scholarly journals A Phase Ib Clinical Trial of Metformin and Chloroquine in Patients with IDH1-Mutated Solid Tumors

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2474
Author(s):  
Mohammed Khurshed ◽  
Remco J. Molenaar ◽  
Myra E. van Linde ◽  
Ron A. Mathôt ◽  
Eduard A. Struys ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Solid Tumors ◽  
Intrahepatic Cholangiocarcinoma ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Idh1 Mutation ◽  
Resonance Spectroscopy ◽  
Isocitrate Dehydrogenase 1 ◽  
Who Grade ◽  
Phase Ib

Background: Mutations in isocitrate dehydrogenase 1 (IDH1) occur in 60% of chondrosarcoma, 80% of WHO grade II-IV glioma and 20% of intrahepatic cholangiocarcinoma. These solid IDH1-mutated tumors produce the oncometabolite D-2-hydroxyglutarate (D-2HG) and are more vulnerable to disruption of their metabolism. Methods: Patients with IDH1-mutated chondrosarcoma, glioma and intrahepatic cholangiocarcinoma received oral combinational treatment with the antidiabetic drug metformin and the antimalarial drug chloroquine. The primary objective was to determine the occurrence of dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD). Radiological and biochemical tumor responses to metformin and chloroquine were investigated using CT/MRI scans and magnetic resonance spectroscopy (MRS) measurements of D-2HG levels in serum. Results: Seventeen patients received study treatment for a median duration of 43 days (range: 7–74 days). Of twelve evaluable patients, 10 patients discontinued study medication because of progressive disease and two patients due to toxicity. None of the patients experienced a DLT. The MTD was determined to be 1500 mg of metformin two times a day and 200 mg of chloroquine once a day. A serum D/L-2HG ratio of ≥4.5 predicted the presence of an IDH1 mutation with a sensitivity of 90% and a specificity of 100%. By utilization of digital droplet PCR on plasma samples, we were able to detect tumor-specific IDH1 hotspot mutations in circulating tumor DNA (ctDNA) in investigated patients. Conclusion: Treatment of advanced IDH1-mutated solid tumors with metformin and chloroquine was well tolerated but did not induce a clinical response in this phase Ib clinical trial.

Lurbinectedin (LUR) in combination with Irinotecan (IRI) in patients (pts) with advanced solid tumors: Updated results from a phase Ib-II trial.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3514-3514
Author(s):  
Santiago Ponce Aix ◽  
Gregory Michael Cote ◽  
Alejandro Falcon Gonzalez ◽  
Juan Manuel Sepulveda ◽  
Elizabeth Jimenez Aguilar ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Antitumor Activity ◽  
Solid Tumors ◽  
Maximum Tolerated Dose ◽  
Fixed Dose ◽  
Advanced Solid Tumors ◽  
Phase Ib ◽  
Starting Dose ◽  
Ecog Ps ◽  
Dose Levels

3514 Background: LUR is a novel agent that exerts antitumor activity through inhibition of trans-activated transcription and modulation of tumor microenvironment. Preclinical synergism/additivity in combination with IRI has been reported, thus prompting the conduct of this clinical trial. Methods: Phase Ib-II trial to evaluate escalating doses of LUR on Day (D) 1 plus a fixed dose of IRI 75 mg/m2 on D1 and D8 every 3 weeks (q3w) in pts with advanced solid tumors (+/- G-CSF, if dose-limiting toxicities [DLTs] were neutropenia). Starting dose was LUR 1.0 m/m2 + IRI 75 mg/m2. Results: 77 pts have been treated to date at 5 dose levels, 51 of them at the recommended dose (RD). Baseline characteristics of all 77 pts were: 48% females, 68% ECOG PS=1; median age 57 years (range, 19-75 years); median of 2 prior lines (range, 0−4 lines). The maximum tolerated dose (MTD) was LUR 2.4 mg/m2 + IRI 75 mg/m2 with G-CSF, and the RD was LUR 2.0 mg/m2 + IRI 75 mg/m2 with G-CSF. DLTs in Cycle 1 occurred in 2/3 evaluable pts at the MTD and 3/13 evaluable pts at the RD, and comprised omission of IRI D8 infusion due to grade (G) 3/4 neutropenia (n=3 pts) or G2-4 thrombocytopenia (n=2). At the RD (n=51), common G1/2 non-hematological toxicities were nausea, vomiting, fatigue, diarrhea, anorexia and neuropathy. G3 non-hematological toxicities (diarrhea 10%, fatigue 10%) and G3/4 hematological abnormalities (neutropenia 49%, thrombocytopenia 10%) were transient. Conclusions: The combination of LUR and IRI had acceptable tolerance, with no unexpected toxicities. Transient myelosuppression was dose-limiting. The RD is LUR 2.0 mg/m2 on D1 + IRI 75 mg/m2 on D1 and D8 q3w with G-CSF. Antitumor activity was observed at the RD in SCLC pts, as well as in endometrial carcinoma pts. Hints of activity were also observed in STS pts. Updated results will be presented. Clinical trial information: NCT02611024 . [Table: see text]

scholarly journals NCOG-38. CLINICAL CHARACTERISTICS OF LOW GRADE GLIOMA PATIENTS WITH NON-CANONICAL IDH1 AND IDH2 MUTATIONS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii137-ii137
Author(s):  
Katherine Peters ◽  
Eric Lipp ◽  
Gloria Broadwater ◽  
James Herndon ◽  
Margaret Johnson ◽  
...  
Keyword(s):  
Clinical Characteristics ◽  
Point Mutations ◽  
Progression Free Survival ◽  
Idh1 Mutation ◽  
Low Grade ◽  
Isocitrate Dehydrogenase 1 ◽  
Who Grade ◽  
Targeted Mutation ◽  
Kaplan Meier ◽  
Idh1 And Idh2 Mutations

Abstract BACKGROUND Low grade gliomas (LGGs) develop in young adults and represent 10-15% of all glial tumors. While LGG patients can have longer survival than higher grade tumors, progression, transformation, and ultimately mortality occurs. Mutations in Isocitrate dehydrogenase 1/2 (IDH1/IDH2) are prevalent in LGG and are responsible for gliomagenesis. The classic IDH1 mutation is located at 132 codon and represented as p.Arg132His, but there are non-canonical IDH1 and IDH2 mutations. We sought to compare clinical characteristics of LGG patients with classic IDH1 p.Arg132His mutation to LGG patients with non-canonical IDH1 and IDH2 mutations. METHODS We queried an IRB-approved registry retrospectively from 12/2004- 9/2019. We included IDH1/IDH2 mutant LGG (WHO grade II) and known IDH1 and IDH2 targeted mutation analysis using standard PCR followed by DNA sequencing to detect point mutations in IDH1/IDH2 genes. We obtained available clinical and histopathological data. We estimated progression-free survival (PFS), time to transformation (TT), and overall survival (OS) using Kaplan-Meier methods. RESULTS We identified 267 LGG patients with median follow-up of 9.1 yrs (95%CI 8.4-9.9 yrs). Classic IDH1 p.Arg132His mutation occurred in 223 (83.9%) patients. IDH2 mutations occurred in 14 (5.2%) patients. Non-canonical IDH1 mutations were in 30 (11.2%) patients and included the following mutations: p.Arg132Cys (13), p.Arg132Gly (10), p.Arg132Ser (4), p.Arg132Leu (1), p.Arg119Gln (1), and p.Arg172Met (1). Initial presentation, OS, and TT did not differ between IDH1/IDH2 groups. PFS differed significantly between groups with improved median PFS in IDH2 mutant LGG (5.4 yrs; 95%CI 3.5-25.2) versus classic IDH1 mutant LGG (4.1 yrs; 95%CI 3.7-4.9 yrs) and non-canonical IDH1 mutant LGG (2.6 yrs; 95%CI 2.1-4.8) (log-rank p=0.019). Notably, non-canonical mutations were more common in astrocytoma (22/30; 73.3%) than other LGG histologies (p=0.018). CONCLUSIONS In this cohort, LGG patients with non-canonical mutations have a shorter time to progression than patients with classic p.Arg132His mutation and IDH2 mutations.

scholarly journals A first-in-human, phase 1 study of the NEDD8 activating enzyme E1 inhibitor TAS4464 in patients with advanced solid tumors

2021 ◽  
Author(s):  
Noboru Yamamoto ◽  
Toshio Shimizu ◽  
Kan Yonemori ◽  
Shigehisa Kitano ◽  
Shunsuke Kondo ◽  
...  
Keyword(s):  
Liver Function ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Enzyme Inhibitor ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Open Label ◽  
Phase 1 Study ◽  
Open Label Phase

SummaryBackground This open-label, phase 1 study investigated TAS4464, a potent NEDD8-activating enzyme inhibitor, in patients with advanced/metastatic solid tumors (JapicCTI-173,488; registered 13/01/2017). The primary objective was dose-limiting toxicities (DLTs). Maximum-tolerated dose (MTD) was investigated using an accelerated titration design. Methods The starting 10-mg/m2 dose was followed by an initial accelerated stage (weekly dosing; n = 11). Based on liver function test (LFT) results, a 14-day, 20-mg/m2 dose lead-in period was implemented (weekly dosing with lead-in; n = 6). Results Abnormal LFT changes and gastrointestinal effects were the most common treatment-related adverse events (AEs). DLTs with 56-mg/m2 weekly dosing occurred in 1/5 patients; five patients had grade ≥ 2 abnormal LFT changes at 40- and 56-mg/m2 weekly doses. Further dose escalation ceased because of the possibility of severe abnormal LFT changes occurring. DLTs with weekly dosing with lead-in occurred in 1/5 patients at a 56-mg/m2 dose; MTD could not be determined because discontinuation criteria for additional enrollment at that particular dose level were met. As no further enrollment at lower doses occurred, dose escalation assessment was discontinued. Serious treatment-related AEs, AEs leading to treatment discontinuation, and DLTs were all related to abnormal LFT changes, suggesting that TAS4464 administration could affect liver function. This effect was dose-dependent but considered reversible. Complete or partial responses to TAS4464 were not observed; one patient achieved prolonged stable disease. Conclusions MTD could not be determined due to TAS4464 effects on liver function. Further evaluation of the mechanism of NEDD8-activating enzyme inhibitor-induced abnormal liver function is required. Trial registration number JapicCTI-173,488 (registered with Japan Pharmaceutical Information Center). Registration date 13 January 2017

scholarly journals Ivosidenib in Isocitrate Dehydrogenase 1–Mutated Advanced Glioma

2020 ◽  
Vol 38 (29) ◽  
pp. 3398-3406 ◽  
Author(s):  
Ingo K. Mellinghoff ◽  
Benjamin M. Ellingson ◽  
Mehdi Touat ◽  
Elizabeth Maher ◽  
Macarena I. De La Fuente ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Isocitrate Dehydrogenase ◽  
Objective Response ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Adverse Event Rate ◽  
Low Grade ◽  
Lower Grade ◽  
Open Label ◽  
Isocitrate Dehydrogenase 1

PURPOSE Diffuse gliomas are malignant brain tumors that include lower-grade gliomas (LGGs) and glioblastomas. Transformation of low-grade glioma into a higher tumor grade is typically associated with contrast enhancement on magnetic resonance imaging. Mutations in the isocitrate dehydrogenase 1 ( IDH1) gene occur in most LGGs (> 70%). Ivosidenib is an inhibitor of mutant IDH1 (mIDH1) under evaluation in patients with solid tumors. METHODS We conducted a multicenter, open-label, phase I, dose escalation and expansion study of ivosidenib in patients with m IDH1 solid tumors. Ivosidenib was administered orally daily in 28-day cycles. RESULTS In 66 patients with advanced gliomas, ivosidenib was well tolerated, with no dose-limiting toxicities reported. The maximum tolerated dose was not reached; 500 mg once per day was selected for the expansion cohort. The grade ≥ 3 adverse event rate was 19.7%; 3% (n = 2) were considered treatment related. In patients with nonenhancing glioma (n = 35), the objective response rate was 2.9%, with 1 partial response. Thirty of 35 patients (85.7%) with nonenhancing glioma achieved stable disease compared with 14 of 31 (45.2%) with enhancing glioma. Median progression-free survival was 13.6 months (95% CI, 9.2 to 33.2 months) and 1.4 months (95% CI, 1.0 to 1.9 months) for the nonenhancing and enhancing glioma cohorts, respectively. In an exploratory analysis, ivosidenib reduced the volume and growth rates of nonenhancing tumors. CONCLUSION In patients with m IDH1 advanced glioma, ivosidenib 500 mg once per day was associated with a favorable safety profile, prolonged disease control, and reduced growth of nonenhancing tumors.

scholarly journals Preclinical investigations and a first-in-human phase I trial of M4112, the first dual inhibitor of indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase 2, in patients with advanced solid tumors

2020 ◽  
Vol 8 (2) ◽  
pp. e000870
Author(s):  
Aung Naing ◽  
Joseph P Eder ◽  
Sarina A Piha-Paul ◽  
Claude Gimmi ◽  
Elizabeth Hussey ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Trial ◽  
Ex Vivo ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Advanced Solid Tumors ◽  
Antitumor Effects ◽  
Dual Inhibitor ◽  
Indoleamine 2,3 Dioxygenase

BackgroundM4112 is an oral, potent, and selective indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) dual inhibitor. Here, we report preclinical data and first-in-human phase I data, including safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy, of M4112 monotherapy in patients with advanced solid tumors.MethodsIn preclinical studies, M4112 was administered to mice with IDO1-expressing tumors to determine tumor IDO1 and liver TDO2 inhibition. In the phase I trial, patients received doses of M4112 two times per day in 28-day cycles until progression, toxicity, or withdrawal of consent. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). The primary endpoint was the incidence of dose-limiting toxicities (DLTs), treatment-emergent adverse events (TEAEs), and treatment-emergent changes in safety parameters. Other endpoints included pharmacokinetics, pharmacodynamics, and antitumor effects.ResultsIn mice, M4112 significantly decreased the kynurenine:tryptophan ratio in the liver and tumor. Fifteen patients received M4112 at five distinct dose levels (three patients per cohort: 100, 200, 400, 600, and 800 mg two times per day orally). Initially, all doses inhibited IDO1 ex vivo, but plasma kynurenine levels returned to or exceeded baseline levels after day 15. Despite initial changes in kynurenine, there was no significant reduction of plasma kynurenine at steady state. There was one DLT (grade 3 allergic dermatitis; 800 mg two times per day) and one grade 2 QT prolongation (800 mg two times per day), resulting in dose reduction (not a DLT). M4112 was well tolerated, and neither the MTD nor the RP2D was established. TEAEs included fatigue, nausea, and vomiting. The best overall response was stable disease (n=9, 60%).ConclusionsThere were no serious safety concerns at any dose. Although M4112 inhibited IDO1 activity ex vivo, plasma kynurenine levels were not reduced despite achieving target exposure.Trial registration numberNCT03306420.

Phase I evaluation of AZD2171, a highly potent and selective inhibitor of VEGFR signaling, in combination with selected chemotherapy regimens in patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3034-3034 ◽  
Author(s):  
P. M. Lorusso ◽  
E. Heath ◽  
M. Valdivieso ◽  
M. Pilat ◽  
A. Wozniak ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Growth Factor Receptor ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Selective Inhibitor ◽  
Minor Response ◽  
Heavily Pretreated ◽  
Grade 3

3034 Background: AZD2171 is an oral, potent, selective inhibitor of vascular endothelial growth factor receptor (VEGFR). Trials have demonstrated that inhibition of the VEGF pathway, in combination with certain chemotherapy, provides benefit to patients with a broad range of solid tumors. Methods: This Phase I trial was conducted in heavily pretreated solid tumor patients. In a single protocol, escalating doses of AZD2171 were evaluated (20, 30 and 45 mg) in combination with four separate chemotherapy regimens: mFOLFOX6 (oxaliplatin 85 mg/m2; 5-FU 400 mg/m2; leucovorin 400 mg/m2 q2 weeks; Arm 1); irinotecan 300 mg/m2 q3 week (Arm 2); docetaxel 75 mg/m2 (Arm 3) and pemetrexed 500 mg/m2 (Arm 4). The primary objective was to evaluate safety and tolerability of the combinations and secondary objective to evaluate pharmacokinetic (PK) interaction and clinical efficacy. Maximum tolerated dose (MTD) toxicity was defined through two cycles. Results: 46 patients have been enrolled: 28/35 evaluable for efficacy/toxicity. The MTD has been reached in two arms: Arm 2 - 20 mg AZD2171 and Arm 4 - 30 mg AZD2171. Arm 3 enrollment continues at 45 mg AZD2171. Two dose-limiting toxicities (DLTs) were observed in eight patients at 30 mg AZD2171 in Arm 1. Enrollment of an additional cohort of less heavily pre-treated patients is ongoing to determine the tolerability of 30 mg AZD2171 with FOLFOX. DLTs have included grade 3 fatigue in Arms 1, 2 & 4; grade 3 diarrhea in Arm 1; grade 3 hand-foot syndrome & grade 4 neutropenic fever in Arm 2; and grade 3 hypertension in Arm 4. AZD2171 did not appear to have a major effect on the PK profile of any chemotherapy regimen tested. Steady-state values are comparable with AZD2171 monotherapy. There have been 13 responses (minor response, n=5; partial response, n=6; complete response, n=2; stable disease ≥ 4 cycles, n=6) in heavily pretreated patients, some having demonstrated resistance to identical chemotherapies. Duration of response has been impressive (4-22+ cycles). Conclusions: AZD2171 combinations have been well tolerated with expected toxicities and encouraging responses. [Table: see text]

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.

Cabazitaxel plus cisplatin coadministration and drug-interaction study in patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e15116-e15116
Author(s):  
Alain C. Mita ◽  
Shankar Sundaram ◽  
John Sarantopoulos ◽  
Monica M. Mita ◽  
Alex R. Lane ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Solid Tumors ◽  
Dose Level ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Primary Tumors ◽  
Grade 3 ◽  
Ecog Ps ◽  
Cyp3a Inhibitor

e15116 Background: Cabazitaxel (Cbz) is a novel taxane with in vivo efficacy in taxane-sensitive and -resistant tumors. Therapeutic synergism of Cbz/cisplatin (Cis) has been shown in tumor-bearing mice. Since Cbz is primarily metabolized by CYP3A, drug interactions may occur with modulators of CYP3A. Methods: The primary objective of part 1 of this phase I study (NCT00925743) was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of Cbz/Cis. Secondary objectives included safety, pharmacokinetics (PK) and efficacy. The objective of part 2 was to assess efficacy at the MTD. The effect of the antiemetic aprepitant (a moderate CYP3A inhibitor) on the PK of Cbz was also examined. Eligible patients (pts) had ECOG PS ≤ 1 and confirmed metastatic or unresectable solid tumors for which Cis therapy was considered appropriate. A 3 + 3 dose escalation at a starting dose (level 0) of 20/75 mg/m2 (Cbz/Cis), administered IV Q3W, was used. The MTD was the highest dose at which 0/3 or ≤ 1/6 pts experienced a DLT in Cycle 1. Results: Pts (n = 25; 10 in part 1; 15 in part 2) with a median age of 56 yrs were enrolled. The most frequent primary tumors were lung (n = 4), prostate, ovary and pancreas (each n = 2). Of 6 evaluable pts, 2 had a DLT at dose level 0 (Grade 3 acute renal failure; febrile neutropenia). The MTD was 15/75 mg/m2 as no DLTs were observed; 18 pts were treated at the MTD and 60 cycles were administered (median = 3; range 1–8). The most frequent non-hematologic treatment-related adverse events (all grades/grade 3–4) were nausea (78%/22%), vomiting (72%/11%), fatigue (61%/17%), anorexia (67%/11%) and diarrhea (44%/0%). Incidence of grade 3–4 neutropenia was 78%; 1 pt had febrile neutropenia. The combined PK profile of Cbz/Cis did not appear to differ vs those of the single agents. The ratio of Cbz clearance with vs without aprepitant co-administration was 0.81 (90% CI 0.36–1.85). Stable disease was seen in 11 pts; 1 pt (prostate carcinoma) had an unconfirmed partial response. Conclusions: The MTD of Cbz/Cis was 15/75 mg/m2. The combination had a manageable safety profile consistent with a platinum/taxane combination. No PK interactions between Cis and Cbz were seen; aprepitant did not appear to alter the PK of Cbz.

Tolerability of split-dose oprozomib (ONX 0912) in patients with advanced refractory or recurrent solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13077-e13077
Author(s):  
Kyriakos P. Papadopoulos ◽  
David S. Mendelson ◽  
Anthony W. Tolcher ◽  
Howard A. Burris ◽  
Michael S. Gordon ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Solid Tumors ◽  
Phase 1 ◽  
Dose Schedule ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Status Change ◽  
Dose Escalation Study ◽  
Split Dose ◽  
Grade 3

e13077 Background: Oprozomib (ONX0912), a structural analog of carfilzomib, is an orally bioavailable proteasome inhibitor that irreversibly binds to its target and is being evaluated in hematologic malignancies and solid tumors (ST). In a dose-escalation study of once-daily (qd) ONX0912, the maximum tolerated dose (MTD) was 150 mg/d. The protocol was subsequently amended to investigate the effects of a split-dose schedule. Presented here are the interim results from this patient (pt) group. Methods: This is an ongoing, phase 1 study in pts with advanced refractory or recurrent ST. The primary objective is to evaluate the safety and tolerability of ONX0912 and determine the MTD. ONX0912 is administered for 5 consecutive days in 14-day cycles. For pts under the amended regimen, treatment is initiated at 60 mg BID, with 4–6 h between doses. Daily doses are escalated in 30 mg increments in successive groups of 3 pts. Groups are expanded to include 6 pts in the event of a dose-limiting toxicity (DLT) or if the MTD is reached. All AEs, including serious AEs (SAEs), are defined per protocol and collected from screening to 30 days after the last dose. Results: 13 pts received a split dose of ONX0912 (4 pts: 60 mg BID; 3 pts: 90/60 mg; 6 pts: 90 mg BID). At least 1 dose reduction was required by 1 pt in the 90/60 mg group and 2 pts in the 90 mg BID group. 9 pts reported treatment-related GI AEs (vomiting, n=9; nausea, n=8; diarrhea, n=5). 2 SAEs, arthralgia and mental status change, were reported at 60 mg BID. 2 SAEs resulting in a dose delay were reported at 90/60 mg (Grade 3/4 anemia [ongoing, also required a dose reduction] and reversible fatigue). There was 1 DLT at 90 mg BID (Grade 3 reversible hypophosphatemia), and this cohort was therefore expanded. Treatment-related vomiting led to discontinuation for 1 patient at 60 mg BID. No AEs led to early withdrawal, and no deaths have been reported in the study. Conclusions: With qd administration, the MTD of ONX0912 was established at 150 mg/d. However, the MTD has not been reached on the split-dose regimen at cumulative doses up to 180 mg/d (90 mg BID). GI AEs were the most common treatment-related AEs. Based on these preliminary observations, split-dose ONX0912 may improve tolerability over qd dosing.

Phase I study of pazopanib (PAZ) in combination with PCI-24781 (PCI) in patients (pts) with metastatic solid tumors with new tumor proliferation imaging correlates in renal cell carcinoma (RCC) and sarcoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS2623-TPS2623
Author(s):  
Thach-Giao Truong ◽  
Jennifer A. Grabowsky ◽  
Stephanie Chen ◽  
Roth Ea ◽  
Andrew H. Ko ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Solid Tumors ◽  
Phase Iii ◽  
Current Status ◽  
Thymidine Uptake ◽  
Tumor Proliferation ◽  
Phase Ib ◽  
Flt Pet ◽  
Expansion Cohort

TPS2623 Background: PAZ is a multi-targeted tyrosine kinase inhibitor of VEGFR, PDGFR, and C-KIT, approved for metastatic RCC and refractory sarcoma based on phase III data showing prolonged PFS (JCO 2010;28:1061-8 and Lancet 2012;379:1879-86). PCI is a potent pan-HDAC inhibitor (pan-HDACi), observed in cell lines to change regulation of genes involved in cell signaling, apoptosis, proliferation, differentiation, and angiogenesis (Anticancer Res 2011;31:1115-23). Pre-clinical models suggest epigenetic modification with an HDACi potentiates PAZ’s efficacy by causing chromatin instability and gene expression changes involved in drug resistance (Can Res 2005;65:3815-22 and BJC 2009;100:758-63). We therefore designed a Phase Ia/b clinical trial combining PCI with PAZ in pts with advanced solid tumors, with an expansion cohort for preliminary efficacy in RCC and sarcoma. Methods: Primary objective of this phase Ia/b study is to evaluate the safety and tolerability of the combination of PAZ and PCI to determine the MTD and RP2D. In phase Ia, we utilized an accelerated phase I design. The phase Ib portion will include up to 20 pts per expansion cohort, for up to 32-70 pts enrolled. In phase 1a, pts receive run-in PCI alone on C1D-7 to D-4. Starting with C1D1, pts receive oral PCI on D1-5, 8-12, 15-19 BID 4 hrs apart and PAZ daily (D1-28) q28D cycle. CORRELATIVES: Pre- and post-treatment (Tx) H3 & H4 acetylation and HDAC activity in PBMCs. In phase Ib, these will also be studied in tumor biopsies. We will measure expression of VEGF, VEGFR, RAD51, HIF, Ki67; and analyze SNPs through genomic profiling. We will correlate response with pre- and post-Tx tumor thymidine uptake using 18F-fluorothymidine (FLT-PET) PET. Current Status: This is the 1st trial exploring the combination of an HDACi with PAZ in RCC and sarcoma, where there is an unmet need for new tolerable therapies. It will study FLT-PET, an imaging correlate that captures tumor proliferation and may have a role as a predictive biomarker. We are currently in phase Ia. Enrollment in the 3rd cohort exploring higher doses of PAZ will begin in Feb 2013. Clinical trial information: NCT01543763.

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