bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II trial of intracerebral administration of CpG oligonucleotide for patients with recurrent glioblastoma
Authors: Ursu R. , Carpentier A. , Metellus P. , Barrie M. , Meng Y. , Laigle-Donadey F. , Tibi A. , Chinot O. , Carpentier A. F.
Published: August 2020

2043

Background: CpG-ODN are immunostimulating oligodeoxynucleotides containing CpG motifs. When injected locally, they can induce tumor rejection in animal models. In a phase I clinical trial, intra-tumoral infusions of CpG-ODN in glioblastoma patients were well tolerated at doses up to 20 mg. This multicenter phase II trial was designed to study the efficacy and tolerance of a local treatment by CpG-ODN in patients with recurrent glioblastoma. Methods: Patients with recurrent GBM occurring at least three months after radiotherapy and previously treated with one at least regimen of chemotherapy received 20mg CpG- ODN (CpG-28) by convection-enhanced delivery. The percentage of patients without tumour progression at 6 months after inclusion was the primary endpoint. Secondary endpoints were tolerance, survival, and radiological response. Results: Thirty-four patients were enrolled in two centers and thirty-one patients received the treatment. The 6-months progression free survival (PFS) was 19%. One partial response and 3 minor responses were observed. Eight patients (24%) were alive after 1 year, and 5 patients (15%) were alive 2 years after inclusion. The median overall survival was 28 weeks.Treatment was usually well tolerated. Among 6 patients studied, the pharmacokinetic profile of CpG-28 in the blood was heterogeneous. CpG-28 reached up to 79 ng/mL at the end of infusion in one patient. Return to baseline concentration occurred at around 70 hours after the start of infusion. Half-life estimates were variable ranging from 3 to 24 hours. The mean area under the plasma concentration-time curve (AUC) ranged from 0.07 to 0.65 μg x hr/ml. Conclusions: CpG-28 induced a few cases of radiological reponses, but the impact on the 6-months PFS was minimal in this population. However, the presence of long-term survivors suggest that this treatment might have been beneficial in some patients, whose molecular or clinical characteristics remain to be defined.

[Table: see text]
Use of neurovascular imaging in GBM patients (pts) to quantify early physiologic changes after treatment with XL184, an inhibitor of multiple receptor tyrosine kinases: Results from a phase II study
Authors: Sorensen A. G. , Jenning D. , Wang M. , Andronesi O. , Chen P. , Prados M. , Wen P. , Jackson E. , Cha S. , deGroot J.
Published: August 2020

2048

Background: Treatment of recurrent glioblastoma by targeting VEGF has gained recent attention. Bevacizumab (bev) or cediranib block VEGFR signaling which is detectable within one day by MRI; early changes on MRI may correlate with clinical outcome. XL184 is a potent orally bioavailable inhibitor of MET, RET, KIT, and VEGFR2; MET and VEGFR2 have been shown to play important roles in tumor angiogenesis. In preclinical models, simultaneous inhibition of MET and VEGFR2 with XL184 results in profound regression of tumor vasculature which is qualitatively different from that observed with other antiangiogenic agents. Methods: A multicenter phase II study of XL184 in 46 pts with relapsed or progressive GBM with primary endpoints of 6-month progression free survival and safety is fully enrolled. Vascular neuroimaging including DCE-MRI, CBV/CBF, diffusion, and magnetic resonance spectroscopy (MRS) is performed in these GBM pts treated with XL184. Lesion volumes are also calculated. Assessments are at baseline, 24 hours post first dose, at 4 weeks and 8 weeks. Results: As of January 1, 2009, 38 pts have undergone imaging. In all 9 pts with imaging available at Day 28, decreases in tumor size were seen on post-Gd T1 (mean drop 51%, SD 31%, p = 0.03 by t-test) and FLAIR (mean drop 53%, SD 20%, p = 0.001) consistent with an anti-vascular/anti-edema effect. In 11 of 14 pts T1 volume decrease was visible on Day 1 (mean drop 20%, SD 12%, p = 0.01), consistent with the rapid changes seen with VEGF inhibition. Two of 3 pts with no Day 1 decrease in enhancing lesion volume were bev-pretreated. Pts treated with other VEGF inhibitors (vandetanib, VEGF-TRAP) responded similarly to naïve pts at Day 1 and 28. Assessment of Ktrans in 5 pts showed a 79% decrease (SD 13%, p = 0.04). MRS from 3 pts showed an increase of the NAA/Choline ratio (10–100%) between the baseline and Day 28 scans, and a decrease in lipid levels (50–100%), suggesting inhibition of tumor progression. Conclusions: Treatment with XL184 results in significant decreases in lesion volume and Ktrans at Day 1 and even greater decreases at Day 28, suggestive of biological activity in GBM.

[Table: see text]
Correlative tumor molecular profiling and plasma biomarker analysis in a phase II study of XL184 in patients with progressive or recurrent glioblastoma multiforme (GBM)
Authors: DePrimo S. , Wu B. , Huang S. , Bautista R. , Cancilla B. , Vysotskaia V. , De Groot J. , Prados M. , Buller R. , Wen P.
Published: August 2020

2049

Background: XL184 is an oral inhibitor of MET, RET, KIT, and VEGFR-2 with potent antitumor effects in preclinical models of GBM. Clinically, elevated levels of MET, KIT, VEGFR-2, and VEGF-A are found in GBM, where MET and KIT levels correlate with poor prognosis. XL184–201 is a fully enrolled GBM study (N = 46) which mandated collection of archival tumors and serial plasma samples. The encouraging clinical activity of XL184 in this study is the subject of a separate abstract. Methods: Tumor profiling focused on genomic alterations prevalent in GBM, reflecting dysregulation of key signaling pathways (Nature 2008; 455:1061), or XL184 targets. Plasma samples were analyzed with ELISA assays. Correlation of results with clinical outcomes is a secondary objective of study XL184–201. Results: Tumor genotyping assessments included EGFR and KIT copy number; PTEN, PIK3CA, PIK3R1, and NF1 sequencing, as well as MGMT and PTEN promoter methylation. Results from the first 12 cases indicate sequence variations & frequencies similar to reports in the literature. IHC analysis of MET, RET, and VEGFR-2 protein expression was also performed. In ∼ 80% of samples, tumor cells stained positive for MET with a lower fraction positive for RET and VEGFR-2 in tumor cells (42% and 58%, respectively). RET and VEGFR-2 expression was often seen in tumor-associated blood vessels, while MET signal in blood vessels was more limited (33%). Preliminary biomarker analysis established significant modulation of plasma levels of VEGF-A, sMET, sVEGFR-2, sKIT, and PlGF, consistent with multiple on target effects. Objective response was observed in the presence or absence of tumor EGFR amplification, PTEN mutation, and MGMT promoter methylation. The potential predictive value of these and other biomarkers is under investigation. Conclusions: Plasma biomarkers confirm pharmacodynamic activity of XL184 in advanced GBM where marked clinical activity has been observed. Upon completed analysis of a full set of biological samples and with mature clinical data, predictive markers for clinical activity of XL184 will be evaluated.

[Table: see text]
Bevacizumab and irinotecan for recurrent oligodendroglial tumors
Authors: Taillibert S. , Vincent L. A. , Granger B. , Marie Y. , Carpentier C. , Guillevin R. , Bellanger A. , Psimaras D. , Sanson M. , Delattre J.
Published: August 2020

2054

Background: Treatment with a regimen of bevacizumab/irinotecan has been shown to be effective in recurrent grade 3 and 4 gliomas, but the effect of this regimen against recurrent oligodendroglial tumors has not been specifically studied. Methods: The bevacizumab/irinotecan regimen was retrospectively evaluated in a consecutive series of 25 patients with recurrent oligodendroglial tumors. All patients had failed previous treatment with radiation therapy and at least one line of temozolomide chemotherapy. Bevacizumab (10 mg/kg) and irinotecan (125 or 340 mg/m2 according to the antiepileptic regimen) were delivered every 14 days. Response was measured clinically and on monthly MRI. Results: The objective response rate was 72% (20% complete response, 52% partial response). After a median follow-up (from the first cycle) of 310 days (95% CI, 47–499), the median progression-free survival was 174 days (95% CI, 116–342), and the median overall survival was 328 days (95%CI, 217-not reached). The 6-month progression-free survival was 42 % (95 % CI, 26% to 67%). Among the 20 patients who progressed at the time of the analysis, the radiological pattern of progression was atypical in seven patients with an isolated multifocal or diffuse spread of the FLAIR signal, or an isolated meningeal spread or FLAIR abnormalities preceding contrast-enhancement recurrence. Among the 10 patients who are still alive, two are still on follow-up since 6 months with a complete response after, respectively, 10 and 12 months of treatment. Among the 17 patients in whom the status of the main molecular alterations of gliomas could be evaluated (search for deletions of chromosomes 1p, 19q, 9p, 10q, and amplification of EGFR, MDM2, CDK4), no relation could be found between the response rate and the type of genetic change (including 1p-19q co-deletion). The profile of tolerance was fair, with treatment discontinuation in 20% of patients. Intratumoral hemorrhages occurred in six patients (24%), but the treatment had to be discontinued because of symptomatic bleeding in only one patient (4%). Conclusions: This regimen is effective in recurrent oligodendrogliomas, and the overall tolerance is acceptable.

[Table: see text]
Phase II trial of temozolomide (TMZ) followed by myeloablative chemotherapy with autologous peripheral blood progenitor cell rescue (APBPCR) for newly diagnosed anaplastic oligodendroglioma: An Oligodendroglioma Study Group trial
Authors: Kaley T. J. , Raizer J. J. , Paleologos N. , Kewalramani T. , Grimm S. , Louis D. N. , Cairncross J. G. , Abrey L. E.
Published: August 2020

2055

Background: Treatment of anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytomas (AOA) is controversial. Radiotherapy (RT) remains the standard therapy, but not without toxicity. Exploiting the chemosensitivity of these tumors using myeloablative chemotherapy with APBPCR is a potential strategy to defer RT. We previously reported results using induction PCV chemotherapy; subsequently the induction regimen was changed to temozolomide (TMZ) which is reported here. Methods: Patients were treated with six cycles of TMZ at 200mg/m2 on standard 5/28 day schedule. MRI was performed after three cycles and then after six cycles. Patients with surgical gross total resection who maintained response or patients who responded to temozolomide (CR or PR defined as >50% reduction in tumor) were eligible for myeloablative chemotherapy with thiotepa 250mg/m2/day for three days followed by busulfan 3.2mg/kg/day for three days, followed by APBPCR. 1p19q status was analyzed prospectively; however, patients were enrolled without regard to deletion status. Results: 19 patients (16 AO, 2 AOA, 1 low-grade oligodendroglioma with radiographic features suggestive of high-grade tumor) with a median age of 42 (28–56) and KPS of 90 (70–100) were enrolled. 13 patients had co-deletion of 1p/19q, 2 had intact 1p/19q, 1 pt had biopsy without enough tissue, and pending in 3. Eleven patients were eligible for APBPCR: 10 patients either maintained surgical CR (9) or had a response to TMZ (1) and went on to transplant; one surgical CR pt refused transplant. Six patients were ineligible for transplant because best response of SD (2), PD (2, both 1p19q intact), insurance denial (2). Two patients are still receiving induction TMZ. Median progression-free (PFS) and overall survivals (OS) have not been reached at a median follow-up of 20 months. 2 of the 10 patients who underwent APBPCR recurred, one at 16.1 and one at 34.2 months. No veno-occlusive disease was observed during transplant and no treatment-related deaths occurred. Conclusions: TMZ followed by myeloablative chemotherapy with APBPCR can be safely administered to newly diagnosed AO patients.

[Table: see text]
Temozolomide for recurrent intracranial supratentorial platinum-refractory ependymoma
Authors: Johnston S. K. , Chamberlain M. C.
Published: August 2020

2061

Background: There is no standard therapy for platinum-resistant ependymoma and hence a need exists for new therapies. Objective: A retrospective evaluation of temozolomide (TMZ) in adults with recurrent supratentorial platinum-refractory WHO grade 2 ependymoma with an objective of determining 6-month progression free survival (PFS). Methods: 25 patients, ages 28–63 years, with recurrent ependymoma were treated. All patients had previously been treated with surgery, radiotherapy, and platinum-based chemotherapy (cisplatin: 15; carboplatin 10). Nine patients underwent repeat surgery. Patients were treated at second recurrence with TMZ (5 consecutive days), once every 4 weeks, defined as a single cycle. Neurological evaluation was performed every 4 weeks and neuroradiographic assessment every 8 weeks. Results: A total of 68 cycles of TMZ (median 2 cycles; range 1–6) was administered. TMZ-related toxicity included leukopenia (7 patients; 1 grade 3), constipation (6 patients; 0 grade 3), fatigue (5 patients; 0 grade 3), anemia (2; 0 grade 3), thrombocytopenia (2; 0 grade 3), and deep vein thrombosis (2; 0 grade 3). One patient (4%) demonstrated a partial radiographic response, nine (36%) stable disease, and 15 (60%) progressive disease following two cycles of temozolomide. Time to tumor progression ranged from 1–7 months (median: 2 months). Survival ranged from 2–8 months (median: 3 months). 6-month and 12-month PFS were 2% and 0% respectively. Conclusions: Temozolomide in this dose schedule demonstrated little efficacy in a cohort of adults with recurrent intracranial platinum-refractory ependymoma.

No significant financial relationships to disclose.
Efficacy and tolerability of intrathecal liposomal cytarabine for central nervous system embryonal tumors
Authors: Partap S. , Murphy P. A. , Vogel H. , Barnes P. D. , Edwards M. S. , Fisher P. G.
Published: August 2020

2064

Background: Liposomal cytarabine (DepoCyt) is a sustained-release intrathecal (IT) preparation of cytarabine, formulated by encapsulating the drug in spherical aqueous chambers within a lipid matrix. While proven effective in lymphomatous meningitis, this drug has shown some activity in medulloblastoma (MB) with spinal metastases in limited pediatric phase I study. Methods: We reviewed all patients at our institution treated with liposomal cytarabine for primary central nervous system (CNS) embryonal tumors-MB, primitive neuroectodermal tumor (PNET), and atypical teratoid rhabdoid tumor (ATRT). Results: A cohort of 17 patients were treated with liposomal cytarabine at diagnosis of CNS embryonal tumor (2 PNET, 3 ATRT) or relapse (12 MB [7 average-risk, 5 high-risk]); nine had leptomeningeal metastases. Drug was dosed at 2 mg/kg up to 50, every 2 weeks to monthly, along with dexamethasone. Concurrent systemic chemotherapy was given in 16 patients. Median age at first dose was 10.8 years (range 0.9 to 27.9 years). A total of 102 doses were administered (lumbar IT 76, Ommaya intraventricular 36) with a mean of six treatments (range 1–16). Only three administrations were associated with adverse effects of arachnoiditis or headache; no dose reductions were required. Median overall survival from relapse was 11.8 months. All six evaluable patients with malignant cerebrospinal fluid (CSF) cytology and treated with at least two doses cleared their spinal fluid (mean 3 doses, range 1–5). No patient developed malignant CSF cytology while receiving liposomal cytarabine. Ten patients developed progressive disease and died, with only one later recurrence in the spinal fluid. Seven patients remain alive (4 initial and 3 relapse) with five in continuous complete remission (2 ATRT) for a median 13.7 months from first liposomal cytarabine. Conclusions: Liposomal cytarabine was well tolerated and easily administered. All patients with neoplastic meningitis cleared malignant cells from their spinal fluid after treatment with IT liposomal cytarabine and systemic chemotherapy. One-third of our cohort remains in remission from otherwise fatal diagnoses. Our findings warrant a phase II trial of liposomal cytarabine in newly diagnosed or recurrent CNS embryonal tumors.

[Table: see text]
Characteristics and outcomes of elderly patients with primary CNS lymphoma (PCNSL)
Authors: Ney D. E. , Reiner A. S. , Skinner H. D. , Panageas K. S. , DeAngelis L. M. , Abrey L. E.
Published: August 2020

2070

Background: The incidence of PCNSL is increasing and is highest in those ≥ 65 years of age. Systemic chemotherapy (CT) ± radiotherapy (RT) improves survival, but treatment related toxicity is greatest in this population. The optimal treatment has yet to be determined. The aim of this study was to characterize older patients with PCNSL at our institution and identify outcomes related to treatment. Methods: We identified patients ≥ 65 years of age treated for PCNSL from 1986 to 2008. Charts were reviewed for demographics, treatment details, tumor progression, and survival. Approval for this study was obtained from the IRB at MSKCC. Results: 174 patients were identified with a median age of 72 years (range: 65–89). 60% of patients had a stereotactic biopsy for diagnosis; 93% had a histologic or cytologic diagnosis. 14 patients had evidence of systemic involvement with detailed staging evaluation. 82% of patients received a high-dose methotrexate (3.5g/m2) regimen, only 13% did not receive CT. Among the patients who received CT, 76% had a radiographic response (CR+PR), 3% had stable disease while 12% progressed. Only 26% had RT as part of initial therapy. CR rate to initial therapy was 67%, 52% of these patients eventually relapsed. Median time to progression was 24 months (range: 1–91). Among the patients who relapsed, 85% received salvage therapy consisting of CT (n = 42), RT (n = 14), or both (n = 7) while 15% received no further treatment. 48% of patients had a CR or PR to salvage therapy while 26% had PD; the remainder were not evaluated. Median overall survival for the entire cohort was 25 months (range: 0.5 to 177+) with a 3-year survival of 36%. 17% developed late treatment-related neurologic toxicity. Administration of RT was associated with the development of neurotoxicity (p < 0.0001). 39 patients remain alive with a median follow-up of 34 months (range: 0.5–177). Conclusions: Elderly patients can receive an aggressive chemotherapeutic regimen with good outcomes. Systemic staging is also valuable as a small subset of patients will have systemic involvement at diagnosis. Clinical trials to optimize treatments for this population are critical.

No significant financial relationships to disclose.
CXCL13 and CXCL12 in central nervous system (CNS) lymphoma patients
Authors: Fischer L. , Korfel A. , Pfeiffer S. , Kiewe P. , Volk H. , Cakiroglu H. , Widmann T. , Thiel E.
Published: August 2020

2071

Background: Homing of malignant lymphocytes to the CNS may play a role in the pathogenesis of CNS lymphoma. Recently, the expression of the chemokine receptors CXCR4 and CXCR5 as well as their chemokine ligands CXCL12 and CXCL13 by tumor cells in primary CNS lymphoma (PCNSL) has been demonstrated. In this study, we evaluated CXCL12 and CXCL13 in cerebrospinal fluid (CSF) and serum of patients with CNS lymphoma. Methods: Samples from 30 patients with CNS lymphoma (23 with PCNSL and seven with secondary CNS lymphoma) and 40 controls (10 patients with other CNS malignancies and 30 without a malignant CNS disease) were examined. CXCL12 and CXCL13 concentrations were measured using enzyme-linked immunosorbent assays. The grade of blood brain barrier (BBB) disruption was estimated by the CSF/serum albumin ratio. Results: CNS lymphoma patients and controls did not differ in CXCL12 serum and CSF levels. Serum levels of CXCL13 were generally low. CXCL13 CSF levels, however, were high only in CNS lymphoma patients but not in controls (p < 0.0001). Chemokine levels in CSF and serum did not correlate. In CNS lymphoma CXCL13 concentration in CSF correlated with BBB disruption (R = 0.66, p = 0.003). Elevated CSF levels of CXCL12 and CXCL13 measured in seven CNS lymphoma patients decreased in five patients which responded to chemotherapy, and increased in two with lymphoma progression. Conclusions: Our results suggest a production of CXCL13 within the CNS of CNS lymphoma patients which decreases with response to therapy. Thus, CXCL13 may represent a marker for further diagnostic and prognostic studies.

No significant financial relationships to disclose.
Whole-body MRI evaluation of tumor burden in the neurofibromatosis tumor suppressor syndromes
Authors: Plotkin S. R. , Singh M. , Cai W. , O'Donnell C. , Esparza S. , Smith M. J. , Harris G. J. , Muzikansky A. , Bredella M. A. , Kassarjian A.
Published: August 2020

2074

Background: Neurofibromatosis 1 (NF1), NF2, and schwannomatosis are a group of related genetic disorders in which affected individuals share the predisposition to develop multiple neurofibromas and schwannomas. The prevalence of internal tumors is not known because current estimates are based on regional MRI scans that may not detect occult tumors. A rapid and sensitive method to detect internal tumors is highly desirable since they can cause neurologic dysfunction, compress vital structures, or transform into malignant tumors. Whole-body MRI (WBMRI) is an imaging technique by which the entire body can be imaged in a relatively short time without the use of ionizing radiation. Methods: We performed WBMRI in subjects with NF1, NF2, or schwannomatosis as part of an IRB-approved research study. Each subject was imaged from head to ankles in the supine position using a 1.5 Tesla magnet, integrated body coil, and no intravenous contrast. Using five acquisitions, the entire body was imaged using a fat suppressed fluid sensitive STIR sequence. The images were then fused into a single whole body DICOM image. The number and type of tumors (discrete vs. plexiform) were identified by a board-certified radiologist and tumor volume was calculated using semi-automated analysis. Results: A total of 100 subjects were imaged (NF1–50; NF2–25, schwannomatosis-25). Sixty-one percent of subjects had ≥1 internal tumor. The median number of tumors in affected individuals was 5 (range, 1 to 63 tumors). Overall, the legs harbored the greatest number of tumors (33%), followed by the pelvis (18%), thorax (15%), abdomen (12%), arms (10%), and head/neck (7%). Only 40% of internal tumors were classified as plexiform yet these tumors contributed 78% of the tumor burden by volume. Conclusions: WBMRI scan is a powerful tool to evaluate the number, size, and distribution of internal tumors in patients with neurofibromatosis. This technique provides unique phenotypic information for genetic studies on NF1, NF2, and schwannomatosis. In addition, WBMRI may prove useful in identifying individual patients at high risk for complications (such as neurologic dysfunction or malignant transformation) due to heavy internal tumor burden and in determining the efficacy of antitumor drugs in this unique patient population.

No significant financial relationships to disclose.
Uridine glucuronosyltransferase 2B7 pharmacogenetics predicts epirubicin clearance and myelosuppression
Authors: Sawyer M. B. , Damaraju S. , Pituskin E. , Damaraju V. , Scarfe A. G. , Bies R. B. , Hanson J. , Clemons M. , Kuzma M. , Mackey J. R.
Published: August 2020

2504

Background: Epirubicin (EPI) is widely used to treat breast cancer. EPI is predominantly metabolized by uridine glucuronosyltransferase (UGT) 2B7 to inactive glucuronides. We previously showed that a UGT enhancer single nucleotide polymorphism (SNP) at position -161 T to C correlated with rates of morphine glucuronidation. Methods: We performed a prospective pharmacogenetic study of effects of this SNP on EPI metabolism in M0 breast cancer patients (PTS) receiving adjuvant or neoadjuvant FEC100 (5-fluorouracil 500 mg/m2, EPI 100 mg/m2 and cyclophosphamide 500 mg/m2) given every 3 wks. PTS with ALT and AST ≤ upper limit of normal (ULN), a total bilirubin ≤ ULN, and normal renal and cardiac function were eligible. EPI levels were drawn at approximately 1 and 24 hrs. Cycle 1 toxicities were assessed using NCIC CTG toxicity criteria. Results: 123 PTS entered this study, mean (range): age 51 (28 - 74), sex 122 F/ 1 M, baseline AST 24 U/L (13–66), ALT 22 U/L (5–90), bilirubin 8 μmol/L (2–26), creatinine 74 μmol/L (50 - 126). PTS were genotyped using Pyrosequencing; 26 PTS were TT homozygotes, 59 were CT heterozygotes, and 33 were CC homozygotes. 5 PTS could not be genotyped. A three compartment population pharmacokinetic model in NONMEM V 1.1 for EPI was used incorporating all PTS. The baseline objective function was 1817, and inclusion of genotype significantly improved the objective function to 1764; CC genotype PTS had decreased EPI clearance 88.9 L/hr compared to CT/TT genotype PTS 129 L/hr, p<0.001. Rates of first cycle grade 3/4 leucopenia were 78% in CC PTS and 48% in CT/TT PTS; consistent with the pharmacokinetic analysis. Conclusions: A SNP in UGT 2B7 is common and appears to predicts EPI clearance and myelosuppresion in non-metastatic breast cancer PTS and may form the basis for a method to individualize EPI treatment.

No significant financial relationships to disclose.
Value of stable disease (SD) in drug development of targeted therapies (TGT)
Authors: Vidaurre T. , Wilkerson J. , Bates S. E. , Simon R. , Fojo A. T.
Published: August 2020

2509

It has been widely asserted that the efficacy of TGT cannot be assessed by traditional response measures since they are not expected to cause tumor shrinkage. Despite the lack of substantiating data, this idea has become conventional wisdom, often guiding clinical trial design. Aware the acceptance of SD as a measure of activity led to its being increasingly reported with traditional cytotoxic agents (CTX), we set about to methodically compare the occurrence of SD in phase II trials of TGT and CTX. We systematically catalogued response assessments in 147 phase II studies reported between 10/06 and 3/08 in 5 journals (Cancer, BJC, CCR, JCO, and Lancet Oncology). Eighty used CTX, 59 used TGT and 8 used both “classes” of agents. Thirty-eight properties including CR, PR, SD, PFS, and OS were recorded for each study. CTX and TGT studies were comparable with similar distribution of histologies and similar PFS and OS in these patients with refractory tumors. For CTX vs. TGT, the median numbers of pts/study was 47.1 vs. 51.9; median PFS, 5.55 vs. 4.54 mos; and median OS, 12.55 vs. 12.88 mos. SD was defined by duration in only 31% of studies, a median duration of 9.5 weeks. SD rates were nearly identical for the two therapy groups - 34.6% for CTX and 33.1% for TGT- and their distribution by histology was similar, suggesting properties other than therapy are responsible for SD. Correlations or lack thereof between %SD and PFS or OS were similar for both CTX and TGT. The overall response rate (CR + PR) was higher with CTX than with TGT (29.4% vs. 13.3%) and demonstrated a strong correlation (p<0.0001) of uncertain importance with PFS and OS for all therapies. Examination of 33 NSCLC studies (16 CTX/17 TGT) found similar results. We conclude that SD as currently defined and measured in not a property of TGT but of the phase II patient population and is similarly found with CTX. Responses are observed with TGT as with CTX, and this analysis suggests that even for TGT it is a measure of activity that should be sought. Assertions that SD is a particular characteristic of TGT should be replaced by definitions that seek clinically meaningful SD.

No significant financial relationships to disclose.
Dose-response relationships in phase I trials: Are patients treated at lower doses at a disadvantage?
Authors: Jain R. , Hong D. , Naing A. , Wheler J. , Lee J. J. , Kurzrock R.
Published: August 2020

2519

Background: A major goal of phase I trials is to determine a drug's maximally tolerated dose (MTD). However, it has been argued that low-dose patient cohorts are at a disadvantage given the clear dose/response relationships seen with cytotoxics. Since an increasing number of targeted/biologic agents are entering the clinic, and the dose/response relationship of these drugs is less clear, we analyzed response versus benefit for patients on phase I trials. Methods: We evaluated 71 consecutive trials treating 1,420 patients with solid tumors or lymphoma from August 2004 to August 2008 in the Department of Investigational Cancer Therapeutics at M.D. Anderson for inclusion in our analysis. Twenty-four trials treating 687 patients met criteria (systemic therapy that has reached an MTD or a maximum test dose). 97.7% of these patients received a targeted/biologic drug. Patients were assigned to low (≤25%), medium (25–75%), or high dose (≥75%), where dose range = maxium - minimum dose for each study (for ≤ MTD analysis, max dose = MTD if it was achieved). Time on treatment (TOT), progression free survival (PFS), overall survival (OS), and response (complete response = CR, partial response = PR, stable disease = SD, progressive disease = PD) were assessed. Results: Of all comers (n = 683), the low-dose group stayed on treatment significantly longer than the high-dose group, primarily due to increased toxicity at higher doses. In ≤ MTD subgroup analysis (n = 588), there was also a trend for the low-dose group to stay on treatment longer (p = 0.06). PFS and OS were similar among groups. Favorable responses (CR/PR/SD) were as common for low dose as other dose groups. Conclusions: In a large cohort of pts treated on phase I studies that predominantly included one or more targeted/biologic agent, there was no downside to being on low versus medium or high doses. These data should alleviate concerns about relative lack of benefit for low-dose patient cohorts on phase I trials, and support the notion that dose/response relationships for targeted agents may be less clear than for cytotoxics.

[Table: see text]

No significant financial relationships to disclose.
Population pharmacokinetic modeling for intravenous temsirolimus and sirolimus metabolite in subjects with various solid tumors
Authors: Sonnichsen D. , Liao S. , Berkenblit A. , Boni J.
Published: August 2020

2522

Background: Temsirolimus (TEMSR) is an mTOR inhibitor approved for treatment of patients with advanced renal cell carcinoma, and under development for relapsed/refractory mantle cell lymphoma (MCL). In MCL, TEMSR showed a dose-related increase in median progression-free survival [4.8 vs. 3.4 mo] and objective response rate [22% vs 6%] for 175 mg x 3 wks then 75 or 25 mg weekly regimens (175/75-mg and 175/25-mg), respectively. We aim to characterize the population pharmacokinetic exposure, covariate influence, and differences afforded by these regimens. Methods: Nonlinear mixed-effects models of TEMSR and sirolimus (SIR; major active metabolite) blood concentrations were defined in healthy subjects and patients. Modeling for TEMSR employed a 4-compartment model with saturable distribution to red cells and peripheral tissue, and modeling for SIR utilized a linear 2- compartment model with factor for dose. Covariates included demographic factors, clinical labs, and disease condition. Following validation, simulations with variability were used to evaluate effects of covariates on exposure. Results: Final datasets comprised 1342 observations from 150 subjects (TEMSR) and 1648 observations from 279 subjects (SIR). In a typical patient (56-year-old male weighing 76.5 kg), disease affected TEMSR clearance (62.4 L/h in MCL, 92.1 L/h in breast cancer vs. 112 L/h for other subjects). Dose, single vs. multiple, and body weight affected SIR apparent clearance. Simulations for the 175/75-mg regimen indicate that significant covariates yield only modest differences on blood exposures. For MCL (175/75-mg regimen), TEMSR Cmax (week 3) was 2574 ng/mL and SIR Ctrough (week 6) was 10.7 ng/mL. AUC for the 75-mg maintenance arm was ∼2.3-fold (TEMSR) and ∼3.5-fold higher (SIR) than respective values of the 25-mg arm. Correlation of average AUC to clinical response was not apparent. Conclusions: No significant differential effects were observed for age, gender, race, or hepatic and renal laboratory measures. Covariates of disease, while significant, have only modest effects on the exposure profile. Higher clinical responses observed with the 175/75-mg regimen as compared with the 175/25-mg regimen may critically derive from differences in exposure.

[Table: see text]
The utility of a specific hepatic CYP-3A4 probe (C14-Erythromycin breath test [EBT]) versus the general CYP-P450 probe (antipyrine clearance [ACL] test), for the prediction of docetaxel (D) pharmacokinetics (PK)
Authors: Michael M. , Booth R. J. , Milner A. , Hatzamihallis A. , Francis P. , Clarke S. J. , Schlict S. , Cullinane C.
Published: August 2020

2523

Background: BSA-based cytotoxic dosing does not account for the individual variability in drug disposition. In the case of D, CYP 3A4 probes such as the EBT have been assessed to individualise dosing, but inconsistently. This report is the first study comparing the EBT directly with the widely available general P450 probe, the ACL test, for the prediction of D PK when given either q 21 days or weekly. Methods: Patients (pts) with pre-treated advanced malignancy suitable for D therapy, Se bilirubin≤1.0xUNL, AST≤1.5xUNL & ALP≤2.5xUNL, were entered. Prior to D therapy, pts underwent EBT and ACL test. Pts were given IV 14C N-methyl-erythromycin and exhaled breath samples were captured for 14CO2 from 5–120 mins post. The EBT parameters determined: 14CO2 flux at 10 min (CO2f10), & 20 min (CO2f20), (iii) terminal rate constant kCO2 (iv) AUCCO2,(0-∞) & AUCCO2,(0–60). For the ACL test, pts was given oral antipyrine 10mg/kg, blood samples were collected from 0, 4 & 24 hrs post, and serum levels measured: ACL was calculated as per Farrell et al.(Br J Clin Pharmacol 18:559). D was given 75mg/m2 q21 days or 35mg/m2 weekly. Samples taken for D PK in course 1 day 1, parameters included: half life (tD1/2), & clearance (CLD). Correlations were sought between EBT parameters, ACL values and D PK parameters. Results: 20 pts accrued, M:F= 12:8, Median age= 65. Mean BSA = 1.77m2 (1.44–2.07). D q21 days:D weekly= 13:7. EBT parameters (N= 19) (Mean, [CV%]): CO2f10 (%/min) 0.051 (106), CO2f20 0.052 (82), kCO2 (min- 1) 0.007 (22), AUCCO2,(0-∞) 7.9 (85), AUCCO2,(0–60) 2.64 (81). ACL (N=19) (ml/min); 35.8 (37). No significant differences observed for EBT parameters and ACL between the q21 days vs weekly dosing. D PK parameters (N=19): CLD (l/hr) 57.2 (36), tD1/2 (hrs) 12.7 (33). No correlations were observed between the D PK and EMBT parameters for all pts and regardless of the regimen given. For D weekly pts, a significant linear relationship was observed between CLD and ACL (P =0.007, R2= 79.47%). Conclusions: The utility of EBT for the prediction of D PK was not confirmed in this study. The Antipyrine Clearance test may be superior in this regard for D, but regimen dependent and hence warrants further evaluation.

No significant financial relationships to disclose.
Pharmacokinetics (PK) of the highly lipophilic and blood stable camptothecin AR-67 (7-t-butyldimethylsilyl-10- hydroxycamptothecin) in adult patients with solid malignancies
Authors: Leggas M. , Horn J. , Tsakalozou E. , Moscow J. A. , Fields S. Z. , Houchins J. C. , Eckardt J. R. , DeSimone P. , Kee B. K. , Rinehart J. J. , Arnold S. M.
Published: August 2020

2546

Background: Camptothecin analogs possess a labile lactone ring, which readily undergoes a pH dependent, albeit reversible, hydrolysis in plasma to yield a carboxylate moiety. The latter is considered inactive due to its electronegative charge that impedes transport into cells. Furthermore, the carboxylate is cleared rapidly and causes toxicity in eliminating organs due to lactonation. AR-67 is a highly lipophilic 3rd generation analog with superior stability of its lactone form in preclinical models. This report describes the PK of AR-67 in patients with refractory solid tumors enrolled in a phase I study. Methods: AR-67 was infused over 1 hr for 5 days every 21-days. PK was performed on the 1st and 4th day of cycle 1. Blood, plasma, and urine were collected (0–24 hrs) from 26 patients (see 09-AB-30336-ASCOAM) treated at 9 dose levels: 1.2–12.4 (mg/m2/day). AR-67 carboxylate and lactone were assayed with a validated chromatography method. Results: AR-67 was detectable at all dose levels. Blood concentrations mirrored those in plasma and were superimposable when adjusted by the hematocrit. AR-67 concentration peaked at the end of the 1-hr infusion and declined biexponentially with a terminal t1/2 of 1.4 hr (plasma lactone). A linear relationship was observed between dose and AUC. The lactone clearance on Day 1 was 16.6 (±5.5) vs. 19.6 (±6.3) L/hr/m2 on Day 5. The carboxylate clearance was ∼ 6-fold higher. Lactone was the major form in all samples and its area under the time vs. concentration curve (AUC) was 85.5% (range 74.0%-94.1%) of the total AUC. Urine (0–24 hr) contained 2.5% (0.3%-6.7%) of the dose on Day 1 vs. 2.7% (0.9–11.1%) on Day 4. Extensive metabolite peaks were not observed in plasma, blood, or urine samples. Plasma protein binding of the carboxylate was 90% (range 80%-96%) vs. 95% (range 90%-98%) for the lactone. Conclusions: AR-67 is a lipophilic camptothecin with a unique PK profile. Unlike other clinically approved analogs with lower lactone stability (35%-65%), over 85% of the AR-67 AUC is in the active lactone form. This high lactone-low carboxylate exposure coupled with the apparently limited metabolism of AR-67 may result in increased activity and decreased toxicity.

[Table: see text]
Elucidation of the metabolic and elimination pathways of panobinostat (LBH589) using [14C]-panobinostat
Authors: Clive S. , Woo M. M. , Stewart M. , Nydam T. , Hirawat S. , Kagan M.
Published: August 2020

2549

Background: Panobinostat (PAN), a hydroxamic acid derivative, is a potent pan-deacetylase inhibitor, demonstrating anti-tumor activities in a wide variety of preclinical models and showing promising clinical activity. This study elucidates the metabolic and elimination pathways of PAN using [14C]-PAN. Methods: Four patients with advanced cancer received a single oral 20 mg dose of [14C]-PAN (50 μCi). Whole blood, plasma, urine, and feces were collected over 7 days. Total radioactivity was measured in blood, plasma, and excreta by liquid scintillation counting. PAN and its metabolite concentrations in plasma and excreta were measured by LC-MS/MS and HPLC with radiometric detection. Patients were monitored for safety. Results: The single PAN dose was well tolerated with no clinically significant laboratory or ECG abnormalities observed. PAN had a rapid oral absorption [median Tmax 0.8 h (range, 0.5–1 h)] and moderate elimination (median t1/2 31 h). The median t1/2 for blood and plasma radioactivity was 54 and 75 hours, respectively. Mass balance was achieved with ≥87% of the administered radioactivity being recovered in the excreta of all patients after 7 days. 44–77% and 29–51% of the dose was recovered in the feces and urine, respectively. Unchanged PAN accounted for ≤3% of the administered dose in the feces, suggesting good oral absorption. The most prominent metabolic pathways involved modifications of the hydroxamic acid (HA) side chain, to form an amide via reduction, carboxylic acid via either hydrolysis or one- and two-carbon (M1) shortening of the HA side chain. Oxygenation and glucuronidation were also observed. PAN accounted for ≤9% of the total radioactivity AUC. The most abundant circulating metabolites in plasma were the glucuronide of M1 (19%) and carbamoyl glucuronide of PAN (13%). At least 40 metabolites, many at trace levels, were observed circulating in plasma. Conclusions: PAN and its metabolites are equally excreted in the urine and feces. Elimination of PAN is primarily by metabolism via reduction, hydrolysis, oxidation and glucuronidation. The balanced elimination and absence of a single major route of PAN metabolism suggest that clinical drug-drug interactions are unlikely with PAN.

[Table: see text]
A UGT1A1 genotype-directed phase I study of irinotecan (CPT-11) combined with fixed dose of capecitabine in patients with metastatic colorectal cancer (mCRC)
Authors: Kim T. , Sym S. , Lee S. , Ryu M. , Lee J. , Chang H. , Kim H. , Shin J. , Kang Y. , Lee J.
Published: August 2020

2554

Background: The risk of severe toxicity of CPT-11 can be in part explained by polymorphism of UGT1A1. The most common polymorphism in Whites is UGT1A1*28. UGT1A1*6 is another common polymorphism in Asians. We designed a phase I study to investigate UGT1A1 genotype-directed maximum tolerated dose (MTD) of CPT-11 plus fixed dose of capecitabine in patients (pts) with Korean mCRC. Methods: Pts with mCRC screened UGT1A1 genotyping (*28 and *6) and were stratified into one of 3 groups according to the number of defective allele (DA): 0 (none of *28 or *6 allele), 1(only one of *28 or *6 allele), and 2 (*28/*28, *6/*6, or double heterozygous for *28 and *6). The dose of CPT-11 was escalated as following: Level -I:200, I:240, II:280, III:320, IV: 350, V: 380 mg/m2 (IV, once every 3 weeks). Capecitabine (1,000 mg/m2 PO BID) was administered on days 2–15 every 3 weeks. Dose limiting toxicity (DLT) and pharmacokinetic analyses was determined at cycle 1. Results: Forty-two pts, median age 50 years, EOOG performance ≤1 were recruited: 0 DA group (18 pts), 1 DA (18), and 2 DA (6). In 0 DA group, two of six pts experienced DLT at 380 mg/m2 with grade III asthenia (1 pts) and febrile neutropenia (1). In 1 DA group, all of two pts experienced DLT at 380 mg/m2 with grade III asthenia. In 2 DA group, two of three pts experienced DLT at 240 mg/m2 with febrile neutropenia (1) and grade IV neutropenia (1). The MTD was defined as CPT-11 350 mg/m2 for pts with 0 and 1 DA group and CPT-11 200 mg/m2 for pts with 2 DA group, with capecitabine. Median SN-38G/SN-38 AUC was 10.45, 8.78, and 1.66 in pts with 0, 1, and 2 DA group, respectively. Conclusions: CPT-11 dosing by UGT1A1*28 and *6 genotypes is feasible in Korean pts with mCRC. A dose of CPT-11 350 mg/m2 IV for pts with 0 and 1 DA group and CPT-11 200 mg/m2 for pts with 2 DA group, with capecitabine every 3 weeks, is recommended for further study.

[Table: see text]

No significant financial relationships to disclose.
Isolated chemotherapeutic perfusion as neoadjuvant therapy for advanced/unresectable pelvic malignancy
Authors: Wanebo H. J. , Begossi G. , Belliveau J. , Gustafson E.
Published: August 2020

2555

Background: Isolated pelvic perfusion (IPP) provides higher tissue drug levels than high-dose systemic therapy and may enhance resectability and survival in patients failing chemo radiation ± surgery. We performed 113 IPP in 68 patients (34 palliative, and 44 pre op) using a simplified balloon occlusion technique. Methods: 42 patients had advanced (irradiated) rectal cancer, 8 pts had advanced anorectal cancer, 5 patients had sarcoma. Other cancers included melanoma (M 4pts), endometrial cancer (EC) 2, ovarian cancer (OC) 2, and bladder cancer (BC) 1. Chemotherapy agents included 5FU, (1,500–2,000mg/M2), cisplatinum (100mg/M2), Oxaliplatin and mitomycin (10–20mg/M2) for epithelial cancer and selected agents (Adriamycin, Ifosamide, DTIC, Phenyl Alanine Mustard (PAM) for the remaining tumors: 6 pts received high dose PAM (110/M2), Paclitaxel 60mg/m2 and Cisplatin 150mg/m2, 3 required stem cell support (advanced M (1 pt), SCC (1 pt), Endometrial ca (1pt). Results: Palliative IPP for advanced rectal cancer pts provided significant pain control (1–4 months) in 11 of 14 pts with narcotic resistant pain and induced tumor regression in 6 pts. Preoperative perfusion in 26 advanced rectal cancer pts induced a complete path response (in pelvis) in 2 pts and significant regression in 11 pts rendering them resectable. 7 had RO resection with clear margins: of the other pts 1 had a path CR negating resection, 3 refused pelvic resection, 2 became inoperable. Median survival post IPP was 24 mos in 12 patients considered resectable vs. 8 mos in 12 patients considered non resectable p<0.05. It was 30 months in 8 pts with advanced anorectal squamous cancer (1pt survived >90 mos), 20 months in 4 patients with endometrial/ovarian recurrence, (1 died NED >48 mos), 13 mos in 4 melanoma pts and only 5 months in 5 pts pelvic sarcoma (4–34 mos-NED). Overall 17 of 44 pts (39%) were resected and 24 had significant palliative benefit. Conclusions: IPP with high dose chemo therapy has promise in palliating or augmenting resectability of advanced pelvic malignancy persisting after conventional surgical and chemoradiation therapy. Stem cell support and biologic therapy merit further exploration.

No significant financial relationships to disclose.
Phase I study of SB939 three times weekly for 3 weeks every 4 weeks in patients with advanced solid malignancies
Authors: Yong W. , Goh B. , Toh H. , Soo R. , Diermayr V. , Goh A. , Ethirajulu K. , Lee S. , Seah E. , Zhu J.
Published: August 2020

2560

Background: SB939 is a novel orally bioavailable inhibitor of class 1 and 2 histone deacetylases. We conducted a phase I study to assess the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics and preliminary efficacy of SB939 in patients with advanced solid malignancies. Methods: SB939 was administered orally every other day 3 times a week for 3 consecutive weeks, in a 4-week cycle. Cohorts of patient were treated with escalating doses of SB939 starting from 10 mg. PK and PD (Acetylated Histone 3 in PBMCs) samples were collected in the first cycle. Results: 31 patients were enrolled at 10 mg (n=3), 20 mg (4), 40 mg (8), 60 mg (10) and 80 mg (6). The median number of treatment cycles received was 3.6. Fatigue, elevation of troponin T and QTc prolongation were the observed dose-limiting toxicities (DLT). At 80mg, one patient each (3/6) experienced a DLT of grade 3 fatigue, grade 3 asymptomatic elevation of troponin T and grade 3 QTc prolongation respectively. All DLTs were reversible and no treatment mortality was observed. Grade 1–2 fatigue occurred in 56% of patients occurring mainly at the 4th week, and 37% of pts had G1–2 anorexia. Grade 3–4 thrombocytopenia was observed in 2 patients at 60 mg at cycles 1 and 6 of treatment. SB939 was rapidly absorbed reaching Tmax between 1–3 h after ingestion, and mean elimination half-life and oral clearance of SB939 were 7.2 + 0.6 hrs and 53 + 8.5 L/h respectively. Cmax and AUC (0-∞) were dose-proportionally increased at this dose range. There was no substantial accumulation of SB939 on day 15 following repeated dosing. Concentrations above IC50 of SB939 for HDAC I was reached at all doses. Acetylation of H3 was dose dependent and consistent at 60mg. Of the 13 patients evaluable for response, stable disease was seen in 1 patient with follicular thyroid carcinoma and 1 with hepatocellular carcinoma for 51 and 164 days respectively. Conclusions: SB939 has similar toxicity profiles as that of other HDAC inhibitors and a favorable PK/PD profile. The MTD of SB939 in this regimen was 80 mg and 60mg is the recommended dose, at which acetylation of H3 is consistently observed. Further phase 2 studies with SB939 in specific indications are being planned.

No significant financial relationships to disclose.