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OV-αmCD47-G2b treatments promote macrophage M1 polarization and NK cell activation in ID8 immunocompetent ovarian cancer metastasis mouse model.

Primers used in this study.

All supplementary data: supplementary figures s1-s13 and table s1

Purpose:mAbs blocking immune checkpoints have emerged as important cancer therapeutics, as exemplified by systemic administration of the IgG1 anti-CD47 mAb that blocks the “don't eat me” pathway. However, this strategy is associated with severe toxicity.Experimental Design:To improve therapeutic efficacy while reducing toxicities for ovarian cancer, we engineered an oncolytic herpesvirus (oHSV) to express a full-length, soluble anti-CD47 mAb with a human IgG1 scaffold (OV-αCD47-G1) or IgG4 scaffold (OV-αCD47-G4).Results:Both IgG1 and IgG4 anti-CD47 mAbs secreted by oHSV-infected tumor cells blocked the CD47–SIRPα signal pathway, enhancing macrophage phagocytosis against ovarian tumor cells. OV-αCD47-G1, but not OV-αCD47-G4, activated human NK-cell cytotoxicity and macrophage phagocytosis by binding to the Fc receptors of these cells. In vivo, these multifaceted functions of OV-αCD47-G1 improved mouse survival in xenograft and immunocompetent mouse models of ovarian cancer when compared with OV-αCD47-G4 and a parental oHSV. The murine counterpart of OV-αCD47-G1, OV-αmCD47-G2b, also enhanced mouse NK-cell cytotoxicity and macrophage phagocytosis and prolonged survival of mice bearing ovarian tumors compared with OV-αmCD47-G3. OV-αmCD47-G2b was also superior to αmCD47-G2b and showed a significantly better effect when combined with an antibody against PD-L1 that was upregulated by oHSV infection.Conclusions:Our data demonstrate that an oHSV encoding a full-length human IgG1 anti-CD47 mAb, when used as a single agent or combined with another agent, is a promising approach for improving ovarian cancer treatment via enhancing innate immunity, as well as performing its known oncolytic function and modulation of immune cells.

Purpose: mAbs blocking immune checkpoints have emerged as important cancer therapeutics, as exemplified by systemic administration of the IgG1 anti-CD47 mAb that blocks the “don't eat me” pathway. However, this strategy is associated with severe toxicity. Experimental Design: To improve therapeutic efficacy while reducing toxicities for ovarian cancer, we engineered an oncolytic herpesvirus (oHSV) to express a full-length, soluble anti-CD47 mAb with a human IgG1 scaffold (OV-αCD47-G1) or IgG4 scaffold (OV-αCD47-G4). Results: Both IgG1 and IgG4 anti-CD47 mAbs secreted by oHSV-infected tumor cells blocked the CD47–SIRPα signal pathway, enhancing macrophage phagocytosis against ovarian tumor cells. OV-αCD47-G1, but not OV-αCD47-G4, activated human NK-cell cytotoxicity and macrophage phagocytosis by binding to the Fc receptors of these cells. In vivo, these multifaceted functions of OV-αCD47-G1 improved mouse survival in xenograft and immunocompetent mouse models of ovarian cancer when compared with OV-αCD47-G4 and a parental oHSV. The murine counterpart of OV-αCD47-G1, OV-αmCD47-G2b, also enhanced mouse NK-cell cytotoxicity and macrophage phagocytosis and prolonged survival of mice bearing ovarian tumors compared with OV-αmCD47-G3. OV-αmCD47-G2b was also superior to αmCD47-G2b and showed a significantly better effect when combined with an antibody against PD-L1 that was upregulated by oHSV infection. Conclusions: Our data demonstrate that an oHSV encoding a full-length human IgG1 anti-CD47 mAb, when used as a single agent or combined with another agent, is a promising approach for improving ovarian cancer treatment via enhancing innate immunity, as well as performing its known oncolytic function and modulation of immune cells.

Background: The objective of the study was to compare family planning and infertility among female and male gynecologic oncologists in the United States Methods: This cross-sectional multiple choice survey was administered to the Society of Gynecologic Oncology gynecologic oncologists. The survey collected information on demographics and practice, family planning, and fertility and infertility experiences. Chi-square and Fisher's exact tests were used to compare experiences by gender. Results: Two hundred eighteen of 1243 (18%) members responded to the survey. The majority were women (71%), Caucasian (78%), and had been practicing fewer than 10 years (56%). One-third (32%) were 35+ years of age at the birth of their first child, and 67% delayed childbearing due to their career. Women were more likely than men to report career choice-influenced family planning. Just under half (44%) expressed current or past concerns about fertility, and this was more prevalent among women; 81% had sought infertility counseling. Among respondents who had fertility struggles, almost half (45%) reported their colleagues were unaware. Forty percent felt their fertility concerns affected work life, and 13% felt stigmatized for their fertility struggles. Conclusions: These findings suggest that a career in gynecologic oncology have an impact on family planning, often resulting in childbearing delays and infertility concerns, especially among women. Support for our colleagues struggling with infertility should be included in wellness initiatives.

ObjectivePreclinical evidence and early clinical trials have demonstrated the activity of SPL-108, a targeted agent that inhibits CD44 mediated induction of multidrug resistance specifically to paclitaxel and platinum agents. We conducted a phase I, open label, dose escalation study of the safety and tolerability of the combination of SPL-108 with weekly paclitaxel in patients with platinum resistant CD44+ ovarian, primary peritoneal, or fallopian tube cancer.MethodsPatients with platinum resistant histologically proven epithelial ovarian, primary peritoneal, or fallopian tube cancers and measurable disease according to RECIST (Response Evaluation Criteria in Solid Tumours) version 1.1 were selected. Tumors were tested for CD44 expression for eligibility, defined as strong (+++) or moderate (++) staining in ≥20% of the tumor tissue or diffuse + staining. Patients were treated with daily and then twice daily SPL-108 subcutaneous injections and weekly intravenous paclitaxel on days 1, 8, and 15 of a 28 day cycle. Endpoints included safety, determination of maximum tolerated dose, and efficacy. Tumors underwent comprehensive genomic profiling, and cell lines and western blotting were used to study markers of response.ResultsWe screened 16 patients, and 14 were enrolled based on CD44+ expression. A total of 86% of patients had high grade serous tumors and all had received multiple prior therapies. There were no grade 4–5 toxicities. One patient had grade 3 peripheral sensory neuropathy attributed to paclitaxel and one patient developed presumed colonic perforation attributed to the study drug. No dose reductions or treatment discontinuations were required. All patients tolerated the maximum planned dose; no maximum tolerated dose was reached. Overall response rate was 36%; 5 (36%) patients had partial response and 5 (36%) patients had stable disease.ConclusionsThe combination of SPL-108 with weekly paclitaxel was safe and well tolerated. Encouraging antitumor activity was observed, with 72% of patients deriving a clinical benefit.Trial registrationNCT03078400.

BACKGROUND: Aggressive angiomyxoma is a rare, locally infiltrative tumor, frequently occurring in female patients. Although wide local excision is considered standard therapy, radical surgery may be needed. CASE: A 49-year-old woman presented with an aggressive angiomyxoma involving the vulva and bladder. Given the hormone receptor status and size of the tumor, the patient was initially treated with fulvestrant and goserelin acetate in an attempt to reduce the size of the mass. She was followed up at 1- to 3-month intervals; after 6 months of treatment, owing to increasing size of the mass and worsening symptoms, the decision was made to proceed with radical surgery. CONCLUSION: Although a less radical surgical approach is preferred, radical surgery is possible for treatment of aggressive angiomyxoma when needed.

To evaluate risk factors for 30-day unplanned readmission and increased length of stay (LOS) following minimally invasive surgery (MIS) for endometrial cancer.This was a retrospective, case-control study using the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP). Multivariable logistic regression was used to assess perioperative variables associated with readmission and increased LOS after MIS for endometrial cancer.The study population included 10,840 patients who met the criteria of having undergone MIS with a resultant endometrial malignancy confirmed on postoperative pathology. Common reasons for readmission included organ/space surgical site infection (65 cases), sepsis/septic shock (19 cases), and venous thromboembolism (20 cases). Notable risk factors for readmission included (Odds Ratio, Confidence Interval, p-value): dialysis dependence (6.77, 2.51-17.80,0.01), increased length of stay (3.00, 2.10-4.10,0.01), and preoperative weight loss (2.80, 1.06-7.17, 0.03); notable risk factors for increased LOS: ascites (8.51, 2.00-36.33,0.01), operation duration5 h (6.93, 5.29-9.25,0.01), and preoperative blood transfusion (5.37, 2.05-14.04,0.01).Identification of risk factors for adverse postoperative outcomes is necessary to inform and improve standards of care in MIS for endometrial cancer. Using nationally reported data from the ACS NSQIP, this study identifies independent risk factors for unplanned readmission and prolonged LOS, and in doing so, highlights potential avenues for quality improvement.

e18040 Background: Therapeutic options for patients with recurrent platinum resistant ovarian cancer are scarce and represent an unmet need in ovarian cancer. Chemotherapy resistance has been linked to many CD44 pathways including P-glycoprotein mediated efflux of chemotherapeutic agents. Our working hypothesis was that chemotherapy resistant ovarian tumors that expressed CD44 would revert drug resistance by using a CD44 inhibitor SPL-108, that had proven safe as a single agent. Methods: Patients with platinum refractory or resistant CD44+ ovarian tumors were eligible. We used a standard 3+3 phase I design, open-label, 2-arm trial of the combination of SPL-108 and IV paclitaxel (PTX): Arm 1 (2 cohorts) Safety Phase: Cohort 1: SPL-108 150 mg SQ Daily +80 mg PTX weekly Cohort 2: SPL-108 300mg daily +80 mg PTX weekly Arm 2 (1 cohort) Exploratory Phase: Cohort 3: SPL-108 daily dose 300 mg +80 mg PTX weekly Days 1-15 in 28 day cycles Primary end points were safety and tolerability. Secondary endpoints included determining molecular signatures of response using NGS. Tumors were sequenced at the time of recurrence or initial diagnosis. Results: Fourteen patients were enrolled in the study. Prior number of treatments ranged from 2-6, except for one patient with platinum refractory disease that progressed during first line of therapy. There was no DLT and all cohorts were completed as designed. The treatment was well tolerated. There was one instance of a bowel micro-perforation that was treated medically. This patient had platinum refractory disease and eventually underwent an interval cytoreduction. There was one patient with grade 3 neurotoxicity. Sixty-two% of the patients had clinical benefit with 36% having a PR. Forty-three % of patient had a PFS of more than 6 months. Two patients enjoyed a PR of 12 months. Molecular profiling of the tumors revealed that all tumors had TP53 alterations and the 4 patients that did not have a response had tumors with TP53 truncations or a lack of function alteration. Conclusions: Daily SPL-108 300mg SQ in combination with weekly PTX is safe and feasible. The promising clinical activity on drug resistant ovarian tumors warrants further investigation. Resistance to SPL-108 are characterized by lack of function of TP53, mostly early truncations. It is possible that SPL-108 may be reactivating TP53 by promoting its active conformation. Once TP53 is active CD44 expression is abrogated at the promoter. Therefore SPL-108 is effectively acting on CD44 through 2 different mechanisms to promote chemotherapy sensitivity. Clinical trial information: NCT03078400.

As cancer therapies improve, patients are living longer. With these improvements in therapy comes a responsibility to optimize patients’ quality of life during cancer therapy and beyond. This report reviews three timely and important topics. The first section reviews the mechanism underlying chemotherapy-induced peripheral neuropathy and evaluates the evidence for interventions to prevent and treat peripheral neuropathy. It also provides a framework for approaching the diagnosis and management of this common and bothersome side effect. The second section addresses the controversial but effective use of cannabinoids for cancer and chemotherapy symptoms. Although clinical trials are difficult to conduct because of the political and social stigma of this class of drugs, this review provides evidence of the efficacy of cannabinoids for treatment of pain and nausea. The last section addresses the mind-body connection, with a focus on the negative emotions patients with cancer often experience. This section assesses the literature regarding mindfulness-based programs to improve cancer-related stress. These three topics may appear unrelated, but all address one common goal: treating the body and the mind to optimize quality of life during and after cancer therapy.

Purpose Preclinical studies performed in our laboratory have shown that high-dose selenium inhibits the development of carboplatin drug resistance in an ovarian cancer mouse xenograft model. Based on these data, as well as the potential serious toxicities of supranutritional doses of selenium, a phase I trial of a combination of selenium/carboplatin/paclitaxel was designed to determine the maximum tolerated dose, safety, and effects of selenium on carboplatin pharmacokinetics in the treatment of chemo-naive women with gynecologic cancers. Correlative studies were performed to identify gene targets of selenium. Methods Chemo-naive patients with gynecologic malignancy received selenious acid IV on day 1 followed by carboplatin IV and paclitaxel IV on day 3. A standard 3 + 3 dose-escalating design was used for addition of selenium to standard dose chemotherapy. Concentrations of selenium in plasma and carboplatin in plasma ultrafiltrate were analyzed. Results Forty-five patients were enrolled and 291 treatment cycles were administered. Selenium was administered as selenious acid to 9 cohorts of patients with selenium doses ranging from 50 μg to 5000 μg. Grade 3/4 toxicities included neutropenia (66.7%), febrile neutropenia (2.2%), pain (20.0%), infection (13.3%), neurologic (11.1%), and pulmonary adverse effects (11.1%). The maximum tolerated dose of selenium was not reached. Selenium had no effect on carboplatin pharmacokinetics. Correlative studies showed post-treatment downregulation of RAD51AP1, a protein involved in DNA repair, in both cancer cell lines and patient tumors. Conclusion Overall, the addition of selenium to carboplatin/paclitaxel chemotherapy is safe and well tolerated, and does not alter carboplatin pharmacokinetics. A 5000 μg dose of elemental selenium as selenious acid is suggested as the dose to be evaluated in a phase II trial.

Objective Overexpression of bcl-2 is a mechanism of drug resistance in cervical cancer. Agents that down-regulate bcl-2 may decrease tumor cell threshold and sensitize tumor cells to chemotherapy. The objective of this multi-institutional phase 2 trial was to evaluate the efficacy and toxicity of paclitaxel and bcl-2 modulators (13-cis retinoic acid and interferon alfa-2b) in patients with advanced-stage or recurrent cervical cancer. Materials and Methods Patients had biopsy-proven metastatic, first relapse, or persistent cervical cancer with no prior chemotherapy except for chemosensitizing agents. The treatment consisted of oral 13-cis retinoic acid, 1 mg/kg, and subcutaneous interferon alfa-2b, 6 mU/m2, days 1 to 4, and intravenous paclitaxel, 175 mg/m2, day 4 until disease progression or adverse events prohibited treatment. The primary endpoint was overall response rate. Results Thirty-three patients were enrolled between March 2001 and June 2009. Thirty-one patients were eligible for evaluation of treatment response. Twenty-seven patients (82%) received prior concurrent chemoradiation or radiotherapy alone before study enrollment. The overall response rate was 30% (6 complete responses and 4 partial responses). Furthermore, 7 patients (21%) had stable disease. Grade 3 or 4 adverse events included neutropenia (n =16 [48%]), febrile neutropenia (n = 1 [3%]), and anemia (n = 1 [3%]). There were no treatment-related deaths. The median progression-free survival was 3.4 months (95% confidence interval, 2.0–7.4 months), and overall survival was 11.2 months (95% confidence interval, 7.5–26.2 months). Of 6 patients with complete responses, 5 patients survived more than 2 years. Conclusions Combination therapy with paclitaxel, 13-cis retinoic acid, and interferon alfa-2b is feasible and safe in treating patients with advanced and recurrent cervical cancer.

Classification of pediatric brain tumors with unusual histologic and clinical features may be a diagnostic challenge to the pathologist. We present a case of a 12-year-old girl with a primary intracranial tumor. The tumor classification was not certain initially, and the site of origin and clinical behavior were unusual. Genomic characterization of the tumor using a Clinical Laboratory Improvement Amendment (CLIA)-certified next-generation sequencing assay assisted in the diagnosis and translated into patient benefit, albeit transient. Our case argues that next generation sequencing may play a role in the pathological classification of pediatric brain cancers and guiding targeted therapy, supporting additional studies of genetically targeted therapeutics.

e17040 Background: HIPEC showed a progression free survival when incorporated into interval cytoreductive surgery for ovarian cancer patients in a recent phase lll trial. This has led to a paradigm shift at many institutions and the consideration of HIPEC. The goal of this study is to report on the initiation of this program and change in practice at a high volume cancer center over a period of 1 year. Methods: Reviewed surgical cases from 1/2018 through 1/2019 where patients were thought to have a primary ovarian or fallopian tube cancer. Variables included age, stage, histology, primary or interval debulking surgery, number of neoadjuvant (NAJ) chemotherapy cycles. HIPEC patients were selected out and variables examined included intraoperative procedures, optimal cytoreduction, type of chemotherapy administered, postoperative complications, and ability to receive consolidation chemotherapy. Results: 35 cases where ovarian cancer known or suspected preoperatively. 23 patients had primary surgery consisting of tah/bso/surgical staging/tumor debulking. 0/23 of these patients were offered HIPEC chemotherapy as an upfront strategy. 12 patients received neoadjuvant chemotherapy for recurrent (2) or advanced (10) disease. 11/12 of these patients proceeded to an interval surgery. 6/11 (54%) were planned for HIPEC. This was aborted in 1/6 because of thrombocytopenia. 5/6 patients went on to receive HIPEC. They received 3-6 cycles of NAJ chemotherapy, platinum and taxane. 3/5 also received preoperative Avastin. All had R0 resection. 1 patient had a bowel resection. Either carboplatin or cisplatin was used for HIPEC over 90 minutes. 2/5 patients had postoperative G2-3 cytopenias. 3/5 patients were able to receive consolidation chemotherapy, 2 of them within six weeks of surgery and with Avastin containing regimens. Conclusions: In a large volume center initiating a HIPEC ovarian cancer program in less than one years’ time, HIPEC was offered to 50% of patients undergoing interval debulking for Stage III or IV serous ovarian cancer after NAJ chemotherapy and in rare cases for patients with recurrent cancer planned for cytoreduction. Patients may go on to receive postoperative chemotherapy but may have prolonged cytopenias and consolidation therapy delays. HIPEC was not incorporated into an upfront surgical strategy.[Table: see text]

Background Pilomatrix carcinomas are rare, frequently occurring in older male patients. We report a case of vulvar pilomatrix carcinoma in a 30-year-old woman, the second known reported case occurring on the external genitalia. Case A 30-year-old female originally presented at an outside institution for the management of an asymptomatic vulvar mass that was biopsied and read as invasive squamous cell carcinoma. Pathology review at our institution reclassified the vulvar mass as a low-grade pilomatrix carcinoma. The patient underwent radical hemivulvectomy without an inguinal–femoral groin node dissection. She has remained without evidence of disease recurrence for more than 5 years since her diagnosis. Conclusion Pilomatrix carcinoma can be confused for an invasive squamous cell carcinoma. Due to its low risk of metastases, a less radical surgical approach can be taken. Consideration of this unusual malignancy is important in the determination of appropriate management., Highlights • We present a rare case of vulvar pilomatrix carcinoma in a 30 year old female. • Pilomatrix carcinoma can be confused for an invasive squamous-cell carcinoma. • Due to its low risk of metastases, a less radical surgical approach can be taken.

PURPOSE: The effectiveness of standard-of-care platinum-taxane chemotherapy in the treatment of patients with advanced gynecologic cancers is limited by the development of chemotherapy resistance in nearly all patients. Based on our preclinical findings that selenium, an essential trace element, inhibits the development of carboplatin drug resistance in an ovarian cancer mouse model, a phase I trial of a combination of selenious acid/carboplatin/paclitaxel was designed to determine the maximum tolerated dose (MTD) and safety of selenium administered with chemotherapy in chemo-naïve women with gynecologic cancers. In addition, the effects of selenium on carboplatin pharmacokinetics were evaluated in this group of patients, and correlative studies were performed to identify potential gene targets of selenium. METHODS: Patients with gynecologic malignancy not previously treated with chemotherapy received 50-5000 µg elemental selenium IV in the form of selenious acid on day 1 followed by carboplatin (cycle 1, AUC 5; subsequent cycles, AUC 6) IV and paclitaxel 175mg/m2 IV on day 3. A standard 3+3 trial design was used in the selenium dose escalation phase. Concentrations of selenium in plasma and carboplatin in plasma ultrafiltrate were analyzed. RNA expression in tumor specimens and breast and ovarian cancer cell lines were compared before and after treatment with selenium plus chemotherapy using the Human Exon 1.0 ST exon microarray platform. In addition, Western immunoblotting was performed to evaluate protein expression of RAD51AP1, a protein involved in DNA repair, in untreated MCF-7/Adr cells and MCF-7/Adr cells treated with selenium, carboplatin, and the combination of selenium and chemotherapy. RESULTS: Forty-five patients were enrolled and a total of 291 treatment cycles were administered. Grade 3/4 toxicities included neutropenia (66.6%), febrile neutropenia (2.2%), as well as pain (20.0%), infection (13.3%), neurologic (11.1%), and pulmonary adverse effects (11.1%). The MTD of elemental selenium was not reached. Selenium had no effect on carboplatin pharmacokinetics. In the subset of patients with stage III/IV ovarian cancer/fallopian tube/peritoneal cancer, median progression-free survival was 15 months; in those patients within this subset with measurable disease, 30%, 35%, and 23% experienced complete response, partial response, and stable disease, respectively. Correlative studies showed downregulation of RAD51AP1 by selenium plus chemotherapy in cancer cell lines as well as in tumors of patients treated within this clinical trial. CONCLUSION: Selenium in combination with carboplatin and paclitaxel is safe and does not affect carboplatin pharmacokinetics. It is possible that selenium-mediated downregulation of RAD51AP1 plays a role in circumventing the development of resistance to carboplatin/paclitaxel chemotherapy. A phase II study to further investigate these findings is underway. Citation Format: Mihae Song, Muthu N. Kumaran, Murugesan Gounder, Darlene Gibbon, Wilberto Nieves-Neira, Ami Vaidya, Mira Hellman, Michael P. Kane, Brian Buckley, Lorna Rodriguez-Rust. Phase I trial of selenium plus chemotherapy in gynecologic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT025.

Objective: The development of drug resistance is a major cause of gynecologic cancer deaths. Selenium (Se) inhibits the development of carboplatin (C) drug resistance in a mouse ovarian cancer xenograft model. Based on this data, a Phase I trial of a combination of Se, (C) and paclitaxel (P) was designed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), safety, and effects of Se in (C) pharmacokinetics (PK) in the treatment of chemo-naive women with gynecologic cancers. Correlative studies identified Se gene targets responsible for reversal of drug resistance. Methods: Se (50-5000 mcg) IV was given on day 1, and (C) (AUC 5 in cycle 1, AUC 6 in subsequent cycles) IV and (P) 175mg/m2 IV on day 3. A standard 3 + 3 design was used in the selenium dose escalation phase. (C) and Se concentrations in plasma and ultrafiltrate were analyzed. Results: 45 patients were enrolled. Worst grade toxicities from 291 cycles included neutropenia (Gr 3, n=24; Gr 4, n=19), febrile neutropenia (Gr 3, n=2), anemia (Gr 3, n=1), constitutional (Gr 3, n=3), gastrointestinal (Gr 3, n=5), neurolgic (Gr 3, n=6), pain (Gr 3, n=12), and pulmonary (Gr 3, n= 5). DLT was not reached but IV site pain was recorded at selenium doses higher than 2000 mcg. GFR did not change with Se treatment. Se also had no effect on (C) pharmacokinetics. The average observed AUC was the same as target AUC in each cycle. Between cycle 1 and cycle 2, the estimated PK parameters, clearance (138 vs 133 ml/min) and half-life (312 vs 305 min), were not significantly different. Plasma Se AUC showed dose proportionate increase at higher doses. Of 38 patients with ovarian cancer, there were 9 complete response, 8 partial response, 6 stable disease and 12 disease progression. The median progression-free survival from these 38 patients was 35 months. 33/45 pts had elevated serum CA125 at initiation of therapy. 21/33 had normalization of CA125 after cycle 2 (n=14), and after cycle 6 (n= 7). RNA expression of the tumors as well as cell lines was measured and compared before and after selenium treatment. The samples were run on the Human Exon 1.0 ST exon microarray platform. The results of this analysis pointed to Rad51-AP1 as a gene that is downregulated by selenium. Validation experiments done in vitro confirmed that treatment with Se decreased Rad51-AP1 protein levels, and the cells become more sensitive to (C). Also, cells treated with increasing amounts of (C) showed increased levels of Rad51-AP1. Conclusion: Se in combination with (C) and (P) is safe, well tolerated and does not affect (C) pharmacokinetics. Although selenium DLT was not reached, at the dose of 5000 mcg, the patients needed central lines for selenium infusion, secondarily to IV site pain. Responses and protracted stable disease are noted in patients with gynecologic cancers. Downregulation of Rad51-AP1, a protein involved in DNA repair, may counteract the development of platinum based drug resistance by selenium. Citation Format: Lorna Rodriguez-Rodriguez, Mihae Song, Neelakandan Muthukumaran, Murugesan Gounder, Darlene Gibbon, Wilberto Nieves-Neira, Ami Vaidya, Mira Hellmann, Susan Goodin, Brian Buckley. Selenium counteracts carboplatin drug resistance through Rad51-AP1 induction: A phase I trial in women with gynecologic cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT219. doi:10.1158/1538-7445.AM2014-CT219