights some of the most important targets that have been identified in OCs, and the drugs that have been developed to target these pathways.

Objective To examine the tolerability and antitumor activity of trebananib plus pegylated liposomal doxorubicin (PLD) or topotecan in recurrent platinum-resistant or partially platinum-sensitive ovarian cancer. Methods In this open-label phase 1b study, patients received trebananib 10mg/kg or 15mg/kg IV QW plus PLD 50mg/m 2 (cohorts A1 and A3, respectively) or topotecan 4mg/m 2 (cohorts B1 and B3, respectively). Endpoints were dose-limiting toxicity (DLT; primary); treatment-emergent adverse events (AEs), overall response rate, anti-trebananib antibodies, and pharmacokinetics (secondary). Results 103 patients were enrolled. One patient in A1 and B1 had DLTs. Across all cohorts, the most common AEs were nausea, fatigue, and peripheral edema. Across both trebananib plus PLD cohorts (A1/A3), grade 4 AEs were pulmonary embolism, disease progression, and anemia. Two patients had grade 5 intestinal perforation (n=1) and sudden death (n=1). Across both trebananib plus topotecan cohorts (B1/B3), grade 4 AEs were neutropenia, hypokalemia, decreased granulocyte count, chest pain, dyspnea, decreased neutrophil count, and pulmonary embolism. Two patients had grade 5 disease progression. One patient had grade 5 pleural effusion associated with progressive disease. Confirmed objective response rates were 36.0% (A1), 34.8% (A3), 16.7% (B1), and 0.0% (B3). Median progression-free survival duration (months) was 7.4 (A1), 7.1 (A3), 3.5 (B1), and 3.1 (B3), respectively. No drug–drug interactions were apparent. Conclusions Trebananib 10mg/kg and 15mg/kg IV QW plus PLD or topotecan appear to have acceptable toxicity profiles in recurrent platinum-resistant or partially platinum-sensitive ovarian cancer. Antitumor activity was evident across all cohorts.

This open-label, multi-institutional phase II trial evaluated activity and safety of rilotumumab (AMG 102), a monoclonal antibody that targets HGF (hepatocyte growth factor), the ligand for the MET receptor, in women with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancer.Women were eligible for treatment with rilotumumab if they had measurable disease, a performance status of 0, 1 or 2, previously received platinum-based therapy with a progression-free interval of12 months or a second recurrence, and adequate bone marrow and organ function. Patients received rilotumumab 20mg/kg IV every 14 days until evidence of unacceptable toxicity or disease progression. The study utilized co-dual primary endpoints of tumor response and six-month PFS to assess the efficacy of rilotumumab. Secondary endpoints included the frequency and severity of adverse events and the duration of progression-free and overall survival.Thirty-one women enrolled and received rilotumumab. All were eligible for analysis. One patient achieved a complete response (3.2%; 90% CI 0.2-14%), and two women had 6-month PFS (6.5%; 90% CI 1.1-19%). Most adverse events were grade 1 or 2, with no grade 4 adverse events. Grade 3 adverse events were gastrointestinal (4), metabolic (3) anemia (3), a thromboembolic event (1), ventricular tachycardia (1), hypotension during infusion (1) and fatigue (1). The study was stopped after the first stage of accrual.Rilotumumab was well-tolerated, but had limited activity. The level of activity does not warrant further evaluation of rilotumumab as a single agent in patients with ovarian cancer.

Purpose To report outcomes following adjuvant high-dose-rate vaginal brachytherapy (VBT) with or without chemotherapy for high-intermediate risk (HIR) and high-risk, early stage endometrial cancer as defined in Gynecologic Oncology Group trial 0249. Material and methods From May 2000 to January 2014, 68 women with HIR and high-risk endometrial cancer underwent surgical staging followed by VBT. Median VBT dose was 21 Gy delivered in three fractions prescribed to 0.5 cm depth. Paclitaxel 175 mg/m2 and carboplatin area under the curve 6 was administered every 21 days in sequence with VBT. Actuarial survival estimates were calculated using the Kaplan-Meier method. Results Patient demographics included a median age of 66 years (range: 36-91) and stages IA (49%), IB (38%), and II (13%), respectively. Thirty-one (46%) patients had HIR disease with endometrioid histology, and 33 (48%) patients had serous or clear cell histology. Thirty-seven (54%) patients received a median 3 cycles (range: 3-6) of chemotherapy in addition to VBT, and 65 patients (96%) completed all prescribed therapy. During a median follow up of 33.1 months (range: 4.0-161.7), four patients have recurred, including one vaginal recurrence. The 3-year estimates of vaginal, pelvic, and distant recurrences were 1.9%, 2.4%, and 9.1%, respectively. The 3-year rates of disease-free and overall survival were 87.7% and 93.9%, respectively. Conclusions Early outcomes with adjuvant VBT with or without chemotherapy demonstrate high rates of vaginal and pelvic control for women with HIR disease. Early vaginal and pelvic relapses in high-risk patients suggest that pelvic external beam radiotherapy is warranted in this subgroup, but additional data from large phase III trials is warranted.

Introduction: FRα is overexpressed in 80% of OC and endometrial carcinoma (EC), with minimal expression in normal tissues. STRO-002 is a novel FRα-targeting ADC designed to circumvent limitations of current ADCs. STRO-002 was generated with Sutro’s cell-free antibody production system (XpressCF™) and site-specific conjugation (XpressCF+™) platform, which uses the non-natural amino acid pAMF. STRO-002 has a drug-antibody ratio (DAR) of 4 and contains the proprietary tubulin-targeting 3-aminophenyl hemiasterlin warhead SC209, a potent cytotoxin that is rapidly cleared and a weak substrate for efflux pumps. STRO-002 demonstrated potent cytotoxic activity in multiple FRα-positive tumor cell lines and significant therapeutic efficacy in OC xenograft models. Toxicology studies demonstrate dose-dependent and reversible neutropenia when STRO-002 is administered to cynomolgus monkeys. No ocular toxicity was observed. Herein we report additional preclinical efficacy in PDX models and preliminary safety experience of STRO-002 in patients (pts) with OC. PDX model methods: FRα expression was evaluated in EC PDX models by IHC. Single agent efficacy of 10 mg/kg STRO-002 was assessed in models with negative, low (+), medium (++) and high (+++) FRα expression. Phase 1 trial methods: STRO-002-GM1 is a first-in-human Phase I, open-label, multicenter, dose escalation (Part 1) study with dose expansion (Part 2) to identify the maximum tolerated dose (MTD), and recommended Phase II dose (RP2D) in pts with advanced, relapsed or refractory OC and EC. STRO-002 is given IV over an hour on Day 1 of each 21-day cycle until disease progression. Results: Statistically significant efficacy was observed in 60% of the FRα-positive PDX models tested, with STRO-002 response appearing to positively correlate with FRα expression levels. Though high FRα PDX models showed the highest response rates, some models with low and medium FRα also exhibited good responses. 5 pts with OC have completed at least one cycle (21 days) of STRO-002 at 3 dose levels: 0.5, 1.0, and 1.8 mg/kg and are evaluable for safety and toxicity. Median age is 63 (r, 52-64). Median ECOG performance status is 0 (r, 0-1). Median # of prior therapies is 6 (r, 2-8). Four pts have received PARP inhibitors. Median number of STRO-002 doses administered is 2 (r, 1-5). 3 additional pts have been treated at the 2.9 mg/kg dose level and continue in the first cycle. No grade ≥ 3 treatment-related adverse events (TRAEs) have been observed. 93% of AEs are grade 1 or 2. The most common TRAEs in ≥20 % of pts includes nausea, vomiting, abdominal pain, fatigue and insomnia. Four grade 3 events occurred in 2 pts after completion of the first cycle and were related to disease progression, including small intestine obstruction, gross hematuria, dehydration and vomiting. 2 pts have discontinued due to disease progression. 6 pts remain on treatment and dose escalation is ongoing. Conclusions: STRO-002 is the first ADC generated with cell-free protein synthesis technology and site-specific conjugation of a novel hemiasterlin linker-warhead to be tested in pts with solid tumors. The potent anti-tumor activity of STRO-002 in PDX models further supports the clinical development of this agent. The preliminary safety profile in 5 OC pts treated with STRO-002 is encouraging. MTD has not been reached, no DLTs have been observed and dose escalation is continuing. Updated results will be presented. This study is registered with clinicaltrials.gov identifier NCT03748186. Citation Format: Denise Uyar, Russell J Schilder, R Wendel Naumann, Fadi S Braiteh, Erika Hamilton, Sami Diab, John Moroney, Richard T Penson, Jennifer Smith, Cristina Abrahams, Michael Palumbo, Venita DeAlmeida, Shannon Matheny, Arturo Molina. Antitumor activity of STRO-002, a novel anti-folate receptor-α (FRα) antibody drug conjugate (ADC), in patient-derived xenograft (PDX) models and preliminary phase I dose escalation safety outcomes in patients with ovarian carcinoma (OC) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C095. doi:10.1158/1535-7163.TARG-19-C095

Background HGSOCs exhibit genomic instability and high replication stress due to universal loss of the G1/S checkpoint (via TP53 mutations), presence of homologous recombination alterations and induction via amplification of MYC and CCNE1 oncogenes. Based on in vitro and in vivo data, we hypothesized that addition of the selective ATR inhibitor M6620 to gemcitabine (gem) would demonstrate acceptable toxicity and superior efficacy in HGSOC. Methods We conducted a multicenter, open-label, RP2 study of gem/M6620 versus gem alone (1:1 randomization) in platinum resistant HGSOC. Randomization was stratified based on platinum free interval (PFI), (PFI≤3 months vs > 3 months). Primary endpoint was progression-free survival (PFS) while secondary endpoints included safety, objective response and clinical benefit rate. Unlimited prior lines but ≤1 prior regimen in the platinum resistant setting were allowed. Patients (pts) received gem 1000 mg/m2 IV on Days 1 and 8 with or without M6620 210 mg/m2 IV on Days 2 and 9 of a 21-day cycle until disease progression (PD) or intolerable toxicity. Pts on gem alone were allowed to crossover to gem/M6620 only if they developed PD by RECIST. In order to have 80% power to detect improvement of median PFS from 15 weeks with gem to 27.3 weeks with gem/M6620 (hazard ratio (HR) =0.55) with a one-sided alpha level of 0.1, 64 total pts were required. Results 70 pts were randomized, 36 to gem and 34 to gem/M6620 arms. Kaplan-Meier estimated median PFS was 14.7 weeks in the gem alone versus 22.9 weeks in the gem/M6620 arm; gem/M6620 HR was 0.57 (90% CI, 0.33-0.997; 1-sided log-rank test p = 0.047). The benefit of addition of M6620 was observed mainly among pts stratified into the PFI≤3 months group (HR = 0.31; 90% CI, 0.13-0.77; 1-sided p = 0.013); insignificant PFS difference between the two arms was observed among pts with PFI>3 months (HR = 0.95; 90% CI, 0.46-1.97; 1-sided p = 0.45). No increase in treatment-related toxic effects was observed in the gem/M6620 arm. Conclusions Addition of the ATR inhibitor M6620 to gem in platinum resistant HGSOC met the primary endpoint of this RP2 trial without increasing toxicity. Further evaluation of gem/M6620 in this setting is warranted. Clinical trial identification NCI CTEP: 9944; NCT02595892. Legal entity responsible for the study National Cancer Institute (NCI). Funding National Cancer Institute (NCI). Disclosure P.A. Konstantinopoulos: Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: Merck; Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: Tesaro; Advisory / Consultancy, Advisory Board: Vertex; Advisory / Consultancy, Advisory Board: Pfizer; Research grant / Funding (institution): Eli Lilly. R.T. Penson: Advisory / Consultancy, Advisory Board: AbbVie; Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: AstraZeneca; Advisory / Consultancy, Advisory Board: Clovis; Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: Tesaro; Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: Eisai; Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: Merck & Co; Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: Genentech/Roche; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Sanofi Aventis; Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: Vascular Biogenics; Advisory / Consultancy, Advisory Board: Sutro Biopharma; Advisory / Consultancy, Advisory Board: Mersana Therapeutics; Research grant / Funding (institution): Array Biopharma. L.R. Duska: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Cerulean; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Pfizer; Research grant / Funding (self), Research grant / Funding (institution): GlaxoSmithKline/Novartis; Research grant / Funding (institution): Morab; Honoraria (self), Research grant / Funding (institution): MorphoTek; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Research grant / Funding (institution): Aduro BioTech; Research grant / Funding (institution): Syndax; Research grant / Funding (institution): Ludwig; Research grant / Funding (institution): LEAP Therapeutics; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Lycera; Research grant / Funding (institution): Inovio; Advisory / Consultancy: Cue Biopharma; Research grant / Funding (institution): Advaxis. M.A. Crispens: Advisory / Consultancy: AbbVie; Research grant / Funding (institution): AstraZeneca. A.B. Olawaiye: Advisory / Consultancy, Advisory Board: Clovis; Advisory / Consultancy, Advisory Board: Tesaro. M.T. McHale: Advisory / Consultancy: Eisai; Research grant / Funding (institution): Verastem. R.J. Schilder: Advisory / Consultancy, Consultant: Incyte; Advisory / Consultancy, Consultant: Immunogen; Advisory / Consultancy, Consultant: Celsion; Advisory / Consultancy, Consultant: Flatiron. G.I. Shapiro: Advisory / Consultancy, Research grant / Funding (self): Eli Lilly; Advisory / Consultancy, Research grant / Funding (self): Merck KGaA/EMD-Serono; Research grant / Funding (self): Merck; Advisory / Consultancy, Research grant / Funding (self): Sierra Oncology; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: G1 Therapeutics; Advisory / Consultancy: Roche; Advisory / Consultancy: Bicycle Therapeutics; Advisory / Consultancy: Fusion Pharmaceuticals; Advisory / Consultancy: Cybrexa Therapeutics; Advisory / Consultancy: Astex; Advisory / Consultancy: Almac; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Bayer; Advisory / Consultancy: Angiex; Advisory / Consultancy: Daiichi Sankyo; Research grant / Funding (institution): Array Biopharma. U.A. Matulonis: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Myriad Genetics; Advisory / Consultancy: Clovis; Advisory / Consultancy: Merck; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Mersana; Advisory / Consultancy: Geneos; Advisory / Consultancy: Fuji Firm; Advisory / Consultancy: Immunogen; Advisory / Consultancy: Cerulean; Advisory / Consultancy: 2X Oncology. All other authors have declared no conflicts of interest.

Background: Folate receptor alpha (FolRα) is overexpressed in 80% of epithelial ovarian cancer (EOC) and endometrial adenocarcinoma (EC), with minimal expression on normal tissues and is thus a relevant target for cancer therapy using antibody drug conjugates (ADCs). STRO-002 is a novel, site-specific FolRα-targeting ADC that was generated using Sutro’s XpressCF+™ cell free protein synthesis platform. STRO-002 has highly specific cytotoxic activity on cells expressing FolRα. STRO-002 demonstrated reproducible and significant therapeutic efficacy in multiple preclinical models in vivo. STRO-002 activity was evaluated in EC patient-derived xenograft (PDX) models with a range of FolRα expression. Statistically significant efficacy was observed in 60% of the FolRα-positive PDX models tested, with response appearing to positively correlate with FolRα expression levels. Toxicology studies in cynomolgus monkeys demonstrate dose-dependent and reversible neutropenia when STRO-002 is administered at up to 9 mg/kg, with no evidence of ocular toxicity (Solis et al. AACR 2019). Methods: This study is a first-in-human Phase 1, open-label, multicenter, dose escalation (Part 1) study with dose expansion (Part 2) to identify the maximum tolerated dose (MTD), recommended phase 2 doses (RP2D) and to evaluate the safety, tolerability, and preliminary anti-tumor activity of STRO-002 in adults with ovarian cancer and endometrial cancer who are refractory to, or intolerant of, therapies known to provide clinical benefit. STRO-002 is given to all patients on study via intravenous infusion on Day 1of each 21-day cycle until disease progression. Dose limiting toxicities will be assessed in the first cycle (Days 1-21) of dose escalation. Part 1 will enroll about 30 ovarian cancer patients to determine the MTD and RP2D for expansion while Part 2 will enroll 2 cohorts based on disease subtypes (ovarian or endometrial). Efficacy will be evaluated per RECIST 1.1 criteria. Key inclusion criteria include relapsed and or progressive disease, adequate bone marrow and renal function, and ability to comply with treatment, testing and pharmacokinetic (PK) schedules. Key exclusion criteria include clear cell, mucinous or sarcomatous ovarian carcinoma, prior treatment with a FolRα-targeting ADC, need for ongoing immunotherapy including systemic corticosteroids and a history of CNS involvement. Samples will be collected to assess FolRα expression levels, PK and immunogenicity. No formal statistical hypothesis testing will be conducted in this study. This study is currently open for enrollment in the US with the ClinicalTrials.gov Identifier: NCT03748186.: Citation Format: Robert Wendel Naumann, Denise S. Uyar, Russell J. Schilder, Michael A. Palumbo, Venita DeAlmeida, Shannon L. Matheny, Arturo Molina. A Phase I, open-label, safety, pharmacokinetic, and preliminary efficacy study of STRO-002, an anti-folate receptor alpha (FolRα) antibody drug conjugate (ADC), in patients with advanced epithelial ovarian cancer (including fallopian tube or primary peritoneal cancers) and endometrial cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT160.

Background: NLG207 (formerly CRLX101) is an investigational nanoparticle-drug conjugate (NDC) composed of a cyclodextrin-based polymer backbone linked to camptothecin, a topoisomerase-1 inhibitor. NDCs enhance drug delivery to tumors where gradual payload release inside cancer cells augments antitumor activity while reducing toxicity. The RP2D of CRLX101 was previously set at 15 mg/m2 Q2W in combination with 80 mg/m2 weekly paclitaxel in Phase I and reported at ESMO 2016. This abstract will include data from both the Phase Ib and the phase II expansion. Methods: In this Phase II single arm study, patients were treated with NLG207 (Q2W) and 80 mg/m2 paclitaxel (3 wks on/1 wk off) repeated q 28 days until progression or toxicity. Primary objective was overall response (CR + PR) via RECIST v1.1 in women with recurrent platinum resistant epithelial ovarian, fallopian tube or primary peritoneal cancer. Progression free survival (PFS), duration of response (DOR), and safety were also assessed. Results: Thirty patients were enrolled and all completed at least one cycle. Median age was 62 (44-76) years. 57% of patients received ≥3 prior therapies. There were 8/30 confirmed responses for an overall response rate (ORR) of 26.7% (95% CI 14.2%, 44.4%), including one complete response (CR). ORR for platinum resistant patients (n=17) was 23.5% (4/17) vs. 30.8% (4/13) for those who were platinum sensitive (n=13) to their most recent platinum regimen. Best response (including unconfirmed) for platinum resistant patients was 41.2% (7/17) including 7 PRs. Five additional platinum resistant patients achieved stable disease (SD). Median PFS (mPFS) for all study patients was 5.4 months. The mPFS was similar for both platinum resistant at 5.5 months and platinum sensitive at 5.4 months. Median DOR was 7.2 months for platinum resistant patients vs. 4.7 months for the platinum sensitive group. The most common grade 3/4 adverse events (AEs) attributed to study treatment were: decreased neutrophil count (13 patients, 43%), anemia (3 patients, 10%), hematuria (2 patients, 7%); urinary tract infection (UTI), cystitis, hypertension, and hypokalemia (all seen in 1 patient, 3%). PK data will be included in the full presentation. Conclusions: NLG207 is a potentially best-in-class topoisomerase 1 inhibitor with demonstrated antitumor activity in recurrent ovarian cancer including those who have become resistant to platinum therapy. AE profile of this combination is consistent with that seen for paclitaxel as a single agent except for cystitis, hematuria and UTI. It was well-tolerated in combination with weekly paclitaxel in heavily pre-treated patients. NLG207 warrants further investigation in combination therapy regimens for recurrent ovarian, fallopian tube or primary peritoneal cancer, particularly in platinum resistant patients. Citation Format: Linda Duska, David M. O'Malley, Carolyn Krasner, Russell J. Schilder, Cara Mathews, Kathleen Moore, Premal Thaker, Austin Miller, Christopher Purdy, A.J. Leyco, Christopher Smith, Deborah Mercier, Lucinda Tennant, Eugene Kennedy, Nicholas Vahanian, Charles Link. A Phase II study of NLG207 (formerly CRLX101) in combination with weekly paclitaxel in patients with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT151.

3122 Background: A broad range of pediatric and adult malignancies harbor TRK fusions involving the NTRK1, NTRK2, and NTRK3 genes. The highly-selective TRK inhibitor, larotrectinib, has previously shown a high overall response rate (ORR) and a favorable safety profile in patients (pts) with TRK fusion cancer. To better delineate efficacy in adults, as pediatric pts have a particularly high ORR, here we report updated efficacy and safety data from the adult subset of pts with TRK fusion cancer treated with larotrectinib. Methods: Adult pts (aged 18 or older) with TRK fusion cancer detected by local testing in 2 larotrectinib clinical trials (NCT02122913 and NCT02576431) were analyzed. Larotrectinib was administered 100 mg PO BID until disease progression, withdrawal, or unacceptable toxicity. Disease status was assessed by both investigator (INV) and independent assessment (IRC) using RECIST v1.1. Results: As of July 30, 2018, 83 adults (median age: 57 y, range 20–80 y) with TRK fusion cancer had been treated. Cancer types included salivary gland (23%) and thyroid cancer (19%), soft tissue sarcoma (14%), lung cancer (13%), colon cancer and melanoma (7% each), GIST (5%), and bone sarcoma, cholangiocarcinoma, and appendiceal, breast, and pancreas cancer (≤2% each). TRK fusions involved NTRK1 (40%), NTRK2 (2%), and NTRK3 (57%). 77% of pts had received prior systemic therapy (median lines: 2, range 0–10). In 74 pts evaluable per INV, the ORR was 76% with 9% CR, 57% confirmed PR, 9% PR pending confirmation, 12% SD, 11% PD, and 1% not determined; 9 pts were non-evaluable (NE) due to lack of post-baseline assessment. In 65 pts evaluable per IRC, the ORR was 68% with 17% CR, 51% PR, 15% SD, 12% PD, and 5% NE. With a median follow up of 17.2 and 17.5 mo per INV and IRC, respectively, the median duration of response had not been reached (ranges identical: 1.9+ to 38.7+ months). At data cutoff, 63% remained on treatment; 30% had discontinued due to disease progression. Adverse events were mostly grade 1–2. Conclusions: Larotrectinib demonstrated robust tumor-agnostic efficacy and a favorable safety profile in adult pts with TRK fusion cancer. These results support testing for TRK fusion cancer in pts with advanced solid tumors, regardless of site of primary diagnosis. Clinical trial information: NCT02122913 and NCT02576431.

2506 Background: Birinapant is a bivalent SMAC mimetic targeting cIAP1. Synergistic effects of combining birinapant with immune checkpoint inhibitors have been demonstrated in preclinical models. Based on these observations, a clinical trial with birinapant and pembrolizumab was initiated (NCT02587962). Methods: Patients ≥18 years with advanced solid tumors without further suitable standard therapeutic options were eligible for inclusion. Birinapant (5.6-22 mg/m2) was administered IV on day 1 and 8 in addition to pembrolizumab 200 mg on day 1 in a 21-day cycle until disease progression using standard 3+3 dose-escalation. The primary objective was to determine the safety and tolerability of the recommended phase 2 dose (RP2D) of birinapant in combination with pembrolizumab. Secondary and exploratory objectives included antitumor activity assessed by RECIST 1.1 and iRECIST, pharmacokinetics and assessment of biomarkers including serum cytokines, cIAP1, PD-L1 expression and tumor infiltrating lymphocytes. Results: Nineteen patients were enrolled at 4 dose levels of 5.6 (n = 3), 11 (n = 3), 17 (n = 6) and 22 (n = 7) mg/m2. Most common tumors were pancreatic (n = 5), colorectal (n = 4), ovarian (n = 3) and sarcoma (n = 3). Median prior therapies were 4 (0-12). The most common AE related to any of the study drugs was rash occurring in 3 patients. Ten patients had 17 SAE's of which only one (stomatitis) was judged related to birinapant. Increased ALT/AST (G3/G2) leading to missed day 8 dose constituted a DLT at 22 mg/m2. Grade 2 lipase increases were seen in 2 patients. No cases of Bell’s palsy were detected. ORR by RECIST 1.1 was 5.6% (n = 1) in 18 evaluable patients. The responding patient had microsatellite stable colorectal carcinoma (MSS-CRC)) and remains on therapy 13+ months after first dose. By iRECIST, ORR was 11.1%. CBR (PR+SD) by RECIST was 22.2%. The exposure to birinapant generally increased with dose. The RP2D was determined to be 22 mg/m2. Conclusions: Birinapant and pembrolizumab is a safe and tolerable combination that has shown encouraging signals of efficacy. A phase 2 study evaluating efficacy of this combination in MSS-CRC is ongoing. Clinical trial information: NCT02587962.

5523 Background: Veliparib, a poly-(ADP-ribose)-polymerase inhibitor, increases anti-tumor activity when combined with platinum chemotherapy and has monotherapy activity in BRCA deficient tumors. This study was done to determine the recommended phase II dose (RP2D) of veliparib in combination with front line treatment for epithelial ovarian cancer (EOC). Methods: Eligible patients had newly diagnosed, stage II-IV EOC. Six regimens were evaluated, 3 variations of chemo delivery with either continuous (D1-21) or intermittent (days-2-5) veliparib BID. Chemo included 1: IV q3week carboplatin (C) (AUC 6) and paclitaxel(T) (175mg/m2); 2, IV q3week C (AUC 6) and weekly T(80mg/m2); and 3, IV T (135mg/m2, day 1), IP cisplatin (75mg/m2, day 1 or 2) and IP T (60mg/m2, day 8). Bevacizumab 15mg/kg started cycle 2 and continued as monotherapy cycles 7-22. A 3+3 dose escalation design evaluated dose-limiting toxicities (DLTs) in cycles 1 and 2. Once < 2/6 patients experienced a DLT, that dose level was expanded to evaluate feasibility over 4 cycles. Results: The study accrued 424 treated patients. For regimen 1, continuous (Reg1c) the maximum tolerated dose (MTD) was 250mg veliparib BID but the feasible dose was found to be 150mg BID. For regimen 1, intermittent (Reg1i) the MTD and feasible dose were 400 and 250mg BID respectively. For Reg2c the MTD and feasible dose were the same at 150mg BID. For Reg2i the MTD and feasible dose were 250 and 150mg BID respectively. For Reg3c the MTD and feasible dose are both 150mg BID and for Reg3i, the MTD was 400mg BID and the feasible dose felt to be 300mg BID. Median PFS by residual disease and BRCA status is: (Positive residual disease) 14.6, 19.1 and 16.9 months for BRCA+, BRCAwt and BRCA ukn respectively. For no gross residual disease the PFS is NR, 34.2 and 24.5 months respectively. Conclusions: Given the difficulty with toxicity not defined as a DLT, the RP2D for all regimens is veliparib 150mg BID. This data informed the dose that moved into the phase III trial GOG 3005/Velia: NCT02470585. Velia also incorporated maintenance veliparib instead of maintenance bevacizumab among all high grade serous patients (BRCA+ and wt). These results will determine utilization of veliparib in this space. Clinical trial information: NCT00989651.

A phase II trial was performed to evaluate the efficacy and safety of gefitinib in patients with persistent/recurrent endometrial cancer.Women with histologically confirmed persistent/recurrent endometrial cancer were treated with 500mg oral gefitinib daily until progression or severe toxicity, with progression-free survival (PFS) at six months as the primary endpoint. Tumor expression of total epidermal growth factor receptor (EGFR), estrogen receptor (ER), progesterone receptor A (PRA) and B (PRB), Ki67, pEGFR and activated extracellular signal-regulated kinase (pERK) were examined pre- and post-treatment. EGFR was sequenced, and serum concentrations of soluble EGFR (sEGFR) at baseline also were examined.Of 29 patients enrolled, 26 were evaluable for efficacy and toxicity. Four patients experienced PFS ≥6 months, and one had a complete response which was not associated with an EGFR mutation. The concentration of sEGFR in pretreatment serum was positively correlated with overall survival (OS), but not with responsiveness to gefitinib in this small patient cohort. Expression of tumor biomarkers was not associated with PFS or OS. Co-expression of ER with PRA in primary and recurrent tumors, and pEGFR with pERK in primary tumors was observed.This treatment regimen was tolerable but lacked sufficient efficacy to warrant further evaluation in this setting. The possible association between serum sEGFR concentrations and OS, and temporal changes in expression of pEGFR and pERK and the documented CR of one patient are interesting and warrant additional investigation.

Objectives Vascular endothelial growth factors (VEGF) and their receptors have a critical role in stimulating the growth of ovarian cancer cells. Motesanib is a small molecule inhibitor of multiple receptor tyrosine kinases including VEGF receptors 1–3, as well as c-KIT and platelet-derived growth factor which are related to the VEGF family. Patients and methods Twenty-two eligible patients with recurrent ovarian, fallopian tube or primary peritoneal carcinoma were treated with an oral daily dose of 125mg of motesanib. Peripheral blood was analyzed for circulating tumor cells (CTC) and circulating endothelial cells/circulating endothelial progenitors (CEC/CEP), VEGF levels and cell-free circulating DNA (cfDNA). Results The study was abruptly halted after four patients developed posterior reversible encephalopathy syndrome. One patient had a partial response and seven patients had stable disease at the time they were removed from study treatment. Twelve of the 22 patients (50%) had indeterminate responses at trial closure. Early closure without clinical efficacy data precludes meaningful correlative studies. Conclusions The serious central nervous system toxicity observed in patients with recurrent ovarian cancer precluded full examination of this agent in this population. There were no clear cut explanations for the high incidence of this known class effect in the study population compared with patients with other cancers.