scholarly journals Phase I Trial of MK-0752 in Children With Refractory CNS Malignancies: A Pediatric Brain Tumor Consortium Study

2011 ◽  
Vol 29 (26) ◽  
pp. 3529-3534 ◽  
Author(s):  
Maryam Fouladi ◽  
Clinton F. Stewart ◽  
James Olson ◽  
Lars M. Wagner ◽  
Arzu Onar-Thomas ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Pediatric Brain Tumor ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Gamma Secretase ◽  
Peripheral Blood Mononuclear ◽  
Once Daily ◽  
Grade 3 ◽  
Cns Malignancies

PurposeTo estimate the maximum-tolerated dose (MTD), describe dose-limiting toxicities (DLTs), and characterize pharmacokinetic properties of MK-0752, a gamma secretase inhibitor, in children with refractory or recurrent CNS malignancies.Patients and MethodsMK-0752 was administered once daily for 3 consecutive days of every 7 days at escalating dosages starting at 200 mg/m2. The modified continual reassessment method was used to estimate the MTD. A course was 28 days in duration. Pharmacokinetic analysis was performed during the first course. Expression of NOTCH and hairy enhancer of split (HES) proteins was assessed in peripheral-blood mononuclear cells (PBMCs) before and following treatment with MK-0752.ResultsTwenty-three eligible patients were enrolled: 10 males (median age, 8.1 years; range, 2.6 to 17.7 years) with diagnoses of brainstem glioma (n = 6), ependymoma (n = 8), medulloblastoma/primitive neuroectodermal tumor (n = 4), glioblastoma multiforme (n = 2), atypical teratoid/rhabdoid tumor (n = 1), malignant glioma (n = 1), and choroid plexus carcinoma, (n = 1). Seventeen patients were fully evaluable for toxicity. No DLTs occurred in the three patients enrolled at 200 mg/m2/dose. At 260 mg/m2/dose, DLTs occurred in two of six patients, both of whom experienced grade 3 ALT and AST. There were no grade 4 toxicities; non–dose-limiting grade 3 toxicities included hypokalemia and lymphopenia. Population pharmacokinetic values (% coefficient of variation) for MK-0752 were apparent oral clearance, 0.444 (38%) L/h/m2; apparent volume of distribution, 7.36 (24%) L/m2; and ka, 0.358 (99%) hr−1.ConclusionMK-0752 is well-tolerated in children with recurrent CNS malignancies. The recommended phase II dose using the 3 days on followed by 4 days off schedule is 260 mg/m2/dose once daily.

Phase I Trial of 17-Allylamino-17-Demethoxygeldanamycin in Patients With Advanced Cancer

2005 ◽  
Vol 23 (6) ◽  
pp. 1078-1087 ◽  
Author(s):  
Matthew P. Goetz ◽  
David Toft ◽  
Joel Reid ◽  
Matthew Ames ◽  
Bridget Stensgard ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Analysis ◽  
Advanced Solid Tumor ◽  
Hsp 70 ◽  
Tumor Patients ◽  
Peripheral Blood Mononuclear ◽  
Client Proteins ◽  
Grade 3 ◽  
Dose Levels

Purpose We determined the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLT) of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when infused on days 1, 8, and 15 of a 28-day cycle in advanced solid tumor patients. We also characterized the pharmacokinetics of 17-AAG, its effect on chaperone and client proteins, and whether cytochrome P450 (CYP) 3A5 and NAD(P)H:quinone oxidoreductase 1 (NQO1) polymorphisms affected 17-AAG disposition or toxicity. Patients and Methods An accelerated titration design was used. Biomarkers were measured in peripheral-blood mononuclear cells (PBMCs) at baseline and on days 1 and 15, and pharmacokinetic analysis was performed on day 1 of cycle 1. CYP3A5*3 and NQO1*2 genotypes were determined and correlated with pharmacokinetics and toxicity. Results Twenty-one patients received 52 courses at 11 dose levels. DLTs at 431 mg/m2 were grade 3 bilirubin (n = 1), AST (n = 1), anemia (n = 1), nausea (n = 1), vomiting (n = 1), and myalgias (n = 1). No tumor responses were seen. 17-AAG consistently increased heat shock protein (Hsp) 70 levels in PBMCs. At the MTD, the clearance and half-life (t1/2) of 17-AAG were 11.6 L/h/m2 and 4.15 hours, respectively; whereas the active metabolite 17-aminogeldanamycin had a t1/2 of 7.63 hours. The CYP3A5*3 and NQO1*2 polymorphisms were not associated with 17-AAG toxicity. The CYP3A5*3 polymorphism was associated with higher 17-AAG clearance. Conclusion The MTD of weekly 17-AAG is 308 mg/m2. 17-AAG induced Hsp70 in PBMCs, indicating that Hsp90 has been affected. Further evaluation of 17-AAG is ongoing using a twice-weekly regimen, and this schedule of 17-AAG is being tested in combination with chemotherapy.

A phase I trial of AEG35156 (XIAP antisense) administered as a continuous intravenous infusion in patients with advanced tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3059-3059 ◽  
Author(s):  
M. Ranson ◽  
C. Dive ◽  
T. Ward ◽  
J. Cummings ◽  
K. Connolly ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Antitumour Activity ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Preliminary Evidence ◽  
Primary Objective ◽  
Peripheral Blood Mononuclear ◽  
Grade 3

3059 Background: The X-linked inhibitor of apoptosis (XIAP) is a potent anti-apoptotic protein. AEG35156 is a synthetic 2nd generation antisense oligonucleotide to human XIAP that enhances cancer cell apoptosis preclinically as a single agent and in combination with chemotherapeutics. Methods: The primary objective was to establish the maximum tolerated dose (MTD) of AEG35156 given as a 7-day continuous infusion every 3 weeks. Other objectives were to determine AEG35156 pharmacokinetics, XIAP inhibition in peripheral blood mononuclear cells and in tumour cells where feasible and document anti-tumour activity. Results: Sixteen adult patients have completed at least one 7-day infusion. Two dose-limiting toxicities (DLT) were observed in five patients treated at 160 mg/m2/day: grade 3 thrombocytopenia for more than 7 days and grade 3 ALT and AST elevation. Seven patients have been treated at 125 mg/m2/day with one DLT of grade 3 transaminase elevation. An approximately 50% decrease in XIAP mRNA was seen in peripheral blood leucocytes three days after the start of infusions at 160mg/m2/day. One patient with small lymphocytic non-Hodgkin’s lymphoma had marked but short lived decreases in peripheral lymphoblasts during AEG35156 administration closely associated with XIAP mRNA knockdown. One patient with breast cancer had an unconfirmed partial response. The trial has now been amended to also determine the MTD of a 3-day continuous infusion every 3 weeks. Three patients have been treated with 3-day infusions at 160mg/m2/day every 3 weeks with no significant toxicities observed and patients are currently being accrued at 213mg/m2/day. Conclusions: AEG35156 can be safely delivered by continuous infusion and preliminary evidence of XIAP mRNA knockdown and antitumour activity has been observed. [Table: see text]

Phase I and Pharmacokinetic Study of Oral Irinotecan Given Once Daily for 5 Days Every 3 Weeks in Combination With Capecitabine in Patients With Solid Tumors

2005 ◽  
Vol 23 (4) ◽  
pp. 889-898 ◽  
Author(s):  
Otto Soepenberg ◽  
Herlinde Dumez ◽  
Jaap Verweij ◽  
Dorothee Semiond ◽  
Maja J.A. deJonge ◽  
...  
Keyword(s):  
Side Effects ◽  
Antitumor Activity ◽  
Solid Tumors ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Variability ◽  
Once Daily ◽  
Disease Stabilization ◽  
Grade 3 ◽  
Dose Limiting Toxicity

Purpose To assess the maximum tolerated dose, dose-limiting toxicity, pharmacokinetics, and preliminary antitumor activity of oral irinotecan given in combination with capecitabine to patients with advanced, refractory solid tumors. Patients and Methods Patients were treated from day 1 with irinotecan capsules given once daily for 5 consecutive days (50 to 60 mg/m2/d) concomitantly with capecitabine given twice daily for 14 consecutive days (800 to 1,000 mg/m2); cycles were repeated every 21 days. Results Twenty-eight patients were enrolled and received 155 cycles of therapy (median, five cycles; range, one to 18 cycles). With irinotecan 60 mg/m2/d and capecitabine 2 × 800 mg/m2/d, grade 3 delayed diarrhea in combination with grade 2 nausea (despite maximal antiemetic support) and grade 3 anorexia and colitis, were the first-cycle dose-limiting toxicities in two of six patients, respectively. At the recommended doses (irinotecan 50 mg/m2/d; capecitabine 2 × 1,000 mg/m2/d), side effects were mostly mild to moderate and uniformly reversible. Pharmacokinetic analysis showed that there was no interaction between oral irinotecan and capecitabine, and that body-surface area was not significantly contributing to the observed pharmacokinetic variability. Confirmed partial responses were observed in two patients with gallbladder carcinoma and in one patient with melanoma. Disease stabilization was noted in 16 patients. Conclusion The recommended phase II doses for oral irinotecan and capecitabine are 50 mg/m2/d for 5 consecutive days, and 2 × 1,000 mg/m2/d for 14 consecutive days repeated every 3 weeks, respectively.

A phase I study evaluating a novel schedule of oral eniluracil (EU) combined with escalating doses of oral 5-fluorouracil (5- FU)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2560-2560
Author(s):  
J. R. Infante ◽  
S. F. Jones ◽  
M. Lawton ◽  
P. Wing ◽  
R. K. Malik ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Therapeutic Option ◽  
Dihydropyrimidine Dehydrogenase ◽  
Maximum Tolerated Dose ◽  
Fixed Dose ◽  
Peripheral Blood Mononuclear ◽  
Previously Treated ◽  
Proportional Increase ◽  
Grade 3 ◽  
Anti Tumor Activity

2560 Background: 5-FU, a commonly utilized cytotoxic, is rapidly catabolized by dihydropyrimidine dehydrogenase (DPD), and requires anabolic conversion for anti-tumor activity. It has poor oral bioavailability due to DPD in the GI tract and liver, and toxicities such as hand-foot skin reaction. In addition, high levels of DPD are associated with 5-FU resistance. EU is a mechanism-based irreversible inactivator of DPD. Early studies in combination with oral 5-FU demonstrated activity; however, 3 Phase 3 studies were negative, due to an unrecognized inhibition of 5-FU anabolic activation by EU (Fourie et al; 2006 ASCO Proceedings; a 2058). Lower doses of eniluracil given 12–20 hrs prior to 5- FU preserves the desired DPD inhibition, without inhibiting these anabolic enzymes. Methods: The objectives are to determine the dose limiting toxicities (DLTs) and maximum tolerated dose (MTD), safety, tolerability, pharmacokinetics (PK), and DPD activity in peripheral blood mononuclear cells (PBMCs) following administration of a fixed dose of EU in combination with escalating doses of 5-FU. The combination of oral 5.0 mg EU 12 to 20 hours prior to oral 5-FU, is given qW for 3 weeks in 28 day cycles. Results: Twenty subjects have been enrolled, at 5-FU doses of 30, 40, 50, 60, and 70 mg. A total of 39 cycles have been administered, with 4 patients currently on study. The oral combination of EU and 5-FU has been well tolerated. All toxicities have been grade 1 or 2 with the exception of two grade 3 toxicities reported at the 50mg dose (anemia and neutropenia). The grade 3 neutropenia is the only observed DLT and resulted in a 1 week delay in initiation of cycle 2. No CR or PR noted, but 4 patients (2 previously treated with 5-FU) with 4 cycles of SD. 95–100% of DPD inhibition achieved at the time of 5-FU dosing and PK results demonstrate a dose proportional increase in 5-FU Cmax and AUC, and a half life of ∼3.5 hours. Conclusions: The oral combination of 5mg of EU given 12–20 hrs prior to 5-FU has been well tolerated and achieves full functional inhibition of DPD in all patients. The MTD is not yet defined and the next cohort is enrolling at the 80mg dose. EU in combination with 5-FU may provide a promising therapeutic option for patients with tumors known to be resistant to 5-FU due to high levels of DPD. No significant financial relationships to disclose.

Phase 1/2 study of eprenetapopt (APR-246) in combination with pembrolizumab in patients with solid tumor malignancies.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS3161-TPS3161
Author(s):  
Ecaterina Elena Dumbrava ◽  
Amit Mahipal ◽  
Xin Gao ◽  
Geoffrey Shapiro ◽  
Jason S. Starr ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Mononuclear Cells ◽  
Phase 1 ◽  
Objective Response ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Tumor Growth Inhibition ◽  
Advanced Solid Tumors ◽  
Peripheral Blood Mononuclear

TPS3161 Background: The p53 pathway has been implicated in antitumor immunity, including antigen presentation and T-cell proliferation. Loss of p53 function can increase resistance to immunotherapy across many tumor types. Eprenetapopt (eprenet) is a small molecule that stabilizes the folded structure of p53, resulting in activation of mutant p53 and stabilization of wild-type (WT) p53. It also targets the cellular redox homeostasis, resulting in induction of apoptosis in tumor cells. In vivo, mice carrying supernumerary copies of the TP53 gene harbor a pro-inflammatory tumor microenvironment, an effect recapitulated in TP53 normal-copy mice treated with eprenetapopt. Combining eprenetapopt and anti-PD1 or anti-CTLA4 therapy resulted in enhanced tumor growth inhibition and improved survival in TP53 WT mice inoculated with B16 melanoma and MC38 colon adenocarcinoma cells . Based on these results, we hypothesized that eprenet-induced p53 stabilization may augment response to immunotherapy. To test this hypothesis, we are conducting a phase 1b/2 study of eprenet in combination with pembrolizumab (eprenet+pembro) in pts with solid tumors. Methods: The primary objectives are to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) and to assess the safety and tolerability of eprenet+pembro in pts with advanced solid tumors. The secondary objectives are to estimate the anti-tumor activity and to describe the pharmacokinetics of the combination. Exploratory objectives include assessing predictive and pharmacodynamic markers of response. The study includes a safety lead-in with a 3+3 dose de-escalation design for pts with advanced solid tumors with known tumor TP53 mutation status ( TP53 WT is acceptable) (max 18 pts), followed by expansion cohorts in pts with NSCLC, gastric/GEJ and urothelial cancer (max 100 pts). In expansion, pts with urothelial and gastric cancers must be naïve to anti-PD-1/ L1 therapy. Eprenet is given IV once daily on Days 1–4 while pembro is administered on Day 3 of each 21-day cycle. The RP2D of eprenet+pembro is considered the dose at which ≤ 1 of 6 pts in a cohort has a dose-limiting toxicity (DLT). Primary endpoints are occurrence of DLTs, adverse events (AEs) and serious AEs with eprenet+pembro. Key secondary endpoints are best objective response, progression free survival and overall survival. Exploratory endpoints include gene mutations by next generation sequencing (including TP53), mRNA expression, multiplex immunohistochemistry and transcriptomics, multiplex flow cytometry on peripheral blood mononuclear cells and cytokines in serum. Continuous monitoring of toxicity will be conducted. The trial opened in May 2020 and is actively enrolling patients. Clinical trial information: NCT04383938.

scholarly journals Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL

Blood ◽  
2019 ◽  
Vol 134 (11) ◽  
pp. 851-859 ◽  
Author(s):  
Constantine S. Tam ◽  
Judith Trotman ◽  
Stephen Opat ◽  
Jan A. Burger ◽  
Gavin Cull ◽  
...  
Keyword(s):  
B Cell ◽  
Dose Escalation ◽  
Mononuclear Cells ◽  
Phase 1 ◽  
Lymphocytic Leukemia ◽  
B Cell Malignancies ◽  
Phase 1 Study ◽  
End Points ◽  
Once Daily ◽  
Grade 3

Abstract Zanubrutinib is a potent and highly selective inhibitor of Bruton tyrosine kinase (BTK). In this first-in-human, open-label, multicenter, phase 1 study, patients in part 1 (3 + 3 dose escalation) had relapsed/refractory B-cell malignancies and received zanubrutinib 40, 80, 160, or 320 mg once daily or 160 mg twice daily. Part 2 (expansion) consisted of disease-specific cohorts, including treatment-naive or relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The primary end points were safety and tolerability, and definition of the maximum tolerated dose (part 1). Additional end points included pharmacokinetics/pharmacodynamics and preliminary efficacy. Reported herein are results from 144 patients enrolled in the dose-finding and CLL/SLL cohorts. No dose-limiting toxicities occurred in dose escalation. Median BTK occupancy in peripheral blood mononuclear cells was >95% at all doses. Sustained complete (>95%) BTK occupancy in lymph node biopsy specimens was more frequent with 160 mg twice daily than 320 mg once daily (89% vs 50%; P = .0342). Consequently, 160 mg twice daily was selected for further investigation. With median follow-up of 13.7 months (range, 0.4-30.5 months), 89 CLL/SLL patients (94.7%) remain on study. Most toxicities were grade 1/2; neutropenia was the only grade 3/4 toxicity observed in >2 patients. One patient experienced a grade 3 subcutaneous hemorrhage. Among 78 efficacy-evaluable CLL/SLL patients, the overall response rate was 96.2% (95% confidence interval, 89.2-99.2). Estimated progression-free survival at 12 months was 100%. Zanubrutinib demonstrated encouraging activity in CLL/SLL patients, with a low incidence of major toxicities. This trial was registered at www.clinicaltrials.gov as #NCT02343120.

Phase I clinical and pharmacologic study of eniluracil plus fluorouracil in patients with advanced cancer.

1998 ◽  
Vol 16 (4) ◽  
pp. 1450-1457 ◽  
Author(s):  
R L Schilsky ◽  
J Hohneker ◽  
M J Ratain ◽  
L Janisch ◽  
L Smetzer ◽  
...  
Keyword(s):  
Washout Period ◽  
Mononuclear Cells ◽  
Dihydropyrimidine Dehydrogenase ◽  
Maximum Tolerated Dose ◽  
Peripheral Blood Mononuclear ◽  
Period 2 ◽  
Daily Schedule ◽  
Starting Dose ◽  
Dose Levels

PURPOSE To determine the highest dose of fluorouracil (5-FU) that could be safely administered with Eniluracil (776C85; Glaxo Wellcome Inc, Research Triangle Park, NC), an inactivator of dihydropyrimidine dehydrogenase (DPD), on a daily schedule for 5 days, and to define the toxicities of the combination and the pharmacokinetics of 5-FU when administered with 776C85. PATIENTS AND METHODS Patients with advanced solid tumors refractory to standard therapy were enrolled at two institutions. The study consisted of three periods designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of 776C85 alone (period 1); the effects of 776C85 on the pharmacokinetics of 5-FU (period 2); and the maximum-tolerated dose (MTD) of 5-FU, with or without leucovorin, that could be safely administered with 776C85 (period 3). Cohorts of at least three patients each received oral 776C85 alone at doses of 3.7 mg/m2/d, 18.5 mg/m2/d and 0.74 mg/m2/d. After a 14-day washout period, each patient then received 776C85 daily for 3 days, with a single intravenous (i.v.) bolus dose of 5-FU 10 mg/m2 on day 2. After a second washout period, patients were treated with 776C85 daily for 7 days and 5-FU i.v. bolus on days 2 through 6. The starting dose of 5-FU 10 mg/m2/d was escalated until the MTD was determined. After determination of the MTD of 5-FU given with 776C85, oral leucovorin 50 mg/d on days 2 through 6 was added to determine the MTD of 5-FU with leucovorin in the presence of 776C85. Near the completion of the study, additional cohorts of patients were treated with 776C85 at 50 mg/d and oral 5-FU with or without leucovorin. RESULTS Sixty-five patients were enrolled onto the study and 60 were assessable for toxicity and response. Bone marrow suppression was the primary and dose-limiting toxicity of this regimen. Other toxicities included diarrhea, mucositis, anemia, anorexia, nausea, vomiting, and fatigue. 776C85 suppressed DPD activity in peripheral-blood mononuclear cells (PBMCs) by at least 90% for at least 24 hours at all dose levels tested. In the presence of 776C85, 5-FU half-life was prolonged, clearance was reduced, and the drug displayed linear pharmacokinetics. Recommended doses for further testing on a daily for 5-day schedule are 776C85 10 mg/d with i.v. 5-FU 25 mg/m2/d; 776C85 10 mg/d with i.v. 5-FU 20 mg/m2/d plus leucovorin 50 mg/d; 776C85 50 mg/d with 5-FU given orally at 15 mg/m2/d with leucovorin at 50 mg/d. CONCLUSION 5-FU can be safely administered with 776C85; however, the MTDs are considerably lower than those conventionally used, caused, at least in part, by marked alterations in 5-FU plasma pharmacokinetics.

scholarly journals Mass balance and metabolite profiling of 14C-guadecitabine in patients with advanced cancer

2019 ◽  
Vol 38 (4) ◽  
pp. 1085-1095
Author(s):  
Jeroen Roosendaal ◽  
Hilde Rosing ◽  
Luc Lucas ◽  
Abadi Gebretensae ◽  
Alwin D. R. Huitema ◽  
...  
Keyword(s):  
Mass Balance ◽  
Mononuclear Cells ◽  
Drug Product ◽  
Systemic Circulation ◽  
Target Site ◽  
The Novel ◽  
Peripheral Blood Mononuclear ◽  
Once Daily ◽  
Phosphodiester Bond ◽  
Intracellular Target

Summary Purpose The objective of this mass balance trial was to determine the excretory pathways and metabolic profile of the novel anticancer agent guadecitabine in humans after administration of a 14C-radiolabeled dose of guadecitabine. Experimental design Included patients received at least one cycle of 45 mg/m2 guadecitabine subcutaneously as once-daily doses on Days 1 to 5 of a 28-day cycle, of which the 5th (last) dose in the first cycle was spiked with 14C-radiolabeled guadecitabine. Using different mass spectrometric techniques in combination with off-line liquid scintillation counting, the exposure and excretion of 14C-guadecitabine and metabolites in the systemic circulation, excreta, and intracellular target site were established. Results Five patients were enrolled in the mass balance trial. 14C-guadecitabine radioactivity was rapidly and almost exclusively excreted in urine, with an average amount of radioactivity recovered of 90.2%. After uptake in the systemic circulation, guadecitabine was converted into ß-decitabine (active anomer), and from ß-decitabine into the presumably inactive metabolites M1-M5. All identified metabolites in plasma and urine were ß-decitabine related products, suggesting almost complete conversion via cleavage of the phosphodiester bond between ß-decitabine and deoxyguanosine prior to further elimination. ß-decitabine enters the intracellular activation pathway, leading to detectable ß-decitabine-triphosphate and DNA incorporated ß-decitabine levels in peripheral blood mononuclear cells, providing confirmation that the drug reaches its DNA target site. Conclusion The metabolic and excretory pathways of guadecitabine and its metabolites were successfully characterized after subcutaneous guadecitabine administration in cancer patients. These data support the clinical evaluation of safety and efficacy of the subcutaneous guadecitabine drug product.

Results of a Phase I Trial of SGN-40 (Anti-huCD40 mAb) in Patients with Relapsed Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3576-3576 ◽  
Author(s):  
Mohamad A. Hussein ◽  
James R. Berenson ◽  
Ruben Niesvizky ◽  
Nikhil C. Munshi ◽  
Jeffrey Matous ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Aseptic Meningitis ◽  
Dose Escalation ◽  
Single Agent ◽  
Objective Response ◽  
Lymphocytic Leukemia ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Grade 3

Abstract SGN-40 is a humanized anti-CD40 monoclonal antibody that has demonstrated potent in vitro and in vivo efficacy against cell lines expressing CD40, a member of the tumor necrosis factor receptor family. CD40 is widely expressed on tumors of B-cell origin, including myeloma, non-Hodgkin’s lymphoma, Hodgkin’s disease, and chronic lymphocytic leukemia. SGN-40 has been evaluated in a phase I, multi-dose, single-agent, dose escalation study for patients with relapsed or refractory multiple myeloma. This single-arm trial was designed to evaluate safety, pharmacokinetics, immunogenicity, and antitumor activity. Thirty-two patients were treated at five clinical sites. Patients had been heavily pretreated with a median of four prior regimens and 4.8 years since diagnosis. Initially, patients were treated with four weekly infusions at a cohort-specific dose. This schedule was well-tolerated at 0.5, 1.0 and 2.0 mg/kg/wk; however, two of three patients experienced dose-limiting toxicities following the first dose at 4 mg/kg. One patient had aseptic meningitis (grade 3) and another had headache (grade 3) and aseptic meningitis (grade 4); both patients fully recovered after several days of symptom management. Subsequently, the protocol was amended to allow intra-patient dose-loading, which resulted in successful dose escalation to 8 mg/kg, the highest dose tested. There was neither recurrence of grade 3 neurotoxicity nor evidence of cumulative toxicity. Drug-related adverse events were mostly grade 1 or 2 and included: fatigue (38%), headache (34%), nausea (16%), conjunctivitis (13%), diarrhea (13%), vomiting (13%), anemia (9%), anorexia (9%), chills (9%), and pyrexia (9%). Transient grade 3 elevation of hepatic transaminases (1) and grade 3 neutropenia (1) were observed. Overall, toxicity did not appear to increase in incidence or severity at higher doses. Patients were evaluated at baseline and end of treatment for development of anti-SGN-40 antibodies. Of 30 patients for whom appropriate samples were available for testing, only one low-titer immune response (16 ng/mL) was detected, suggesting that immunogenicity does not appear to be a significant problem in this patient population. Pharmacokinetic analysis demonstrates dose-proportional changes in Cmax and AUC with a relatively short terminal half-life, similar to that seen in non-human primates. Final analysis of SGN-40 serum levels is ongoing. Although several patients demonstrated decreased M-protein and improvement in subjective symptoms, no patients met criteria for objective response. Five patients (16%) had stable disease at the time of restaging. In summary, dose-dependent toxicity was established only in relation to the first dose of SGN-40, which may be due to partial agonistic signal transduction. Using a dose-loading schedule, SGN-40 was administered up to 8 mg/kg without reaching a maximum tolerated dose. Some patients with advanced myeloma appeared to derive clinical benefit from therapy, and further development of this antibody, either as monotherapy or in combination with other anti-myeloma therapies, is indicated.

Pharmacokinetic and pharmacodynamic analysis of topotecan administered in combination with PS 341 in patients with advanced malignancy

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2033-2033
Author(s):  
M. Tomita ◽  
L. Xin ◽  
B. Freeman ◽  
S. Twomey ◽  
G. Pizzorno ◽  
...  
Keyword(s):  
Topoisomerase I ◽  
Mononuclear Cells ◽  
Day Treatment ◽  
Pharmacokinetic Analysis ◽  
Dna Breaks ◽  
Peripheral Blood Mononuclear ◽  
Advanced Malignancy ◽  
Pharmacodynamic Analysis ◽  
Dose Escalating

2033 Background: In vitro exposure to camptothecin results in down-regulation of the target enzyme, topoisomerase I (topo) via multi-ubiquitination and proteasomal degradation of the protein-linked DNA breaks. To prevent loss of topo, and thus circumvent a possible mechanism of resistance to the topo inhibitors, we conducted a dose escalating phase I study of topotecan in combination with the proteosome inhibitor PS 341. We now report the pharmacokinetic and pharmacodynamic analysis of the trial. Methods: Patients with advanced cancer were treated with topotecan alone at the following dose escalating levels: 0.75, 1.0,1,25 and 1.5 mg/m2 as a 60 min infusion d x 5 during cycle 1. In subsequent cycles (21 days), cohorts of 3–6 patients received PS 341 as a 30 min infusion on days 1, 4, 8 and 11 at the following dose levels: 0.6, 0.8, 1.0 and 1.3 mg/m2. Topo expression was determined by western blot on peripheral blood mononuclear cells (PBMCs) sampled throughout the first 5-day treatment period of cycles #1 and 2. Total topotecan plasma pharmacokinetics were studied with the first doses of topotecan on cycle #1 (topotecan alone) and cycle #2 (topotecan after PS 341). Results: Samples were collected from 22 patients and 38 patient-cycles. In the first week of cycle #1, 9 of 22 (41 %) patients demonstrated a significant decrease in topo expression (range 0.2 - 1 fold) compared with the baseline level. Topo levels did not change (7/22, 32%) or increased (6/22, 27%) in the remaining patients. After administration of PS 341 during cycle #2, PBMC from 10 of 17 patients (59 %) analyzed showed a greater than 0.3 fold increase (range: 0.32 to 63) in topo concentration, and topo levels in 4 patients (23 %) were unchanged. Preliminary pharmacokinetic analysis indicates that PS 341 may interact with topotecan. Conclusions: There is a heterogeneous response in PBMC topo levels following administration of topotecan. However, addition of PS 341 to topotecan stabilized or increased PBMC topo I levels in the majority of patients, suggesting a possible role for PS341 in inhibiting camptothecin-induced topo protein degradation. Further studies combining proteasome inhibitors with topotecan to overcome drug resistance based on topo degradation are warranted. No significant financial relationships to disclose.

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