bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I combination study of plitidepsin and carboplatin in advanced solid tumours
Authors: Oaknin A. , Plummer R. , Salazar R. , Robinson A. , Pardo B. , Razak A. A. , Cuadra C. , Flores L. , Izquierdo M. A. , Calvert H. 
Published: March 2020

2558 Background: Plitidepsin is a cyclic depsipeptyde isolated from the marine tunicate Aplidium albicans, nowadays manufactured by synthesis. It is a rapid and potent inductor of apoptosis. In phase I trials, muscle (myalgia and CPK increase) and liver toxicities were dose-limiting and preliminary activity was observed in malignant melanoma, renal, head and neck, lung, neuroendocrine, colorectal and hematological malignancies. Preclinical synergism with carboplatin (CBCDA) against solid tumors and acute leukaemia suggest plitidepsin can reverse platinum chemoresistance in vivo through reduction of glutathione levels. This phase I trial was initiated in order to evaluate the safety, pharmacokinetics (PK) and antitumour activity of the combination of CBCDA and weekly administration of plitidepsin (Recommended dose (RD) in monotherapy: 3.2 mg/m2). Methods: Patients (pts) with advanced solid tumours and good performance status (WHO PS = 2) were enrolled. Plitidepsin was given over 1 hr infusion on days 1 , 8 and 15 every 4 weeks followed by CBDCA (AUC 5) as a 1 hr infusion on day 1. Dose levels planned for plitidepsin were 1.8, 2.4 and 3.0 mg/m2 in cohorts of 3 pts. PK sampling was performed during the first cycle (cy) of treatment. Results: 18 pts have been treated to date (8M/10F). Median age (range): 59 (39–73) yrs. WHO PS>0: 3pts. Tumour types included colorectal (5), malignant melanoma (4), ovary (2), other gastrointestinal tumors (7). No DLT was observed at plitidepsin 1.8 and 2.4 mg/m2 (3 pts treated in each cohort). Two out of 5 pts exhibited DLT at pltidepsin 3.0 mg/m2, consisting of delay of second cy >2 weeks (grade 3 transaminitis and grade 3 thrombocytopenia) and omission of second infusion in first cy (grade 3 ALT increase). Plitidepsin at 2.4 mg/m2 was expanded to 8 pts. There were 4 pts with stable disease (cholangio, liver, colorectal, gatro-esophageal junction and esophagus carcinomas). Conclusions: The RD for the combination is plitidepsin 2.4 mg/m2 (0.8 mg/m2 lower than in monotherapy) days 1, 8 and 15 every 4 weeks followed by CBDCA (AUC 5). DLTs of the combination at the highest dose were different vs single plitidepsin (liver and haematological vs muscular). PK analyses from the three cohorts to detect interactions and updated safety data for the RD cohort are in progress. [Table: see text]
Phase I clinical trial of ixabepilone and pegylated liposomal doxorubicin in patients with advanced breast or ovarian cancers: New York Cancer Consortium Trial P7229
Authors: Chuang E. , Vahdat L. , Caputo T. , Goldberg G. , Flam A. , Christos P. , Colevas A. , Muggia F. , Wadler S. 
Published: March 2020

2570 Background: Ixabepilone (IX) is a semisynthetic epothilone B analog with activity in patients (pts) with taxane refractory cancer. Two phase III clinical trials in breast cancer (BC) and a phase II study in ovarian cancer (OC) have recently been completed. Pegylated liposomal doxorubicin (PLD) is used for the treatment of platinum refractory OC and has activity in patients with metastatic BC. Methods: We have completed enrollment of a phase I study of PLD IV and ixabepilone IV over 3 hours. 18 pts with metastatic cancer (10 BC and 8 OC) with median age 51 were enrolled from 1/13/06 to 12/22/06. A total of 60 cycles has been administered to date. 3 OC patients enrolled at dose level 3 have not yet completed 2 cycles of treatment and are not yet evaluable. Results: Dose limiting toxicities (DLT) based on toxicities experienced during the first 2 cycles is provided in the table below. Adverse events (AE) occurring in any cycle were: Grade 4 AE: neutropenia < 7 days (1 pt). Grade 3 AE: palmar plantar erythrodysesthesia (PPE) (4), mucositis (3), infection (2), fatigue (2), neutropenia (2), thrombocytopenia (2), anemia (1), neuropathy (1), bilirubin (1). Non-hematological grade 2 AEs included: mucositis (4), PPE (3), infection (2), neuropathy (2), rash (3), pain (3), fever (1), myalgias (1), and anorexia (1). Responses so far for 10 BC pts are PR (1) SD (3) PD (6) and for 5 OC pts are PR (1) SD (2) PD (2). Updated results will be presented. Conclusions: Although the recommended phase II dose when given every 3 weeks is 30 mg/m2 for PLD and 32 mg/m2 for IX by our criteria, PPE and mucositis became problematic when treatment was continued beyond 2 cycles. We are therefore exploring a 4 week PLD schedule, evaluating IX given either every 4 weeks (as shown) or weekly (on days 1, 8, and 15). A phase II trial of the combination in platinum refractory OC will be initiated upon completion of the phase I. Supported by N01-CM-62204 [Table: see text] [Table: see text]
Phase I trial of KOS-1584 (a novel epothilone) using two weekly dosing schedules
Authors: Stopeck A. , Moulder S. , Jones S. , Cohen J. , McDowell M. , Cropp G. , Zhong Z. , Wells S. , Hannah A. , Burris H. 
Published: March 2020

2571 Background: KOS-1584 is an epothilone with increased potency and improved pharmacologic profile (enhanced water solubility, tumor penetration and reduced CNS exposure). Methods: Define the MTD, toxicity, PK, pharmacodynamics (PD), and early activity of KOS-1584 when administered to pts with advanced malignancies via 1-hr infusion on one of 2 schedules: Days 1, 8 & 15 every 4 weeks and Days 1 & 8 every 3 weeks. PD: assessed by serial sampling of PBMCs for soluble and polymerized microtubules by immunoblot. Methods: 37 pts enrolled in 10 cohorts (0.8 - 25 mg/m2) on the 4-week schedule (22 F; median age/ECOG/prior regimens of 56, 1 and 4, respectively). One pt has been enrolled at 16 mg/m2 on the 3-week schedule. For the 4-week schedule: DLTs were observed at 20 and 25 mg/m2; the 16 mg/m2 cohort is being expanded (using antidiarrheal prophylaxis). All episodes of DLT except 1 involved diarrhea with increasing severity after successive infusions despite maximal supportive care; 1 pt had typhlitis upon biopsy. An ovarian cancer pt experienced DLT consisting of Grade 3 weakness, neutropenia and peripheral sensory neuropathy (this pt had high plasma drug concentrations, possibly related to pre-existing severe hypoalbuminemia and ascites). Common all-grade drug- related toxicities (n=37): nausea (51%), diarrhea, fatigue (both 49%), vomiting (32%), anorexia (24%), constipation (24%), peripheral sensory neuropathy (19%) and anemia (16%). Neutropenia/leucopenia (Grade 1–2) observed at 16–25 mg/m2 dose levels. Except for the DLT involving peripheral neurotoxicity, all neurotoxicity was mild-to-moderate. PK (n=37): t½ 28.1 ± 8.7, Vz 627 ± 291 L, CL 18.0 ± 8.3 L/h. Cmax/AUC (25 mg/m2): 1,069 ± 2,456 ng/mL, 3,764 ± 2,579 ng/mL*h. Dose proportional increase in AUC and Cmax observed. ↑polymerized microtubules observed with maximal effect at end of infusion. Antitumor activity: NSCLC (1pt: confirmed PR; 10 cycles), ovarian cancer (1pt: 40% ↓CA125; 6 cycles), and H&N (1 pt: SD), these pts had all received doses ≥ 7.5 mg/m2. Conclusions: Accrual continues to define the optimal dose on both schedules; use of aggressive anti-diarrheal prophylaxis has been implemented. No significant financial relationships to disclose.
Clinical and Immunological responses in patients with malignant melanoma treated with a dendritic cell-based vaccine. Preliminary report from a multi-institutional phase II clinical trial
Authors: Ross M. , Camacho L. H. , Hersh E. M. , Brown C. K. , Richards J. , Mitsky P. , Wasserman E. , Lee S. , Bercovici N. , Landais D. , Ribas A. 
Published: March 2020

3004 Background: We have previously reported that vaccination with IDM therapeutic vaccine (IDD-3/Uvidem [Uvidem is co-developed with SANOFI-AVENTIS]) composed of dendritic cells (DC) loaded with three allogeneic lysates from tumor cell lines can elicit immune and anti-tumor responses. We describe here the preliminary results from a phase II clinical trial in metastatic melanoma patients. Methods: DC-MEL-202 is a single arm, two-stage phase II trial designed to evaluate clinical and immunological activities and the safety of a multivalent DC vaccine in patients with in-transit or low volume metastatic melanoma. There was no HLA restriction. Autologous DC were generated, under GMP conditions, from monocytes cultured in GM-CSF and IL-13, loaded with three allogeneic melanoma tumor lysates (M44, SK-MEL 28 and COLO 829) and matured with a combination of bacterial extract (FMKP) and IFN-γ, generating up to 15 doses of the vaccine containing 25x106 DC. Patients received six bi-weekly and two 6-weekly injections (id and sc). Clinical responders were eligible to receive additional doses. Immune response against tumor-associated antigens (TAA) peptides was assessed, at several time points, by detection of IFN-γ producing cells by flow cytometry Results: 33 patients were treated. To date: Vaccination is well tolerated with toxicity limited to mild events (only one possibly related SAE, age-related macular degeneration, was reported). Clinical response (RECIST): 6 patients showed evidence of clinical benefit (1CR, 1PR and 4 SD) with duration of response ranging from 7.5 to 22 months. Assessment of pathological response in target sites in 2 pts (1 PR, 1 SD) showed no residual disease.. 23/33 patients are still alive with a mean follow-up of 11mo (range 3–22mo). Mature data of PFS and OS will be presented. Immune response: 21 (84 %) out of 25 evaluated patients showed detectable TAA-specific CD8+ T cells with ten showing boosted or appearance of anti-TAA specific CD8+ T cells. Conclusions: Vaccination with IDD-3/Uvidem is safe and can elicit tumor specific CD8+ T cells not limited to HLA-A2+ patients. Substantial clinical benefit warrants further development of IDD3. No significant financial relationships to disclose.
A safety and efficacy trial of lethally irradiated allogeneic pancreatic tumor cells transfected with the GM-CSF gene in combination with adjuvant chemoradiotherapy for the treatment of adenocarcinoma of the pancreas
Authors: Laheru D. , Yeo C. , Biedrzycki B. , Solt S. , Lutz E. , Onners B. , Tartakovsky I. , Herman J. , Hruban R. , Piantadosi S. , Jaffee E. 
Published: March 2020

3010 Background: Pancreatic cancer remains the fourth leading cause of cancer related deaths in the US in 2006. Surgical resection provides the only possibility of cure. A standard adjuvant treatment approach for patients with resected disease has not yet been determined. We have developed an irradiated GM-CSF transfected allogeneic whole cell line pancreas adenocarcinoma vaccine. We have previously reported a follow-up 60 patient study in this same population using the highest bioactive vaccine dose identified in the initial phase I study. Methods: Single institution phase II study of 60 patients with resected pancreatic adenocarcinoma administered a total of 5 vaccines using two pancreatic cancer cell lines each delivering 2.5 X 10 8 cells ID. Vaccine one was administered 8–10 weeks following surgical resection. Patients subsequently were treated with 5-FU CI based chemotherapy integrated with radiotherapy. Patients who were disease-free one month after completion of chemoradiotherapy received vaccines 2–4, each 1 month apart. A fifth and final booster vaccine was administered 6 months after vaccine 4. The objectives of the study were: 1. To estimate overall survival and disease-free survival in patients with minimal residual disease treated with adjuvant chemoradiotherapy in sequence with the irradiated allogeneic GM-CSF transfected pancreatic tumor cell lines. 2. To characterize toxicities associated with intradermal injections of the vaccine. Results/Conclusions: The study completed enrollment of new patients in January 2005. Median follow-up for these patients is approximately 36 months. 1) The administration of a GM-CSF allogeneic pancreas cancer vaccine is safe and well tolerated; 2) The median survival is approximately 26 months. These results compare favorably with published data for resected pancreas cancer; 3) A matched cohort analysis comparing patients enrolled on this adjuvant vaccine study to the Johns Hopkins Surgery database of patients receiving surgery followed by chemoradiotherapy alone will be presented at this meeting; 4) Immune correlates will be presented at this meeting. No significant financial relationships to disclose.
Prospective evaluation of front-line chemo-immunotherapy (C-IT) with oregovomab (2 alternative dosing schedules) carboplatin-paclitaxel (C-P) in advanced ovarian cancer (OC)
Authors: Braly P. , Chu C. , Collins Y. , Edwards R. , Gordon A. , McGuire W. , Smith L. M. , Nicodemus C. , Method M. 
Published: March 2020

3024 Background: Chemotherapy (C) induced bone marrow suppression has been assumed to inhibit the generation of augmented immune responses. This has limited investigation of front-line C-IT in OC. Temporal relationship of IT administration relative to C has not been established. Oregovomab is a CA125 specific MAb in development as an OC adjuvant treatment to induce tumor specific immunity. Methods: Patients (pts) awaiting staging laparotomy for presumptive OC were consented to the study and contributed primary tumor samples. Qualifying pts were subsequently randomized to concurrent C-IT with antibody administered at cycles 1, 3, and 5 (Arm A) or 8 ± 2 days following cycles 1, 3, and 5 (Arm B) of standard C-P. Both arms received additional infusions of oregovomab every 12 weeks until progression; response to C-IT was assessed at 36 weeks. Results: Forty stage III/IV pts (18 Arm A; 22 Arm B) were randomized and dosed. More pts in Arm A (39%) were stage IV vs Arm B (14%) however 27% of Arm B pts had >2cm residual disease vs. 11% in Arm A. Complete clinical response (CR) to surgery and C-IT was achieved in 15 pts (83%) in Arm A and 17 pts (77%) in Arm B. For pts with = 2 cm residual disease, 88% in Arm A had = 65 U/mL CA125 prior to/at cycle 3, normalized CA125 and a CR post C-IT compared to 75% of pts in Arm B. Robust Ab2 antibody response (>100 ng/mL) was achieved in 94% of Arm A and 68% of Arm B pts. The immune response developed earlier in Arm A. After one injection of oregovomab, 31% of pts in Arm A vs. 0% in Arm B generated HAMA > 3000 ng/mL and Ab2 > 100 ng/mL (P=0.016 Fisher’s Exact Test). Such an early and vigorous response pattern has not been seen in previous oregovomab studies which have not included concomitant front-line C. There were no IT related serious adverse events. Conclusions: Contrary to expectations, concurrent C-P resulted in enhanced immune stimulation with oregovomab. Interestingly, concurrent infusion of oregovomab was more immunogenic than delayed infusion. Clinical activity was favorable and safety profiles were similar to that expected for C alone. Further randomized evaluation of front-line CP-oregovomab vs CP is warranted. [Table: see text]
A phase Ib trial of atacicept (TACI-Ig) to neutralize APRIL and BLyS in patients with refractory or relapsed B-cell chronic lymphocytic leukemia (B-CLL)
Authors: Kofler D. M. , Elter T. , Gianella-Borradori A. , Busby S. , Wendtner C. M. , Hallek M. 
Published: March 2020

3029 Background: B-CLL cells are resistant to apoptosis and thus exhibit prolonged survival and accumulation in vivo. Exogenously added soluble BLyS (B-Lymphocyte Stimulator) and APRIL (A PRoliferation-Inducing Ligand) have been shown to protect B-CLL cells from apoptosis in vitro. Nurse-like cells derived in vitro from CLL patients express high levels of APRIL and BLyS and thereby support CLL cell survival. Inhibition of APRIL significantly reduces CLL viability in vitro, indicating an important role for APRIL in this setting. Methods: This is an open-label, dose-escalation phase I trial to assess the safety, pharmacokinetics and biological effects of atacicept administered intravenously once weekly for 5 weeks to patients with refractory or relapsed B-CLL. Eligible patients are being enrolled in sequential cohorts of 3 to receive atacicept at 1, 4, 10, 15, 20 or 27 mg/kg. Evaluation of response is being assessed using NCI-WG criteria. Results: Preliminary results of the first 4 cohorts of the dose-escalation study are reported. Twelve CLL patients have entered the trial. No dose limiting toxicity has been observed and no SAE related to study drug has been reported to date. One case of mild nausea is the only drug-related toxicity reported to date. Three of six patients treated with 10 mg/kg and 15 mg/kg experienced a stabilization of their disease during the treatment period; prior to start of atacicept treatment, all had rapidly increasing leukocyte counts. One of these patients (10 mg/kg cohort), who was refractory to fludarabine therapy, has had stable disease according to NCI-WG criteria for over six months and is still receiving atacicept treatment. This same patient had a slight decrease (approximately 14% change from baseline) in absolute CLL cell concentration by Day 29 before final dosing. At lower dose levels all patients demonstrated progressive disease. Conclusions: Treatment with atacicept was well tolerated at the dose levels tested so far. The multiple cases of disease stabilization at higher dose levels in this heavily pre-treated patient population are promising, and support further study with atacicept in CLL. Accrual of patients at higher dose levels is ongoing. No significant financial relationships to disclose.
BK viral infections in patients treated with alemtuzumab
Authors: Sharma K. , Wilson W. H. , Dunleavy K. , Shovlin P. M. , Chen H. X. , Janik J. E. , Gea-Banacloche J. 
Published: March 2020

3033 Background: Alemtuzumab is a humanized monoclonal antibody against CD52 resulting in profound, prolonged T-cell depletion that may be associated with opportunistic infections and reactivation of latent viruses (e.g., CMV). BK virus is a polyomavirus that infects most humans during childhood and remains latent in the urinary tract. Reactivation of BK virus is an important cause of tubular nephropathy following renal transplantation and hemorrhagic cystitis after allogeneic stem cell transplant. Methods: A single institution pilot trial of alemtuzumab and Dose-Adjusted (D-A) Etoposide, Prednisone, Doxorubicin, Vincristine, and Cyclophosphamide (EPOCH) investigating efficacy and toxicity in chemotherapy naïve aggressive T- and NK-cell lymphomas was undertaken. BK virus was detected in urine by polymerase chain reaction (PCR) methods to quantify genomic copies in pts with dysuria and hemorrhagic cystitis. Results: Four of 20 pts treated with alemtuzumab and DA-EPOCH developed five episodes of hemorrhagic cystitis. One had grade 1 and 2 cystitis, two had grade 2 cystitis and one had grade 3 cystitis. In contrast, only one of over 200 pts treated with EPOCH alone or in combination with rituximab developed hemorrhagic cystitis. Hemorrhagic cystitis occurred at a median of 88 days after initiation of therapy and lasted a median of 22 days. Even if considered an unlikely cause, steps to minimize cyclophosphamide toxicity were taken; in one, mesna was given during the fifth cycle and cyclophosphamide was withheld from the final cycle of therapy. Another received a reduced dose of cyclophosphamide during the final cycle of therapy and the third did not receive the final cycle of therapy altogether. The fourth pt developed hemorrhagic cystitis after completion of therapy. PCR for BK virus showed a median of 8.87 x 108 (range 2.3 x 105-8.7 x 109) genomic copies per ml. Conclusions: Hemorrhagic cystitis secondary to BK virus reactivation may occur following Alemtuzumab therapy. Symptoms tend to abate after 1 to 7 weeks with conservative measures alone. [Table: see text] No significant financial relationships to disclose.
Prospective phase II study of post-surgical adjuvant chemo-immunotherapy using autologous dendritic cells and activated killer cells from tissue culture of tumor draining lymph nodes in primary lung cancer patients
Authors: Kimura H. , Iizasa T. , Ishikawa A. 
Published: March 2020

3048 Background: We conducted a phase II study to evaluate the efficacy and toxicity of adjuvant chemo-immunotherapy using dendritic cells and activated killer cells from tissue culture of tumor-draining lymph nodes (TDLN) in primary lung cancer patients. Methods: Pathological N2 lung cancer patients were selected for the post-surgical adjuvant chemo-immunotherapy. Activated killer cells and dendritic cells obtained from tissue cultures of TDLN or TDLN co-cultured with peripheral blood lymphocytes (TDLN-Pb) were used for the adoptive transfer of immunotherapy. Patients received 4 courses of post-surgical chemotherapy or chemotherapy along with immunotherapy (immunotherapy group) every 2 months for 2 years. Results: There were 57 N2 patients eligible for the study, 28 for immunotherapy and 29 for chemotherapy. For the 28 immunotherapy cases, a total of 313 courses of immunotherapy were administered. The main toxicities were fever (78.0%), chill (83.4%). The 5-year survival rates in the immunotherapy and chemotherapy groups were 56.5% and 12.5% respectively. Among the variables analyzed, immunotherapy was the most significant independent prognostic factor (p=0.0042.) Conclusions: Adoptive transfer of activated killer cells and dendritic cells from the tumor draining lymph nodes of primary lung cancer patients is safe and feasible, and a large-scale multi-institutional study is necessary for the evaluation of the efficacy of this treatment. No significant financial relationships to disclose.
A dose finding pharmacokinetic study of the tumor-targeting human L19-IL2 monoclonal antibody-cytokine fusion protein in patients with advanced solid tumors
Authors: Curigliano G. , Spitaleri G. , De Pas T. , Noberasco C. , Giovannoni L. , Menssen H. , Zardi L. , Milani A. , Neri D. , de Braud F. 
Published: March 2020

3057 Background: L19-IL2 is a tumor targeting immunocytokine constituted by a single chain Fragment variable format directed against ED-B domain of fibronectin and the human cytokine interleukin-2 (IL-2). It has striking anticancer activity in preclinical models. We evaluated safety, pharmacokinetic profile (PK) and activity of L19-IL2 in advanced cancer patients. Patients and Methods: Five cohorts of patients with recurrent/refractory solid tumors received a dose escalation intravenous infusion of L19-IL2 (5, 10, 15, 22.5 e 30 Mio IU IL2 equivalent dose) on days 1, 3 and 5 every 21 days. Serum samples for PK assessment, immunophenotyping and assays for detection of human antifusion protein antibodies to L19 (HAFA) were collected at screening and on day 1, 3, 5 and 10 of each cycle. Results: Eighteen solid cancer patients were enrolled from 11/05 to 9/06 (6 colorectal and 3 renal cell cancer (RCC) patients, 3 with melanoma, and 1 neuroendocrine tumor, thymic carcinoma, biliary tract carcinoma, breast cancer, peritoneal mesothelioma and parotid gland carcinoma). Median age was 49 years (range 35–69), 14 patients were male and 4 female. All patients were evaluable for safety and activity. The maximum tolerated dose was determined to be 22.5 Mio IU IL-2 equivalent. Drug-related dose-limiting toxicities at 30 Mio IU L19-IL2 were hypotension requiring vaso-pressor support and acute renal failure. Treatment-related deaths did not occur, and all toxicities were reversible. Five patients achieved stable disease (RCC, n=3; biliary tract carcinoma, n=1; peritoneal mesothelioma, n=1). All other patients progressed. Immunophenotyping disclosed IL2-typical transient activation of T-cell subsets. Very preliminary data showed a weak induction of HAFA at day 10 in 5 patients. These data could not be confirmed by competition ELISA experiments. Conclusions: Up to 22.5 Mio IU IL2 equivalent of L19-IL2 can be safely administered to advanced solid cancer patients in an outpatient setting. Some evidence of clinical activity in patients susceptible to immunomodulatory therapy (RCC) was found. All observed toxicity was mild and reversible. An expanded study at recommended dose in RCC patients is currently ongoing. [Table: see text]