bluuebunny/crossref_metadata_2025 huggingface dataset:
Frequency of biopsies (BX) and colposcopy (CP) of intraepitelial lesions (IL) in the cervical cancer screening program (CCSP)
Authors: Holgado S. , Sanchez Segura M. , Zarba J. J. , Monroy C. , Lorente C. , Elias A.
Published: March 2020

11000

Background: Cervical cancer is a public health problem in developing countries that can be prevent by screening programs. The loss of patients with PAP smears with IL is one of the main concern in the CCSP. The objectives of this study were establish the frequency of IL in the CCSP of Tucumán and determine the frequency of BX and CP in patients with IL within the program. Methods: Data was taken from the clinic-epidemiological charts of CCSP, and pathology reports of 29,169 cytologies (CX) done in women entered in CCSP of Tucumán between 1997 and 2004 The PAP smears were done and informed following Bethesda system and centralized in Hospital Centro de Salud: Zenón Santillán of Tucumán. Results: 2% of the CX were IL. In the beginning of program in 1997 in HSIL and LSIL a BX was performed in 22% and 18% of patients respectively and in 2004 BX was performed in 61% and 25% respectively. There were no data of CP before 2001 but in 2001 a CP was performed in HSIL and LSIL in 21% and 9% and in 2004 CP was performed in 43% and 14% respectively. Conclusion: The percentage of BX and CP performed in IL patients included in the CCSP, increased in the last year of program achieving a 60% and 43% in HSIL which is quite acceptable in a developing country.

No significant financial relationships to disclose.
The power of the biomarker for cervical cancer control
Authors: Markovic N. S. , Markovic O. , Henderson E. S.
Published: March 2020

11001

Background: At ASCO 2001, the Cervical Acid Phosphatase - Papanicolaou Test (CPT) was introduced as a biomarker-based technology as a potential in vitro diagnostic device. At ASCO 2004 and 2005, we reported results from clinical trials on 2,000 subject/specimens. In a setting of standard cervical cancer screening, the safety and effectiveness of CPT (MarkPap® Test) was compared with control Pap smear and LBP. The favorable results motivated us to expand this translational research in areas where this biomarker is crucial: self-sampling and digital evaluation. We report a pilot study designed to assess whether upgrading CPT with digital image processing (IT technology) could create a new device for an effective telecytopathology. Methods: Material: Cervical specimens self-obtained by volunteers, specimens collected in prior clinical trials (Library of MarkPap slides), and control slides. Instruments and methods: We have assembled a set of instruments and procedures to create images from microscopic slides, to convert analog into digital images, to capture and store digital images and clinical data in computer files, to transfer image files via Internet to a central server for evaluation by cytotechnologist/pathologists, and to return the reports within hours. At the end, the results of reading digital and direct images were available for comparison. Results: Since each instrument was “fit-for-use”, we have tested different “conditions-for-use” for providing digital images comparable to direct images. Images of self-sampled specimens, controls and existing slides were processed through a new setup of five modules: image acquisition, image and data transferring, image evaluation, results reporting and quality control. It was made possible by upgrading software. There was no difference between results obtained after evaluation of digital or direct images. Conclusion: Using CPT and available instruments and software, we have developed a prototype in vitro diagnostic medical device, which could permit expert evaluation of cervical specimens to be performed rapidly and at affordable cost for developing countries. This device should be able to use self-obtained specimens, field laboratory personnel and equipment, but to provide high-qualified evaluation within hours for an easy affordable cost.

[Table: see text]
Combined regimen of temozolomide and liposomal pegylated doxorubicin in glioblastoma—Toxicity and efficacy
Authors: Bogdahn U. , Jauch T. , Beier C. , Beier D. , Gänβbauer S. , Glas M. , Koch H. , Wismeth C. , Steinbrecher A. , Hau P.
Published: March 2020

11501

Background: Temozolomide (Temodar, TMZ) recently showed promising efficacy in an EORTC trial on first-line therapy of glioblastoma (Stupp R, 2005). Pegylated liposomal doxorubicin (Caelyx, PEG-DOX) was evaluated in patients with recurrent high-grade glioma and showed an overall response rate of 40% (Hau P, 2002). Therefore, a combination of both agents seems promising. Methods: TMZ was given orally 75 mg/m2 daily during standard radiotherapy (initiation) and 150–200 mg/m2 days 1–5 in 28 days starting 4 weeks after radiotherapy (maintainance). PEG-DOX was given as a short-time infusion in a dose-escalation regimen once prior to radiotherapy and on days 1 and 15 starting 4 weeks after radiotherapy. PEG-DOX was escalated for 5 mg/m2 in groups of three patients starting with 5 mg/m2 (group 1) and a highest dose of 20 mg/m2 (group 4). Results: In the dose escalation part of this study, the regime detailed above was feasible, tolerable, and able to induce objective responses and stabilizations in patients with glioblastoma. In the first treatment group (5 mg/m2 of PEG-Dox), one out of 7 evaluable patients had a dose limiting toxicity (DLT). In the second, third and fourth treatment groups, the regimen was tolerated without DLT. Concerning efficacy in the “treated-patients” analysis of 18 patients, 1 had a partial response in MRI, and 12 patients had tumor stabilization 4 weeks after conclusion of radiotherapy. Only 5 patients progressed early. Twelve patients responded with progression free survival times of 13 to 76 weeks. One patient is still progression free after 120 weeks of treatment. Conclusion: As no DLT was observed in dose group 4, MTD was not reached and we proceed to the efficacy phase of the trial with PEG-DOX in a dose of 20 mg/m2. Seventeen patients are included so far. Results will be compared to the published study EORTC 26981/22981 (Stupp R et al., 2005) which did set a new standard in the first-line treatment of glioblastoma as survival times of more than 14 months and a 2-year overall survival of 26% were reached. Regarding the promising preliminary survival data of study RNOP-09, we expect even better results with the regimen used in this protocol.

[Table: see text]
High dose chemotherapy with autologous stem cell rescue (ASCR) for recurrent medulloblastoma
Authors: Diez B. , Garcia Lombardi M. , Chantada G. , Dengra C. , Fernandez Sasso D. , Koziner B.
Published: March 2020

11507

Background: Medulloblastoma is a highly lethal disease when it recurs and very few patients survive with conventional treatment. This study evaluated the use of high-dose carboplatin, thiotepa, and etoposide with autologous stem-cell rescue (ASCR) in patients with recurrent medulloblastoma. Methods: Between 8/97 and 8/05 14 patients (M/F 12/2) with recurrent medulloblastoma, aged 2 to 33 years (median, 10.5 years) at ASCR, were treated. Thirteen had relapsed after chemotherapy and craniospinal + posterior fossa irradiation and one after chemotherapy (Baby POG) at a median time of 19 months (7 to 148). One had a local relapse and 13 had dissemination at relapse (M1: 1, M2: 7 and M3: 5) Chemotherapy consisted of carboplatin 500 mg/m2 (or area under the curve = 7 mg/ml × min via Calvert formula) on days −8, −7, −6; and thiotepa 300 mg/m2 and etoposide 250 mg/m2 on days −5, −4, and −3 respectively; followed by ASCR on day 0. Results: Four patients died of treatment-related toxicities at 0, +23, +42 and +51 days post ASCR (bacterial sepsis in 2, CMV infection in 1 and CNS hemorrhage in 1). It should be remarked that all the toxic deaths were observed in patients auto grafted before October 2000. Five of 14 patients (35%) are event-free survivors at a median of 70 months post-ASCR (range: 5 to 86 months). Tumor recurred in the remaining 5 patients at a median time of 2 months post ASCR (2 to 15). All died at +23, +16, +12, +9 and +4 month post ASCR. Conclusions: Our results seem consistent with those published by Dunkel IJ (J. Clin Oncol; 16:222 - 8 1998) and argue about the efficacy of high dose chemotherapy with ASCR to provide long-term survival for some patients with recurrent medulloblastoma.

No significant financial relationships to disclose.
Electrical spinal cord stimulation during radiotherapy and temozolomide in high grade gliomas. A phase II report
Authors: Clavo B. , Robaina F. , Cabezon A. , Jorge I. J. , Ponce P. , Pinar B. , Ruiz A. , Otermin E. , Hernandez M. A. , Carreras J. L.
Published: March 2020

11510

Background: Ischemia-hypoxia in high grade gliomas (HGG) turns tumor cells more aggressive and more resistant to radiotherapy (RT) and temozolomide (TMZ). Higher glucose metabolism pre-treatment has been correlated with better response to TMZ using 18-FDG-PET. In preliminary works, we have reported that electrical spinal cord stimulation (SCS) can modify loco-regional oxygenation, blood flow and metabolism in HGG. The aim of this study was to evaluate tumor response and toxicity in HGG using SCS during RT plus TMZ. Methods: 10 patients (males/females: 8/2; median age: 51 years (30–68)) were enrolled in this trial. Tumors were 6 glioblastomas and 4 relapsed anaplastic gliomas. Diagnosis was after complete resection (1), subtotal resection (6), biopsy (1) or MRI + PET (2 relapsed HGG). Tetrapolar electrode for SCS was percutaneously inserted on the posterior surface of the cervical spinal cord at C2-C4 level. RT was at 2 Gy/fraction, 5 fractions/week, total dose 60 Gy (40 Gy in previously irradiated tumors). TMZ was administered at 75 mg/m2 daily during RT, followed by at least 6 cycles of adjuvant TMZ at 200 mg/m2. Tumor response was evaluated by CT and PET. Results: After concurrent RT+TMZ, CT showed: 5 partial response (PR), 3 complete response (CR), 2 stable disease (SD). After 6 adjuvant cycles of TMZ, CT (median 10 months after surgery) showed: 4 PR, 3 CR, 3 progression disease (PD). PET showed post-surgical residual tumor in the 9 evaluated patients. After 6 cycles of TMZ, PET showed: 4 CR, 2 PR (they obtained delayed CR after 12 and 18 cycles of TMZ), PD n = 2, and two patients without PET assessment (1 with PR in CT, and 1 without tumor in CT). For the study group median overall survival (OS) was 22 months (95% CI = 14–30) and for glioblastomas 16 months (95% CI = 6–26). For relapsed anaplastic gliomas mean OS was 37 months (95% CI = 22–52). One patient did not finish scheduled adjuvant TMZ and only one patient experienced hematological toxicity with neutropenia G-I and thrombopenia G-III. Conclusions: Electrical SCS during RT+TMZ did not increase toxicity. Preliminary data about tumor response and OS seem to be encouraging and they support further research. Supported by Grants: FUNCIS 03/09 and ISCiii, RTICCC C03/10.

No significant financial relationships to disclose.
Yttrium-90-labeled ibritumomab tiuxetan for primary CNS lymphoma
Authors: Kiewe P. , Jahnke K. , Maza S. , Korfel A. , Munz D. L. , Thiel E.
Published: March 2020

11512

Background: Salvage treatment has not yet been established in primary CNS lymphoma (PCNSL). Here we report first results of an ongoing phase II study with a single treatment course of Y-90 anti-CD20 antibody ibritumomab tiuxetan in relapsed/resistant PCNSL. Methods: Eligibility criteria include histologically confirmed, recurrent PCNSL after at least one prior treatment, HIV negativity and adequate bone marrow and cardiac function. Primary endpoint is overall response, secondary endpoints are response duration, survival, and toxicity including late neurotoxicity. Treatment includes rituximab 250 mg/m2 on day -7 and day 0, followed by Y-90-ibritumomab tiuxetan 15 MBq/kg IV. Response evaluation by contrast-enhanced magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET) is scheduled before, one month and two months after treatment as well as every three months thereafter in responders. In two patients single photon emission computed tomography (SPECT) target imaging with gamma-emitting 111-Indium-ibritumomab tiuxetan was performed repeatedly. Results: To date, four patients have been enrolled. Complete response on MRI and decreased but still detectable FDG-uptake in PET was seen in one patient; the response duration was one month. In another patient uncertain complete response with minimal residual contrast enhancement lasting 12+ months was observed. Two patients had disease progression. One patient developed CTC grade 3 pneumonia during CTC grade 2 leukopenia, two patients had CTC grade 3 thrombocytopenia lasting up to 6 weeks. SPECT indicated target accumulation in the tumor starting 48 hours and still ongoing 7 days after injection of 111-Indium-ibritumomab tiuxetan. Conclusions: This is the first report on a successful treatment of PCNSL with Y-90-ibritumomab tiuxetan and penetration of a therapeutic antibody into PCNSL, warranting further investigation.

No significant financial relationships to disclose.
Phase III randomized multicenter trial of surgical resection, BCNU-impregnated wafers, and irradiation versus surgical resection and irradiation alone for treatment of operable, solitary brain metastasis from systemic cancer
Authors: Newton H. B. , Volpi C. , Burkart J. , Miner M. E. , Gahbauer R. , Pearl D. K. , Ryken T. , Albright R. E. , Quigley M.
Published: March 2020

11513

Background: Metastatic brain tumors (MBT) are the most frequent complication of systemic cancer. With conventional radiotherapy, survival remains poor, ranging from 24 to 32 weeks. Recent randomized trials suggest that surgical resection and irradiation of solitary MBT can extend survival and improve neurological quality of life. However, the role of chemotherapy remains unclear. A phase I/II trial demonstrated that interstitial chemotherapy with BCNU-impregnated wafers was well tolerated in this cohort, with an extended median survival and infrequent local recurrences. Methods: A randomized, multicenter phase III trial was begun to evaluate the ability of BCNU-impregnated wafers to improve survival and local time to progression in comparison to surgical resection and irradiation alone, with an expected accrual of 170 patients. Eligible patients were adults with systemic cancer of the lung or breast, with a solitary, accessible MBT that did not cross the midline or violate the ventricular system. Results: A total of 22 patients (female - 14; 20 with lung cancer), median age 60 years (range 39–77), were enrolled and randomized before the study was closed due to slow accrual. Each patient had undergone maximal surgical resection of the MBT and radiation therapy (35 Gy); wafers were placed in 12 patients (range 2–8 wafers). The median overall survival for the wafer and non-wafer groups were 35.0 and 47.4 weeks, respectively (log rank test, p = 0.54), with a 6-month survival rate of 67% and 56%, respectively (Fishers exact test, p = 0.67). Wafer placement was well tolerated. Conclusions: In this small cohort limited by slow accrual, the use of BCNU-impregnated wafers did not improve survival over surgical resection and irradiation alone. The wafers were well tolerated and did not adversely impact on quality of life. Although animal studies and phase I/II data are suggestive of activity, a large, multicenter, phase III comparative trial will be necessary to determine the efficacy of BCNU-impregnated wafers in patients with solitary, resectable MBT.

[Table: see text]
Identification of prognostic factors in patients with brain metastases: A review of 493 patients
Authors: Baltalarli B. P. , Yalman D. , Akagündüz O. , Ozsaran Z. , Anacak Y. , Ozkok S. , Esassolak M. , Aras A. , Haydaroglu A.
Published: March 2020

11516

Background: Choice of treatment for an individual patient with brain metastases is based on a number of factors: number and localization of brain metastases, systemic tumor activity, performance score, and age are major determinants for selection of treatment modality. Future trials in patients with brain metastases depend on selection of patients with favorable prognosis to allow adequate long-term follow-up to draw conclusions about survival and late toxicity, further stressing the importance of prognostic parameters. Our aim is to report the outcome of patients with brain metastases from solid tumors treated with whole brain radiotherapy (WBRT) in a single institution and identify the prognostic subgroups who will benefit from treatment. Methods: The records of 493 patients with brain metastases who had been admitted for WBRT in the Department of Radiation Oncology in Ege University Hospital between January 1997 and December 2002 was retrospectively evaluated. WBRT at this institution comprised of parallel opposed lateral fields, dosed to the midplane in a cobalt 60 teletherapy device. Radiotherapy fractionation were 10 fr. × 3 Gy, 5 fr × 4 Gy and 2 fr. × 8 Gy. Survival was calculated using the Kaplan-Meier method. Cox regression modeling was used for multivariate analysis and prognostical factors were determined on the basis of log rank test (SPSS 10.00 version). Results: Clinical response evaluation revealed that 254 patients (51%) had response to tretament whereas 104 patients (21.1%) had stable response and the other 43 patients (8.7%) had progressive disease.The median survival was 3 months (1–62 months) and 6 months survival was 41% and one year survival was 19%. Univariate analysis revealed that prognostical factors for survival were younger age (age <57) (p=0.043), female gender (p=0.019) and operation (p=0.0004), and for multivariant analysis female gender (p=0.027) and operation were determined (p=0.000). Conclusion: The prognosticators for survival in this retrospective analysis for patients with brain metastases are age, gender and operation. These factors affecting survival must be taken into consideration when the therapeutic management is to be made. And they may allow better selection of individual treatments.

No significant financial relationships to disclose.
Remarkable response of adult-onset ganglioneuroblastoma in the advanced stage to unrelated cord blood transplantation: Case report
Authors: Takahashi T. , Morii T. , Amano I. , Tanaka H. , Tojo T. , Taniguchi S. , Kimura H.
Published: March 2020

11524

Background: Adult-onset ganglioneuroblastoma (GNB) is a rare disease that carries the gravest prognosis. In this case report, we discuss a case of adult-onset GNB in the advanced stage which has responded favorably to unrelated cord blood transplantation (UCBT). Methods: The patient was a 22-year-old male. Posterior mediastinal tumor was excised and a diagnosis of GNB was made. The severity of GNB was classified as stage IV because bone metastasis affected the entire body. Three courses of combination chemotherapy using cisplatin (CDDP), cyclophosphamide (CY), vincristine sulfate (VCR) and pirarubicin hydrochloride-adriamycin (THP-ADR) turned out to be ineffective. Local radiation therapy to control the tumor metastasis to the right great wing of the sphenoid bone resulted in augmentation of the tumorous lesion. Then, bone marrow destructive pretreatment consisting of anticancer therapy [etoposide (VP-16) and thiotepa] and total body irradiation (TBI, 12Gy) was followed by UCBT. Cyclosporin and mycophenolate mofetil were administered to prevent graft versus host disease (GVHD). Results: The blood type compatible two-loci HLA mismatch transplant had 3.2x107 nucleated cells/kg. After the cord blood transplantation, the patient suffered complications such as acute GVHD (grade III), veno-occlusive disease (VOD) and viral hemorrhagic cystitis. Neuron-specific enolase (NSE), a GNB tumor marker, gradually decreased from 220 ng/ml to the normal level. The bone metastatic tumors were reduced in a stepwise manner. Fluorodeoxyglucose-positron-emission tomography (FDG-PET) scan demonstrated complete disappearance of abnormal accumulation. Three hundred days have passed since the unrelated cord blood transplantation. The patient is surviving and in the disease-free state. Conclusion: The remarkable response of adult-onset GNB in the advanced stage to UCBT has demonstrated the definite graft versus tumor (GVT) effect of UCBT on GNB. UCBT is regarded as a promising therapeutic intervention in solid tumors that are not associated with blood disorder.

No significant financial relationships to disclose.
Chemoradiotherapy in multicentric glioblastoma multiforme—A clinical study
Authors: Papaiah Susheela S. , Bahl A. , R P. , Sharma D. , Julka P. , Rath G.
Published: March 2020

11525

Background: Glioblastoma multiforme constitutes 40% of primary brain tumors. Multicentric Glioblastoma multiforme is rare about 3%.No definite guidelines is available in literature for management of these tumors. Methods: All Multicentric Glioblastoma multiforme were analyzed retrospectively from Jan 2003 to July 2005 for clinical behavior and response to chemoradiotharpy. Either Temozolamide or Carboplatin or Paclitaxel is used concurrently with radiation. Radiation dose 60 Gy/30 fractions over 6 weeks by bilateral parallel opposed fields was delivered using Cobalt-60 machine. Results: 27 cases were found, Male: Female 24:3, KPS 60 [40–70], Majority of them are symptomatic for 4 months, main symptoms were seizures, headache, vomiting, neurological deficite. 89% of them underwent one form of other surgical intervention. 11% were diagnosed on basis of radiological findings. 85% were supratentorial, 15% were both supra and infratentorial, one of which had spinal cord lesion. 6 [22%] patients did not receive any treatment. Among 21 patients 4 were treated only with radiotherapy, 17 with concurrent Chemoradiotherapy [Paclitaxel-8, Temozolamide-7 and Carboplatin-2]. 5 patients did not complete treatment. Among 16 patients only 6 came for first follow up, 5 of were concurrent Chemoradiotherapy [Temozolamide-4, Paclitaxel-l and RT alone 1]. At the end of 3 months only 2 patients with Temozolamide were alive. Conclusions: Multicentric Glioblastoma multiforme is an aggressive disease. Concurrent Chemoradiotherapy with Temozolamide has better role.

No significant financial relationships to disclose.
Combined focal radiotherapy (FRT) and temozolomide (TEM) in the management of high grade malignant gliomas (HGMG): Romanian single centre experience
Authors: Bujor L. , Oprea C. , Pop M. , Perin R. , Vasile C.
Published: March 2020

11526

Background: Standard treatment of HGMG is surgical resection followed by adjuvant FRT; chemotherapy is under investgation in postoperative setting combined with external FRT. The phase III study of Stupp et al favours the combined TEM and FRT for newly diagnosed HGMG with encouraging results in terms of both survival and disease free survival. We present the experience achieved in our centre with 18 consecutive patients with HGMG treated with FRT and TEM either concomitant or sequential. Methods: In the period January 2004–January 2006 eighteen consecutive adult patients age range 25–72 years, median 55 years, sex ratio M/F 10/8 with histologically proven HGMG have been refferd in our centre for adjuvant treatment. Most of the patients had deep situated tumors that precluded complete resection which has been performed in 6 out of 18 patients. For the remaining patients stereotaxic biopsy was the procedure of diagnosis. A maximum dose of 60 Gy FRT was delivered with dual energy photon (6–15 MV) linear accelerator over six weeks in 30 sessions. TEM was administered concomitant in continuous low daily doses 75 mg/sqm in five patients (all males) followed by maintenance 150–200 mg/sqm for up to six cycles. For three patients TEM was co-administered for two cycles of 200 mg/sqm during the days 1–5 and 29–33 of radiotherapy course and whereas for the remaining patients the TEM was given sequentially after the completion of FRT up to six cycles in 5/28 days schedule. Results: With a median follow-up of 11.5 months the overall survival was 9.7 months and the survival rate of 78.5%. Clinical examination was performed every week during FRT with neurological improvement and a decrease in the need of anticonvulsivants in all patients. According to CTC criteria no grade 3 and 4 grade toxicities were recorded. After the completion of FRT imaging evaluation (CT/MRI) was performed at 6 weeks time period with tumor regression in 75% of the patients and early recurrence in only 2 cases. Conclusions: Concomitant FRT and TEM is a safe and promising treatment in newly diagnosed cases of HGMG. Our preliminary experience confirms the data from literature and we will present updated results by the ASCO meeting time.

No significant financial relationships to disclose.
Phase I dose and schedule finding study of pegylated liposomal doxorubicin (D) and weekly docetaxel (T)
Authors: Shaye O. S. , El-Khoueiry A. B. , Garcia A. , Wei D. , Groshen S. , Cole S. E. , Gitlitz B. J. , Chung C. T. , Lenz H. J. , Iqbal S.
Published: March 2020

12012

Background: The combination of D and T has many potential applications, particularly in breast and ovarian cancers. A phase 3 trial is examining D + T versus T in first-line metastatic breast cancer ( NCT00091442 ). D has better tumor localization and penetration in solid tumors than conventional doxorubicin. In previous studies, the maximum tolerated dose (MTD) of the combination was identified as D 30 mg/m2 and T 75 mg/m2 q4 weeks (wks), with a recommended dose and schedule of D 30 mg/m2 and T 60 mg/m2 q3wks without G-CSF. We conducted a phase I study to determine the MTD of D with weekly T. Our hypothesis was that the lower incidence of myelosuppression with weekly T would allow for higher doses of both drugs. Methods: There were 2 schedules. Arm A: D q4wks starting at 25 mg/m2 with weekly T for 3 wks starting at 30 mg/m2. Arm B: D q2wks starting at 15 mg/m2 with weekly T for 3 wks starting at 30 mg/m2. One cycle was 28 days. Standard 3+3 design was used with MTD defined as the highest dose level causing dose limiting toxicity (DLT) in ≥ 2/6 patients (pts). Results: 32 pts were treated; 13 females, 19 males, median age of 60 years. Median number of cycles administered was 2 (1–13) with a median follow-up of 11.5 months. Tumor types included lung (16%), thyroid (9%), esophagus (9%), nasopharynx, breast, colorectal, stomach and kidney (6% each). Arm A (13 pts) was closed after 2/7 evaluable pts at dose level 2 (D 33mg/m2; T 30 mg/m2) experienced DLT in the form of grade 3 stomatitis. The most common grade 3/4 toxicities were neutropenia (3/13), stomatitis (3/13) and fatigue (3/13). Arm B accrued 19 pts. The trial was closed at the highest planned dose in Arm B (D 20mg/m2 q2wks and T 35 mg/m2 weekly) with only 1/6 evaluable pts experiencing DLT in the form of grade 4 fatigue and weakness. The most common grade 3/4 toxicities in Arm B included neutropenia (5/19 pts), fatigue (5/19 pts) and stomatitis (2/19 pts). There was no grade 3/4 hand-foot syndrome or cardiotoxicity. 2 partial responses were observed in nasopharyngeal and salivary gland carcinomas, with 13 pts achieving stable disease. Conclusions: The combination of D q2 wks and T weekly for 3/4 wks is well tolerated and results in a higher dose intensity of both drugs than in previously evaluated regimens.

[Table: see text]
A phase I clinical study of biweekly carboplatin and gemcitabine in patients with advanced solid tumors
Authors: Kumar P. , Keshtgarpour M. , Kumar H. , Dudek A.
Published: March 2020

12024

Background: Carboplatin (CBDCA) and gemcitabine (GEM) in combination is used commonly in lung cancer and is administered on a 21 day cycle. The purpose of this study was to determine the maximum tolerated dose (MTD) of CBDCA and GEM administered on a biweekly schedule and to assess safety and efficacy of this schedule. Methods: GEM was given intravenously (IV) over 30 minutes followed by CBDCA also given IV over 30 minutes. This combination was given on day 1 every 2 weeks. The dose levels examined are shown in the Table . A total of 26 patients were studied (18 male, 8 female) with median age of 56 (range 41–83 years); ECOG performance status of 24 patients were 0 (5), 1 (16), 2 (2), 3 (1); prior chemotherapy ranged from 0 to 4 regimens; median number of cycles administered per patient was 3 (range 1–9) with a total of 81 cycles. The primary tumors were lung (11), melanoma (4), head and neck (3), squamous cell penile/toe (2), bladder (2), kidney (1), gastric (1), esophageal (1) and ovary (1). Results: No DLTs were seen in any of these patients and the MTD was not reached. Delay in treatment was seen in total of 6 cycles due to myelosuppression and 1 cycle due to nausea and anorexia. Grade 3/4 hematological toxicity rates: anemia - 3/81 cycles (3.7%), neutropenia - 20/81 cycles (25%), and thrombocytopenia - 4/81 cycles (5%). Non-hematological toxicity was mild. The median time to progression was 40 days (range 4–133) and of 18 evaluable patients partial response or stable disease was seen in 7 (38.8%). Conclusions: Even at maximum tested dose of GEM at 2000 mg/m2 and CBDCA at AUC of 3.0, this schedule is well tolerated. Hematological toxicity such as neutropenia and thrombocytopenia was minimal. We plan to study this schedule of GEM and CBDCA in appropriate tumor types in combination with biologic agents.

[Table: see text]

[Table: see text]
Ex vivo generation and expansion of autologous anti-tumor CTL lines for adoptive cell therapy in patients with solid tumors
Authors: Pedrazzoli P. , Tunin I. , Tullio C. , Montini E. , Schiavo R. , La Grotteria M. , Locatelli F. , Maccario R. , Siena S. , Montagna D.
Published: March 2020

12516

Background: Ex-vivo generation of cytotoxic T cell (CTL) lines able to selectively kill autologous tumor cells (TC) is crucial for adoptive cell therapy of cancer. We have described the ex vivo generation of anti-tumor HLA-restricted CTL using CD8-enriched blood mononuclear cells (PBMC) and dendritic cells, pulsed with apoptotic TC as source of tumor antigens (Montagna, Int J Cancer 2004). These cells possess a marked cytotoxicity against TC but very low levels of cytotoxicity against autologous non-malignant controls, suggesting their safe in vivo use. Aim of this study was to evaluate the possibility of generating a large number of anti-tumor CTL lines, in compliance with good manufacture procedure (GMP), to be utilized for adoptive cell therapy. Methods: Four patients with advanced, pretreated solid tumors have been evaluated: 2 sarcoma, 1 renal carcinoma and 1 ovarian carcinoma. Tumor sample was obtained during surgical procedures planned for therapeutic purposes, while PBMC were obtained by a single apheresis. All reagents employed for cultures were produced under GMP. Based on our reported method, the current protocol included two or three rounds of tumor-specific stimulation, followed by two rounds of antigen-independent expansion. Results: We have obtained, after the first round of expansion and in total, a range of 0.5–2×109 and 5–20×109 CTL, respectively. Such large amounts of anti-tumor CTL were generated even if a low number of viable TC was available. In 3 out of 4 anti-tumor CTL lines, >85% of effector cells were CD3+/CD8+. Conclusions: We demonstrated the feasibility of obtaining, in GMP conditions, large quantities of anti-tumor specific CTL suitable for in vivo use. A phase I protocol of lymphoablative therapy followed by CTL transfer in vivo has been designed and submitted for approval to the competent regulatory agency.

No significant financial relationships to disclose.
Safety and pharmacokinetics (PK) of AMG 706, panitumumab, and gemcitabine/cisplatin (GC) for the treatment of advanced solid malignancies
Authors: Crawford J. , Burris III H. A. , Stein M. , Stephenson J. , Gilbert J. , Underwood S. , Sun Y. , Yang L. , Wiezorek J. , Schwartzberg L. S.
Published: March 2020

13005

Background: AMG 706 is an investigational, oral, multi-kinase inhibitor with both antiangiogenic and direct antitumor activity targeting vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and Kit receptors. Panitumumab is a fully human monoclonal antibody directed against the epidermal growth factor receptor (EGFr) and has shown efficacy and tolerability in pts with solid tumors. The primary objectives of the first part of this multicenter, 2-part, dose-finding study were to establish the safety and tolerability of AMG 706 + panitumumab with GC. Secondary objectives included PK of all agents. Methods: Pts were sequentially enrolled in 1 of 5 AMG 706 dose cohorts: no AMG 706, 50 mg, 75 mg, 100 mg, and 125 mg QD; all pts received panitumumab (9 mg/kg i.v. on day 1), G (1250 mg/m2 i.v. on days 1 and 8), and C (75 mg/m2 i.v. on day 1) Q3W. Pts had advanced cancer for which GC is indicated, ECOG of 0 or 1, no symptomatic or untreated CNS metastases, no history of venous thrombosis, and no more than 1 prior chemotherapy regimen for advanced disease. Results: As of 8/05, 15 pts were enrolled (n = 7, no AMG 706; n = 8, AMG 706 50 mg QD). Baseline characteristics included 8M/7F, median (range) age of 61 (32, 72) years, 9 with ECOG 0 and 6 with ECOG 1. Tumor types included: non-small cell lung (8), pancreatic (3), esophageal (2), ovarian (1), and unknown (1). Safety for all 15 pts is presented (see table ). The PK of AMG 706 at 50 mg when coadministered with panitumumab/GC was similar to the PK for AMG 706 monotherapy at the same dose. Conclusions: These data suggest that AMG 706 can be safely combined with panitumumab and GC with no effect on the PK of AMG 706 at 50 mg QD. Updated safety and PK data will be presented.

[Table: see text]

[Table: see text]
Evaluation of platinum-based chemotherapy, glutathione metabolic genes, and survival in advanced non small cell lung cancer: A NCCTG 97–24–51 based study
Authors: Yang P. , Mandrekar S. J. , Hillman S. L. , Allen K. L. , Sun Z. , Wampfler J. , Cunningham J. M. , Jett J. R. , Adjei A. A. , Perez E. A.
Published: March 2020

13013

Background: The glutathione metabolic pathway is directly involved in the inactivation of platinum compounds. Our earlier work indicated that genotypes corresponding to varied glutathione-related enzyme activities may predict survival in patients with advanced lung cancer. Herein, we evaluated the role of glutathione-related genotypes on clinical outcomes in stage IIIB/IV non-small cell lung cancer patients who were stable or responding from one prior platinum-based chemotherapy. Methods: DNA samples from patients who had tumor regression or stable disease after treatment with one platinum based chemotherapy regimen were analyzed using 6 polymorphic DNA markers that encode 5 important enzymes in the glutathione metabolic pathway. The contrasting genotypes used in the analysis were GCLC (homozygous repeat 77 vs. heterozygous 7*), GPX1 (CC vs. other), GSTP1-I105V (AA vs. other), GSTP1-A114V (CC vs. other), GSTM1 (null vs. present), and GSTT1 (null vs. present). Multivariable Cox proportional hazards models adjusted for age, gender, treatment arm, ECOG performance status, stage, and prior tumor response, were used to evaluate the prognostic significance of the genotypes at each locus. Results: Data from 112 patients with a median follow-up of 10.6 (range: 0.4–56.3) months was used. No significant difference in time to disease progression was observed for any of the genotypes. Among the 6 genomic DNA markers, the GCLC genotype was an important prognostic factor for overall survival after adjusting for other factors. In particular, patients carrying a 77 repeat genotype (homozygous) had a significantly worse survival (Hazard ratio = 1.67, 95% CI: 1.05–2.63). Conclusions: Genotypes of glutathione-related enzymes, especially GCLC, may be used as host factors in predicting patients’ prognosis after platinum-based chemotherapy. Further investigation to define and measure the effects of these genes in chemotherapeutic regimens is needed. (This work was partly supported by NIH research grants CA77118, CA80127, and CA84354.)

No significant financial relationships to disclose.
A phase II study of the antisense oligonucleotide GTI-2040 plus docetaxel and prednisone as first line treatment in hormone refractory prostate cancer (HRPC)
Authors: Sridhar S. S. , Canil C. M. , Hotte S. J. , Chi K. , Ernst S. , Pond G. R. , Dick C. , Zwiebel J. A. , Moore M. J.
Published: March 2020

13015

Background: Despite initial responses to chemotherapy, median survival in HRPC remains a dismal 18 mos. Novel therapeutic approaches are clearly needed. The enzyme ribonucleotide reductase (RNR) composed of 2 subunits, R1 and R2 is essential for DNA synthesis and repair. The R2 subunit is often overexpressed in tumors increasing their malignant potential and promoting drug resistance. GTI-2040 (Lorus Therapeutics, Canada) is an antisense oligonucleotide to the R2 subunit downregulating its expression. In preclinical studies, GTI-2040 has shown antitumor activity in prostate cancer xenografts, synergy and non-overlapping toxicity with the taxanes. It is therefore a rational choice for combination with docetaxel in HRPC. Objectives: To determine efficacy of this regimen using PSA response rate. Secondary objectives include: duration of response, TTP, objective tumor response rate, safety and tolerability. Pharmacokinetic (PK) studies will be performed. PBMC will be used to determine RNR activity and R2 subunit quantitation. Methods: HRPC patients with PS 0–2, adequate organ function and no prior chemotherapy were treated with GTI-2040 5mg/kg/d continuous infusion for 14d, docetaxel 75 mg/m2 IV every 21d, and prednisone 5mg twice daily. Results: Twenty-two pts in 5 centers have been enrolled. Pts have received a total of 107 cycles to date. Median age 63 (52–77); median baseline PSA 140 (26–1256); ECOG 0:1:2: 14:7:1; prior radiotherapy in 14 pts. Pts received a median of 5 cycles (2–10). Grade 3/4 hematologic toxicities were lymphophenia (10pts), leukopenia (7pts), and neutropenia (7pts). Anemia (any grade) was seen in 19 pts across 92 cycles. Most frequent non-hematologic toxicities were fatigue and pain. PSA responses seen in 9/22 pts. Objective tumor response:1 PR, 9 SD, 3 PD, 3 off due to toxicity prior to objective response measurement, 3 no measureable lesions, 3 to be assessed. 19 pts off treatment: 9 PD, 4 toxicity (1 toxic death), 2 completed 10 cycles, 2 at investigator’s discretion and 2 withdrew consent. Three pts remain on study. Median TTP estimated at 17 wks. Accrual has been sufficient to meet stage 1 requirements. Final response, toxicity, pK, RNR and R2 subunit analysis will be available and presented.

No significant financial relationships to disclose.
Results from a phase I dose escalation study of PEGylated glutaminase in combination with 6-diazo-5-oxo-L-norleucine (DON) in advanced malignant solid tumors
Authors: Unger C. , Müller C. , Jäger E. , Bausch M. , Roberts J. , Al-Batran S. , Sethuraman N.
Published: March 2020

13017

Background: To cope with the increased demand with concomitant down-regulation of glutamine synthesis, tumor cells in general have an upregulated glutamine uptake. The rationale is based on the premise that the therapeutic effectiveness of the glutamine anti-metabolite 6-diazo-5-oxo-L-norleucine (DON) is enhanced by strong depletion of the available pool of glutamine through PEGylated glutaminase (PEG-PGA). The optimal dose of PEG-PGA was found in step one of this study. Methods: Step two of this Phase I study was designed to determine the safety and tolerability of 120 I.U./m2 PEG-PGA in combination with increasing dose levels of DON both administered i.v. twice weekly. DON was administered four hours after PEG-PGA at levels of 5–185 mg/m2 with cohorts of three patients. Cohorts were expanded in case of possibly drug related AEs≥G3. All patients exhibited solid tumors of various indications refractory to standard treatment. Toxicity was measured according to NCI-CTC criteria. Response was evaluated according to RECIST criteria. Results: 61 patients have been enrolled in step two of this study wherein 58 received at least one treatment and 46 (57% male) were available for preliminary evaluation. Median age was 62.5 years (range 43–79) and 36% had a Karnofksy-index <90%. At 25 mg/m2 of DON three patients exhibited G3 nausea and vomiting which was managed effectively with antiemetic therapy. Possibly drug related AEs ≥ G3 like dyspnoea (n = 1), allergic reaction (n = 1), haematemesis (n = 1), 1 thrombosis (n = 1) and neurological diseases (n = 4) were reported in 19.6% of the patients. Haematological toxicities were neither frequent nor severe. No G4 toxicity in any dose level has been observed. DLT (two AEs ≥ G3 in one cohort) was reached in the 11th escalation step resulting in an adequate MTD which will be used in the following studies. In 38 patients available for tumor response 1 confirmed PR (renal) and at least 12 SDs have been reported. Conclusions: PEG-PGA in combination with DON has shown promising efficacy in heavily pre-treated solid tumors with a favourable toxicity profile. A clinical proof of concept study with statistically sufficient number of patients is ongoing.

[Table: see text]
Phase I study of ON-01910.Na, a novel cell cycle inhibitor in adult patients with solid tumors
Authors: Donehower R. C. , Jimeno A. , Li PhD J. , Galvin K. , Anthony F. , Reddy R. , Reddy P. , Messersmith W. , Laheru D. , Baker S. D.
Published: March 2020

13026

Background: ON-1910.Na is a new chemical entity, novel cell cycle inhibitor which arrests cells in G2/M, affects phosphorylation of several regulatory kinases and lacks cross resistance to other standard chemotherapy agents. This is a first-in-man Phase I dose escalation study to determine the dose limiting toxicities, recommended Phase II dose, and pharmacokinetic (PK) profile, and to document any antitumor activity of ON-01910.Na. Methods: Patients had histologically confirmed solid tumors refractory to standard therapy. ON-1910.Na, formulated as a solution in PEG400, was administered as a 2-hour infusion on days 1, 4, 8, 11, 15, and 18 followed by a 10 day observation period for a total of 28 days per cycle. The initial dose was 80 mg and was escalated using an accelerated titration schedule; one patient was treated per cohort until grade 2 toxicity was documented. A dose confirmation cohort of up to 12 patients will be treated at the maximun tolerated dose (MTD). A comprehensive PK study was performed on days 1 and 15 of the first cycle, plus trough samples were collected. Results: Thirteen patients (7F, 6M; ages 46–73) have received 20 cycles. Dose levels of 80, 160, 320, 480, 800, 1280, 2080, and 3120 mg were evaluated in 8 patients, and a further dose of 4370 mg has been evaluated in 5 patients. Toxicities have been anemia (2 G1, 1 G2), leucopenia (1 G1, 1 G2), hyperglycemia (2 G1), elevated AST/ALT (1 G1, 1 G2), nausea (3 G1), diarrhea (3 G1), skeletal pain (5 G1, 1 G2), abdominal pain (2 G1), tumor pain (1 G2), and fatigue (3 G1, 1 G2), and have clustered at the latter 3 dose levels. PK analysis shows increasing ON-1910.Na exposure with increasing doses. ON-1910.Na has a low clearance (13 L/h), long half-life (20 h), distribution in excess of blood volume (58 L) and PK parameters are similar on days 1 and 15. Approximately 3-fold and 5-fold inter-subject variation in ON-1910.Na clearance was observed on days 1 and 15, respectively. No antitumor activity has been documented by standard criteria. Conclusions: Dose escalation is continuing.

[Table: see text]
Clinical and immunological analysis of melanoma patients receiving immunization using particle-mediated gene transfer of genes for gp100 and GM-CSF into uninvolved skin
Authors: Cassaday R. , Sondel P. , King D. , Warner T. , Bridges A. , Gan J. , Schalch H. , Hank J. , Mahvi D. , Albertini M.
Published: March 2020

13033

Background: To investigate a new method of activating melanoma-specific immune responses, we examined in vivo particle-mediated gene transfer (PMGT) of cDNAs for gp100 and GM-CSF into uninvolved skin of melanoma patients (pts). We now report the analysis of a completed Phase I clinical study. Methods: Two treatment groups of 6 pts each were evaluated. Group I received PMGT with cDNA for gp100 during each 3 week cycle; Group II received PMGT with cDNA for GM-CSF followed 3 days later by PMGT for gp100 at the same site. PMGT used 0.25 ug DNA and 250 ug gold/treatment. Endpoints included vaccine toxicity, transgene expression, immunological activation, and antitumor effects. Results: No systemic toxicity could be attributed to the vaccines, while local toxicity in both groups included mild erythema and induration which resolved within 2 weeks. Monitoring for autoimmunity showed no induction of pathologic autoantibodies. Biopsies of vaccine sites obtained 2 days after the gp100 PMGT showed 16% of gold beads to be in the dermis in Group I vs 3% in Group II, suggesting the prior GM-CSF PMGT inhibited bead penetration (p < 0.001 by chi-square; each bead penetration was analyzed as an independent event). Biopsies in Group I obtained 2 days after vaccination showed 16% of beads in the dermis vs 22% after 4 days (p < 0.001 by chi-square; each bead penetration was analyzed as an independent event). Transgene expression in vaccinated skin sites was detected by ELISA (GM-CSF) and IHC (gp100). One of 4 HLA-A2+ subjects showed a 5 × 5-mm DTH response to gp100 peptide 210M after Cycle 1. Preliminary in vitro studies suggest minimal immunological activation. Of 4 pts who enrolled with no evidence of disease, 2 remain disease-free after 61–73 months of follow-up. Conclusions: PMGT with cDNA for gp100 and GM-CSF yields transgene expression in normal human skin with minimal local or systemic toxicity. Pathologic autoimmunity was not demonstrated. Bead concentration in the dermis increases over time, suggesting persistence of beads in this skin level. Conclusions related to melanoma-specific immune induction await T-cell and antibody studies. Supported in part by the UW General Clinical Research Center (M01 RR03186).

No significant financial relationships to disclose.
A phase 1, dose-escalation trial of STA-5312, a microtubule inhibitor with a novel binding site, in advanced or metastatic solid malignancies
Authors: Desai A. , Ratain M. J. , Moshier K. , Tipton M. , Dooley W. , Hocknell K. , Dahl T. , Sherman M. , Limentani S.
Published: March 2020

13040

Background: STA-5312 is a novel microtubule inhibitor with a distinct binding site from other agents such as vincristine, colchicine, or paclitaxel, which has demonstrated antitumor activity against a range of solid tumors in chemotherapy-resistant cancer. Methods: The trial assessed the safety, toxicity, pharmacokinetics (PK) and maximum tolerated dose (MTD) level of STA-5312 when administered as an IV infusion weekly for the first 3 weeks of a 4 week cycle. Assessment of activity is a secondary objective. The starting dose level was 6mg/m2. Dose escalation was based on evaluation of toxicity through the first cycle, with dose doubling in cohorts of 1–2 patients (pts) until a grade (gr) 2 or greater toxicity occurred, followed by at least 3 pts/cohort and 50% dose escalations. After a dose limiting toxicity (DLT), cohorts were expanded to at least 6 pts and subsequent escalations limited to 33%. The dose below the lowest dose at which 1/3 of 6 or more patients show DLT will be declared the MTD. PK sampling was performed during cycle 1. Results: To date, 25 pts have been treated: median age 58 years (35–77), ECOG performance status of 0–2, and median treatment duration 43 days. No serious drug-related toxicity was observed until a DLT (ataxia) was reported in the only patient treated at 64mg/m2, leading to de-escalation to 48 mg/m2, where the only patient experienced aphasia and ataxia. Enrollment is being expanded at a lower dose level of 32 mg/m2. Other adverse events attributable to STA-5312 include (>10%) anemia, fatigue, constipation, nausea, and anorexia. Exposure (AUC) was linear with respect to dose. Five patients have had disease stabilization. Conclusions: STA-5312 appears to be well tolerated when given weekly in doses up to 32mg/m2. The MTD has not been determined and enrollment is ongoing.

[Table: see text]