Phase I Study of the Proteasome Inhibitor Bortezomib in Pediatric Patients With Refractory Solid Tumors: A Children's Oncology Group Study (ADVL0015)

2004 ◽  
Vol 22 (23) ◽  
pp. 4804-4809 ◽  
Author(s):  
Susan M. Blaney ◽  
Mark Bernstein ◽  
Kathleen Neville ◽  
Jill Ginsberg ◽  
Brenda Kitchen ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Proteasome Inhibitor ◽  
Pediatric Patients ◽  
Maximum Tolerated Dose ◽  
Proteasome Activity ◽  
20S Proteasome ◽  
Intravenous Bolus ◽  
Recommended Phase Ii Dose ◽  
Dose Dependent ◽  
Dose Limiting Toxicity

PurposeTo determine the maximum-tolerated dose, dose-limiting toxicity (DLT), and pharmacodynamics of the proteasome inhibitor bortezomib (formerly PS-341) in children with recurrent or refractory solid tumors.Patients and MethodsAn intravenous bolus of bortezomib was administered twice weekly for 2 consecutive weeks at either 1.2 or 1.6 mg/m2/dose followed by a 1-week rest. The pharmacodynamics of bortezomib were evaluated by measurement of whole blood 20S proteasome activity.ResultsFifteen patients, 11 assessable, were enrolled between November 2001 and February 2003. Dose-limiting thrombocytopenia, which prevented administration of a complete course (four doses in 2 weeks) of therapy, occurred in two of five assessable children enrolled at the 1.6 mg/m2dose level. There were no other DLTs. Inhibition of 20S proteasome activity seemed to be dose dependent. The average inhibition 1 hour after drug administration on day 1 was 67.2% ± 7.6% at the 1.2 mg/m2/dose and 76.5% ± 3.3% at the 1.6 mg/m2/dose. There were no objective antitumor responses.ConclusionBortezomib is well tolerated in children with recurrent or refractory solid tumors. The recommended phase II dose of bortezomib for children with solid tumors is 1.2 mg/m2/dose, administered as an intravenous bolus twice weekly for 2 weeks followed by a 1-week break.

Phase I study of topotecan in combination with cyclophosphamide in pediatric patients with malignant solid tumors: a Pediatric Oncology Group Study.

1998 ◽  
Vol 16 (3) ◽  
pp. 945-952 ◽  
Author(s):  
R L Saylors ◽  
C F Stewart ◽  
W C Zamboni ◽  
D A Wall ◽  
B Bell ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Pediatric Patients ◽  
Wilms Tumor ◽  
Systemic Exposure ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Studies ◽  
Phase Ii Trials ◽  
Pediatric Solid Tumors ◽  
Dose Limiting Toxicity

PURPOSE To determine the maximum-tolerated dose (MTD) and dose-limiting toxicity of topotecan when combined with cyclophosphamide in pediatric patients with recurrent or refractory malignant solid tumors. PATIENTS AND METHODS A total of 33 patients received cyclophosphamide (250 mg/m2/dose) followed by topotecan in escalating doses (0.6 to 0.75 mg/m2/dose), each given as a 30-minute infusion daily for 5 days. A total of 154 fully assessable treatment courses were given to these patients. RESULTS Neutropenia was the dose-limiting toxicity of the therapy at both topotecan dose levels. The addition of filgrastim allowed escalation of the topotecan dose to the 0.75-mg/m2 level with acceptable neutropenia. Other significant toxicities were anemia and thrombocytopenia. Nonhematopoietic toxicity of grades > or = 3 was not observed. Responses were reported in patients with Wilms' tumor (one complete response [CR], one partial response [PR]), neuroblastoma (one CR, one PR), rhabdomyosarcoma (one PR), and osteosarcoma (one PR). Pharmacokinetic studies indicate that cyclophosphamide administered on the schedule used in this study did not alter topotecan disposition on day 5. As with previous studies, a pharmacodynamic relation between systemic exposure and myelosuppression was noted. CONCLUSION The combination of topotecan and cyclophosphamide shows activity in a wide variety of pediatric solid tumors and can be given with acceptable hematopoietic toxicity with the use of filgrastim support. We recommend that pediatric phase II trials use cyclophosphamide 250 mg/m2 followed by topotecan 0.75 mg/m2 daily for 5 days with filgrastim for amelioration of neutropenia.

A phase I/II study of LDE225, a smoothened (Smo) antagonist, in pediatric patients with recurrent medulloblastoma (MB) or other solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 9519-9519 ◽  
Author(s):  
Birgit Geoerger ◽  
Isabelle Aerts ◽  
Michela Casanova ◽  
Julia C. Chisholm ◽  
Darren R Hargrave ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Preliminary Data ◽  
Pediatric Patients ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Pathway Activation ◽  
Wide Range ◽  
Hh Signaling ◽  
Dose Limiting Toxicity

9519 Background: Hedgehog (Hh) signaling is crucial in the development and homeostasis of many human organs and tissues. Aberrant Hh signaling is involved in tumorigenesis through promotion of cell proliferation, survival, and differentiation in wide range of human cancers, including approximately 30% of MBs. LDE225 is a potent and selective inhibitor of Smo, a key positive regulator of Hh signaling. The phase I is exploring the safety and pharmacokinetics of LDE225 in pediatric patients with advanced solid tumors that are potentially dependent on Hh signaling. Preliminary data from the ongoing phase I are presented. Methods: Dose-escalation was performed according to a Bayesian design starting at 372 mg/m2 of continuous once daily oral LDE225. Safety and preliminary efficacy of LDE225 at the maximum tolerated dose will be assessed in pediatric and adult patients with recurrent MB in a phase II expansion part. Pharmacokinetic profiles were performed at Day 1 and 21. Tumor samples were analyzed for Hh pathway activation status using a 5-gene Hh signature assay. Results: Thirty-three patients (24 MB, 3 rhabdomyoscarcoma [RMS], 3 osteosarcoma, and 1 each of neuroblastoma, gliomatosis and oligoastrocytoma) with a median age of 13 years (range, 4–17 y) have enrolled. Dose-limiting toxicity of Grade 4 creatine phosphokinase elevation occurred in 1 RMS patient out of 7 patients treated at 372 mg/m2. No dose-limiting toxicity was observed at 233 and 425 mg /m2. LDE225 at 233 and 372 mg/m2 was absorbed with a median Tmax of 2 h (range, 1–24 h). Systemic exposures were comparable with adults. Two MB patients achieved a confirmed complete response (CR) at doses of 372 and 425 mg/m2. Analysis of 14 available MB tumor samples using the 5-gene Hh signature assay showed that the 2 CR patients have Hh‑activated tumor. The remaining 12 tumor samples were from patients who did not achieve response and were determined to be Hh pathway non-activated. Conclusions: LDE225 is well tolerated in pediatric patients with advanced malignancies. Preliminary data show promising efficacy in medulloblastoma patients and support the use of the 5-gene Hh signature assay as a pre-selection tool in future trials.

Phase I Study of O6-Benzylguanine and Temozolomide Administered Daily for 5 Days to Pediatric Patients With Solid Tumors

2005 ◽  
Vol 23 (30) ◽  
pp. 7646-7653 ◽  
Author(s):  
Katherine E. Warren ◽  
Alberta A. Aikin ◽  
Madeleine Libucha ◽  
Brigitte C. Widemann ◽  
Elizabeth Fox ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Pediatric Patients ◽  
Maximum Tolerated Dose ◽  
Biologically Active ◽  
Conventional Dose ◽  
Daily Schedule ◽  
Dose Levels ◽  
Dose Limiting Toxicity ◽  
Active Dose

Purpose This pediatric phase I trial of O6-benzylguanine (O6BG) and temozolomide (TMZ) on a daily schedule for 5 days, every 28 days was performed to determine the maximum-tolerated dose of TMZ when given with a biologically active dose of O6BG and to define the toxicity profile of the combination in children with solid tumors. Patients and Methods Patients ≤ 21 years old with refractory solid tumors were eligible. O6BG was administered intravenously over 60 minutes daily for 5 days. TMZ was administered orally 30 minutes after completion of each O6BG infusion. Starting doses of O6BG and TMZ were 60 mg/m2/d and 28 mg/m2/d, respectively. O6BG was escalated to 90 and 120 mg/m2/d; TMZ was subsequently escalated to 40, 55, 75, and 100 mg/m2/d. Cycles were repeated every 28 days. Results Forty-one patients were enrolled; 32 patients were assessable for toxicity. The combination of O6BG and TMZ was tolerable at TMZ doses less than half of the conventional dose of 200 mg/m2/d. Myelosuppression occurred sporadically at all dose levels and was the dose-limiting toxicity (DLT) at 100 mg/m2/d of TMZ combined with 120 mg/m2/d O6BG. Nonhematologic toxicities were generally mild. Evidence of antitumor activity was observed at 120 mg/m2/d O6BG combined with TMZ doses of 55 mg/m2/d and above. Conclusion The recommended doses of O6BG administered with TMZ on a 5-day schedule in children are 120 mg/m2/d of O6BG and 75 mg/m2/d of TMZ. Evidence of activity was observed at these doses. Myelosuppression was the DLT.

Phase I Trial of the Proteasome Inhibitor PS-341 in Patients With Refractory Hematologic Malignancies

2002 ◽  
Vol 20 (22) ◽  
pp. 4420-4427 ◽  
Author(s):  
Robert Z. Orlowski ◽  
Thomas E. Stinchcombe ◽  
Beverly S. Mitchell ◽  
Thomas C. Shea ◽  
Albert S. Baldwin ◽  
...  
Keyword(s):  
Proteasome Inhibitor ◽  
Proteasome Inhibition ◽  
Complete Response ◽  
Hematologic Malignancies ◽  
Maximum Tolerated Dose ◽  
20S Proteasome ◽  
Dependent Manner ◽  
Mantle Cell ◽  
Heavily Pretreated ◽  
Systemic Hypersensitivity

PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacodynamics (PD) of the proteasome inhibitor bortezomib (previously known as PS-341) in patients with refractory hematologic malignancies.PATIENTS AND METHODS: Patients received PS-341 twice weekly for 4 weeks at either 0.40, 1.04, 1.20, or 1.38 mg/m2, followed by a 2-week rest. The PD of PS-341 was evaluated by measurement of whole blood 20S proteasome activity.RESULTS: Twenty-seven patients received 293 doses of PS-341, including 24 complete cycles. DLTs at doses above the 1.04-mg/m2MTD attributed to PS-341 included thrombocytopenia, hyponatremia, hypokalemia, fatigue, and malaise. In three of 10 patients receiving additional therapy, serious reversible adverse events appeared during cycle 2, including one episode of postural hypotension, one systemic hypersensitivity reaction, and grade 4 transaminitis in a patient with hepatitis C and a substantial acetaminophen ingestion. PD studies revealed PS-341 induced 20S proteasome inhibition in a time-dependent manner, and this inhibition was also related to both the dose in milligrams per meter squared, and the absolute dose of PS-341. Among nine fully assessable patients with heavily pretreated plasma cell dyscrasias completing one cycle of therapy, there was one complete response and a reduction in paraprotein levels and/or marrow plasmacytosis in eight others. In addition, one patient with mantle cell lymphoma and another with follicular lymphoma had shrinkage of nodal disease.CONCLUSION: PS-341 was well tolerated at 1.04 mg/m2on this dose-intensive schedule, although patients need to be monitored for electrolyte abnormalities and late toxicities. Additional studies are indicated to determine whether incorporation of dose/body surface area yields a superior PD model to dosing without normalization. PS-341 showed activity against refractory multiple myeloma and possibly non-Hodgkin’s lymphoma in this study, and merits further investigation in these populations.

Phase I trial of 9-aminocamptothecin in children with refractory solid tumors: a Pediatric Oncology Group study.

1998 ◽  
Vol 16 (7) ◽  
pp. 2494-2499 ◽  
Author(s):  
A M Langevin ◽  
D T Casto ◽  
P J Thomas ◽  
S D Weitman ◽  
C Kretschmar ◽  
...  
Keyword(s):  
Steady State ◽  
Phase I ◽  
Solid Tumors ◽  
Phase I Trial ◽  
Malignant Tumors ◽  
Hepatic Metabolism ◽  
Pharmacokinetic Profile ◽  
Maximum Tolerated Dose ◽  
Volume Of Distribution ◽  
Recommended Phase Ii Dose

PURPOSE A phase I trial of 9-aminocamptothecin (9-AC) was performed in children with solid tumors to establish the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and the pharmacokinetic profile in children and to document any evidence of activity. PATIENTS AND METHODS A 72-hour infusion of 9-AC dimethylacetamide formulation was administered every 21 days to 23 patients younger than 21 years of age with malignant tumors refractory to conventional therapy. Doses ranged from 36 to 62 microg/m2 per hour. Pharmacokinetics were to be performed in at least three patients per dose level. The first course was used to determine the DLT and MTD. RESULTS Nineteen patients on four dose levels were assessable for toxicities. At 62 microg/m2 per hour, three patients experienced dose-limiting neutropenia and one patient experienced dose-limiting thrombocytopenia. Pharmacokinetics were performed on 15 patients (nine patients had complete sets of plasma sampling performed). The pharmacokinetics of both lactone and total 9-AC were highly variable. The percentage of 9-AC lactone at steady-state was 10.8% +/- 3.6%. Total 9-AC and its lactone form had a terminal half-life of 8.1 +/- 3.8 and 7.1 +/- 3.9 hours, respectively, and a volume of distribution at steady-state (Vdss) of 21.2 +/- 13.3 L/m2 and 135.3 +/- 52.5 L/m2, respectively. Hepatic metabolism and biliary transport had an important role in 9-AC disposition. CONCLUSION The recommended phase II dose of 9-AC administered as a 72-hour infusion every 21 days to children with solid tumors is 52 microg/m2 per hour. Neutropenia and thrombocytopenia were dose limiting.

Phase I study of CPT-11 and etoposide in patients with refractory solid tumors.

1993 ◽  
Vol 11 (10) ◽  
pp. 2030-2035 ◽  
Author(s):  
A Karato ◽  
Y Sasaki ◽  
T Shinkai ◽  
K Eguchi ◽  
T Tamura ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Topoisomerase I ◽  
Phase Ii Trial ◽  
Supportive Therapy ◽  
Maximum Tolerated Dose ◽  
Granulocyte Colony Stimulating Factor ◽  
Small Cell Lung ◽  
Dose Levels ◽  
Stimulating Factor ◽  
Dose Limiting Toxicity

PURPOSE To determine the maximum-tolerated dose (MTD) and acceptable dose level of a cytotoxic regimen of CPT-11, a new camptothecin derivative, in combination with etoposide (VP-16) and to describe the principal toxicities associated with it. PATIENTS AND METHODS Patients with refractory solid tumors received VP-16 and CPT-11 daily for 3 consecutive days (days 1 through 3) every 3 or 4 weeks. Groups entered the trial at escalating CPT-11/VP-16 dose levels of 40/60, 60/60, 60/80, and 80/60 mg/m2. Thirty-four patients entered this study, of whom 33 were assessable for toxicity and 22 for therapeutic efficacy. RESULTS Granulocytopenia was so severe that this regimen required supportive therapy with recombinant human granulocyte colony-stimulating factor (G-CSF). The majority of the patients experienced a 5% weight loss and diarrhea was the dose-limiting toxicity. The MTDs were 60/80 and 80/60 mg/m2 administered on days 1 through 3. Five of seven previously untreated patients with non-small-cell lung cancer (NSCLC) achieved partial responses (PRs) to this therapy, as did two with NSCLC who had received prior chemotherapy, two with head and neck cancer, and one with an adenocarcinoma (primary tumor unknown). CONCLUSION The recommended dose of CPT-11/VP-16 for this regimen with G-CSF is 60/60 mg/m2 on days 1 through 3 every 3 to 4 weeks. We suggest that the combination of topoisomerase I and II inhibitors is likely to be an effective treatment strategy. The activity of this regimen against NSCLC is particularly encouraging and should be evaluated in a phase II trial.

Phase I and pharmacologic study of estramustine phosphate and short infusions of paclitaxel in women with solid tumors.

1998 ◽  
Vol 16 (9) ◽  
pp. 2959-2963 ◽  
Author(s):  
A A Garcia ◽  
S Keren-Rosenberg ◽  
D Parimoo ◽  
M Rogers ◽  
S Jeffers ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Maximum Tolerated Dose ◽  
Estramustine Phosphate ◽  
Antitumor Effects ◽  
Ovarian Cancers ◽  
P Glycoprotein ◽  
Grade 3 ◽  
Recommended Phase Ii Dose ◽  
Pharmacologic Study

PURPOSE We sought to determine the tolerance of estramustine phosphate (EMP) combined with a 3-hour paclitaxel infusion in women with solid paclitaxel-pretreated solid tumors. Paclitaxel pharmacology was to be studied at the recommended phase II dose. PATIENTS AND METHODS Paclitaxel was administered to cohorts of at least three assessable patients at doses of 150, 180, 210, and 225 mg/m2, while EMP was given at 900 and 1,200 mg/m2/d in divided doses orally for 2 days preceding and on the day of paclitaxel. The pharmacologic study was performed at 225 mg/m2 paclitaxel given in the absence and 3 weeks later in the presence of EMP 900 mg/m2/d. RESULTS Thirty-eight patients received a total of 178 courses. Grade 3 nausea, vomiting, and diarrhea were common at EMP 1,200 mg/m2 and paclitaxel 225 mg/ m2; this was considered the maximum-tolerated dose. Since these toxicities appeared related to EMP, the pharmacologic study used a dose of 900 mg/m2 of this agent with 225 mg/m2 paclitaxel. Antitumor activity was documented against breast and ovarian cancers at all levels. Paclitaxel pharmacokinetics without and with EMP did not differ. CONCLUSION EMP 900 mg/m2 for 3 days and 225 mg/m2 paclitaxel by 3-hour infusion are well tolerated; antitumor activity was seen in women with paclitaxel-pretreated solid tumors. This apparent enhancement of antitumor effects is unlikely to be mediated by P-glycoprotein.

A phase I dose escalation trial of ispinesib (SB-715992) administered days 1–3 of a 21-day cycle in patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2026-2026 ◽  
Author(s):  
E. I. Heath ◽  
A. Alousi ◽  
J. P. Eder ◽  
M. Valdivieso ◽  
L. S. Vasist ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Level ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Data ◽  
Advanced Solid Tumors ◽  
Minor Response ◽  
Level 3 ◽  
Grade 3 ◽  
Tumor Types ◽  
Dose Limiting Toxicity

2026 Background: Ispinesib, a novel cytotoxic agent inhibiting the kinesin spindle protein (KSP) has demonstrated significant antitumor activity in multiple murine tumor models. The primary objectives of the study were to assess the safety and tolerability of SB-715992, to determine the dose limiting toxicity (DLT), and the maximum tolerated dose (MTD). Methods: Ispinesib was administered days 1–3 intravenously over 1 hour every 21 days, starting at a dose of 1 mg/m2/day. Traditional 3-patient cohort trial design was utilized with dose levels of 2, 4, 6, 8 mg/m2/day. Results: Twenty-seven patients (24 Caucasians, 3 African-Americans, 16 males, 11 females) with various tumor types were enrolled; colorectal (7), renal (5), bladder (2), lung (2), pharynx (2), pancreas (2), others (7). Grade 3/4 toxicities were noted starting at the 4 mg/m2 dose level with two patients developing grade 4 neutropenia; one for < 5 days, one for > 5 days (with grade 3 leukopenia). At the 6 mg/m2 dose level, grade 3 neutropenia and leukopenia were reported. At the 8 mg/m2 dose level, 3 of 3 patients had grade 4 neutropenia and leukopenia. The 6 mg/m2 dose level was declared the MTD. Toxicities seen in the additional 6 patients included grade 1 fatigue (1/6), grade 1 infusion- related flushing (1/6), grade 3 febrile neutropenia (1/6), and grade 4 neutropenia and leukopenia (1/6). The MTD cohort has been expanded to 10 evaluable patients for confirmation of tolerability and pharmacodynamic endpoints including phosphohistone 3 (PH3), cyclin E, and TUNEL assay on serial tumor biopsies. Preliminary pharmacokinetic data appear linear, but not dose proportional. As predicted, between days 1 and 3, accumulation ranged from 40 to 106%. Exposures appear comparable between cycles 1 and 2. Stable disease in 2 patients with renal cell carcinoma (4 and 5 cycles) and minor response in one patient with bladder cancer were seen. Conclusions: Treatment with ispinesib at the MTD of 6 mg/m2/day x 3 days in patients with advanced solid tumors was well tolerated with consistent dose limiting toxicity of myelosuppression. No significant financial relationships to disclose.

Phase I study of oral S-1 in combination with oxaliplatin (oxali) and bevacizumab (bev) in patients with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4091-4091
Author(s):  
J. Zhang ◽  
K. Chung ◽  
C. Zergebel ◽  
P. Urrea ◽  
M. Quinones ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Dose Level ◽  
Cyanuric Acid ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Advanced Solid Tumors ◽  
Clinical Pharmacokinetics ◽  
Progression Of Disease ◽  
Recommended Phase Ii Dose

4091 Background: S-1 is a novel oral fluoropyrimidine (tegafur, CDHP and potassium oxonate) designed for enhanced DPD inhibition and reduced GI toxicity. Bev and oxali have demonstrated safety and synergistic anti-tumor activity with oral and IV fluoropyrimidines. The primary objective is to investigate the safety and maximum tolerated dose (MTD) of S-1 combined with bevacizumab and oxaliplatin in patients with advanced solid tumors. Secondary objective is to investigate the clinical pharmacokinetics (PK) of the components of S-1 (FT, CDHP, Oxo), 5-FU, a-fluoro-β-alanine, cyanuric acid, uracil, and oxali and to document any antitumor activity. Methods: ECOG 0/1 patients with advanced or metastatic solid tumors received oral S-1 starting at 20 mg/m2/dose BID x 14 days (classic 3+3 cohort dose escalation by 5mg/m2/dose until MTD), plus fixed doses of bev 7.5 mg/kg IV day 1, and Oxali 130 mg/m2 IV day 1 of every 3 week cycle, with discontinuation of oxali after 4 cycles. Reintroduction of oxali was allowed upon progression of disease. Toxicity, antitumor activity and PKs were assessed. The MTD was defined as the highest dose level at which < 33% of the patients experience a dose- limiting toxicity (DLT) during the first 2 cycles. Results: Of 22 evaluable patients, 3 patients were treated at 20mg/m2 S1 and 13 patients were treated at 25mg/m2 S1 without a DLT. At 30mg/m2, two patients experienced a DLT(Grade 3 diarrhea, Grade 4 mucositis). The MTD and recommended phase II dose of S-1 is 25mg/m2 in combination with oxali and bev. A median of 8 cycles of S-1 were initiated at the 25 mg/m2 dose level. Common MTD level toxicities included fatigue (62%), nausea (62%) and diarrhea (46%), with no grade 4 toxicities observed. Best responses (RECIST): stable disease(16 patients), partial response (2 patients), non-measurable disease (3 patients). The Day 8 AUC(0–8) of 5-FU at 20/25/30 mg/m2 dose level were 230±115 hr*ng/ml, 470±172 hr*ng/ml and 502±169 hr*ng/ml, respectively. Conclusions: The MTD combination of 25mg/m2 S-1, oxali and bev can be given safely. The study will be expanded to test S-1 one week on, one week off schedule in combination with oxali/bev every two weeks. No significant financial relationships to disclose.

Tumor drug distribution and target engagement of MLN9708, an investigational proteasome inhibitor, in patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3077-3077 ◽  
Author(s):  
Alessandra Di Bacco ◽  
Allison Berger ◽  
Neeraj Gupta ◽  
Feng Gao ◽  
Stephen Blakemore ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Proteasome Inhibitor ◽  
Phase 1 ◽  
Active Form ◽  
Drug Distribution ◽  
Maximum Tolerated Dose ◽  
Target Engagement ◽  
Learning Program ◽  
Post Dose ◽  
Tumor Biopsy

3077 Background: MLN9708 is a potent investigational proteasome inhibitor, which upon intravenous (IV) administration immediately hydrolyzes to the active form MLN2238. MLN9708 is currently being evaluated in a phase 1 trial in solid tumors (NCT00830869). This trial has a dose-escalation arm and five expansion cohorts: non-small cell lung cancer (NSCLC), soft tissue sarcoma, head and neck cancer, prostate cancer, and a tumor biopsy cohort of mixed histology. The purpose of the tumor biopsy cohort was to obtain pre- and post-dose biopsies to determine drug distribution and target engagement in post-dose tumor samples. The latter was measured by the increase in levels of ATF-3, a marker of unfolded protein response/endoplasmic reticulum stress, which is upregulated in response to proteasome inhibition. Methods: The tumor biopsy cohort included 20 patients dosed at the maximum tolerated dose who consented to core needle biopsies during screening and after either the first or second dose of MLN9708 (IV 1.76 mg/m2; 4–20 hours post-dose). Tumor biopsies were individually weighed, homogenized, and analyzed for the presence of MLN2238 using a quantified LC/MS/MS methodology. ATF-3 levels in tumors were determined by an immunohistochemical assay (IHC) on six sections for each tumor biopsy. Tumor area was identified using Aperio Genie, a machine learning program for pattern recognition, and the percentage of ATF-3 positive area in the tumor was measured. Results: Biopsies from 20 patients were collected for assessment of drug distribution and target engagement. Ten patients with paired pre- and post-dose biopsies of sufficient size were considered evaluable for PK analysis; MLN2238 was present in all 10 (100%) post-dose biopsies analyzed. Tumor pairs from 7 patients passed quality control by H&E staining for tumor content and were evaluable for ATF-3 IHC. Six of 7 paired samples (86%) showed a statistically significant (p<0.05) increase in post-dose ATF-3 levels. Conclusions: Overall, emerging data from MLN9708 phase 1 solid tumor analysis show that MLN2238 is present in tumors and demonstrates target engagement upon inhibition of the proteasome in tumor tissue biopsies.

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