bluuebunny/crossref_metadata_2025_split huggingface dataset:
Survival by stage and tumor measurability in metastatic melanoma patients treated with autologous dendritic cell tumor cell vaccines.
Authors: Dillman Robert O. , Cornforth Andrew N , McClay Edward Francis , DePriest Carol 
Published: May 2019

2637 Background: Survival of cancer patients is greatly affected by stage and tumor burden. The purpose of this study was to determine survival for melanoma patients who were treated with patient specific vaccines in the context of prospective clinical trials, by cohorts defined by stage and tumor measurability. Methods: Metastatic melanoma patients were treated with autologous dendritic cells loaded with antigens from irradiated cells from short-term autologous tumor cell lines (DCV). All patients had a metastatic melanoma lesion surgically resected, from which a tumor cell line was established. Irradiated tumor cells (ITC) were incubated with autologous dendritic cells (DC) to produce the DCV, which were injected s.c. in 500 micrograms GM-CSF weekly x 3 weeks, then monthly for 5 months. Data was pooled for DCV-treated patients enrolled in either of two phase II trials: one single-arm (NCT00948480), one randomized (NCT00436930). Patients were assigned to one of three cohorts based on their most advanced stage of disease prior to treatment, and whether they had measurable disease at the time of treatment. Survival was determined per Kaplan and Meier. Results: The final therapeutic products consisted of autologous DC with non-phagocytosed ITC making up 0% to 20% of cells in the final product. There were 45 men and 27 women. Median age was 52 years (range 17 to 83). Tumor sources were 37-lymph node, 20-viscera, and 15-soft tissue. No patients were lost to follow up; all surviving patients were followed 5 years. Toxicity was minimal. Median overall survival (OS) for all 72 patients was 49.4 mos; 5-year OS 46%. There was no correlation between survival and the number of DC or ITC in the first three injections. Patients with recurrent stage 3 disease that had not recurred (n=18) had a 72% 5-year OS; patients with non-measurable stage 4 (n=30) had a 53% 5-year OS. Patients with measurable stage 4 (n=18) had received an average of four prior therapies. They had a median OS of 18.5 months, and 2-year OS of 46%. Conclusions: This patient-specific DCV was associated with encouraging survival in all three clinical subsets. Because of its mechanism of action and absence of toxicity, it should be evaluated further. Clinical trial information: NCT00948480, NCT00436930.
Preliminary results of a phase I clinical trial using an autologous dendritic cell cancer vaccine targeting HER2 in patients with metastatic cancer or operated high-risk bladder cancer (NCT01730118).
Authors: Maeng Hoyoung M. , Wood Lauren Virginia , Moore Brittni , Bagheri Mohammadhadi H. , Webb Santhana , England Lee , Martinez Giselle , Steinberg Seth M. , Pack Svetlana , Stroncek David , Morris John Charles , Terabe Masaki , Berzofsky Jay A. 
Published: May 2019

2639 Background: We developed a HER2 targeting autologous dendritic cell (DC) vaccine transduced with an adenovirus expressing the extracellular and transmembrane domains of HER2 (AdHER2). In mice, the homologous vaccine cured virtually all mice with established or metastatic tumors. Protection was dependent on antibodies against HER2 that inhibited phosphorylation, but was ADCC independent. We translated these findings into a clinical trial. Methods: This is an open-label, phase I study in patients with 1) metastatic cancer that progressed after ≥ 1 standard therapies, or 2) history of high risk bladder cancer with definitive treatment, whose tumor is HER2 immunohistochemistry (IHC) score ≥ 1+ or FISH HER2/CEP17 ratio ≥ 1.8. Part 1 of the study enrolled patients naïve to HER2-directed therapies and Part 2 enrolled patients who progressed with ≥ 1 anti-HER2 therapy. Results: In Part 1, the lowest dose level (5E+6 viable DCs, N=7, 2 inevaluable) showed no benefit. At the second and third dose level (10E+6 and 20E+6; N=7 and N=4; 0 and 1 inevaluable in each), 1 CR (ovarian), 1 PR (stomach), and 3 SD (1 ovarian carcinosarcoma and 2 colon) were observed. Two bladder cancer patients who received vaccine as an adjuvant did not recur for +24 and +36 month each. In Part 2 (N=6, 2 inevaluable), 1 male breast cancer patient showed SD. Response assessed by Modified Immune Related Response Criteria is summarized in the Table. Injection-site reactions occurred in all patients and were self-limited. Echo, EKG and troponin follow up to 2 years showed no cardiac toxicity. Dose-expansion cohort (40E+6) is enrolling. Conclusions: We have translated a cancer vaccine from mice to a clinical trial. Preliminary results of a phase I trial of an autologous AdHER2 DC vaccine show potential clinical benefit in select patients with HER2 expressing tumors with no cardiac toxicity. Clinical trial information: NCT01730118. [Table: see text]
A phase I study (E011-MEL) of a TriMix-based mRNA immunotherapy (ECI-006) in resected melanoma patients: Analysis of safety and immunogenicity.
Authors: Arance Fernandez ANA Maria , Baurain Jean-Francois , Vulsteke Christof , Rutten Annemie , Soria Ainara , Carrasco Javier , Neyns Bart , De Keersmaecker Brenda , Van Assche Tim , Lindmark Bertil 
Published: May 2019

2641 Background: ECI-006 is a combination of TriMix (mRNAs encoding for dendritic cell [DC] activating molecules [CD40L, CD70 and caTLR4]), and mRNAs encoding for melanoma-specific tumor-associated antigens (TAAs): tyrosinase, gp100, MAGE-A3, MAGE-C2, and PRAME. DCs transfected ex vivo with TriMix and TAAs mRNAs showed significant clinical activity in combination with ipilimumab in metastatic melanoma without increasing toxicity. This study aims to assess the safety and immunogenicity of ECI-006 vaccine administered intranodally (i.n.) in an adjuvant setting for patients with resected melanoma. Methods: Twenty patients who underwent resection of stage IIc/III/IV cutaneous melanoma received 5 administrations of ECI-006 (either 600 µg or 1800 µg [n = 10, each]) injected i.n. on Day 1 and after 2, 4, 6 and 14 weeks. Treatment-emergent adverse events (TEAEs) were graded using CTCAE version 4.0.3. Blood samples for immune monitoring (ELISPOT and intracellular cytokine staining [ICS]) were collected pre-dose and at weeks 4, 7, 14 and 15. Results: Nineteen patients completed the treatment. One patient in the low dose group discontinued the study after 4 doses due to disease relapse. Administration of ECI-006 was well tolerated. No serious adverse events or TEAEs Grade 3 or higher were reported. Of all TEAEs, myalgia and fatigue were the most reported in 3 (15%) and 5 (25%) patients, respectively. ELISPOT and ICS were performed on T cells pre-stimulated in vitro for 10-12 days, using a previously in-house validated protocol. Vaccine-induced immune responses according to predefined criteria were detected in 4/10 and 3/9 patients treated with the low and high dose, respectively. Samples from these patients are currently being subjected to T-cell receptor repertoire analysis. Conclusions: Among patients undergoing resection of stage IIc/III/IV melanoma, i.n. administration of ECI-006 at 600 or 1800 µg was generally well tolerated. ECI-006 demonstrated to be immunogenic in a proportion of patients. These results warrant further development of ECI-006 in combination with anti-PD-1 therapy in melanoma patients. Clinical trial information: NCT03394937.
A phase I study of mirvetuximab soravtansine (IMGN853) and gemcitabine (G) in patients with FOLR1-positive recurrent epithelial ovarian (EOC), endometrial cancer (EC), or triple-negative breast cancer (TNBC).
Authors: Cristea Mihaela C. , Frankel Paul Henry , Synold Timothy W. , Mortimer Joanne E. , Stewart Daphne B. , Wang Edward Wenge , Jung Alex , Wilczynski Sharon P. , Konecny Gottfried E. , Parungao Dia , Eng Melissa , Kilpatrick Lindsay , Chen Yi-Jen , Glaser Scott , Han Ernest Soyoung , Dellinger Thanh Hue , Hakim Amy , Lee Stephen , Morgan Robert , Wakabayashi Mark Tsuneo 
Published: May 2019

3009 Background: IMGN853 is an antibody-drug conjugate targeting the folate receptor alpha (FOLR1), linked to maytansinoid, DM4. IMGN853 has promising single agent activity in FOLR1+ EOC. The recommended phase 2 dose (RP2D) is 6 mg/kg, based on adjusted ideal body weight (AIBW) IV every 3 wks. This study evaluates IMGN853 and G. Methods: Patients (pts) with FOLR1+ tumors including: platinum resistant EOC with ≤4 prior chemotherapy (CT) regimens, EC with ≤2 CT and TNBC ≤4 CT are eligible. FOLR1 + is defined as ≥25% of tumor staining (all tumors) ≥2+ intensity (EOC, EC) and ≥1+ (TNBC). A standard 3+3 design combines IMGN853 and G. EOC pts undergo one research biopsy to assess intratumoral vs. circulating DM4 level and biopsy vs. archival tissue FOLR1 expression. Dose-limiting toxicity (DLT) is assessed during cycle 1. Responses as per RECIST 1.1 are assessed at 12 wks. and adverse events (AEs) are evaluated by CTCAE v4.0. Results: From 10/2017 to 1/2019 a total of 15 pts. were treated (3 additional pts have consented on dose level [DL] 4):10 EOC, 3 EC and 2 TNBC. One pt. on DL1 had grade (G) 4 thrombocytopenia (PLT) DLT. Three pts were inevaluable for DLT and were replaced: 1 pt. at DL1 with G4 neutropenia without fever of unknown duration due to delayed follow up blood work, 1 pt. at DL2 and 1 pt. at DL3 due to incomplete cycle 1. No DLTs were observed on DL2-3. Day 8 cycle 1 dose modifications were required in 3 of 4 patients on DL3 (for mucositis [1 pt.], and PLT [2 pts]). We are now enrolling at the RP2D for both agents, and MTD will be determined prior to May 2019. Conclusions: IMGN853 in combination with G is achievable at clinically relevant doses and the recommended Phase 2 dose and MTD will be reported. Support: NCCN grant; with support from ImmunoGen Corp and Cancer Center Support Grant P30CA033572. Clinical trial information: NCT02996825. [Table: see text]
Phase 1 dose escalation study of XMT-1536, a novel NaPi2b-targeting antibody-drug conjugate (ADC), in patients (pts) with solid tumors likely to express NaPi2b.
Authors: Tolcher Anthony W. , Ulahannan Susanna Varkey , Papadopoulos Kyriakos P. , Edenfield William Jeffery , Matulonis Ursula A. , Burns Timothy F. , Mosher Rebecca , Fielman Barbara , Hailman Eric , Burris Howard A. , Moore Kathleen N. , Hamilton Erika Paige 
Published: May 2019

3010 Background: XMT-1536 is a Dolaflexin ADC targeting the sodium-phosphate cotransporter NaPi2b, expressed in ovarian, non-squamous lung, papillary thyroid, endometrial, papillary renal and salivary duct cancers. Methods: In this ongoing Phase 1 study, pts with solid tumors likely to express NaPi2b, who progressed on standard therapy, are treated with intravenous XMT-1536 using a 3+3 design with a modified Fibonacci escalation. NaPi2b expression by IHC is being examined retrospectively in archived tumors. Primary objectives in dose escalation are safety and tolerability and determination of maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). (ClinicalTrials.gov NCT03319628). Results: As of Jan. 28, 2019, 36 pts (22 ovarian, 7 endometrial, 4 NSCLC, 3 other) have received treatment with XMT-1536. Treatment was initially given every 3 weeks (q3w); 20 pts were treated in dose cohorts from 3 to 40 mg/m2. There was one DLT of reversible AST elevation at 40 mg/m2. The dosing interval was then changed to every 4 weeks (q4w), and dose escalation was restarted at 20 mg/m2. There was one DLT of reversible AST elevation at 30 mg/m2 on the q4w schedule. Further followup and dose escalation are ongoing. The most common (≥10% of patients) treatment-related adverse events (TRAEs) have been nausea, fatigue, headache, increased AST, anorexia, increased alkaline phosphatase, fever, increased GGT, myalgia, and vomiting. Grade 3 TRAEs were reversible AST increases in 3 patients and increased GGT, decreased lymphocytes, and systolic congestive heart failure in 1 patient each. Treatment-related serious AEs of fever and systolic congestive heart failure occurred in 1 patient each. Among patients dosed at 20 mg/m2 or higher who had restaging scans (n=20), there were 2 PR, in ovarian cancer pts at 30 mg/m2 q3w and 20 mg/m2 q4w, and 11 SD, with disease control maintained for up to 24 weeks. Patient-level results for NaPi2b expression will be presented. The systemic exposure of total payload showed approximately dose-proportional increase. Plasma concentration of free drug payload and its active metabolite were low. Conclusions: XMT-1536 has been well-tolerated up to the 30 mg/m2 dose level with early signs of anti-tumor activity. Dose escalation continues in pts with advanced solid tumors likely to express NaPi2b. Clinical trial information: NCT03319628.
Phase 1, first-in-human study of TRAIL receptor agonist fusion protein ABBV-621.
Authors: Ratain Mark J. , Doi Toshihiko , De Jonge Maja J. , LoRusso Patricia , Dunbar Martin , Chiney Manoj , Motwani Monica , Glasgow Jaimee , Petrich Adam Matthew , Rasco Drew W. , Calvo Emiliano 
Published: May 2019

3013 Background: ABBV-621 is a potent tumor-necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor agonist fusion protein that induces apoptotic cell death, particularly in DR4/5 expressing tumor models. Methods: Patients (pts) with previously treated solid tumors and ECOG 0–2 were administered ABBV-621 (2.5–15 mg/kg IV) on day (D) 1 (dose level [DL] 1) or D1D8 (DL2 and beyond) of each 21-day cycle. Dose escalation (DE) was guided by a Bayesian continual reassessment method. In addition to PK studies, blood-based PD markers of apoptosis (M30, M65) and drug binding were assessed. Results: As of 14 December 2018, 57 pts were enrolled in the DE portion, of which 30% had pancreatic, 23% colorectal cancer, and 47% other tumor types; 13 were KRAS mutant. Median age was 61 yrs. 60% were male; pts had a median of 4 prior regimens (range 1–10). Pts per DL: 2.5 (5 on D1, 16 on D1D8), 3.75 (12), 5 (6), 6.5 (6), 8.5 (4), 11 (4), and 15 mg/kg (4). Median duration of ABBV-621 exposure was 2 cycles (range 1–11). Seven pts had dose-limiting toxicities: respiratory failure (5 mg/kg; Grade 5, the only treatment-related death), blood bilirubin increased (3.75, 6.5 mg/kg), nausea (3.75 mg/kg), fatigue (3.75 mg/kg), increased ALT (2.5, 3.75, 6.5, 15 mg/kg), and increased AST (6.5 mg/kg). Summary of AEs is shown in Table. Clinical trial information: NCT03082209. A partial response (duration 20 weeks) was observed in a pt with pancreatic cancer (2.5 mg/kg D1D8). 27 pts had stable disease (6 pts for > 12 weeks). ABBV-621 PK was linear (mean ± SD clearance was 1.79 mL/h/kg ± 0.44) with a terminal half-life of 36.7 ± 5.55 h (n = 49). ABBV-621 bound to decoy receptors on neutrophils for up to 168 h; the duration of binding was dose-dependent. M30 and M65 increased at 8, 24, and 48 h following ABBV-621, but effect was independent of dose. Conclusions: ABBV-621 shows evidence of antitumor activity and effect on blood-based markers of apoptosis, with acceptable toxicity (MTD not reached). NCT03082209.[Table: see text]
Phase I trial of IACS-010759 (IACS), a potent, selective inhibitor of complex I of the mitochondrial electron transport chain, in patients (pts) with advanced solid tumors.
Authors: Yap Timothy A , Rodon Ahnert Jordi , Piha-Paul Sarina Anne , Fu Siqing , Janku Filip , Karp Daniel D. , Naing Aung , Ileana Dumbrava Ecaterina Elena , Pant Shubham , Subbiah Vivek , Tsimberidou Apostolia Maria , Hong David S. , Rose Kelsey Meagan , Xu Quanyun , Vellano Christopher P. , Mahendra Mikhila , Jones Philip , Di Francesco Maria Emilia , Marszalek Joseph R. , Meric-Bernstam Funda 
Published: May 2019

3014 Background: A subset of tumors possess genetic or microenvironmental alterations that render cells dependent on mitochondria oxidative phosphorylation (OXPHOS) for survival. IACS, a potent oral selective inhibitor of mitochondrial complex I, showed robust responses in multiple preclinical tumor models, providing strong rationale for clinical testing. Methods: Pts with advanced cancers received IACS in increasing dose levels (DL) using 3+3 dose escalation. 7-day QD induction of IACS was followed by maintenance weekly (QW) or twice weekly (BIW) dosing. Phamacokinetics (PK), lactate and pH were assessed serially. Paired tumor biopsies were assessed for pharmacodynamic and predictive biomarkers. Results: 18 pts were treated; M/F 16/2; ECOG PS 0/1: 3/15. Mean age 49 (23-69) yrs. Tumors comprised advanced colorectal (n = 4), castration resistant prostate cancer (CRPC) (n = 3), pancreatic (n = 2), other cancers (n = 9). DL1: 2mg QD 7 days induction/0.5mg QW maintenance (n = 3); DL2: 2.5mg QD 7 days/1mg QW (n = 3); DL3: 3mg QD 7 days/3mg QW (n = 3); DL4: 2.5mg QD 7 days/2.5mg BIW (n = 4); DL5: 2mg QD 7 days/2mg BIW (n = 5). IACS was well tolerated with 12 (67%) pts reporting G1-2 IACS related toxicities, such as raised lactate (n = 10), nausea (n = 8), fatigue (n = 7), vomiting (n = 5), myalgia (n = 4) and peripheral neuropathy (n = 4). 1 pt in DL3 and 2 pts in DL4 had ≥G3 IACS related toxicities, such as nausea (n = 2), vomiting (n = 1), raised lactate (n = 1), dehydration (n = 1), visual changes (n = 1), and peripheral neuropathy (n = 1). Raised lactate was not associated with acidosis. DL5 is now being expanded to assess the maximum tolerated dose (MTD). PK showed good oral bioavailability, with long T1/2 and low intrapatient variability. Cmax = 14nM on Day 7 at the end of DL5 induction phase, confirming biologically active doses. 7 pts had best response of RECIST stable disease. A pt with heavily pretreated CRPC achieved RECIST partial response with resolution of CRPC related pain. Conclusions: IACS is well tolerated with preliminary evidence of antitumor activity. MTD expansions include CRPC, TNBC, pancreatic cancer and molecularly selected (ENO1 loss; SMARCA4 mutation) tumor cohorts. Clinical trial information: NCT03291938.
Circulating androgen receptor (AR) gene amplification and resistance to 177Lu-PSMA-617 in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Results of a phase II clinical trial.
Authors: De Giorgi Ugo , Severi Stefano , Sarnelli Anna , Sansovini Maddalena , Monti Manuela , Gurioli Giorgia , Nicolini Silvia , Scarpi Emanuela , Casadei Chiara , Conteduca Vincenza , Matteucci Federica , Di Iorio Valentina , Amadori Dino , Paganelli Giovanni 
Published: May 2019

3020 Background: Plasma AR gain is associated with poor prognosis in mCRPC pts treated with abiraterone/enzalutamide, however these pts could benefit from docetaxel (Conteduca et al, Eur Urol 2019). In a phase 2 clinical trial with 177Lu-PSMA-617 in mCRPC pts who progressed after standard survival-prolonging treatments, we aimed to determine if plasma AR gene status enable early assessment of 177Lu-PSMA-617 activity for mCRPC. Methods: Between April 2017 and November 2018, 43 mCRPC pts were treated with 177Lu-PSMA-617 in a phase 2 study. Pts younger than 75 years and not heavily pretreated received 5.5 GBq of 177Lu-PSMA-617, while other pts received 4.2 GBq per cycle, for a total of 4-6 cycles, q8 weeks. We determined AR copy number by droplet digital polymerase chain reaction (ddPCR) on pretreatment plasma samples. We evaluated associations between plasma AR amplification and PSA response (≥50% PSA decline from baseline) and imaging response/progression (as measured by bone scan, CT, and PSMA PET/CT). Logistic regression was used to estimate the odds ratio (OR) and 95% confidence intervals (95% CI) in order to evaluate the independent relevance of AR status and pts without PSA response and those with early progressive disease defined as treatment interruption occurring within 4 months of the start of 177Lu-PSMA-617. Results: Forty of 43 pts (median age: 72 years, range 54-86) were fully evaluable for this analysis. A PSA response was reported in 15 (37.5%) of the 40 pts, 3 of 15 (20%) with AR gene gain, and 12 of 25 (48%) with no gain (P = 0.080). Early progressive disease was observed in 17 (42.5%) of the 40 pts, 12 of 15 (80%) with AR gene gain and 5 of 25 (20%) with no gain (P = 0.0002). The OR for pts without PSA response (decline < 50%) having AR gain was 3.69, 95% CI 0.83-16.36, p = 0.085. The OR for pts with early PD having AR gain was 16.00, 95% CI 3.23-79.27, p = 0.0007. The evaluation of germline alterations in DNA damage repair (DDR) genes is ongoing (i.e., BRCA2, BRCA1, ATM). Conclusions: Plasma AR status assessment using ddPCR identifies mCRPC resistant to 177Lu-PSMA-617. These data suggest potential better activity of 177Lu-PSMA-617 in earlier phases of prostate cancer. Prospective evaluation of treatment decision making based on plasma AR status is warranted. Clinical trial information: NCT03454750.
Phase 1a study results investigating the safety and preliminary efficacy of ABL001 (NOV1501), a bispecific antibody targeting VEGF and DLL4 in metastatic gastrointestinal (GI) cancer.
Authors: Lee Jeeyun , Kim Seung , Lee Su Jin , Park Se Hoon , Park Joon Oh , Ha Eunsin , Park Doo-Hong , Park Neunggyu , Kim Hoon-Kyo , Lee Sang Hoon , You Weon-Kyoo , Lim Ho Yeong , Park Young Suk , Kang Won Ki 
Published: May 2019

3023 Background: Antiangiogenic therapy has been a successful clinical strategy for the treatment of various cancer types. To date, all approved antiangiogenic drugs primarily inhibit the VEGF/VEGFR pathway. Delta-like ligand 4 (DLL4) has been identified as a potential drug target in VEGF-independent angiogenesis. A dual blockade of both VEGF and DLL4 could be a promising strategy to overcome anti-VEGF therapy resistance. ABL001 (NOV1501) has been developed as a bispecific antibody to bind and inhibit both DLL4 and VEGF thereby significantly suppressing tumor angiogenesis. Methods: In a classical 3+3 dose-escalation design, ABL001 was administered IV at doses ranging from 0.3, 1, 2.5, 5, and 7.5 mg/kg biweekly (NCT03292783: the next doses of ABL001 are 10 and 12.5 mg/kg). After the first administration of ABL001 in each cohort, DLT (dose limiting toxicity) was observed for 3 weeks. Tumor assessments were performed every 6 weeks and cardiac assessments were performed every cycle. Results: From 2017 November to February 2019, 18 patients were enrolled on this trial. All patients were heavily pre-treated with at least 3 prior lines of chemotherapy. All patients in cohort 4 and 5 were either metastatic colorectal cancer or gastric cancer. Of the 5 cohorts, there was no DLT observed during dose escalation. In addition, there was no maximum tolerated dose identified up to 7.5 mg/kg dose. The most common treatment-related adverse events (AEs) (including all dose levels and all grades) occurred were hypertension, anorexia, general weakness, headache and anemia. Preliminary results of pharmacokinetic (PK) analysis demonstrated slightly shorter mean half-life than conventional monoclonal tantibodies due to the bispecific nature of the ABL-001. In addition, preliminary pharmacodynamic (PD) biomarker analysis using PBMC and plasma samples showed engagement of both VEGF/VEGFR and DLL4/Notch1 pathway modulation after ABL001 administration. One gastric cancer patient at 7.5 mg/kg achieved unconfirmed partial response at the time of this writing. Conclusions: ABL001 therapy has been well tolerated up to 7.5 mg/kg with no significant treatment related adverse events and showed preliminary anti-tumor activity in heavily pre-treated cancer patients. After completion of this ongoing phase 1a study, phase 1b/2a study is planned in combination of ABL001 with chemotherapy or anti-PD-1 antibody. Clinical trial information: 03292783.