bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and safety of cancer vaccine with 4-fold gene-modified allogeneic tumor cells: Results of the phase I/II ASET study in patients with advanced renal cell carcinoma.
Authors: Weikert Steffen , Grünwald Viktor , Schmidt-Wolf Ingo GH , Hauser Stefan , Kapp Kerstin , Schmidt Manuel , Schroff Matthias , Weith Ekaterina , Tschaika Marina , Wittig Burghardt
Published: March 2020

4636

Background: MGN1601 was tested in the first-in-man phase I-II clinical study in patients with advanced renal cell carcinoma (RCC) who failed several previous therapy lines and had no further standard therapy available. MGN1601 consists of two active pharmaceutical ingredients in fixed combination: fourfold gene-modified allogeneic tumor cells expressing IL-7, GM-CSF, CD80 and CD154 through MIDGE vectors and a TLR-9 agonist, the immunomodulator dSLIM. Methods: The ASET study is a multicentric, single-arm phase I-II clinical trial. Clinical response was evaluated using CT scans (RECIST 1.1 or immune related Response Criteria, irRC). Efficacy data were evaluated in terms of PFS and OS for the intended to treat and the treated per protocol (TPP) populations, clinical parameters and quality of life. Immune response was determined using DTH to MGN1601, LTT assay, frequency and activation of blood cells, and mRNA, chemokine and cytotoxic T cells analysis as well as tumor tissue evaluation. Results: Nine of 19 included patients completed the TPP, the others discontinued the study earlier due to PD. Median PFS in the TPP group was 12 wks (3 months) and OS (not reached yet) 46 wks (11 months). Three patients achieved disease control (1 PR, 2 SD) after 12 wks. Two patients are continuing treatment in the extension phase and are progression free since 37 and 46 wks, respectively. Re-evaluation of tumor response data using irRC revealed 1 additional patient with a delayed tumor response 4 wks after treatment stop. Herewith, 4 out of 9 TPP patients (45%) achieved disease control. Of 7 patients receiving targeted therapy upon stop of study treatment, 4 had substantial objective responses, providing evidence that the study drug is able to render their tumors more vulnerable to subsequent therapies. Immune analysis showed trends towards increases of T-, NKT-cell and pDC frequencies and other immune parameters in those patients with clinical responses, indicating anti-tumor immunity of study treatment. Conclusions: The therapeutic cancer vaccine MGN1601 shows promising efficacy in late stage mRCC patients. Results warrant further clinical studies with MGN1601.
Adjuvant radiotherapy after primary surgical resection in patients with adrenocortical carcinoma: Retrospective cohort analysis.
Authors: Habra Mouhammed Amir , Ejaz Shamim , Feng Lei , Das Prajnan , Deniz Ferhat , Grubbs Elizabeth Gardner , Phan Alexandria T. , Waguespack Steven , Ayala-Ramirez Montserrat , Jimenez Camilo , Vassilopoulou-Sellin Rena
Published: March 2020

4641

Background: Adrenocortical carcinoma (ACC) is a rare malignancy with high recurrence and mortality rates. The role of adjuvant radiotherapy (RT) to improve outcome remains unclear. Considering the rarity of ACC, we conducted a historical cohort study to ascertain the effect of adjuvant RT on overall survival and recurrence rates. Methods: Patients were selected from the MD Anderson Cancer Center (MDACC) ACC registry (1998- 2011) who had primary tumor resection with no evidence of distant metastasis at the time of initial diagnosis and a minimum follow-up of 6-months. The adjuvant RT group included patients who received adjuvant RT within 3 months of diagnosis. Control group included patients who did not receive RT and matched based on resection margin status and stage at diagnosis. Results: There were no significant differences between the adjuvant RT group (n=15) and comparison group (n =45) in gender distribution, age, tumor size, functional status, and use of adjuvant mitotane therapy. On multivariate Cox proportional hazard model for overall survival, the adjuvant RT group had hazard ratio of 1.981(95% confidence interval [CI] 0.894-4.391, p=0.0922) compared to the control group. The differences in median time to local recurrence, distant recurrence and of recurrence free survival were not significant between the two groups. In subgroup analysis including only the patients whose initial treatments were from outside of MDACC, RT group (n=15) had hazard ratio of overall survival of 1.604 (95% CI 0.712- 3.613, p=0.2543) compared to group without adjuvant RT (n= 32). Median times to local recurrence, distant recurrence, or of recurrence free survival were also not significantly different between the two groups. Conclusions: To our knowledge, this is the largest single institution report about adjuvant RT use in ACC. In our study, RT did not appear to cause a significant difference in overall survival, recurrence rate, or time to recurrence. However, it is still possible that patients offered adjuvant RT and control groups may have been inherently different. Hence, a prospective study is needed to clarify the role of adjuvant RT in patients with resectable ACC.
Polymorphisms in fragile histidine triad gene (FHIT) associated with aggressive prostate cancer and cancer specific mortality.
Authors: Ding Yan , Black Amanda , Hsing Ann W , Andriole Gerald L.
Published: March 2020

4646

Background: FHIT is a 1.5 Mb gene encoding a 16.8 kD triphosphatase known to promote apoptosis responding to DNA damage in epithelial cells. It resides in the most frequently observed fragile site in the human genome, FRA3B, and is frequently deleted in early development of multiple cancer types. More importantly, down regulation of FHIT protein has been associated with clinical features of tumors, such as the presence of extraprostatic extension and Gleason Score > 8 in prostate cancer (CaP), advanced diseases in breast cancer, and shorter survival after platinum-based treatment for advanced non-small cell lung cancer. Previously, a genetic locus for CaP has been reported in FHIT. Here we evaluated association of aggressive CaP and death due to CaP with Single nucleotide polymorphisms (SNPs) in FHIT using cases and controls of European origin nested in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening trial with 13 years of follow-up. Methods: We analyzed 659 SNPs on FHIT in 1,164 CaP patients (476 with nonaggressive CaP, Gleason < 7 and stage < III; 688 with aggressive CaP, Gleason >= 7 and/or stage III/IV; 63 with death due to CaP) and 1,167 controls using an incidence density sampling strategy. Stratified Cochran-Mantel-Haenszel test and logistic regression were performed to test association. Results: We detected significant association (p < 0.05) of incident CaP to 48 SNPs and aggressive CaP to 52 SNPs. After 50,000 permutations, two SNPs within a 7 kb region, one for incident CaP and the other for aggressive CaP, remained marginally significant (corrected p = 0.053 and 0.093, respectively). The same risk allele for aggressive CaP was also associated with CaP-specific mortality (OR = 1.50, p = 0.027). The association was stronger after adjusting for Gleason, stage, and PSA at diagnosis, treatment options after diagnosis. Test on imputed SNPs within the 7 kb intronic region identified 7 additional SNPs in 2 linkage disequilibrium groups at higher risk to CaP-specific death (OR = 1.98, p = 0.00015 and OR = 2.51, p = 0.0027). Conclusions: Risk SNPs in FHIT were implicated for aggressive disease and CaP specific death. Replication of these SNPs in other populations is warranted.
A national survey of radiation oncologists and urologists on active surveillance for low-risk prostate cancer.
Authors: Kim Simon P. , Karnes R. Jeffrey , Nguyen Paul Linh , Leibovich Bradley C. , Ziegenfuss Jeanette Y. , Thompson R. Houston , Boorjian Stephen A. , Han Leona C. , Costello Brian Addis , Tilburt Jon C.
Published: March 2020

4657

Background: While active surveillance (AS) is well recognized as an acceptable treatment strategy for low-risk prostate cancer (PC), the extent to which radiation oncologists and urologists perceive AS as effective and routinely recommend it to patients is unknown. Therefore, we sought to assess the attitudes and treatment recommendations for low-risk PC from a national survey of PC specialists. Methods: A mail survey was sent to a population-based sample of 1,439 physicians in the U.S. from late 2011 and early 2012. Physicians were queried about their attitudes regarding AS and treatment recommendations for patients diagnosed with low-risk PC (PSA<10 ng/dl; T1c; Gleason 6 in one of twelve cores). Pearson Chi-square and multivariate logistic regression were used to test for differences in attitudes and treatment recommendations by physician demographics, compensation structure, primary place of employment, and specialty. Results: Overall, 321 radiation oncologists and 322 urologists completed the survey for a 45% response rate. Most physicians reported that AS is effective for low-risk PC (71%) and stated that they were comfortable routinely recommending AS (67%). Urologists were more likely to agree that AS is effective (77% vs. 67%; p=0.005) and were comfortable recommending AS (74% vs. 61%; p=0.001) compared with radiation oncologists. Most physicians recommended radical prostatectomy (47%) or radiation therapy (32%), but fewer endorsed AS (21%) for low-risk disease. After adjusting for physician covariates, radiation oncologists were more likely to recommend radiation therapy (OR: 10.97; p<0.001), while urologists were more likely to recommend surgery (OR: 4.69; p<0.001) and AS (OR: 2.18; p=0.001) for low-risk PC. Conclusions: Although AS is widely viewed as effective by both radiation oncologists and urologists, most urologists continue to recommend surgery, while most radiation oncologists recommend radiation therapy. Our results may explain in part the relatively low contemporary use of AS in the U.S.
Prostate-specific membrane antigen antibody drug conjugate (PSMA ADC): A phase I trial in metastatic castration-resistant prostate cancer (mCRPC) previously treated with a taxane.
Authors: Mega Anthony E. , Petrylak Daniel Peter , Kantoff Philip , Stephenson Joe , Vogelzang Nicholas J. , Dreicer Robert , Shore Neal D. , Stambler Nancy , Carpenito Jennifer , D'Ambrosio Paul , Israel Robert Joseph
Published: March 2020

4662

Background: The abundant expression of prostate specific membrane antigen (PSMA) type II transmembrane glycoprotein on prostate cancer cells provides a rationale for antibody therapy. PSMA ADC, a fully humanized antibody to PSMA linked to the potent antitubulin agent monomethyl auristatin E (MMAE), binds PSMA and is internalized within the prostate cancer cell where cleavage by lysosomal enzymes and releases free MMAE, causing cell cycle arrest and apoptosis. We report results from an ongoing phase 1 dose escalation study of PSMA ADC in subjects with taxane-refractory mCRPC. Methods: Eligibility requirements include progressive mCRPC following taxane-containing chemotherapy and ECOG status of 0 or 1. PSMA ADC was administered by IV infusion Q3W for up to 4 cycles. Adverse events, pharmacokinetics (PK), PSA, circulating tumor cells, clinical disease progression and immunogenic response to PSMA ADC were assessed. Serum PSMA ADC and total antibody were measured by ELISA, and free MMAE was measured by LC/MS/MS.The dosing cohorts range from 0.4 mg/kg to 2.8 mg/kg, with dose escalation continuing. Results: 40 subjects have been dosed in nine dose levels (0.4, 0.7, 1.1, 1.6, 1.8, 2.0, 2.2, 2.5, 2.8 mg/kg). To date, PSMA ADC has been well tolerated with the most commonly seen adverse events being anorexia and nausea, and the most common laboratory abnormalities being reversible hematologic parameters and liver function tests. Antitumor activity has been manifested as reductions either in PSA or circulating tumor cells in the higher dose cohorts. Exposure to PSMA ADC increased with dose and was ~1,000-fold greater than MMAE exposure. Similar PK metrics were observed after the first and third doses. Dosing at the 2.8 mg/kg cohort is continuing and an MTD has not yet been reached. Conclusions: PSMA ADC is generally well tolerated in subjects with mCRPC, previously treated with taxane in doses up to 2.8 mg/kg. Antitumor activity at higher dose levels has been observed. The MTD has not yet been reached and enrollment is ongoing at higher dose levels.
Phase I clinical trial of galeterone (TOK-001), a multifunctional antiandrogen and CYP17 inhibitor in castration resistant prostate cancer (CRPC).
Authors: Montgomery Robert B. , Eisenberger Mario A. , Rettig Matthew , Chu Franklin , Pili Roberto , Stephenson Joe , Vogelzang Nicholas J. , Morrison Jodie , Taplin Mary-Ellen
Published: March 2020

4665

Background: Galeterone is an oral steroid analog that suppresses prostate cancer growth by inhibiting CYP17, blocking androgen receptor and reducing androgen receptor levels. Methods: Open label, multicenter dose-finding study assessing the safety, pharmacokinetics and clinical effect of escalating doses of galeterone in chemotherapy naïve CRPC patients (pts). Pts were enrolled in cohorts from 650-2,600mg of galeterone daily for 12 wks. Study also explored effects of food supplement and scheduling. Pts remained on study until disease progression or dose limiting toxicity. Results: Pt characteristics included median age 69 (47-92), median PSA 24 (6-200), and 46.9% with metastases. 36 of 49 pts completed 12 wks of study with early discontinuation for toxicity (6), progression (5), or withdrawal of consent (2). Maximal tolerated dose was not reached. The frequency of AEs was 58% grade 1, 30% grade 2, 8% grade 3 and 1% grade 4. Transient LFT elevations were seen in 15 men (5 with suspected or confirmed Gilberts). There was no trend for increasing toxicity with dose escalation and no PK difference in Gilberts pts. 9 SAEs were reported with one considered related to galeterone (rhabdomyolysis with acute renal failure in the context of high dose statin use). Overall 11/49 pts (22%) demonstrated >50% PSA decline and an additional 13/49 (26%) had 30-50% declines. Partial response by RECIST was seen in 2 pts. Consistent with lyase inhibition, increased corticosteroids and suppressed androgens were seen with dose escalation. Analysis of limited plasma collected 4 - 30 hours after dosing showed high interpatient variability with no consistent relationship to dose or time after dosing. Conclusions: Galeterone was well tolerated in CRPC pts and demonstrated clinical activity. Galeterone is being reformulated with additional PK and phase II trials planned. [Table: see text]
The impact of prior therapy with ketoconazole (keto) on clinical outcomes after subsequent docetaxel treatment in metastatic castration-resistant prostate cancer (mCRPC) patients: Results from a randomized phase III trial (CALGB 90401).
Authors: Small Eric Jay , Halabi Susan , Carducci Michael Anthony , Ryan Charles J. , George Daniel J. , Mahoney John Francis , Stadler Walter Michael , Morris Michael J. , Kantoff Philip , Monk J. P. , Kelly William Kevin
Published: March 2020

4667

Background: Small retrospective reviews have suggested the possibility of a decreased benefit of docetaxel in mCRPC patients (pts) previously treated with abiraterone acetate, a novel androgen synthesis inhibitor (ASI). CALGB 90401 was an intergroup (CALGB, ECOG) randomized phase 3 trial in which 1050 mCRPC pts were treated with docetaxel, which offered the opportunity to evaluate the effect of prior treatment with keto, an earlier generation ASI, on clinical outcomes following docetaxel treatment in mCRPC pts. Methods: Data from 1,050 men randomized on CALGB 90401 to treatment with docetaxel and prednisone with either bevacizumab or placebo were used. Pts were chemotherapy naïve, had evidence of progressive mCRPC, an ECOG performance status ≤ 2, and adequate bone marrow, hepatic and renal function. Randomization was stratified by age, prior history of a thromboembolic event, and 24-month predicted survival using the CALGB nomogram. The effect of prior keto use on overall survival (OS), progression-free survival (PFS), PSA decline, and objective response rate (RR) was estimated using proportional hazards and logistic regression models. Results: 277/1050 pts (26%) had received prior keto. Baseline characteristics including the 3 stratification factors, race, performance status, measurable disease, and baseline alkaline phosphatase and Hgb were balanced between prior keto treated pts and keto untreated pts. LDH and PSA were higher in the keto treated patients (211 vs. 201, p = 0.01; and 121 vs. 73, p < .0001; respectively.) There were no statistically significant differences in keto vs. non-keto treated patients with regards to OS (21.1 vs. 22.3 m, p = 0.643); PFS (8.1 vs. 8.6m p = 0.394 ); >50% decline in PSA (61% vs. 66% p=.112); or objective response (39% vs. 43% p = 0.34). Conclusions: As measured by OS, PFS, PSA and RR, prior treatment with the ASI ketoconazole has no impact on the subsequent clinical impact of docetaxel in mCRPC pts.
Incidence-based analysis of lethal prostate cancer in Swedish counties with high versus low incidence of prostate cancer in nationwide, population-based registries.
Authors: Stattin Pär , Holmström Benny , Robinson David , Vickers Andrew J. , Lilja Hans , Hugosson Jonas , Jonsson Håkan
Published: March 2020

4668

Background: Current data from randomized trials differ in the ratio of benefit to harms from screening for prostate cancer (PC) using prostate specific antigen (PSA) testing and it is further unclear if decreases in PC mortality in the US can be attributed to introduction of screening or to changes in treatment. The aim of this study was to investigate if rapidly increased incidence of PC diagnosis due to early and rapidly increased rate of PSA testing, is associated with decreased incidence of lethal PC. Methods: In this incidence-based study using highly representative data from nation-wide population-based registries we analysed the incidence of lethal prostate cancer in eight Swedish counties with the most rapid and largest increased incidence of PC diagnosis (high incidence counties) from 1995 through 2002, and six counties with the smallest increased PC incidence (low incidence counties). We analysed the rate ratio (RR) in high vs. low incidence counties of cases with metastatic PC at diagnosis, (positive bone scan or PSA above 100 ng/ml), PC-specific mortality, and excess mortality (death among PC cases regardless of cause). Participants were men aged 50-74 years during 2000 to 2009 in the high versus low incidence counties contributing 4,528,134 versus 2,471,373 person-years at risk, respectively. There were 33,780 incident PC diagnoses and 1,577 PC deaths in high incidence counties and 16,377 PC cases and 985 PC deaths in low incidence counties. Results: In high vs. low incidence counties, RR of metastatic PC was 0.85 (95% confidence interval [CI] = 0.79 to 0.92), RR of PC-specific mortality was 0.87 (95% CI = 0.81 to 0.95) and RR of excess mortality in men with PC was 0.75 (95 %CI = 0.66 to 0.86). Conclusions: Our study provides data on a population-level indicating a decreased incidence of lethal PC in areas with rapid and large increase in incident PC diagnosis due to increased rates of PSA testing, early diagnosis, and treatment with curative intent.
Impact of adjuvant therapy in lymph-node positive vulvar cancer: The AGO CARE 1 study.
Authors: Mahner Sven , Jueckstock Julia Kathrin , Hilpert Felix , Lubbe Dirk , Harter Philipp , De Gregorio Nikolaus , Iborra Severine , Chen Frank , Stoenescu Adela , Hillemanns Peter , Fuerst Sophie , Strauss Hans-Georg , Baumann Klaus H. , Thiel Falk , Mustea Alexander , Meier Werner , Du Bois Andreas , Wimberger Pauline , Griebel Lis-Femke , Woelber Linn Lena ,   AGO-CaRE-1 Investigators
Published: March 2020

5007

Background: While the majority of patients with vulvar cancer can be cured by surgery alone, women with lymph-node metastases often show unfavorable outcome. Improved treatment strategies are therefore strongly needed. Methods: Patients with primary squamous-cell vulvar cancer treated at 29 gynecologic cancer centers in Germany between 1998 and 2008 were included in a centralized database and analyzed retrospectively. Results: A total of 1,637 patients were documented with a median follow-up of 121 months. UICC-Stage distribution was 597 (36.5 %) T1, 816 (49.8 %) T2, 160 (9.8 %) T3 and 31 (1.9 %) T4, 33 (2.0 %) were missing. 491 patients had lymph-node metastasis to the groins (N+). 214 N+ patients (43.6 %) developed recurrent disease within a median of 21.4 months. 190 N+ patients (38.7%) died, median overall survival (OS) was 43.4 months, compared to 212 months for node-negative patients. An increasing number of metastatic lymph-nodes was associated with shorter OS: 169 (34.4%) patients had 1, 101 (20.6%) patients 2, 62 (12.6%) patients 3 and 86 (17.5%) patients >3 positive lymph-nodes, with a corresponding OS of 22.4, 17.2, 18.4 and 10.2 months, respectively (for 73 patients the number of nodes was not available). 240 N+ patients were treated with adjuvant radiotherapy (85.8%) or radiochemotherapy (14.2%). Median OS in these patients was significantly longer (66.9 months) compared to N+ patients without adjuvant treatment (35.7 months), the corresponding hazard ratio (HR) was 0.72 (95 % CI: 0.53 - 0.97 p = 0.029). This impact on OS remained consistent in multivariate analysis adjusted for age, ECOG, stage, grading, invasion depth and number of positive nodes (HR 0.68; 95% CI: 0.49 - 0.94 p = 0.020) and was observed irrespective of the number of affected nodes. Conclusions: To this day, this is the largest multicenter study on vulvar cancer. Our findings strongly suggest that the unfavorable prognosis of patients with node positive vulvar cancer can be improved by adjuvant therapy irrespective of the number of affected nodes. As adjuvant radiochemotherapy was shown to be superior to radiotherapy alone in many other squamous cell carcinomas, we are preparing a prospective phase III trial in node-positive vulvar cancer (AGO-CaRE 2 trial).
Effect of osteoporosis in postmenopausal breast cancer patients randomized to adjuvant exemestane or anastrozole: NCIC CTG MA.27.
Authors: Shepherd Lois E. , Chapman Judy-Anne W. , Ali Suhail M. , Zhu Liting , Leitzel Kim , Goss Paul Edward , Lipton Allan
Published: March 2020

501

Background: NCIC CTG MA.27 compared adjuvant steroidal [exemestane (E)] and non-steroidal [anastrozole (A)] aromatase inhibitors (AIs) and showed neither to be superior in breast cancer outcomes. AIs are known to increase the risk of osteoporosis. We examined the effects of baseline or subsequent self reported osteoporosis on disease outcomes. Methods: MA.27 enrolled 7,576 women. Event free survival (EFS) was the primary endpoint. Distant disease-free-survival (DDFS) was a secondary outcome. MA.27 permitted bisphosphonates to prevent or treat osteopenia or osteoporosis unless prohibited by enrollment to one of two cohorts in a bone substudy. Osteoporosis was considered present for this analysis if reported at baseline or prior to relapse or breast cancer death. Multivariate stratified Cox regression was used to examine the effects of trial therapy, osteoporosis, baseline patient and tumour characteristics on EFS; DDFS; bone only relapse; bone concurrent with other relapse; and non-bone recurrence. Bone marrow recurrence (N=8) was excluded. Results: Osteoporosis was reported at baseline by 654 of 7576 (8.6%) women, and prior to relapse by an additional 661 women. EFS events occurred in 693/7576 (9.15%). Osteoporosis was significantly associated with better EFS [HR 0.81 (95% CI 0.66-0.99), p=0.04] with no difference in multivariate HR of E vs A: 1.02, 95% CI 0.88-1.19, p=0.77. Women experienced 313 (4.1%) DDFS events. Osteoporosis was associated with better DDFS [HR 0.71 (95% CI 0.51-0.98), p=0.04], adjusted HR of E to A: 0.94 (95% CI of 0.75-1.17), p=0.56. Both EFS and DDFS interactions of osteoporosis with trial therapy were not significant (p>0.05). Osteoporosis was not significantly associated with the site of relapse. Conclusions: Osteoporosis had a significant prognostic association with improved EFS and DDFS in women treated with AIs. We plan to investigate the use of bisphosphonates, raloxifene treatment prior to randomization, and markers of bone resorption with outcome.
A phase II, open-label, multicenter study of IMC-1121B (ramucirumab; RAM) monotherapy in the treatment of persistent or recurrent epithelial ovarian (EOC), fallopian tube (FTC), or primary peritoneal (PPC) carcinoma (CP12-0711/NCT00721162).
Authors: Penson Richard T. , Moore Kathleen N. , Fleming Gini F. , Braly Patricia S. , Schimp Veronica L. , Nguyen Hoa , Matulonis Ursula , Banerjee Susana N. , Haluska Paul , Gore Martin Eric , Bodurka Diane C. , Morozov Alexei , Xu Yihuan , Rutstein Mark D. , Schwartz Jonathan D. , McGuire William P.
Published: March 2020

5012

Background: VEGF receptor-mediated-signaling contributes to ovarian cancer pathogenesis. Elevated VEGF expression and serum levels are associated with poor clinical outcomes. We investigated RAM, a fully human VEGFR-2 antagonist antibody, in patients (pts) with persistent or recurrent EOC/FTC/PPC. Methods: Adult women with EOC/FTC/PPC who had completed ≥1 platinum (P)-based chemotherapeutic (ct) regimen and had a P-free interval (PFI) of <12 months (m), progression on, or persistent disease after P-based therapy were eligible. Any number of prior ct regimens was allowed. ECOG PS 0-1 and adequate organ function were required. Pts received 8 mg/kg RAM IV every 2 weeks. Primary endpoints were progression-free survival at 6m (PFS-6) and confirmed objective response rate (ORR) by RECIST 1.0. Results: 60 pts were treated; 1 remains on study as of Dec 2011. Median age was 62 years (range 27-80). Median number of prior regimens was 3 (range 1– 14). 51 pts (85%) received ≥ 2 prior regimens; 25 pts (42%) received >3 prior regimens. 45 pts (75%) were P resistant or refractory, with 65% (39 pts) serous tumors. PFS-6: 34.2% (95% CI: 21.7% – 47%). Best overall response: 3 PR (5%), 34 SD (57%), 20 PD (33%) and 3 not evaluable (5%). Median duration of PR: 5.6m (3.7, 5.6, 17.5); median PFS: 3.5m (95% CI: 2.3 – 5.3). Median OS: 11.1m (95% CI: 8.3 – 17.0). No unexpected toxicities were observed. Grade (G) 3 adverse events (AEs) observed in >5% of pts were: headache (10%) and fatigue (8%). No G4 AEs were observed in >5% of pts. 5 deaths occurred on RAM or within 30 days of discontinuation; 4 due to PD, and 1 due to intestinal perforation. 1 G4 bowel perforation and one G4 colo-vaginal fistula were noted. All 3 cases of perforation/fistula occurred in the setting of progressive, large-volume disease. Correlative biomarker studies are ongoing to identify patients most likely to benefit. Conclusions: Ramucirumab was reasonably tolerated and demonstrated single-agent activity in persistent or recurrent ovarian carcinoma, with approximately one-third of patients progression free at 6 months.
Phase II trial of irinotecan plus bevacizumab for heavily pretreated recurrent ovarian cancer.
Authors: Jain Salvia Sanjay , Makeyev Yan G. , Muggia Franco , Speyer James L. , Curtin John Patrick , Blank Stephanie V. , Boyd Leslie R. , Pothuri Bhavana , Fishman David , Li Xiaochun , Goldberg Judith D. , Tiersten Amy
Published: March 2020

5016

Background: Irinotecan and bevacizumab have single agent activity in platinum sensitive (PSen) and resistant (PRes) ovarian cancer patients (pts). We sought to evaluate the efficacy and toxicity of irinotecan plus bevacizumab in these pts. The trial was designed to evaluate whether the progression free survival (PFS) at 6 months is at least 40% and with secondary objectives of estimating response rate (RR), duration of response (DoR), time to progression and toxicity. Methods: No limitation on number of prior regimens was placed, and prior use of study drugs was allowed. Irinotecan 250mg/m2 and bevacizumab 15mg/kg every 3 weeks were given. Due to treatment-related grade 3 toxicity (diarrhea and neutropenia) experienced by the first 5 pts on the study, the dose of irinotecan was amended to 175mg/m2. Results: 20 pts with recurrent ovarian cancer [PSen 5, PRes 15] of a planned 35 have been recruited thus far. Median age is 59 (45-78). Median number of prior regimens is 5 (3-12) with 9 pts demonstrating progressive disease (PD) on prior topotecan-containing regimens and 7 pts exhibiting PD on prior bevacizumab-containing regimens. 4 pts discontinued treatment before 2 cycles (2 for protocol defined toxicity, 2 by patient/physician choice). Partial response (PR) was observed in 2 PSen pts and 1 PRes pt, while stable disease (SD)was seen in 9 (2 PSen, 7 PRes) out of the 15 pts assessable for response at this time. 3 pts demonstrated PD after 2 cycles of treatment. 12 of 13 pts with PR or SD by RECIST also had response by CA125 criteria. Median DoR thus far (SD plus PR) is 18 weeks (4-37). 6 pts have ongoing response (4-18 weeks). Of 19 pts that received > 2 cycles, 3 had grade 3 diarrhea (2 before protocol amendment and 1 after). 2 pts had grade 3/4 neutropenia (1 before and 1 after protocol amendment). Median PFS is 9.6 months (mts). Median overall survival is 15.5 mts. PFS rate at 6 mts is 61% with 95% confidence interval: (40%, 92%). Conclusions: Results of the trial to date suggest the hypothesis that the PFS at 6 mts is less than 40% can be rejected. Activity of this regimen is encouraging given the heavily pretreated nature of the pts. Dose-limiting diarrhea and neutropenia required protocol amendment. We continue to accrue study subjects at the amended dosing.
Randomized trial of oral cyclophosphamide (C) with or without veliparib (V), an oral poly (ADP-ribose) polymerase (PARP) inhibitor, in patients with recurrent BRCA-positive ovarian, or primary peritoneal or high-grade serous ovarian carcinoma.
Authors: Kummar Shivaani , Oza Amit M. , Fleming Gini F. , Sullivan Daniel , Gandara David R. , Erlichman Charles , Villalona-Calero Miguel Angel , Morgan Robert , Chen Alice P. , Ji Jiuping Jay , Allen Deborah , Lih Chih-Jian , Steinberg Seth M. , Williams P. Mickey , Conley Barbara A. , Doroshow James H.
Published: March 2020

5020

Background: V+C was well tolerated in a phase I trial and responses and prolonged disease stabilization were observed in BRCA + patients (pts).To assess the relative contribution of the PARP inhibitor to the efficacy observed for the combination, we conducted a randomized multicenter trial comparing the response rate (RR) of V and C to the RR of C alone in patients with deleterious BRCA mutations and recurrent ovarian, or primary peritoneal, fallopian tube or high-grade serous ovarian cancer. Methods: Pts were ≥ 18 yrs, KPS ≥ 70%, had adequate organ function, prior therapy with PARP inhibitors was allowed.Both drugs were administered orally qd; C 50 mg, V 60 mg; 21 day cycles. Pts were randomized to receive either C alone or V+C. At disease progression, pts on C alone were allowed to cross over to the combination. Radiologic imaging was performed at baseline and q 3 cycles for assessment of response. Dose reduction of V was allowed to 40 mg for gr 3 non-hematologic or gr 4 hematologic toxicities. The study design had an 88% power to detect the difference between a 15% RR for C alone versus 35% for V+C, early closure if fewer responses were observed on the combination arm in the first 65 pts enrolled (half of the total projected accrual). Results: Total of 74 pts were enrolled (36 pts C, 38 pts V+C), median age 58 (37-79 yrs), # of prior therapies: median 4 (1-9), 2 pts had prior PARP therapy. Treatment was well tolerated, Gr ≥ 2 toxicities per arm for initial regimen (# of pts): C alone: lymphopenia (2), mucositis (1); V+C: lymphopenia (4), anemia (2), leucopenia (2), neutropenia (2). Of the 74 pts evaluable for response at the interim analysis, 3 PRs observed in 36 pts on V+C and 5 PRs of 38 pts on C alone arm; thus accrual was stopped. PAR levels assessed by validated ELISA were inhibited (>80%) in PBMCs in 9/10 pts 4 hours post V, no inhibition with C alone. Conclusions: Addition of V, a PARP inhibitor, to C did not improve RR versus C alone. Exomic sequencing, gene expression studies, and Fanconi Anemia triple stain immunofluorescence (FATSI) assay for FancD2 nuclear foci formation using archival tissue are ongoing.
Phase II trial of temsirolimus and bevacizumab for initial recurrence of endometrial cancer.
Authors: Einstein Mark H. , Wenham Robert M , Morgan Robert , Cristea Mihaela C. , Strevel Elizabeth Laureen , Oza Amit M. , Kaubisch Andreas , Fruth Briant , Qin Rui , Erlichman Charles
Published: March 2020

5025

Background: We report the interim results of the endometrial arm of a multi-tumor protocol using temsirolimus and bevacizumab in endometrial cancer (EMCA) patients at the time of their initial recurrence. The primary aim of this trial is to assess treatment efficacy in terms of both confirmed tumor response and 6-month progression free survival (PFS). Methods: Women with a performance status of 0 or 1 who have had their first recurrence for EMCA were eligible. Subjects who had chemotherapy as part of their adjuvant treatment after front line surgical staging were also eligible. The regimen included Temsirolimus 25 mg IV weekly followed by bevacizumab 10mg/kg IV on days 1 and 15 of a 28 day cycle. A modified two-stage Simon design with fixed sample size was adopted with the null hypothesis being that the true tumor response rate is at most 25% and the true 6 month PFS rate is at most 50%. Results: We enrolled 26 evaluable subjects to the first stage of which one did not proceed with treatment. The median age at enrollment was 60 (range 40-80). 22 (85%) were white and 19 (73%) were not Hispanic/Latino. 19 (73%) of subjects had prior raditation therapy, with 4 having a prior para-aortic boost. 5 (20%) subjects had a confirmed PR and 12 (48%) were progression-free at 6 months, which fell short of the futility stopping rule. An additional 5 (20%) subjects had a best response of confirmed SD, so 10 (40%) had overall clinical benefit from this regimen. AEs attributable to treatment were modest and included 16 grade 3 adverse events, of which the most common ones included hypertension, hyperglycemia, and neutropenia. There were 2 grade 4 events that were possibly treatment related including a duodenal perforation and an anorectal infection. Conclusions: While there was clinical benefit of this regimen in women at the time of their first recurrence of EMCA, the combination of temsirolimus and bevacizumab did not achieve our prespecified efficacy assumptions. This differs from what has been reported with this combination as a second line therapy for recurrent EMCA, where prespecified response assumptions differ. Also, the regimen had comparable safety and toxicity to other cytotoxic chemotherapy regimens used in this setting.
Whole genome sequencing to characterize luminal-type breast cancer.
Authors: Ellis Matthew James , Ding Li , Shen Dong , Luo Jingqin , Suman Vera J. , Goiffon Reece J. , Wallis John W. , Goldstein Theodore C. , Chen Ken , Allred Donald Craig , Leitch A. Marilyn , Olson John A. , Ota David M. , Watson Mark , Piwnica-Worms David , Bose Ron , Stuart Joshua M. , Wilson Richard K. , Hunt Kelly , Mardis Elaine
Published: March 2020

503

Background: To correlate clinical features of estrogen receptor positive breast cancer with somatic mutations, massively parallel sequencing (MPS) was applied to tumor and normal DNAs accrued from patients treated with neoadjuvant aromatase inhibitors (AI). Methods: MPS was applied to 77 baseline tumor biopsy samples from the preoperative letrozole trial (JACS 2009: 208, 906) and the Z1031 trial (JCO 2011: 29, 2342) followed by targeted sequencing in another 240 trial samples. Standard statistical approaches were used to compare mutation status and clinical parameters and pathway-based correlation was used to assess interactions between signaling perturbations induced by gene mutations and response to neoadjuvant AI. Results: Eighteen genes were significantly mutated above background. Aside from PIK3CA mutations, the list is dominated by loss-of-function mutations in tumor suppressor genes. Five (RUNX1, CBFP, MYH9, MLL3 and SF3B1) have been previously linked to benign and malignant hematopoietic disorders. Clinical correlation revealed that TP53 mutation was associated with PAM50 LumB status, high-grade histology and high proliferation rates whereas loss-of-function mutations in MAP3K1 associate with PAM50 lumA status, low proliferation rates, and low grade histology. Mutations in GATA3 were associated with greater suppression of proliferation upon AI treatment suggesting mutGATA3 may predict endocrine response. Notably, mutations in MAP3K1 were more common in PIK3CA mutant cases, suggesting cooperation. Pathway analysis demonstrated that rare MAP2K4 mutations produce similar pathway perturbations as MAP3K1 mutation, a logical finding since MAP2K4 is a substrate for MAP3K1. Signaling network patterns driven by lncRNA MALAT1 mutations were associated with multiple poor clinical outcome features. Rare mutations in druggable kinases included two in the kinase domain of HER2. Conclusions: Tumor heterogeneity in luminal-type breast cancer is driven by specific patterns of somatic mutations, however most druggable or potentially prognostic mutations are infrequent. Prospective clinical trials based on these findings will require comprehensive genome sequencing approaches and large scale investigations.
Use of an optimized primary ovarian cancer xenograft model to mimic patient tumor biology and heterogeneity.
Authors: Dobbin Zachary C. , Katre Ashwini A. , Ziebarth Angela , Shah Monjri , Steg Adam D. , Alvarez Ronald David , Conner Michael G. , Landen Charles N.
Published: March 2020

5036

Background: Current xenograft and transgenic models of ovarian cancer are mainly homogeneous and poorly predict response to therapy. Use of patient tumors may represent a better model for tumor biology and offer potential to test personalized medicine approaches, but poor take rates and questions of recapitulation of patient tumors have limited this approach. We have developed a protocol for improved feasibility of such a model and examined its similarity to the patient tumor. Methods: Under IRB and IACUC approval, 23 metastatic ovarian cancer samples were collected at the time of tumor reductive surgery. Samples were implanted either subcutaneously (SQ), intraperitoneally (IP), in the mammary fat pad (MFP), or in the subrenal capsule (SRC) and monitored for tumor growth. Cohorts from 8 xenolines were treated with combined carboplatin and paclitaxel or vehicle, and response to therapy compared between xenografts and patients. Expression of tumor-initiating cell (TIC) markers ALDH1, CD133, and CD44 was assessed by immunohistochemistry in tumors from patients and treated and untreated xenografts. Results: At least one SQ implanted tumor developed in 91.3% of xenografts, significantly higher than in the MFP (63.6%), IP (23.5%), or SRC (8%). Xenografts were similar in expression of putative TIC’s compared to patient tumors. The patients and the xenografts also have similar responses to chemotherapy in that xenografts from patients with a partial response responded more slowly than those from patients achieving a complete response (45 vs 21 days, p=.004). Treated xenografts were more densely composed of TICs. ALDH1 increased to 36.1% from 16.2% (p=0.002) and CD133 increased to 33.8% from 16.2% (p=0.026). Conclusions: Xenoline development can be achieved at a high rate when tumors collected from metastatic sites are implanted SQ. These xenografts are similar to patient tumors with regard to chemotherapy response and TIC expression.. This model may be a more accurate model for in vivo pre-clinical studies as compared to current models. Also, as treated xenografts become chemoresistant, this model is well positioned to evaluate targeted therapies aimed at the most aggressive populations in a heterogeneous tumor.
Effect of weekly administration of bevacizumab, gemcitabine, and oxaliplatin in patients with heavily pretreated ovarian cancer.
Authors: Ikeda Yuji , Kikuchi Yoshihiro , Takano Masashi , Goto Tomoko , Kouta Hiroko , Sasaki Naoki , Kudoh Kazuya , Oda Katsutoshi , Nagasaka Tsuneki , Kita Tsunekazu
Published: March 2020

5037

Background: The combination therapy of gemcitabine with oxaliplatin (GEMOX) has high activity in patients with ovarian cancer. Bevacizumab (B), a vascular endothelial growth factor specific antibody, enhances chemotherapeutic efficacy through its anti-angiogenic function in various types of tumors. We evaluated the effect of weekly administration of B and GEMOX in heavily-pretreated patients with recurrent or refractory ovarian cancers (ROC). Methods: Nineteen patients with ROC received at least three or more cycles of weekly-B and GEMOX consisting of B (2mg/kg), gemcitabine (300mg/m2) and oxaliplatin (30mg/m2). The treatment was continued until the development of progressive disease. The response and adverse effects (AE) were evaluated using the response evaluation criteria in solid tumors (RECIST), CA125 Gynecologic Cancer Intergroup (GCIG) criteria, and common terminology criteria for adverse events (CTCAE) version 3.0. Results: Seventeen (89%) of the 19 patients were primarily stage 3 or 4. Fifteen patients (79%) had received more than three regimens of chemotherapy. All patients were pretreated with a platinum-containing regimen within 6 months and 16 of these patients (84%) were pretreated within 3 months. According to the RECIST evaluation, 2 patients (11%) had a complete response (CR), 6 patients (32%) had a partial remission (PR) and 5 patients (26%) had a stable disease (SD). The response rate (RR; CR+PR) and clinical benefit rate (CBR; CR+PR+SD) were 42% and 68%, respectively. In 10 patients with serous adenocarcinoma, RR was 60%. In 6 patients pretreated with weekly B and pegylated liposomal doxorubicin (PLD), RR was 50%. Median progression-free survival was 5 months (range: 2-11 months). Hematological adverse effects (AE) with grade 3/4 were leukopenia (16%), neutropenia (10%), thrombocytopenia (5%), however, all AE were manageable. Conclusions: Weekly B and GEMOX administration had significant activity with mild AE in patients with ROC especially in serous adenocarcinoma. Notably, the activity was also observed in patients pretreated with weekly B and PLD. These results warrant further prospective study.
ESA use in women with cancer: Consequences of the 2008 FDA clinical alert.
Authors: Dickinson Kimberly M. , Sakr Bachir Joseph
Published: March 2020

5040

Background: Erythropoietin stimulating agents (ESA) are used clinically as an alternative to blood transfusions in cancer patients suffering from symptoms of anemia. However, more recent randomized controlled trials of ESA usage concluded that its use is associated with an increased risk of tumor progression and death. As a result, in July 2008 the FDA issued a clinical alert restricting the use of ESA. A reduction in the prescribing of ESA was immediately seen but changes in blood transfusion rates have not been examined. Methods: A retrospective chart review was conducted drawing from patients under treatment in the Program in Women’s Oncology at Women and Infant’s Hospital from one year before the clinical alert (August 2007-July 2008) to one year afterward (August 2008-July 2009). The primary outcomes were blood transfusion and ESA administration rates compared across the two time periods. Results: The study population (n=776) included patients with a cancer diagnosis who received chemotherapy during one or both time periods. 165 (21.3%) patients received ESA treatment. The total number of ESA treatments administered in the study period of interest was 1,277, with the majority (60%) given prior to the FDA alert. The mean number of ESA treatments in the first time period was 6.39 per person as compared to 0.61 per person in the second time period. Of the study population, 186 (23.8%) patients received at least one blood transfusion. A total of 463 blood transfusions were administered during the entire study period but a significant difference was not observed in the proportion of those delivered prior to the FDA alert (52%) versus after the FDA alert (48%). The average number of transfusions given in the first time period was 2.34 per person, as compared to 2.17 per person in the second period. Conclusions: Our results indicate that despite a steep decline in the use of ESA for chemotherapy-induced anemia, blood transfusion rates were not significantly different between the two periods. Interestingly, a slight downward trend was observed from before the FDA alert to after the alert. While more work is needed to understand the implications of these findings, it suggests that resource utilization did not increase despite the reduction in ESA use.
Panitumumab and pegylated liposomal doxorubicin in platinum-resistant epithelial ovarian cancer with KRAS wild-type: The PaLiDo study, a phase II nonrandomized multicenter study.
Authors: Steffensen Karina Dahl , Waldstrøm Marianne , Pallisgaard Niels , Lund Bente , Bergfeldt Kjell , Wihl Jessica , Keldsen Nina , Marth Christian , Vergote Ignace B. , Jakobsen Anders Kristian Moeller
Published: March 2020

5052

Background: Ovarian cancer (OC) patients with platinum-resistant recurrent disease have few therapeutic options and the response rates are only 10-20% using non-cross-resistant chemotherapeutic agents. The increasing number of negative trials for OC treatment has prompted an evaluation of new biologic agents, which in combination with chemotherapy may result in improvement in survival. Panitumumab is a fully human monoclonal antibody specific to the epidermal growth factor receptor (EGFR). No previous studies have evaluated the effect of panitumumab in OC based on KRAS mutation status. The main purpose was to investigate the response rate in platinum-resistant, KRAS wild-type OC patients treated with pegylated liposomal doxorubicin (PLD) supplemented with panitumumab. Methods: Major eligibility criteria were confirmed stage I-IV primary epithelial ovarian/fallopian/peritoneal cancer patients with progression either during or within 6 months after end of first or second line platinum-based chemotherapy. Only patients with measurable disease by CA125 criteria and with KRAS wild type were eligible. Patients were treated with panitumumab 6 mg/kg day 1 and day 15 and with PLD 40 mg/m² day 1, every 4 weeks. Tumor assessment was performed at baseline and at every third cycle according to CA-125 criteria. Results: A total of 46 patients were enrolled by 6 study sites in this multi-institutional phase II trial. Within the population evaluable for response (N=33), there was 8 CA125 responders for an overall response rate of 24.3 %. Progression-free and overall survival in the intention-to-treat population (N=43) was 2.7 months (2.5-3.2 months, 95%CI) and 8.1 months (5.6-11.7 months, 95%CI), respectively. The most common treatment related grade 3 toxicities included skin toxicity (42%), fatigue (19%) and vomiting (12%). Conclusions: The combination of PLD and panitumumab demonstrates efficacy in platinum refractory/resistant patients although the dermatologic toxicity was considerable.