A phase I study of a novel taxane, TL310, orally administered every week in patients (pts) with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2544-2544 ◽  
Author(s):  
R. M. Glasspool ◽  
A. V. Boddy ◽  
T. R. Evans ◽  
M. J. Griffin ◽  
A. Anthoney ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Study Drug ◽  
Maximum Tolerated Dose ◽  
Model Systems ◽  
Clinical Activity ◽  
Neutropenic Sepsis ◽  
Grade 3 ◽  
Ecog Ps

2544 Background: TL310 is a novel, oral taxane with potent pre-clinical activity in taxane-resistant model systems. This is the first study to evaluate the safety, tolerability and pharmacokinetics (PK) of TL310 in pts with advanced refractory solid tumors. Methods: Pts with adequate hematologic, renal, and liver function received TL310 administered orally on days 1, 8 and 15 of a 28-day cycle. Pts were continuously assessed for safety and dose-limiting toxicity (DLT) was based on first cycle toxicity only. A rapid dose escalation schedule was used (1 pt per dose level until ≥ grade 2 toxicity then 3–6 patients per cohort). The maximum tolerated dose (MTD) was defined as the dose level below that at which ≥ 2 of 3–6 pts experienced DLT. PK sampling was performed on days 1, 2, 3–4, 8, 15, 16, 17–18, 22 of cycle one. Serial imaging with CT was performed every 8 weeks to assess response. Results: 18 patients [M=11, F=7], ECOG PS ≤ 2 were treated with doses of 5 (1 pt), 10 (1pt), 20 (1pt), 40(2pts), 80 (5pts), 120 (3pts) and 160 mg/m2 (5pts). 1 pt had grade 2 vomiting at 80mg/m2. This, and subsequent, dose levels were expanded to include 3 pts. 3 pts (2 at 80 and 1 at 160 mg/m2) vomited immediately after drug administration during cycle 1 and were replaced. 1/5 patients experienced a DLT at 160 mg/m2 with G5 neutropenic sepsis, G4 neutropenia and G4 thrombocytopenia. No other grade 3/4 toxicities attributed to study drug have occurred. Of 18 patients assessable for response, 1 had a partial response (gastric cancer) at 80 mg/m2 and 6 had stable disease for > 2 cycles (esophageal 3, melanoma 1, ovary 1, cervix 1). The maximum concentration (Cmax) increased with dose up to 120 mg/m2, but appeared to plateau (86±6 ng/ml) in 4 of 5 patients at 160 mg/m2. TL310 has a half-life of up to 80 hours, but PK were very similar on successive courses of treatment. Conclusions: TL310 can be administered orally up to 160 mg/m2 on day 1, 8, 15 of a 28 day cycle and shows promising activity at doses below the MTD. The MTD has not yet been defined and dose escalation continues. 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.

Phase Ib dose-escalation trial of the AKT inhibitor (AKTi) MK2206 in combination with paclitaxel (P) and trastuzumab (H) in patients (pts) with HER2-overexpressing (HER2+) cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2605-2605 ◽  
Author(s):  
Amy Jo Chien ◽  
Thach-Giao Truong ◽  
Michelle E. Melisko ◽  
Mark M. Moasser ◽  
Robin Katie Kelley ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Dose Level ◽  
Dose Escalation ◽  
Day Treatment ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Akt Inhibitor ◽  
Prior Therapy ◽  
Duration Of Response ◽  
Grade 3

2605 Background: AKT plays a key role in the survival, resistance, and overall aggressive pathogenesis of HER2+ malignancies, suggesting that AKTis may be of therapeutic value. MK2206 is a selective allosteric AKTi that has demonstrated synergy in combination with both H and P in preclinical studies. Methods: We conducted a phase 1b study of MK2206 in combination with weekly P 80 mg/m2 and H 2 mg/kg in pts with HER2+ solid tumors. MK2206 was given orally at a starting dose of 135 mg once a week (QW). Dose escalation was performed using a modified Ji method. The maximum tolerated dose (MTD) was defined as the dose level resulting in 3 or fewer dose limiting toxicities (DLTs) in 11 pts, then confirmed in 4 additional pts. Circulating tumor cells and PK samples were collected for all pts. Results: A total of 17 pts were enrolled, and 15 pts were evaluable for toxicity. All pts had HER2+ tumors (11 breast, 3 gastric, 1 esophageal). Based on interim toxicity data from other studies, the dose of MK2206 was not escalated beyond 135 mg QW. All 15 pts were treated at this dose level which was determined to be tolerable. Two DLTs were observed including grade 3 rash and grade 3 neutropenia resulting in a >7 day treatment delay. There were no severe adverse events (AEs) related to study treatment. Other grade 3/4 AEs were neutropenia (6 pts), febrile neutropenia (1 pt), peripheral neuropathy (1 pt), and depression (1 pt). The most common all-grade AEs include rash (13 pts), hyperglycemia (13 pts), neutropenia (13 pts), peripheral neuropathy (10 pts), diarrhea (9 pts), fatigue (9 pts), anorexia (9 pts), stomatitis (7 pts). Of the 14 pts evaluable for response, 9 pts (64%) had tumor response (2 CR, 7 PR), and 4 pts had SD. The median duration of response was 5.5 months. Pts were heavily pretreated (median lines of prior therapy 3, 11 prior taxane, 12 prior H). Conclusions: MK2206 at a dose of135 mg QW in combination with weekly P and H is safe and well-tolerated. 135 mg QW is the recommended phase 2 dose for this combination. Preliminary data indicate significant clinical activity in pts with HER2+ tumors despite extensive prior therapy. MK2206 is now being tested in the neoadjuvant ISPY2 trial. Clinical trial information: NCT01235897.

Pooled analysis of phase I dose-escalation and dose cohort expansion studies of IMP4297, a novel PARP inhibitor, in Chinese and Australian patients with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3059-3059 ◽  
Author(s):  
Junning Cao ◽  
Pin Zhang ◽  
Paul L. de Souza ◽  
Bo Gao ◽  
Mark Voskoboynik ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Single Agent ◽  
Response To Treatment ◽  
Clinical Activity ◽  
Dose Cohort ◽  
Phase Ii Studies ◽  
Grade 3

3059 Background: Poly (ADP-ribose) polymerase (PARP) enzymes play critical roles in DNA damage detection and repair. IMP4297 is a novel, potent PARP1/2 inhibitor (IC50 6.27nM/1.57nM) and has demonstrated to be 20-fold more potent than Olaparib in anticancer animal models. Two phase I studies were performed to evaluate and characterize the tolerability and safety, pharmacokinetics, and antitumor activity of single agent IMP4297 in Chinese and Australian patients with advanced ovarian, breast, prostate and other solid tumors. Methods: Dose escalation used a 3+3 design with a modified Fibonacci escalation. Dose cohort expansion was planned after efficacy was observed at the lowest dose level. Patients received IMP4297 monotherapy orally once a day until disease progression or unacceptable toxicity. Results: As of Jan 12, 2019, 56 patients, including 23 BRCA mutation carriers (BRCA+), had been enrolled at 2-100 mg dose level. No DLT was observed. In these two studies, the most frequent treatment-related adverse events (TRAEs) were leukopenia (20%), followed by anemia (18%), nausea (18%) and thrombocytopenia (14%). The majority of TRAEs were grade 1 or 2. Grade 3 TRAEs occurred in five patients (anemia, n=2; vomiting, n=1; thrombocytopenia, n=1; elevated AST, n=1). Only one patient had a dose reduction due to grade 3 thrombocytopenia. No serious TRAEs were observed. In 15 BRCA+ patients who had measurable lesions, the ORR was 33% and the DCR was 80%. There were 4 BRCA+, platinum-sensitive ovarian cancer patients with an ORR of 75% and a DCR of 100%. One patient with somatic BRCA mutated urothelial carcinoma showed a 76% decrease in tumor size. Conclusions: IMP4297 has been well-tolerated with significant anti-tumor activity. The 100 mg daily dose was selected as the RP2D based on safety, pharmacokinetics and clinical activity, and will be further characterized in dose expansion and phase II studies. Tumor response to treatment (RECIST 1.1) in patients with measurable lesions. Clinical trial information: NCT03508011 and NCT03507543. [Table: see text]

Bevacizumab (B) plus everolimus (E) and panitumumab (P) in refractory advanced solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3551-3551
Author(s):  
L. A. Howard ◽  
K. E. Bullock ◽  
J. C. Bendell ◽  
H. E. Uronis ◽  
G. Vlahovic ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Level ◽  
Study Drug ◽  
Maximum Tolerated Dose ◽  
Exposure Dose ◽  
Egfr Inhibitors ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Minor Response ◽  
Level 1

3551 Background: In preclinical models, VEGF, mTOR, and EGFR inhibitors have anti-tumor and anti-angiogenesis effects as monotherapies and in combination. B inhibits VEGF; E inhibits mTOR; P inhibits EGFR. There is also potential for interaction between the pathways. Previously BE and BE + erlotinib were evaluated and showed signs of clinical activity. Methods: Patients (pts) with refractory advanced solid tumors were accrued in a phase I dose escalation of B + E + P on a 28d cycle. Dose levels are shown in the table below. DLT was defined as any treatment-related grade 4 heme, grade 3/4 non-heme adverse event (AE), or receiving <85% any study drug in Cycle 1. Blood, skin, and tumor biopsies pre- and on-treatment were collected for correlative biomarkers of angiogenesis. Results: At this time, 12 pts (3M: 9F) are evaluable for toxicity; 9 for efficacy. Median age: 54 years (range 23–72). 9 of 12 pts had prior B exposure. Dose level 1 was expanded due to 1/3 DLT, with total of 3/6 DLT (Grade (Gr) 3 mucositis (n=2), Gr3 hypokalemia (n=1)). Dose level -1 had 3/3 DLT (Gr3, Gr4 mucositis (n=2), Gr3 non-acneform rash (n=1)). Dose level -2 had 0/3 pts DLT. Gr 3–4 related toxicities in cycle 2+: hypokalemia (n=4); hypophosphatemia (n = 1); hypomagnesemia (n = 1); diarrhea (n=1); hoarseness (n=1). Other events of interest were: Gr1–2 mucositis (n=7); Gr1 hyperlipidemia (n=5); Gr1–2 hyperglycemia (n=4); Gr2 hypertension (n=2); Gr1–2 neutropenia (n=5); Gr1–2 thrombocytopenia (n=5). 8/9 evaluable pts had SD as best response (median 26 wks, range 8+ to 32+ wks): 1 pt with pancreatic cancer and progression on 2 prior EGFR inhibitors had prolonged 32+ wk SD. There was 1 minor response (23.3%) in a pt with bevacizumab-refractory ovarian cancer (32+ wks). No CR or PR were seen. Conclusions: B + E + P at full doses has dose limiting toxicities of rash and mucositis. B 10 mg/kg q2wks + E 5 mg q48h + P 4.8 mg/kg q2wks is the maximum tolerated dose. This dose is currently being expanded in 20 patients with extensive pre- and on-treatment biomarker analyses. Updated clinical and biomarker data will be presented. [Table: see text] [Table: see text]

A phase I study of the safety and pharmacokinetics of DSTP3086S, an anti-STEAP1 antibody-drug conjugate (ADC), in patients (pts) with metastatic castration-resistant prostate cancer (CRPC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 5020-5020 ◽  
Author(s):  
Daniel Costin Danila ◽  
Russell Zelig Szmulewitz ◽  
Celestia S. Higano ◽  
Houston Gilbert ◽  
Robert S. Kahn ◽  
...  
Keyword(s):  
Study Drug ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
Antibody Drug Conjugate ◽  
Grade 3 ◽  
Prostate Cancers ◽  
Recommended Phase Ii Dose ◽  
Expansion Cohort ◽  
Ecog Ps

5020 Background: Six-transmembrane epithelial antigen of the prostate-1 (STEAP1) protein is a cell-surface antigen overexpressed in human epithelial prostate cancers. The ADC DSTP3086S contains the humanized IgG1 anti-STEAP1 monoclonal antibody linked to the potent anti-mitotic agent MMAE. Methods: This study evaluated safety, pharmacokinetics, and pharmacodynamic activity of intravenous DSTP3086S (0.3-2.8 mg/kg) given every 3 weeks (q3w) to pts with CRPC. A traditional 3+3 design was used to determine maximum-tolerated dose, followed by cohort expansion at the recommended Phase II dose (RP2D). Clinical activity was evaluated per PCWG criteria. Dose escalation results are presented. Results: Twenty-eight pts were enrolled with a median age of 67 (43-76), all ECOG PS 0-1, and with a median of 7 prior systemic regimens (including a median of 4 hormonal and 3 non-hormonal regimens). Pts received a median of 3 doses (range 1-10) of DSTP3086S. Reversible Grade 3 transaminitis DLTs occurred in one pt each in the 2.25 mg/kg and 2.8 mg/kg cohorts. Serious AEs (SAE) related to study drug (3 total) included one DVT (Grade 3) in the 1.5 mg/kg cohort, as well as one GI hemorrhage (Grade 3) and one sepsis event (Grade 5) in the 2.25 mg/kg cohort. The most common related AEs across all doses were fatigue (36%), nausea (32%), constipation (25%), decreased appetite and diarrhea (each 21%), and musculoskeletal pain and vomiting (each 18%). Exposure for total antibody, free MMAE, and conjugated MMAE was dose proportional. Approximately 60% of the tumor samples assessed showed high STEAP1 expression. CTC reductions were most robust at 2.8 mg/kg; 4/4 patients with unfavorable CTCs at baseline (median of 99, range: 21-205) exhibited CTC conversions from unfavorable to favorable (<5) after a single dose of DSTP3086S. CTC conversions were also observed at lower doses. PSA decreases of ≥ 50% were observed in 1 pt at 2.25 mg/kg, and 2 pts at 2.8 mg/kg who also had PCWG2 radiologic responses. Conclusions: DSTP3086S at the RP2D of 2.8 mg/kg q3w has a tolerable safety profile and shows evidence of anti-tumor activity. Enrollment in the expansion cohort is ongoing.

A phase I, first-in-human, open-label, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of oral TP-1287 administered daily to patients with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3611-3611
Author(s):  
Ben George ◽  
Donald A. Richards ◽  
William Jeffery Edenfield ◽  
Steven L Warner ◽  
Lars Mouritsen ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Grade 3

3611 Background: TP-1287 is a an orally bioavailable phosphate prodrug of alvocidib, a cyclin dependent kinase 9 (CDK9) inhibitor. TP-1287 exhibits potent inhibition of intracellular kinases including CDK9. Inhibition of CDK9 leads to downregulation of the BCL-2 family member, MCL-1, which in turn inhibits tumor growth in preclinical animal models of prostate, breast, and lung carcinomas. Methods: This is a 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-1287 in patients with advanced solid tumors. Patients will be added at the maximum tolerated dose (i.e. expansion cohort) to test TP-1287 as a single agent in patients with castrate resistant prostate cancer. Results: Twenty-two patients who were enrolled between December 2018 and January 2020 received a range of doses from 1 mg QD to 11 mg BID over 7 cohorts. Data are available for 20 patients as of the data cutoff date. TP-1287 plasma PK Cmax and AUC increased in near linear fashion over cohorts 1 thru 6, reaching 80 ng/mL and 499.3 ng*h/mL in cohort 6 for Cmax and AUC, respectively. TP-1287 treatment resulted in dose-dependent reductions of phospho-RNA Pol II, consistent with CDK9 inhibition, as measured by a flow cytometric assay assessing pharmacodynamic changes in phosphorylation state in PBMCs. The most frequently observed Grade 3 AE was unrelated anemia in 2 patients. All other events of Grade 3 (9 events/7 patients) and Grade 4 (1 event/seizure with new CNS mets) were unlikely related or unrelated. Clinical benefit was seen in one sarcoma patient with PR (15+cycles), one RCC patient with SD (7+cycles) and 2 bladder cancer patients with SD (6 and 8 cycles). Conclusions: These findings suggest that TP-1287 is tolerated as a monotherapy in patients with heavily pretreated, relapsed, refractory solid tumors and further clinical development in selected indications is warranted. Clinical trial information: NCT03298984 .

A three schedule phase I trial of CP-4055, weekly and q2 weeks in patients with advanced or metastatic solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2067-2067 ◽  
Author(s):  
T. Delaunoit ◽  
E. Raymond ◽  
A. Awada ◽  
F. Savinelli ◽  
S. Culine ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Trial ◽  
Dose Intensity ◽  
Maximum Tolerated Dose ◽  
Preliminary Evidence ◽  
Clinical Activity ◽  
Ecog Ps ◽  
Tumor Types

2067 Background: CP-4055 (ELACYT, ara-C 5’-elaidic acid ester) is a novel cytotoxic agent with broad preclinical antitumor activity in solid tumors. CP-4055 is based on Lipid Vector Technology and has a different cellular uptake compared to ara-C. An initial phase I trial of a day 1–5 q4 weeks (w) schedule (sch) determined a recommended dose of 200 mg/m2/day and showed clinical activity (Aamdal et al, AACR 2005). We report a multiple sch, parallel, dose intensity-guided dose escalation phase I trial, with pharmacokinetic (PK) assessment, intended to determine Maximum Tolerated Dose (MTD). Methods: Patients (pts) with refractory solid tumors received i.v. CP-4055 over 2 hours according to 3 sch: days 1, 8 q3w (Sch 1); days 1, 15 q4w (Sch 2); days 1, 8, 15 q4w (Sch 3). Dose escalation: dose level (DL) 1: 80 mg/m2/w, DL2: 160; DL3: 240; DL4: 320; DL5: 400; DL6: 440; DL7: 520, with standard definitions of dose limiting toxicity (DLT). Results: Since June 2004, 45 pts have been treated in 4 European centers; 3 are still ongoing, 37 discontinued for progressive disease, 3 for refusal, 2 for AE (1 treatment-related grade [gr] 3 paresthesia), trial is ongoing. Demographics: male/female: 27/18; median age 54 (range 35–79); ECOG PS 0/1/2: 19/24/2. Main tumor types: colorectal 6, breast 5, head & neck 5; median 3 lines prior chemotherapy (range 0–5). Exposure: 128 cycles administered, including 5 pts with ≥ 6 cycles. MTD: No DLT has been observed and dose escalation is ongoing. Safety (NCI-CTCAE v3): 45 pts assessable. Principal toxicities by pt (gr 1–2/3): anemia 34/1; nausea and vomiting 29/3; asthenia 24/1; neutropenia 12/2; headache 8/0; thrombocytopenia 3/0. No clear association with sch or DL was observed for this mild/moderate toxicity. There were no dose reductions. PK: ara-U/ara-C AUC ratio exceeds by 3-fold the standard ara-U/ara-C AUC ratio. Efficacy: 41 pts were assessable, 10 pts had stable disease (lasting > 6 months in 4 pts: 2 NSCLC, 1 colorectal, 1 kidney). Conclusions: CP-4055 shows preliminary evidence of activity and is well tolerated up to a dose of 440 mg/m2/w. PK results indicate that a majority of ara-U in plasma originates from intracellular deamination of ara-C from CP-4055, confirming intracellular retention of CP-4055. Accrual is ongoing at the DI of 520 mg/m2/w. [Table: see text]

Phase I Study of Clofarabine Plus Idarubicin and Clofarabine Plus Idarubicin Plus Cytarabine (ARA-C) in Patients (PTS) with Relapsed and Primary Refractory Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), and Myeloid Blast Phase of Chronic Myeloid Leukemia (CML).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1809-1809 ◽  
Author(s):  
Stefan Faderl ◽  
Alessandra Ferrajolil ◽  
William Wierda ◽  
Srdan Verstovsek ◽  
Farhad Ravandi-Kashani ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Myeloid Leukemia ◽  
Phase I Study ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Acute Leukemias ◽  
First Remission ◽  
First Relapse ◽  
Grade 3

Abstract Phase I and II clinical studies demonstrated activity of Clofarabine in acute leukemias. In previous studies we have investigated clofarabine, plus ara-C combinations and reported a CR rate of 24% in relapsed AML and 52% in previously untreated AML ≥ 50 years (yrs) with acceptable toxicity profile. Anthracyclines are active in AML. To explore clofarabine further in AML combinations we conducted a phase I study of clofarabine with idarubicin with or without ara-C in pts with relapsed AML, MDS, and CML. Considered as dose-limiting toxicities (DLT) are ≥ grade 3 drug-related toxicities. Maximum tolerated dose (MTD) will be determined by “3+3” dose escalation scheme. On the clofarabine (C)/idarubicin (I) combination (CI), 9 AML pts are enrolled (2 primary refractory, 7 first relapse). Median age: 58 yrs (range 24–71). Median first remission duration (CRD1): 3.1 mos. (0–7.6). For the first dose level, C was given at 22.5mg/m2 i.v. daily x 5d and I at 12mg/m2 i.v. daily x 3d. Among the first 6 pts, 2 ≥ gr. 3 toxicities (diarrhea, rash, ↑ bili) occurred necessitating dose de-escalation of C to 15mg/m2 i.v. daily x 5 and I 8mg/m2 i.v. daily x 3. Among 3 pts, 1 ≥ gr.3 toxicity (↑ bili) was observed. No responses occurred. On the CI + ara-C arm (CIA), 7 AML pts are enrolled (1 primary refractory, 6 first relapse). Median age: 58 yrs. (24–78). Median CRD1: 11.2 mos. (0–13.1). First dose level: C 22.5mg/m2 i.v. daily x 5d, I 8mg/m2 i.v. daily x 3d, A 1g/m2 i.v. daily x 5d. Of 3 pts, 2 developed ≥ gr.3 toxicities (↑ bili, diarrhea) leading to the following de-escalation: C 15mg/m2 i.v. daily x 5d, I 6mg/m2 i.v. daily x 3d, A 0.75g/m2 i.v. daily x 5d. Of 4 pts (1 ≥ gr. 3 rash, ↑ bili), 3 pts achieved CR. The phase I study is ongoing until determination of DLT and MTD for each arm. Our preliminary results indicate clinical activity of CIA even at the low dose level.

A Phase I Trial of Two Sequence-Specific Schedules of Decitabine and Vorinostat in Patients with Acute Myeloid Leukemia (AML).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 908-908 ◽  
Author(s):  
Karen W.L. Yee ◽  
Mark D. Minden ◽  
Joseph Brandwein ◽  
Aaron Schimmer ◽  
Andre Schuh ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase I Trial ◽  
Concurrent Schedule ◽  
Maximum Tolerated Dose ◽  
Leukemic Cells ◽  
Clinical Activity ◽  
Cell Transplant ◽  
Sequential Schedule ◽  
Grade 3

Abstract Background: Epigenetic silencing of genes has been documented in AML. This phase I trial evaluates the safety, tolerability, and maximum tolerated dose (MTD) of two schedules of administration of the hypomethylating agent decitabine in combination with the pan-selective histone deacetylase inhibitor vorinostat. Methods: Patients receive escalating doses of oral vorinostat administered either sequentially [100 mg bid (n=4), 200 mg bid (n=4), or 200 mg tid (n=8) Days 6–21] or concurrently [100 mg (n=3) or 200 mg (n=6) bid Days 1–21 or 200 mg tid (n=2) Days 1–14] with decitabine (20 mg/m2/d IV Days 1–5) every 28 days. Results: Twenty-seven patients with AML have been treated. Median age was 67 years (range, 32–82 years). Median ECOG status 1 (range, 0 to 2). Eighteen patients (67%) had received prior therapy (median, 1 regimen; range, 0 to 4 regimens); 3 had received a prior allogeneic stem cell transplant. A total of 85 cycles have been administered, with a median of 2 cycles (range, 1 to 13 cycles); 10 patients (37%) have received 3 or more cycles of therapy. One of 7 patients treated at dose level 3 of the sequential schedule developed dose-limiting toxicities (DLT), consisting of grade 3 fatigue, weakness, and mucositis. Therefore, the MTD was not reached in the 3 planned dose levels of the sequential schedule. One DLT (grade 3 fatigue) occurred in 6 patients treated at dose level 2 of the concurrent schedule. Most common drug-related non-hematological toxicities of any grade (all CTCAE grades 1 or 2) were nausea (71%), fatigue (54%), diarrhea (54%), vomiting (42%), anorexia (25%), constipation (13%), abdominal pain (13%), dehydration (13%), and headache (13%). No other non-hematological grade 3 or 4 toxicities were observed. Of the 25 evaluable patients, one patient achieved an incomplete CR (without neutrophil recovery), one a morphologic leukemia-free state (without blood count recovery), and three partial remissions (1 achieved red cell transfusion independency and a second normalization of platelet counts). Seven of these patients remain on study for 2.7 to 13.5+ months. Correlative studies examining histone acetylation and gene promoter methylation in leukemic cells at baseline and after treatment, as well as plasma pharmacokinetic levels for both decitabine and vorinostat are being evaluated. Conclusions: The combination of decitabine and vorinostat is safe, well-tolerated, and has clinical activity in patients with AML. Enrollment is ongoing.

Final results from a phase I trial of ixabepilone in patients with advanced malignancies and lymphoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2039-2039
Author(s):  
C. Aghajanian ◽  
O. O’Connor ◽  
M. Cohen ◽  
R. Peck ◽  
H. Burris
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Solid Tumors ◽  
Phase I Trial ◽  
Objective Response ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Hematologic Toxicity ◽  
Phase Ii Studies ◽  
Grade 3

2039 Background: Ixabepilone is the first analog in a new class of antineoplastic agents, the epothilones, which stabilizes microtubules and induces apoptosis. Ixabepilone has shown clinical activity in a broad range of tumors. Methods: This Phase I trial was designed to establish the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), efficacy, safety, pharmacokinetics and pharmacodynamics of ixabepilone when administered as a 1-hour infusion every 3 weeks to patients with advanced solid tumors or lymphoma. Eligible patients were aged ≥18 years with histologically/cytologically confirmed non-hematologic cancer, or a pathologic diagnosis of relapsed/primary refractory non-Hodgkin’s lymphoma (NHL) or relapsed/primary refractory mantle cell lymphoma, with ≤CTC Grade 1 neuropathy. Ixabepilone doses ranged from 7.5–65 mg/m2. Response was assessed every 6 weeks using RECIST. DLT was defined as Grade 4 neutropenia and/or febrile neutropenia, thrombocytopenia, ≥Grade 3 nausea/vomiting and non-hematologic toxicity, or treatment delay of >2 weeks due to delayed recovery. Results: Of 61 patients (median age 58, range 18–81), 75% had solid tumors; 25% had lymphoma. 98% and 67% of patients had received one or ≥ two prior chemotherapy regimens, respectively. The MTD of ixabepilone as a 1-hour infusion every 3 weeks was established as 50 mg/m2. The most common DLTs were neutropenia, myalgia, arthralgia and stomatitis/pharyngitis. A total of eight patients (13%) achieved a durable objective response. Complete responses were achieved in two patients with primary peritoneal cancer and NHL. A partial response was seen in six patients. The most common Grade 3/4 treatment-related adverse events (only observed at doses ≥40 mg/m2) were sensory neuropathy (13%), fatigue (13%), myalgia (10%), arthralgia (7%), nausea (5%), febrile neutropenia (5%) and neutropenia (5%). Recovery to baseline or ≤Grade 1 neuropathy occurred in some patients. Conclusions: The recommended dose of ixabepilone for the initiation of Phase II studies based on this study is 50 mg/m2 over 1 hour every 3 weeks. Ixabepilone demonstrates promising safety in patients with solid tumors or lymphoma who have failed standard therapy. Encouraging activity was reported in several tumor types. [Table: see text]

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