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SummaryBackground Selinexor, a first-in-class, oral selective inhibitor of nuclear export (SINE) compound inhibits Exportin-1(XPO1), had demonstrated synergistic activity with many chemotherapies and conferred in vivo antitumor efficacy in hematologic as well as solid tumors. Methods This open-label, single-center, multi-arm phase 1b study used a standard 3 + 3 design and a “basket type” expansion. Selinexor with intravenous topotecan was given in one of the 13 parallel arms. Patients with advanced or metastatic relapsed/refractory solid tumors following prior systemic therapy, or in whom the addition of selinexor to standard chemotherapy deemed appropriate, were eligible. Results Fourteen patients with the median age of 61 years (range, 22–68years) were treated, and the most common cancer types were gynecological cancers; ovarian (n = 5), endometrial (n = 2), and 1 each with fallopian tube and vaginal cancers. Of the 14 patients treated, 12 (86 %) had at least one treatment-related adverse event (TRAE). The most common TRAEs were anemia (71 %), thrombocytopenia (57 %), hyponatremia (57 %), vomiting (57 %), fatigue (50 %), nausea (50 %), and neutropenia (36 %). Two patients had dose limiting toxicities. One patient dosed at selinexor 80 mg had grade 3 nausea and vomiting and one patient dosed at selinexor 60 mg experienced grade 4 neutropenia and thrombocytopenia. Of the 13 efficacy evaluable patients, one (8 %) with endometrial cancer achieved unconfirmed partial response (uPR) and the time-to-treatment failure (TTF) was 48 weeks, whereas 6 of the 13 (46 %) patients had stable disease (SD) contributing to the clinical benefit rate of 46 %. The median TTF for all patients was 9 weeks (range, 2–48weeks). Conclusions Once weekly selinexor in combination with topotecan was viable and showed some preliminary tumor efficacy. The recommend phase 2 dose of selinexor was 60 mg once weekly in combination with IV topotecan.Trial registration: NCT02419495. Registered 14 April 2015, https://clinicaltrials.gov/ct2/show/NCT02419495

Selinexor is a first-in-class, oral selective inhibitor of nuclear export (SINE) compound which blocks Exportin-1 (XPO1). Our objective was to determine maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of selinexor and weekly paclitaxel.This was an open label, single-center, multi-arm phase 1b study utilizing a "3 + 3" design and a "basket-type" expansion in recurrent solid tumors. Selinexor (60 mg or 80 mg twice weekly orally) and weekly paclitaxel (80 mg IV 2 week on, 1 week off) were one of 13 parallel arms. Efficacy was evaluated using RECIST version 1.1.All 35 patients treated were evaluable for toxicity and 31 (88%) were evaluable for response. Patient diagnoses included platinum-resistant/refractory ovarian (n = 28), breast (n = 4), prostate (n = 2), and cervical (n = 1) cancer. Patients had a median of four prior therapies (range 1-10), and 47% had a prior taxane in the recurrent setting. There were no DLTs and 60 mg was chosen as the RP2D due to long-term tolerability. Ninety-seven percent of patients had at least one treatment-emergent adverse event (TEAE), and the most common grade ≥ 3 TEAE were neutropenia (46%), anemia (31%), and nausea (21%). Among 24 evaluable patients with ovarian cancer, response rate was 17%, CBR was 58%, and median PFS was 6.8 months (95% CI 3.7, not reached (NR)).Oral selinexor in combination with weekly paclitaxel demonstrated promising clinical activity with manageable toxicity. This combination should be considered for further exploration in a randomized study, especially in ovarian malignancies.

Purpose Acute radiation-induced esophagitis (ARIE) leads to treatment delays, decreased quality of life (QOL), and secondary adverse events such as weight loss. Grade 3 ARIE occurs in 15%–30% of patients undergoing radiotherapy to the esophagus, leading to disruption or discontinuation of treatment. The purpose of this study was to assess the effects of glutamine, a common nutritional supplement, on ARIE in patients with thoracic malignancies. Patients and methods This double-blind, placebo-controlled trial enrolled patients with advanced thoracic malignancies receiving concurrent chemotherapy/radiotherapy or radiotherapy alone, with radiation doses to the esophagus ≥45 Gy. Patients were randomized (1:1) to receive 4 g of glutamine or glycine placebo twice daily. The primary objective was to determine whether glutamine decreases the severity of ARIE in these patients. Secondary objectives included assessment of the effects of glutamine on other measures of ARIE, weight, symptom burden measure assessed by the MD Anderson Symptom Inventory (MDASI-HN) questionnaire and the toxicity profile of glutamine. Results At the time of interim analysis, 53 patients were enrolled: 27 in the glutamine arm and 26 in the placebo arm. There was no difference in the incidence of esophagitis in the first 6 weeks of radiotherapy between the glutamine and placebo arms (74% versus 68%; P = 1.00). There were no significant differences between the two arms for time to onset of esophagitis. The duration of ARIE was shorter (6.3 versus 7.1 weeks; P = 0.54) and median weight loss was lower (0.9 kg versus 2.8 kg; p = 0.83) in the glutamine arm versus the placebo arm. The groups differ significantly in core symptom severity (2.1 vs 1.5, p

SummaryBackground. Carboplatin and paclitaxel (CT) is one of the standard chemotherapy regimens used in various tumor types. Preclinical models have suggested that selinexor, a first-in-class oral potent selective inhibitor of nuclear export Exportin-1, and CT exerts antitumor activity in multiple malignancies. Methods. This was a single-center, multi-arm phase Ib study utilizing a “basket type” expansion. CT and selinexor was employed as one of the 13 parallel arms. Advanced relapsed/refractory solid tumors following standard therapy or where the addition of selinexor to standard regimens deemed appropriate, were eligible. Results. Of 13 patients treated, 12 patients were evaluable for response. The most common cancers were breast (n = 4), esophageal (n = 2), ovarian (n = 2) and non-small cell lung cancers (n = 2). All 13 patients had at least one treatment-related adverse events (TRAEs) and the most common were neutropenia (85%), leukopenia (85%), thrombocytopenia (85%), anemia (69%), nausea (54%), vomiting (46%), and fatigue (46%). One patient at 60 mg QW experienced DLT with grade 3 nausea and vomiting lasting 3 days. Unconfirmed partial response (uPR) was observed in 3 patients; one patient each with esophageal, breast, and ovarian cancer. One patient with esophageal adenocarcinoma had confirmed PR, however, was discontinued from the study due to clinical progression. Five patients achieved stable disease (SD). Disease control rate was 8%. Majority of patients (77%), including two patients who had uPR, had prior exposure to carboplatin and/or paclitaxel. Time-to-treatment failure (TTF) ranged from 1 to 153 weeks. Conclusion. The RP2D of selinexor was 60 mg QW in combination with CT. The combination conferred viable clinical activity with durable objective responses which should further be explored in tumor types for which CT is used as standard of care. Trial information. ClinicalTrials.gov Identifier: NCT02419495. Sponsor(s): Karyopharm Therapeutics. (Trial registration: NCT02419495. Registered 14 April 2015, https://clinicaltrials.gov/ct2/show/NCT02419495).

IntroductionImmunotherapies have revolutionized the treatment of various cancers, but little is known about their symptomatic toxicity. Assessing these symptoms is best accomplished by asking the patients themselves. However, such reports are subjective and may face challenges as bonafide scientific data. Demonstrating the validity of symptom assessment tools, mainly through the reduction of measurement errors, has the potential to improve patient care if these tools are widely adopted. To that end, we present herein the psychometric properties of the Immunotherapy for Early-Phase Trials module of the MD Anderson Symptom Inventory (MDASI-Immunotherapy EPT) in patients receiving various immunotherapies in early phase trials at a major cancer center.MethodsOne hundred forty-five patients completed the inventory at baseline, with 85 of them also doing so after 9 weeks of treatment. The mean (±SD) age of the patients was 57.0±12.9 years. Also, 56% of the patients were women, 79% identified as white, and 49% had at least some college education.ResultsThe internal consistency reliability of the MDASI-Immunotherapy EPT was excellent, as the Cronbach’s alphas for all of its subscales were at least 0.88 (range 0.88–0.95). Known-group validity based on Eastern Cooperative Oncology Group performance status groupings was excellent at 9 weeks after the start of an immunotherapy trial for the MDASI-Immunotherapy EPT severity (effect size, 0.96) and interference (effect size, 0.82) subscales. We found substantial changes in the symptom items difficulty remembering (effect size, −0.85), fever and/or chills (effect size, −0.63), disturbed sleep (effect size, −0.52), diarrhea (effect size, −0.42), and swelling of hands, legs, or feet (effect size, −0.39).ConclusionsIn conclusion, the MDASI-Immunotherapy EPT is a valid, reliable, and sensitive tool for measuring symptomatic toxicity.

5565 Background: Selinexor is a first-in-class novel, oral potent selective inhibitor of nuclear export (SINE) which blocks Exportin-1 (XPO1) leading to nuclear accumulation and activation of tumor suppressor proteins and prevention of translation of proto-oncogenes. Weekly paclitaxel is a standard chemotherapy regimen used in various tumor types. Preclinical models show that selinexor with paclitaxel exerts antitumor activity against multiple solid tumors. Our objective was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of selinexor and weekly paclitaxel. Methods: This was an open label, single-center, multi-arm phase 1b study utilizing a “3 + 3” design and a “basket type” expansion. Selinexor (twice weekly orally) and weekly paclitaxel (80mg IV 2 week on, 1 week off) was employed as one of 13 parallel arms. Two dose levels (DL) of selinexor were explored: DL1 selinexor 60mg; DL2 selinexor 80mg. Patients (pts) with advanced or metastatic solid tumors were eligible if they had adequate bone marrow and organ function. There was no limit on prior lines of therapy. Efficacy was evaluated using RECIST 1.1. Progression free survival (PFS) was defined as time from treatment until disease progression or death. Results: Of 35 pts treated, all were evaluable for toxicity, and 31 (88%) were evaluable for response. Pt diagnoses included ovarian (n = 28), breast (n = 4), prostate (n = 2), and cervical (n = 1) cancer. Pts had a median of four prior therapies (range 1-10), and 47% had a prior taxane. All pts with ovarian cancer had platinum resistant/refractory disease; high grade serous histology was most common. There were no DLTs and DL1 was chosen as the RP2D given its long term tolerability. 97% of pts had at least one treatment-emergent adverse event (TEAE) and the most common TEAEs were anemia (74%), nausea (57%), fatigue (51%), leukopenia (51%), neutropenia (49%), thrombocytopenia (46%), and vomiting (31%). The most prevalent grade ≥ 3 TEAE were neutropenia (46%), anemia (31%), leukopenia (17%), and fatigue (9 %). Partial responses (PR) were noted in 4 pts (13%); 10 pts (32%) achieved stable disease for > 4 months for a clinical benefit rate (CBR) of 45%. 16 pts (47%) had prior exposure to a taxane, including 1 pt who achieved PR. Among 24 evaluable pts with ovarian cancer, response rate was 17%, CBR was 58%, and PFS was 6.83 months (95% CI 3.73, not reached (NR)). Median duration of clinical benefit in ovarian cancer was 7.57 months (95% CI: 4.43, NR). Conclusions: Oral selinexor in combination with weekly paclitaxel demonstrated promising clinical activity with manageable toxicity, and further evaluation with once weekly selinexor is warranted. This combination should be considered for further exploration in a randomized study, especially in ovarian malignancies. Clinical trial information: NCT02419495.

BackgroundPatients with advanced rare cancers have poor prognosis and few treatment options. As immunotherapy is effective across multiple cancer types, we aimed to assess pembrolizumab (programmed cell death 1 (PD-1) inhibitor) in patients with advanced rare cancers.MethodsIn this open-label, phase 2 trial, patients with advanced rare cancers whose tumors had progressed on standard therapies, if available, within the previous 6 months were enrolled in nine tumor-specific cohorts and a 10th cohort for other rare histologies. Pembrolizumab 200 mg was administered intravenously every 21 days. The primary endpoint was non-progression rate (NPR) at 27 weeks; secondary endpoints were safety and tolerability, objective response rate (ORR), and clinical benefit rate (CBR).ResultsA total of 127 patients treated between August 15, 2016 and July 27, 2018 were included in this analysis. At the time of data cut-off, the NPR at 27 weeks was 28% (95% CI, 19% to 37%). A confirmed objective response (OR) was seen in 15 of 110 (14%) evaluable patients (complete response in one and partial response in 14). CBR, defined as the percentage of patients with an OR or stable disease ≥4 months, was 38% (n=42). Treatment was ongoing in 11 of 15 patients with OR at last follow-up. In the cohort with squamous cell carcinoma (SCC) of the skin, the NPR at 27 weeks was 36%, ORR 31%, and CBR 38%. In patients with adrenocortical carcinoma (ACC), NPR at 27 weeks was 31%, ORR 15%, and CBR 54%. In the patients with carcinoma of unknown primary (CUP), NPR at 27 weeks was 33%, ORR 23%, and CBR 54%. In the paraganglioma–pheochromocytoma cohort, NPR at 27 weeks was 43%, ORR 0%, and CBR 75%. Treatment-related adverse events (TRAEs) occurred in 66 of 127 (52%) patients, and 12 (9%) had grade ≥3 TRAEs. The most common TRAEs were fatigue (n=25) and rash (n=17). There were six deaths, all of which were unrelated to the study drug.ConclusionsThe favorable toxicity profile and antitumor activity seen in patients with SCC of skin, ACC, CUP, and paraganglioma–pheochromocytoma supports further evaluation of pembrolizumab in this patient population.Trial registration numberNCT02721732

Purpose Complementary and alternative medicine (CAM) has been popular among patients with cancer for several decades. The objectives of this study were to evaluate the prevalence of CAM use and to identify the factors affecting CAM use in a large patient cohort seen at a comprehensive cancer center in Turkey. Patients and Methods An investigator-designed survey was completed by volunteer patients who visited the outpatient clinic in the medical oncology department. CAM use encompassed pharmacologic agents including vitamins, dietary supplements, and herbal products or nonpharmacologic methods like prayer, meditation, hypnosis, massage, or acupuncture. Results Of 1,499 patients who answered the survey, 1,433 (96%) used nonpharmacologic CAM and 60 (4%) used pharmacologic CAM (pCAM). The most frequent types of CAM used were prayer (n = 1,433) followed by herbal products (n = 42). pCAM use was not significantly associated with age ( P = .63), sex ( P = .15), diagnosis ( P = .15), or income level ( P = .09). However, it was significantly associated with the level of education ( P = .0067) and employment status ( P < .001). Patients with higher education levels used more pCAM products ( P = .025). Among 60 pCAM users, six patients (10%) used pCAM for more than 2 years and 22 (36%) did not consult their physicians about their pCAM use. Only nine patients (15%) reported unpleasant adverse effects related to pCAM. Conclusion Although CAM use was high among our patients, prevalence of pCAM use was lower than expected. Patients with higher education levels tended to use more pCAM.

Mammalian target of rapamycin (mTOR) inhibitors like temsirolimus may result in undesirable AKT upregulation. Metformin inhibits mTOR through different mechanisms and may enhance temsirolimus’s antitumor activity. We conducted an open-label phase I dose escalation trial of this drug combination in patients with advanced/refractory cancers. Temsirolimus, 25 mg weekly, was combined with an escalating daily dose of metformin (level 1: 500; level 2: 1000; level 3: 1500; level 4: 2000 mg) by utilizing a standard 3 + 3 trial design. Treatment was administered in 28-day cycles following initial 2-week metformin titration during the first cycle. Twenty-one patients (median age, 56 years) with sarcoma (n = 8), colorectal (n = 3), endometrial (n = 4), uterine carcinosarcoma (n = 2), ovarian (n = 2), and other (n = 2) cancers were enrolled. Patients had received median of four prior systemic treatments. Two dose-limiting toxicities were observed (grade 3 mucositis, grade 3 renal failure); both patients continued treatment after dose modification. Fifty-six percent patients had stable disease as best response; clinical benefit rate was 22 %. Patients continued treatment for median of 11 weeks. Combination temsirolimus/metformin was well tolerated with modestly promising effectiveness among this heavily pretreated patient cohort. We recommend a dose of temsirolimus 25 mg weekly and metformin 2000 mg daily for phase II study.

Mucositis may limit the therapeutic window for mammalian target of rapamycin inhibitor-based combination therapy, necessitating treatment interruptions and/or dose reductions. Optimizing treatment or prophylactic interventions for mucositis will enable patients to continue effective treatment while maintaining good quality of life.

TPS3103 Background: Cancer of unknown primary is a biopsy proven malignancy for which an anatomic primary remains unidentified after a focused search. It accounts for 3-4 % of all solid cancers and most investigators limit it to epithelial and undifferentiated cancers. Patients with metastatic melanoma and sarcoma are excluded. Sophisticated imaging, robust pathologic evaluation including immunostains, and genomic and proteomic characterization of these cancers have challenged the management of CUP. The paradigm has shifted from empiric platinum based combination doublets to a personalized approach. Nevertheless, without an anatomic primary, clinical trial opportunities are limited. There remains an unmet research need to evaluate the role of immunotherapy, specifically checkpoint blockade drugs in specific subsets of CUP patients. Methods: Adult Patients ≥ 18 years of age with ECOG PS 0-1, must meet the definition of a CUP cancer. Patients must be intolerant and/or refractory to at least one line of established therapy known to provide clinical benefit for their condition within the last 6 months (often, a platinum based therapy for carcinomas). Patients must have either measurable (RECIST 1.1) or evaluable disease. Although not limited to subtypes, there is a signficant interest in enrolling patients with isolated disseminated lymphadenopathy, HPV (+) CUP and those who have an IHC profile of those known cancers for which anti-PD therapy has been approved (lung, renal, others) The primary objective of this trial is to evaluate efficacy by evaluation of non-progression rate (NPR) at 27 weeks (9 cycles) as defined as the percentage of CUP patients who are alive and progression-free at 27 weeks (9 cycles) as assessed by RECIST 1.1. Secondary objectives include evaluating safety and tolerability of pembrolizumab (MK-3475); correlating efficacy, non-progression rate (NPR) at 27 weeks (9 cycles), objective response (CR or PR), progression-free survival (PFS), overall survival (OS) and duration of response (DOR) to PD-L1 status; and identifying imaging characteristics associated with immunological changes in tumor following treatment with pembrolizumab. Enrollment is ongoing. Clinical trial information: NCT02721732.

Background The purposes of this study were to establish a novel blood pressure (BP) scoring method and to correlate it with clinical response in advanced cancer patients treated with anti-vascular endothelial growth factor (VEGF) therapies. Methods We retrospectively analyzed data for 368 patients from 23 clinical trials that included at least one anti-VEGF agent. We determined BP scores using the traditional Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and our novel method that considers both BP readings and number of anti-hypertensive medications the patient received. BP scores were categorized at baseline and four months. Logistic regression analysis correlated elevated scores with clinical response. Agreement between the CTCAE and the new method was assessed. Results Under the new BP scoring method, partial response rates were 20 % in patients with an elevated score at four months versus 6 % in patients without elevated score (P < 0.001). When adjusted for tumor type, age, sex, history of anti-VEGF treatment, and number of anti-VEGF treatments, elevated BP under the new scoring method had an odds ratio of 3.8 (95 % confidence interval [CI]: 1.8, 8.2; P < 0.001). The kappa statistic for agreement between the CTCAE and new scoring methods was 0.57 (95 % CI: 0.47, 0.67; P < 0.001), indicating significant concordance. Conclusion Using the novel scoring method, an increase in BP scores was a marker for favorable clinical response in patients who received anti-VEGF treatment. This new method ultimately provides information with regard to clinical tumor response over and above that provided by the CTCAE scoring method.

We conducted this retrospective study to identify reasons that patients referred to a phase I clinical trial failed to enroll or delayed enrollment onto the trial.Outcome analyses were conducted independently on data collected from electronic medical records of two sets of consecutive patients referred to a phase I clinical trial facility at MD Anderson Cancer Center. Data from the first set of 300 patients were used to determine relevant variables affecting enrollment; data from the second set of 957 patients were then analyzed for these variables.Results from the two sets of patients were similar. Approximately 55% of patients were enrolled in a phase I trial. Patients referred from within MD Anderson were more likely to be enrolled than patients seen originally outside the institution (p = .006); black patients were more likely than white patients to enroll (69% vs. 43%; p = .04). The median interval from the initial visit to initiation of treatments was 19 days. Major reasons for failure to enroll included failure to return to the clinic (36%), opting for treatment in another clinic (17%), hospice referral (11%), early death (10%), and lack of financial clearance (5%). Treatment was delayed for three weeks or more in 250 patients; in 85 patients (34%), the delay was caused by financial and insurance issues.Failure to return to the clinic, pursuit of other therapy, and rapid deterioration were the major reasons for failure to enroll; lengthy financial clearance was the most common reason for delayed enrollment onto a phase I trial.

Objective. To determine whether appendectomy is warranted in patients with apparent early-stage ovarian cancer who undergo surgery for staging and cytoreduction and to determine the complication rate associated with appendectomy in such patients. Methods. We reviewed the medical records of all patients who underwent appendectomy at the time of primary surgery for ovarian cancer at The University of Texas M. D. Anderson Cancer Center between January 1992 and December 2004 and who did not meet any of the following exclusion criteria: stage III or IV ovarian cancer, appendectomy as part of a second-look procedure or secondary tumor-reductive surgery, primary appendiceal cancer, primary gastrointestinal malignancy with metastasis to the appendix, incomplete clinicopathologic data, appendicitis as a preoperative diagnosis, primary fallopian tube cancer, primary peritoneal cancer, or documented dual primary tumors. Results. Fifty-seven patients were included in this analysis. The median age was 47 years (range, 13–75). Median follow-up was 53 months (range, 3–147). Histologic diagnoses were as follows: invasive epithelial carcinoma, 35 patients (61%); tumor of low malignant potential, 15 patients (26%); malignant germ cell tumor, 4 patients (7%); and other, 3 patients (5%). Twenty-three patients (40%) had pure mucinous tumors. Forty-six patients (81%) had stage I and 11 patients (19%) had stage II disease. The median CA-125 level was 36.2 U/mL (range, 7–7900). No patient had evidence of appendiceal involvement. No patient suffered an intraoperative or postoperative complication directly related to appendectomy. Conclusions. Appendectomy at the time of surgery for apparent early-stage ovarian cancer is not associated with complications but should not be routinely recommended.

Objective: We evaluated preoperative data that may predict benefit from secondary cytoreductive surgery (CRS) to assist in selecting therapy for patients with platinum-sensitive recurrent epithelial ovarian cancer. Materials and Methods: Inclusion criteria included recurrent epithelial or primary peritoneal carcinoma with an initial disease-free interval more than 6 months after chemotherapy, evidence of disease on imaging studies and indication for surgery being to debulk residual disease. Preoperative CA125 values, computed tomographic findings, and time to progression were evaluated as predictors of survival in addition to postoperative information and perioperative morbidity. Results: Sixty-two patients met the inclusion criteria. In the 35.5% of patients debulked to no visible disease, median survival was significantly longer than in those with less than 1 cm of visible residual disease (5.95 vs 2.73 years, P = 0.004), but debulking to less than 1 cm visible disease was not better than those with less than 1 cm residual disease (2.02 years). Mean preoperative CA125 levels were significantly lower in the patients who could be debulked to no visible residual disease compared to less than 1 cm or more than 1 cm residual disease (69.1 vs 290.7 vs 1978.4, P = 0.001). Generation of a receiver operating characteristic curve determined that a CA125 cutoff of 250 U/mL best predicted successful cytoreduction to no visible disease. Conclusions: Only patients cytoreduced to no visible disease achieved a survival advantage, and the only preoperative factor that could predict surgical success regarding prolonging survival was a CA125 less than 250 U/mL. These data can guide physicians and patients in deciding whether or not to undergo secondary cytoreduction for first recurrence of ovarian cancer.

Organ-specific delivery of agents by the aerosol route offers many advantages since it targets the organ where metastases are and provides significantly less toxic effects. The purpose of this study is to evaluate safety of aerosol IL-2 in patients > 12 yrs. with lung metastases to establish the maximum tolerated dose (MTD) to use for combination therapies with infused natural killer cells and/or autophagy inhibitors in patients with Osteosarcoma (OS) lung metastases. Lung metastases constitute the main cause of death in patients with OS. Survival has remained the same in the past 15 years. Using a human OS mouse model we demonstrated therapeutic efficacy of aerosol IL-2 in OS lung metastases (p = 0.03) and there was significant increase in apoptosis measured by TUNEL (p= 0.003). In addition, aerosol IL-2 significantly increased proliferation of local infused NK cells in the lungs (p= 0.03 and p=0.007 at 24 and 72 hours respectively) with no proliferation demonstrated in other organs including bone marrow. Moreover, immunocompetent mice treated with aerosol IL-2 had significant increase in the number of local NK cells in the lung and there was no evidence of T regulatory cells, a group of cells known to abrogate immune response. Additionally, there is recent evidence to suggest that IL-2 induces autophagy, an evolutionary, conserved, intracellular self-defense mechanism, in CD4+ T cells and NK cells and contributes to growth factor withdrawal cell death. Inhibition of autophagy augments immune cell function allowing a better anti-tumor effect. We initiated a Phase I/II clinical trial of aerosol IL-2 to include patients > 12 years with lung metastases. The primary objective is to determine feasibility and safety of aerosol IL-2. The secondary objective is to determine local effects of aerosol IL-2 by analyzing pre and post-treatment surgical samples for evidence of increase NK cell number, function and autophagy induction. Patients received aerosolized IL-2 for 3 consecutive weeks (21 day cycle) for 2 cycles with 1-week rest between cycles providing no drug limiting toxicities (DLTs) occur. The first treatment is delivered in the hospital. Subsequent treatments are given at home providing patients had been educated. From dose levels 1-4 only 1 patient/dose level was enrolled. From dose level 5 on, 3 patients will be enrolled. Once MTD is reached an additional 14 patients will be treated. 34 to 56 patients may be enrolled. Clinical response will be assessed by chest CT and determined using modified Response Evaluation Criteria in Solid Tumor (RECIST) after 2nd cycle. We have reached dose level 4 and the only side effects were grade 1 fatigue (n= 1), grade 1 cough (n= 2), and grade 1 wheezing (n=1) Adverse events were not attributed to the IL-2 therapy since symptoms resolved without intervention. Serum levels of IL-2 were undetectable in the first three patients. The fourth patient has detectable but low serum levels of IL-2. All patients had progressive disease. In conclusion, feasibility and safety of aerosol IL-2 therapy will set the ground for future combination therapies with NK cells and/or autophagy inhibitors as potential therapeutic options for patients with recurrent and resistant OS lung disease. Citation Format: Nancy B. Gordon, Peter Anderson, Sergei Guma, Hsuan-Chu Chien, Lacey M. McQuinn, Joshua P. Hein, Ralph Zinner, Eugenie S. Kleinerman, Aung Naing. Feasibility and safety of aerosol IL-2 in patients with lung metastases for future combination therapies for the treatment of osteosarcoma lung metastases. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A82.

The purpose of this study is to test aerosol delivery of Interkeukin-2 (IL-2) in patients > 12 yrs. with lung metastases to establish feasibility and safety in the pediatric population and determine the maximum tolerated dose (MTD) for potential combination therapies in patients with Osteosarcoma (OS) lung metastases. Organ-specific delivery of agents by the aerosol route offers many advantages for the treatment of OS since it targets the organ where metastases are and provides significantly less toxic effects. OS survival has remained at 65-70% for the last 20 years. Our pre-clinical data using a human OS mouse model demonstrated therapeutic efficacy of aerosol IL-2 in OS lung metastases (p = 0.03) and increase apoptosis measured by TUNEL (p= 0.003). In addition, aerosol IL-2 increased local immune cell proliferation as demonstrated by an increase in CD4+ T cells and NK cells with no evidence of T regulatory cells. Most recently, IL-2 was shown to induce autophagy, an evolutionary, conserved, intracellular self-defense mechanism, in CD4+ T cells and NK cells and contributes to growth factor withdrawal cell death. Inhibition of autophagy augments immune cell function allowing a better anti-tumor effect. Immunohistochemistry staining of OS lung tumors from mice treated with aerosol IL-2 showed an increase in Beclin expression as evidence of autophagy induction. We initiated a Phase I/II clinical trial of aerosol IL-2 to include patients > 12 years with lung metastases. The primary objective is to determine feasibility and safety of aerosol IL-2. The secondary objective is to determine local effects of aerosol IL-2 by analyzing pre and post-treatment surgical samples for evidence of increase NK cell number, function and autophagy induction. Patients received aerosolized IL-2 for 3 consecutive weeks (21 day cycle) for 2 cycles with 1-week rest between cycles providing no drug limiting toxicities (DLTs) occur. The first treatment is delivered in the hospital. Subsequent treatments are given at home providing patients had been educated. From dose levels 1-4 only 1-patient/dose level was enrolled. From dose level 5 on, 3 patients will be enrolled. Once MTD is reached an additional 14 patients will be treated. 34 to 56 patients may be enrolled. Clinical response will be assessed by chest CT and determined using modified Response Evaluation Criteria in Solid Tumor (RECIST) after 2nd cycle. Results: 5 patients have been enrolled, ages 18, 35, 66, 20 and 15; all male, 3 with Ewing's Sarcoma and 2 with Osteosarcoma. No side effects had been detected and serum levels of IL-2 were only detected in the fourth patient but were very low. Conclusion: Aerosol IL-2 seems so far feasibly and safe. Completion of the Phase I will provide information on the maximum tolerated dose (MTD) to use on the Phase II where only patients with OS lung metastases will be enrolled. Culmination of this trial will provide the basis for future combination therapy trials. Citation Format: Nancy Beatriz Gordon, Najat Daw Bitar, Peter Anderson, Sergei Guma, Hsuan-Chu Chien, Lacey M. McQuinn, Joshua P. Hein, Ralph Zinner, Eugenie S. Kleinerman, Aung Naing. Aerosol interleukin-2 for the treatment of patients ≥ 12 years old with osteosarcoma lung disease: A phase I/II study. [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 CT406. doi:10.1158/1538-7445.AM2014-CT406

The purpose of this study is to determine safety of aerosol IL-2 in patients ≥12 yrs. with lung metastases to establish the maximum tolerated dose (MTD) to use for combination therapy with infused natural killer (NK) cells in patients with osteosarcoma (OS) lung metastases. OS survival has remained at 65-70% for the last 20 years. One recent therapeutic approach has been to use adoptive cell-therapy to non-specifically augment immune function in vivo. However, therapeutic efficacy of immune cells depends upon proliferation and persistence in the tumor area. Organ-specific delivery of interleukin-2 (IL-2) offers that benefit. We initiated a Phase I/II clinical trial of aerosol IL-2 to include patients ≥12 years with lung metastases. The primary objective is to determine feasibility and safety of aerosol IL-2. Patients only received aerosolized IL-2 for 3 consecutive weeks (21 day cycle) for 2 cycles with 1-week rest between cycles providing no drug limiting toxicities (DLTs) occur. Each patient is educated on treatment administration the first time in the hospital. Further treatments are administered at home and remote spirometry and pulse oximetry are recorded before each treatment. Data is downloaded on a web portal and captured into the patient's medical record. We anticipated the maximum tolerated dose (MTD) to be at dose level 5. From dose levels 1-4 only 1 patient/dose level was enrolled. From dose level 5 on, 3 patients will be enrolled and the 3 x 3 model will be followed. Once MTD is reached an additional 14 patients will be treated at the MTD. 34 to 56 patients may be enrolled. Clinical response will be assessed by chest CT and determined using modified Response Evaluation Criteria in Solid Tumor (RECIST) after 2nd cycle. So far, 4 patients have been enrolled, ages 18, 35, 66, and 20; all male, 3 with Ewing's Sarcoma and 1 with osteosarcoma. Side effects were grade 1 fatigue (n= 1), grade 1 cough (n= 2), and grade 1 wheezing (n=1). None of these adverse events have been attributed to the IL-2 therapy since symptoms resolved without intervention while on therapy. Serum levels of IL-2 in the first three patients were undetectable and they had progressive disease. The fourth patient is on treatment. Supporting this clinical study is pre-clinical data from our lab. Immunocompetent mice treated with aerosol IL-2 had significant increase in the number of local NK cells in the lung when compared with aerosol phosphate buffer saline (PBS) group. Using a human OS mouse model we demonstrated therapeutic efficacy of aerosol IL-2 in OS lung metastases when compared with aerosol PBS group (p = 0.03) and there was significant increase in apoptosis measured by TUNEL (p= 0.003). In addition, aerosol IL-2 significantly increased proliferation of local infused NK cells in the lungs when compared with aerosol PBS group (p= 0.03 and p=0.007 at 24 and 72 hours respectively) with no proliferation demonstrated in other organs including bone marrow. In conclusion, clinical evaluation of aerosol IL-2 therapy will potentially benefit patients with OS who succumb almost always due to lung disease and allow future combination therapy with infused NK cells. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C64. Citation Format: Nancy B. Gordon, Peter Anderson, Sergei R. Guma, Hsuan-Chu Chien, Lacey M. McQuinn, Joshua P. Hein, Ralph G. Zinner, Eugenie S. Kleinerman, Aung Naing. Clinical evaluation of aerosol IL-2 in patients with lung metastases to test feasibility and safety for future combination therapy using infused natural killer cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C64.

Meeting abstracts To circumvent significant toxicities associated with high dose systemic IL-2 treatment, organ-specific delivery such as inhalational IL-2 has been studied. Our pre-clinical data demonstrated therapeutic efficacy of aerosol IL-2 in a human OS mouse model with no toxicity. The

e13575 Background: Mucositis is a well-known side effect of mTOR inhibitor (temsirolimus) treatment of cancer patients, limiting the use of mTOR inhibitors. We investigated whether combination treatment of temsirolimus with another agent that was not known to cause mucositis would result in a higher or lower incidence of mucositis. We further investigated if there was an association between the severity of mucositis and tumor response to the temsirolimus-based combination treatment. Methods: This retrospective data review was approved by IRB and conducted in the department of Investigational Cancer Therapeutics at MD Anderson Cancer Center. We reviewed the electronic medical records of 87 patients who were enrolled in temsirolimus-based combination phase I trials (n=3), including physician notes from the date they enrolled on the study to the date they came off treatments. We first examined the incidence of mucositis during the course of study and its severity. We assessed patient response to the study treatment with severity of the mucositis. Results: The overall incidence of mucositis in the 3 temsirolimus-based combination trials was 46%, similar to the published data for the single agent of 41%. The grades of mucositis were: for grade 1 (n=14), grade 2 (n=17) and grade 3 (n=9). No grade 4 mucositis was observed. Neither gender nor ethnicity altered the incidence of mucositis. The median onset time was 14 days after the start of the studies. Of 87 patients, 20 responded to the study treatments with at least stable disease for longer than 6 months or a partial or complete response. The incidence of the mucositis was not associated with the response to temsirolimus-based treatment. Severity of mucositis did not correlate with response to the temsirolimus-based regimen. (grades 1/2 vs. ≥ grade 3; p=0.512). Conclusions: The incidence of mucositis did not increase significantly in patients who received a temsirolimus-based regimen compared to single-agent temsirolimus. Severity of mucositis did not correlate with tumor response to the temsirolimus-based regimen. Future study is warranted to optimize management for mTOR inhibitor-induced mucositis.