Effect of ketoconazole on the pharmacokinetics and pharmacodynamics of ixabepilone

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2005-2005 ◽  
Author(s):  
S. Goel ◽  
G. Goldberg ◽  
L. C. Iacono ◽  
M. Cohen ◽  
T. Griffin ◽  
...  
Keyword(s):  
Oxidative Metabolism ◽  
Mononuclear Cells ◽  
Phase 1 ◽  
Geometric Mean ◽  
Single Agent ◽  
Recommended Dose ◽  
Clinical Activity ◽  
Open Label ◽  
Peripheral Blood Mononuclear

2005 Background: Ixabepilone (Ixa) is the first analog in a new class of antineoplastic agents, the epothilones, which stabilizes microtubules and induces apoptosis. Ixa has shown clinical activity in a broad range of tumors. Oxidative metabolism by CYP3A4/5 appears to be a prominent route of Ixa biotransformation in vitro. As a single agent, the recommended dose is 40 mg/m2 over 3 hours once every three weeks. Methods: This was an open-label, sequential study to assess the effect of CYP3A4/5 inhibition on the pharmacokinetics (PK) and pharmacodynamics (PD) of Ixa. Ketoconazole (K) was used as a model inhibitor of CYP3A4/5. Patients were administered a single 10 (n=4), 20 (n=12), 25 (n=7) or 30 (n=4) mg/m2 intravenous (iv) infusion of Ixa with K (400 mg/d orally x 6 days) during cycle 1, and a single 40 mg/m2 iv infusion of Ixa during Cycle 2. Cycles were repeated every 21 days. Detailed PK and PD analysis was performed in cycles 1 and 2. Results: The observed adjusted geometric mean of Ixa AUC for subjects with K was 2892 vs. 1628 ng/mL*hr in subjects without K. The ratio of the geometric means of normalized Ixa AUC and Cmax in Cycle 1/Cycle 2 were 1.78 and 1.07, respectively. The percent of peripheral blood mononuclear cells with tubulin bundle formation after administration of 20 mg/m2 Ixa with K was similar to that observed with single agent Ixa at a dose of 40 mg/ m2. The maximum tolerated dose of Ixa with K was 20 mg/m2. Dose limiting toxicities of Ixa with K were similar to those observed in previous Phase 1 studies of single agent Ixa and included prolonged neutropenia, febrile neutropenia, mucositis, elevated liver function enzymes, and fatigue. Conclusions: Oxidative metabolism by CYP3A4/5 appears to be a clinically important route of Ixa biotransformation. Inhibition of CYP3A4/5 by K affects the Ixa tolerable dose, increases the AUC and results in similar PD effects at half the recommended dose. [Table: see text]

First-in-human phase I trial of the dual mTORC1 and mTORC2 inhibitor AZD2014 in solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3004-3004 ◽  
Author(s):  
Udai Banerji ◽  
Emma Jane Dean ◽  
Michael Gonzalez ◽  
Alastair P Greystoke ◽  
Bristi Basu ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Platelet Rich Plasma ◽  
Geometric Mean ◽  
Study Drug ◽  
Experimental Models ◽  
Oral Solution ◽  
Clinical Activity ◽  
Peripheral Blood Mononuclear

3004 Background: AZD2014 is a potent, dual mTORC1/mTORC2 inhibitor with clear activity in in vivo and in vitro experimental models. Methods: This 2-part study consisted of "rolling six" dose escalation (Part A) and expansion (Part B) phases. Part A: 3–6 pts per cohort received an oral solution of AZD2014 BD starting at 50 mg. A further 6 pts were treated in Part A below the MTD to study changes in pharmacodynamic (PD) biomarkers. Part B: additional pts were dosed at the MTD, including a group of ER+/PR+ or HER2+ patients with breast cancer. Primary endpoint: safety and tolerability; secondary endpoints: pharmacokinetics (PK), PD and efficacy. Biomarkers assessed: mTORC1: pS6 (S235/236) and p4EBP1 (T37/46); mTORC2: pAKT (S473). Results: 50 pts have been enroled in this ongoing study and interim data are reported: Part A, n=23 (25 mg, n=6; 50 mg, n=8; 70 mg, n=5; 100 mg, n=4; all BD); Part B, n=27. The MTD was 50 mg BD. DLTs were seen at both 100 mg (Gr 2 and 3 lethargy/fatigue, n=4/4) and 70 mg (Gr 3 mucositis, Gr 2 lethargy, n=2/4); no DLTs were seen at 25 mg or 50 mg. The most common AEs in order of incidence were fatigue, stomatitis, decreased appetite, nausea and diarrhea. Seven SAEs (nausea, vomiting, lethargy, abdominal pain, mucositis) reported by 3 pts were considered ‘possibly related’ to the study drug by investigators. AZD2014 is rapidly absorbed following single and BD multiple doses with a short t1/2 of ~3 h. At 50 mg (n=32), preliminary data show geometric mean AUCss=7.4 µg.h/ml and Cmax ss=1.7 µg/ml. One pt with acinar pancreatic cancer had a RECIST partial response. pAKT and p4EBP1 reductions were observed between 2–8 h in platelet-rich plasma and peripheral blood mononuclear cells respectively. Target modulation in paired tumor biopsies was seen at the MTD. Reduction in the phosphorylation of S6 and 4EBP1 was evident in 8/10 and 3/9 paired biopsies respectively. pAKT was reduced in 3/6 evaluable paired biopsies. As opposed to rapalogs, pAKT was not upregulated in any of the evaluable post-treatment biopsies. Conclusions: The MTD for AZD2014 is 50 mg BD. Further clinical evaluation of AZD2014 is now warranted based on the safety, PK and proof-of-mechanism PD data, as well as its preliminary clinical activity. Updated results will be presented.

A phase I, first-in-human, open-label, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of oral TP-3654 administered daily for 28 days to patients with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3586-3586
Author(s):  
Ignacio Garrido-Laguna ◽  
Patrick Michael Dillon ◽  
Stephen Patrick Anthony ◽  
Margit Janat-Amsbury ◽  
Nissa Ashenbramer ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Mononuclear Cells ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Peripheral Blood Mononuclear

3586 Background: TP-3654 is an oral, second generation, potent PIM-1 kinase inhibitor with activity against PIM 2, 3 and favorable selectivity against other kinases. These cytoplasmic serine/threonine kinases are highly expressed in many cancers and their oncogenic potential has been largely attributed to supressing apoptosis downstream of stimuli including inflammatory cytokines and other immune effectors. TP-3654 has efficacy in various hematologic and solid tumor models inducing stromal Pim-1 also has been shown to mediate various aspects of the tumor microenvironment. Thus, Pim kinases are attractive targets for the treatment of many human malignanices. Methods: A first in human, multicenter, phase 1, dose escalation study using a standard 3+3 design with a modified Fibonacci scheme to examine the safety and clinical activity of TP-3654 in patients with advanced solid tumors. Results: Ten patients were enrolled between 30Apr and 31Dec2019 receiving 480, 720, and 1080 mg respectively. Grade 3 AEs were scrotum wound infection, altered mental status, anemia, fall, and lower extremity edema, none were related to study drug and all were manageable with supportive care. There were no Grade 4 or 5 AEs and no DLTs. Median duration of SD was 5.5 months (6/10) and with prolonged SD > 16wks (4/10). One CRC patient with 4 lines of prior therapy had a 22% reduction in tumor volume (SD > 5+ mos). TP-3654 plasma PK values (Cmax, AUC) continuously increased through all 3 cohorts. Average Cmax (ng/mL) and AUC0-24 (ng*hours/mL) were 195, 1965 (480mg); 357, 3310 (720mg); 735, 6922 (1080mg), respectively. PK values increased linearly with higher doses without reaching saturation. Peripheral Blood Mononuclear Cells were isolated from subjects prior and up to 24hours after treatment. Western Blot from protein lysates revealed a decrease in phosphorylation of BAD and p70s6K proteins, both regulated by PIM-1 kinase. Conclusions: These findings suggest that TP-3654 is tolerated as a monotherapy in patients with heavily pretreated, relapsed, and resistant solid tumors warranting further clinical development in selected indications.

First-in-human phase 1/1b expansion of PMD-026, an oral RSK inhibitor, in patients with metastatic triple-negative breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e13043-e13043
Author(s):  
Muralidhar Beeram ◽  
Pavani Chalasani ◽  
Judy S. Wang ◽  
Lida A. Mina ◽  
Rebecca Arielle Shatsky ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Mononuclear Cells ◽  
Phase 1 ◽  
Single Agent ◽  
Metastatic Breast ◽  
Clinical Activity ◽  
Open Label ◽  
Phase 1B

e13043 Background: P90 ribosomal S6 kinase (RSK) is an actionable molecular target against metastatic triple negative breast cancer (mTNBC). RSK is a major convergence point in the integral TNBC signaling pathways, MAPK and PDK-1. PMD-026 is a first-in-class oral RSK inhibitor with high selectivity. The dose escalation portion of this study established the RP2D of PMD-026 as 200 mg Q12. PMD-026 demonstrated good plasma exposure following oral dosing, with a T1/2 of ̃ 6 h (range 4-8 h), and achieved the targeted preclinical efficacious concentrations using a Q12h dosing schedule. PMD-026 also demonstrated a tolerable safety profile and initial signs of efficacy in patients with metastatic breast cancer. The intensity of RSK2 activation ranged from an H Score of 110-268 based on a CLIA companion immunohistochemistry assay. We present initial data from the expansion cohort. Methods: The primary aim of this single-arm, open-label, first-in-human phase 1/1b study is to evaluate the safety of single agent PMD-026 in patients with mTNBC. Secondary endpoints are clinical activity, pharmacokinetics, and correlative biomarker expression on tumor specimens. Patients are dosed at 200 mg twice daily in 21-day cycles. Eligible patients have measurable disease as per RECIST v1.1 and have had disease progression on or after standard of care treatment. Tumor tissue is assessed to retrospectively correlate RSK2 activity by immunohistochemistry (IHC) with clinical outcomes. Pharmacokinetics are assessed along with a food effect (sub-study with n=12). In addition, a pharmacodynamic marker, YB-1 phosphorylation, is being explored in peripheral blood mononuclear cells before and during treatment. Results: As of February 16, 2021, 7 patients with mTNBC (median age 62 years, range 33-74) have been enrolled in the phase 1b Expansion (median of 7 prior lines of therapy). Notable prior therapies in the phase 1b include sacituzumab govitecan (n=4) and atezolizumab/nab-paclitaxel (n=1). Patients in escalation and expansion treated with the RP2D had median progression free survival of 30 vs 99 days for low vs high RSK2 expression, respectively. This cut-off will be further evaluated in the expansion phase of the study. Conclusions: Updated safety, clinical activity, pharmacokinetic, and biomarker analyses will be presented. Target accrual for phase 1b Expansion is a minimum of 20 patients with mTNBC. Clinical trial information: NCT04115306.

scholarly journals An open-label, phase II multicohort study of an oral hypomethylating agent CC-486 and durvalumab in advanced solid tumors

2020 ◽  
Vol 8 (2) ◽  
pp. e000883
Author(s):  
Kirsty Taylor ◽  
Helen Loo Yau ◽  
Ankur Chakravarthy ◽  
Ben Wang ◽  
Shu Yi Shen ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Mononuclear Cells ◽  
Dna Demethylation ◽  
Lessons Learned ◽  
Clinical Activity ◽  
Open Label ◽  
Peripheral Blood Mononuclear ◽  
Global Methylation ◽  
Hypomethylating Agent ◽  
Tumor Biopsies

PurposeTo evaluate whether administration of the oral DNA hypomethylating agent CC-486 enhances the poor response rate of immunologically ‘cold’ solid tumors to immune checkpoint inhibitor durvalumab.Experimental designPD-L1/PD-1 inhibitor naïve patients with advanced microsatellite stable colorectal cancer; platinum resistant ovarian cancer; and estrogen receptor positive, HER2 negative breast cancer were enrolled in this single-institution, investigator-initiated trial. Two 28 day regimens, regimen A (CC-486 300 mg QD Days 1–14 (cycles 1–3 only) in combination with durvalumab 1500 mg intravenous day 15) and regimen B (CC-486 100 mg QD days 1–21 (cycle 1 and beyond), vitamin C 500 mg once a day continuously and durvalumab 1500 mg intravenous day 15) were investigated. Patients underwent paired tumor biopsies and serial peripheral blood mononuclear cells (PBMCs) collection for immune-profiling, transcriptomic and epigenomic analyzes.ResultsA total of 28 patients were enrolled, 19 patients treated on regimen A and 9 on regimen B. The combination of CC-486 and durvalumab was tolerable. Regimen B, with a lower dose of CC-486 extended over a longer treatment course, showed less grade 3/4 adverse effects. Global LINE-1 methylation assessment of serial PBMCs and genome-wide DNA methylation profile in paired tumor biopsies demonstrated minimal changes in global methylation in both regimens. The lack of robust tumor DNA demethylation was accompanied by an absence of the expected ‘viral mimicry’ inflammatory response, and consequently, no clinical responses were observed. The disease control rate was 7.1%. The median progression-free survival was 1.9 months (95% CI 1.5 to 2.3) and median overall survival was 5 months (95% CI 4.5 to 10).ConclusionsThe evaluated treatment schedules of CC-486 in combination with durvalumab did not demonstrate robust pharmacodynamic or clinical activity in selected immunologically cold solid tumors. Lessons learned from this biomarker-rich study should inform continued drug development efforts using these agents.Trial registration numberNCT02811497.

A Phase 1/2 Study Of KW-2478, An Hsp 90 Inhibitor, In Combination With Bortezomib (BTZ) In Patients (Pts) With Relapsed/Refractory (R/R) Multiple Myeloma (MM)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1967-1967
Author(s):  
Cavanagh Jamie ◽  
Honorata Giongco Baylon ◽  
Priscilla B. Caguioa ◽  
Faith E. Davies ◽  
Mecide Gharibo ◽  
...  
Keyword(s):  
Phase 1 ◽  
Single Agent ◽  
Xenograft Model ◽  
Clinical Activity ◽  
Synergistic Activity ◽  
Dependent Manner ◽  
Phase 2 ◽  
Hsp90 Inhibition ◽  
Hsp 90

Abstract Background KW-2478 is a potent Hsp 90 inhibitor that binds to Hsp 90 with an IC50 value of 3.8 nmol/L. In preclinical studies, KW-2478 inhibited the in vitro growth of myeloma cell lines at GI50 values of 0.12 – 0.39 µM and markedly inhibited the growth of myeloma xenografts in SCID mice in a dose-dependent manner. In vitro, KW-2478 and BTZ demonstrated synergistic activity against OPM-2/GFP cells and in the NCI-H929 xenograft model, the combination of KW-2478 and BTZ showed greater anti-growth activity than either agent alone. A single-agent Phase 1 study (KW-2478 administered daily x 5 every 14 days), showed no dose limiting toxicity (DLT) and Hsp90 inhibition was observed at doses >71 mg/m2. Aim To establish safety, tolerability and recommended Phase 2 dose (RP2D) of KW-2478 plus BTZ in pts with R/R myeloma and assess overall response rate (ORR) based on International Myeloma Working Group (IMWG) response criteria. The PK and PD of KW-2478 plus BTZ were characterized and progression-free survival (PFS) was investigated. Methods All patients had MM by IMWG criteria, had received at least 1 and no more than 3 prior MM regimens and had not responded or had relapsed, and had adequate renal function. Patients who received prior BTZ could not be refractory. This open-label study had 2 parts: A Phase 1 dose escalation (3 + 3 design) part followed by a Simon 2-stage Phase 2. KW-2478 and BTZ were administered on Days 1, 4, 8 and 11 of a 21-day cycle. In Phase 1, the doses of KW-2478 and BTZ were sequentially escalated until observation of DLT, MTD, or achievement of the maximal planned dose levels (KW-2478 175 mg/m2, BTZ 1.3 mg/m2). PK and PD samples were collected in C1 on Days 1 and 11, and Days 1, 4, 8, and 11, respectively. In Phase 2, if 11 or more responses were observed in the first 27 evaluable pts, then an additional 50 evaluable pts would be enrolled. Response was assessed at the end of each cycle and safety was assessed continuously. Results The study enrolled 95 pts who received at least one dose of study drug: 15 in Phase 1 and 80 in Phase 2; 86 pts received the RP2D (highest planned dose of KW-2478 175 mg/m2 /bortezomib 1.3 mg/m2). Median age was 65; 57% of pts were male. There was 1 DLT (presyncope) in Phase 1. The most common adverse events (AEs) were diarrhea (74%), nausea (61%), fatigue (55%), constipation (46%), vomiting (40%) and peripheral neuropathy (30%). Most AEs were Grade 2; 5 pts had Grade 4 AEs. Five pts had a Grade 4 thrombocytopenia and 3 pts had a Grade 4 neutropenia. The PK profiles for KW-2478 plus BTZ in combination were comparable to each agent’s individual PK profile. In the Phase 1 portion of the trial, Hsp70 levels, a marker of Hsp90 inhibition, increased in the peripheral blood mononuclear cells in all subjects (N = 13). Of the pts who received the RP2D, 79 pts were evaluable for IMWG response. The ORR was 39% (4% CR, 14% VGPR, and 22% PR); in pts who were bortezomib naïve (n = 50), the ORR was 48%. Median PFS was 26.4 weeks and median duration of response had not been reached at the time of this report. Six pts continue treatment at the time of data cut-off. Conclusions KW-2478 plus BTZ was well-tolerated when administered at the doses and schedule studied. Clinical activity was demonstrated in pts with R/R MM (ORR of 39%). PFS was 26.4 weeks Disclosures: Akinaga: Kyowa Kirin Pharmaceuticals: Employment, Equity Ownership. Kurman:Kyowa Kirin Pharmaceuticals: Consultancy. Novak:Kyowa Kirin Pharmaceuticals: Employment.

A phase I study of bortezomib (PS-341) in pediatric patients with relapsed or refractory leukemia: A Children’s Oncology Group study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 9021-9021 ◽  
Author(s):  
T. M. Horton ◽  
P. A. Thompson ◽  
L. R. Bomgaars ◽  
P. C. Adamson ◽  
M. Krailo ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Mononuclear Cells ◽  
Phase 1 ◽  
Single Agent ◽  
Altered Mental Status ◽  
26S Proteasome ◽  
Leukemic Cells ◽  
Peripheral Blood Mononuclear ◽  
Pediatric Leukemia ◽  
Leukemia Treatment

9021 Background: Bortezomib is a 26S proteasome inhibitor that is effective as a single agent for the treatment of multiple myeloma in adults. Bortezomib at a dose of 1.2 mg/m2 is well tolerated as a single agent in pediatric patients with solid tumors. This phase 1 study examined the tolerability and efficacy of bortezomib in pediatric patients with relapsed/refractory leukemia. Methods: Cohorts of 3–6 patients received bortezomib administered twice weekly (days 1, 4, 8 and 11) for two weeks every 21 days. Pharmacokinetics and NF-κB activation status were examined in peripheral blood mononuclear cells (PBMC) at 6, 12, and 24 hours following the first dose of bortezomib, and from bone marrow leukemic cells before treatment and on days 8 and 18 of the first treatment cycle. Results: Twelve patients (4 female, 8 male) (ALL=9, AML=3), median age 11y (range 1–18y), were enrolled at the 1.3 mg/m2 (6 enrolled, 3 evaluable) or 1.7 mg/m2 (6 enrolled, 2 evaluable) dose levels. Patients not fully evaluable for toxicity experienced disease progression prior to completing the first 21-day cycle of therapy. Two DLTs occurred at the 1.7 mg/m2 dose level. One patient had altered mental status and the other patient had febrile neutropenia associated with Grade 3 hypotension, Grade 4 renal insufficiency and hypoxia, followed by death on day 9 of cycle 1. No CRs or PRs were observed in the 10 patients evaluable for response. One patient had SD for 2 cycles. PK analysis (n= 5) revealed a Cl of 0.62 L/min/m2, Vd of 13 L/m2, and a terminal T1/2 of 12.6 h. NF-κB activation was inhibited in the leukemic blasts of 2 patients examined to date. Conclusions: Bortezomib was tolerated at 1.3 mg/m2 in children with relapsed/refractory leukemia. Although bortezomib appeared to inhibit NF-κB activation, it was ineffective as a single agent for pediatric leukemia treatment. No significant financial relationships to disclose.

A phase I, first-in-human, open label, dose-escalation and cohort expansion study of MGD019, a bispecific DART protein binding PD-1 and CTLA-4 in patients with unresectable or metastatic neoplasms.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS2661-TPS2661
Author(s):  
Jason J. Luke ◽  
Manish Sharma ◽  
Rachel E. Sanborn ◽  
Gregory Michael Cote ◽  
Johanna C. Bendell ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Dose Escalation ◽  
Cell Function ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Single Agent ◽  
Open Label ◽  
Biopsy Specimens

TPS2661 Background: Immune checkpoint molecules, including CTLA-4 and PD-1, attenuate the duration and strength of adaptive immune responses to limit immune-mediated tissue damage. Tumors may inhibit cellular immune activation by expressing ligands that bind checkpoint molecules and inhibit T-cell function in the tumor microenvironment. Blockade of these inhibitory pathways is the primary mechanism of action of several novel cancer immunotherapy agents. Combined blockade of PD-1 and CTLA-4 with two checkpoint inhibitors, ipilimumab and nivolumab, increases antitumor activity beyond either single agent alone in patients with metastatic melanoma or other malignancies. MGD019, a novel bispecific molecule that co-engages and coordinately inhibits both PD-1 and CTLA-4 signaling, was developed to potentially improve antitumor activity and/or safety relative to the monoclonal antibody combination. MGD019 is an Fc-bearing tetravalent DART molecule (bivalent for each antigen) that can independently block either checkpoint molecule, with preferential co-blockade in cells co-expressing both molecules demonstrated in vitro. It is hypothesized that MGD019 might be clinically active in either checkpoint naïve or checkpoint experienced patients after prior PD-1/PD-L1 inhibitors. Methods: This Phase 1 study will characterize safety, dose limiting toxicities, and maximum tolerated dose (MTD)/maximum administered dose (MAD) of MGD019. Dose Escalation will enroll patients with advanced solid tumors of any histology in sequential escalating doses in cohorts of 3 to 9 patients in a 3+3+3 design. Once the MTD/MAD is reached, a Cohort Expansion phase will characterize safety and initial antitumor activity per RECIST v1.1 and irRECIST in patients with specific tumor types anticipated to be sensitive to dual checkpoint blockade. Additional endpoints include pharmacokinetics; immunogenicity; impact of MGD019 on various measures of immune-regulatory effects in peripheral blood and biopsy specimens; and relationship between antitumor activity and gene profiles, tumor mutational burden, and PD-1, PD-L1, and CTLA-4 expression on tumor cells and immune cell infiltrates within biopsy specimens. Patients will be followed for survival approximately every 3 months for 2 years. Clinical trial information: NCT03761017.

A phase Ib/II study of olutasidenib in patients with relapsed/refractory IDH1 mutant solid tumors: Safety and efficacy as single agent.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16643-e16643
Author(s):  
Robin Lewis Jones ◽  
Teresa Macarulla ◽  
John A. Charlson ◽  
Brian Andrew Van Tine ◽  
Lipika Goyal ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase 1 ◽  
Single Agent ◽  
Median Number ◽  
Clinical Activity ◽  
Tumor Type ◽  
Dna Hypermethylation ◽  
Efficacy Evaluation ◽  
Open Label ◽  
Isocitrate Dehydrogenase 1

e16643 Background: Isocitrate dehydrogenase 1 mutations (mIDH1) are present in a variety of solid tumors resulting in production and accumulation of (R)-2-hydroxyglutarate causing DNA hypermethylation and promoting tumorigenesis. Olutasidenib is an oral, potent and selective inhibitor of mutated IDH1 protein. We report preliminary results from the ongoing, first-in-human, Phase 1, open-label, single-arm study of olutasidenib in non-CNS solid tumors. Methods: Patients with advanced relapsed/refractory (R/R) mIDH1 solid tumors received olutasidenib 150 mg BID, orally. Following a dose confirmation cohort (Phase 1b), patients with intrahepatic cholangiocarcinoma (IHCC), chondrosarcoma (CS), or unspecified mIDH1 solid tumors (Other) were enrolled in a Phase 2 efficacy evaluation (NCT: 03684811). Results: As of 31-Oct-2019, 44 patients with relapsed or refractory mIDH1 solid tumors were treated with olutasidenib. Diagnosis included: IHCC (n = 26), CS (n = 13), and Other (n = 5). The median age was 58 years (range: 29-81) and 43% were male. Median number of prior treatments was 2 (1-10). mIDH1 status was locally determined (IHC, NGS or PCR): R132C (61%), R132G (7%), R132S (7%), R132H (2%), R132L (2%), Others (2%) & unspecified (18%). Fourteen patients discontinued treatment (disease progression [n = 6; 3 IHCC, 2 CS, 1 Other], AE [n = 4; 3 IHCC, 1 CS], PI decision [n = 3; IHCC] & withdraw consent [n = 1; IHCC]). Treatment emergent adverse events (all grades, regardless of attribution) that occurred in > 15% of pts were: nausea (43%), fatigue (25%), decreased appetite (22%), AST increase (18%), ALT increase (16%), and constipation (16%). No protocol-defined DLTs occurred. Best responses by tumor type are shown in the table. Conclusions: Single agent olutasidenib at 150 mg BID demonstrates acceptable safety and tolerability with preliminary clinical activity in patients with R/R mIDH1 solid tumors. Updated safety and clinical activity, as well as exploratory evaluations of PK/PD will be provided. Clinical trial information: 03684811 . [Table: see text]

Lumiliximab with fludarabine, cyclophosphamide, and rituximab (FCR) for patients with relapsed chronic lymphocytic leukemia (CLL)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6597-6597 ◽  
Author(s):  
S. O’Brien ◽  
J. C. Byrd ◽  
T. J. Kipps ◽  
A. Forero-Torres ◽  
I. W. Flinn ◽  
...  
Keyword(s):  
Safety Profile ◽  
Phase 1 ◽  
Performance Status ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Hematologic Toxicity ◽  
Phase 2 ◽  
Open Label ◽  
Prior Therapy

6597 Background: Lumiliximab, an anti-CD23 monoclonal antibody, had pharmacologic activity and an outstanding safety profile in a recently completed phase 1, single-agent study. Based on evidence of clinical activity, favorable safety profile, and preclinical data suggesting synergy with both fludarabine and rituximab, we initiated a combination study of lumiliximab with FCR in previously treated patients. Methods: Patients ≥18 years of age with relapsed CD23+ B-cell CLL were eligible for this open-label, dose-escalation, phase 1/2 study. Sample size was planned for ≤37 patients. Patients received either 375 mg/m2 or 500 mg/m2 of lumiliximab in combination with each 28-day cycle of FCR for 6 cycles. Primary objectives were to determine the safety profile, recommended phase 2 dose, and clinical activity of lumiliximab with FCR. Results: Accrual began in June 2004; 30 of the 31 patients were enrolled by December 2005; data are available for 28 patients. No dose-limiting toxicity was noted in the phase 1 component (375 mg/m2 dose, n=3, and 500 mg/m2 dose, n=6) and 500 mg/m2 was chosen for the phase 2 dose. All enrolled patients had progressive, symptomatic CLL as defined by NCI criteria, median 2 prior treatments (range, 1 to 9), median age 58, 64% males, 96% WHO performance status of ≤1. Seventeen patients experienced CTC Grade 3 or 4 adverse events (hematologic toxicity typically associated with FCR). Sixteen patients completed ≥3 cycles of treatment and were evaluated for response using NCI-WG criteria: 7 (44%) patients with confirmed complete responses (CRs); 1 with unconfirmed CR (pending marrow confirmation), 3 with partial responses (PRs), 4 with PRs awaiting confirmation, and 1 with disease progression. Twelve patients are not yet evaluable for response. Conclusions: Lumiliximab in combination with FCR is well tolerated and may enhance the activity of FCR for treatment of patients with progressive CLL after prior therapy. [Table: see text]

Decitabine (DAC) in combination with doxorubicin (DOX) and cyclophosphamide (CTX) in relapsed neuroblastoma (NBL): A Children's Oncology Group Study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 9565-9565
Author(s):  
R. George ◽  
J. Lahti ◽  
M. Ingle ◽  
M. Krailo ◽  
S. Blaney ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Low Dose ◽  
Mononuclear Cells ◽  
Phase 1 ◽  
Surrogate Marker ◽  
Tumor Burden ◽  
Caspase 8 ◽  
Peripheral Blood Mononuclear ◽  
Pre Treatment

9565 Background: Loss of caspase-8 expression causes resistance to apoptosis-inducing agents and potentiates metastasis in NBL. In vitro treatment of NBL cell lines with DAC results in increased caspase-8 expression and enhanced apoptosis following exposure to DOX. As a component of a pediatric phase 1 study, we evaluated low-dose DAC with DOX and CTX in a cohort of children with relapsed NBL. Promoter specific DNA methylation in peripheral blood mononuclear cells (PBMC) was studied. Methods: Patients received a 1-hour infusion of DAC, 5 mg/m2, daily on days 0–6, followed on day 7 by 45 mg/m2 of DOX (with dexrazoxane) and 1 g/m2 of CTX. All patients received G-CSF. Cycles were repeated every 28 days. Methylation-specific and quantitative PCR were used to measure promoter-specific DNA methylation in PBMC prior to and after DAC (day 7 and day 28). Results: Twelve patients with recurrent NBL (median age 9 years, 10 males) were enrolled. DAC/DOX/CTX was well tolerated with grade 4 myelosuppression being the predominant toxicity. Grade 4 neutropenia, median 11 days duration, occurred in 10 pts and grade 4 thrombocytopenia, median 10 days, in 7 patients. Eight patients had progressive disease after = 2 courses of therapy. The remaining 4 patients had stable disease with 5 to 8 courses. Methylation and subsequent demethylation (40–90% decreased methylation) of the MAGE-1 promoter was detected before and after DAC respectively, in PBMC from 6 of 9 patients analyzed to date. Re-expression of MAGE-1 mRNA was also demonstrated in post treatment samples. Caspase-8 demethylation was not detected in PBMC; nor was hypermethylation of caspase-8 detected in pre-treatment PBMC, possibly due to low tumor burden in blood. Conclusions: DAC in combination with cytotoxic chemotherapy was relatively well tolerated in heavily pre-treated children with relapsed NBL. Low-dose DAC induces demethylation and re-expression of MAGE-1 in PBMC, and may be a potential surrogate marker of demethylation within tumor cells. The use of low dose DAC in combination with other agents warrants further study in NBL. No significant financial relationships to disclose.

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