A phase I study of TGF-β inhibitor, vactosertib in combination with imatinib in patients with advanced desmoid tumor (aggressive fibromatosis).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 11557-11557 ◽  
Author(s):  
Hyo Song Kim ◽  
Jin-Hee Ahn ◽  
Jeong Eun Kim ◽  
Jung Yong Hong ◽  
Jeeyun Lee ◽  
...  
Keyword(s):  
Phase I ◽  
Desmoid Tumor ◽  
Phase I Study ◽  
Safety Evaluation ◽  
Aggressive Fibromatosis ◽  
Primary Objective ◽  
Phase 2 ◽  
Connective Tissues ◽  
Biomarker Analysis ◽  
Dose Levels

11557 Background: Desmoid tumor (aggressive fibromatosis) is fibroproliferative neoplasm arising from deep connective tissues. TCGA pan-cancer analysis revealed high expression TGF-β responsive signature in desmoid tumor. This phase I study assessed the safety, tolerability, and pharmacokinetics of the TGF-β inhibitor, vactosertib in combination with imatinib for desmoid tumor. Methods: Patients with advanced desmoid tumors not treatable by surgery or radiotherapy were eligible. The primary objective is to assess the safety and recommended phase 2 dose (RP2D) of vactosertib given 5 days on and 2 days off in combination with imatinib (400 mg QD). Two dose levels of vactosertib were tested; cohort -1 (100 mg BID) and cohort 1(200 mg BID). Secondary objectives include pharmacokinetics, anti-tumor activity by response rate (RECIST v1.1), and biomarker analysis. Results: Seven patients (cohort -1, n = 4; cohort 1, n = 3) were enrolled and finished the safety evaluation. The most frequently reported treatment related adverse events were myalgia (57.1%), fatigue (42.8%), diarrhea (42.8%), anemia (28.5%) and stomatitis (28.5%) with mostly grade 1. No dose limiting toxicity was observed. Tumor response included 2 (28.5%) partial response (PR) and 2 stable disease (SD) in the cohort -1, and 3 SD in the cohort 1. The time to response were 5.5 and 8.2 months and all 7 cases are ongoing. Updated safety, pharmacokinetics, efficacy and biomarker data will be presented at the meeting. Conclusions: The combination of vactosertib plus imatinib was well tolerated and showed promising activity in desmoid tumor. RP2D of vactosertib was defined as 200 mg BID. Further efficacy will be explored in the phase 2 part of the study. Clinical trial information: NCT03802084 .

Immunomodulation by HDAC inhibition: Results from a phase I study with entinostat in combination with atezolizumab and bevacizumab in metastatic renal cell carcinoma patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5064-5064
Author(s):  
Roberto Pili ◽  
Nabil Adra ◽  
Nur Damayanti ◽  
Theodore F. Logan ◽  
Vivek Narayan ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
T Cells ◽  
Phase I ◽  
Cell Carcinoma ◽  
Phase Ii ◽  
Renal Cell ◽  
Phase I Study ◽  
Checkpoint Inhibitors ◽  
Primary Objective ◽  
Dose Levels

5064 Background: Immunosuppressive regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) limit the efficacy of immunotherapies. We have previously reported that the HDAC inhibitor entinostat has synergistic antitumor effect in combination with immunotherapies in preclinical models by inhibiting Tregs and MDSCs function. The combination of atezolizumab (PD-L1 inhibitor) and bevacizumab (VEGF inhibitor) is active in renal cell carcinoma (RCC). Thus, we have conducted a Phase I study with entinostat, atezolizumab and bevacizumab in patients (pts) with metastatic RCC. Methods: The primary objective was to evaluate safety and tolerability. The phase I portion included 3 dose levels of entinostat (1 mg, 3 mg or 5 mg, PO weekly) and fixed, standard doses of atezolizumab (1200 mg IV every 21 days) and bevacizumab (15 mg/Kg IV every 21 days). Pts with any histological type and prior therapies were included. Results: Dose levels were completed with up to 1 DLT/dose level. 5 mg was the Phase II recommended dose for entinostat. DLTs included hypertension, encephalopathy, hyponatremia and pruritus. The most common resolved grade 3/4 toxicities were hypophosphatemia (33%), hypertension (17%), and pneumonitis (11%). We have enrolled 18 pts (17 evaluable for ORR by RECIST). 5 pts continue on treatment. 3 pts discontinued treatment because of adverse events, 9 pts for disease progression, and one pt for physician decision. Good risk and intermediate risk pts were 61% and 39%, respectively. Overall ORR was 47.1% (95% CI 23.0-72.2) and median PFS was 7.6 months (95% CI 1.6-16.3). In pts with no prior therapies (12) the ORR was 58.3% (95% CI 27.7-84.8) and median PFS was 13.4 months (95% CI 1.5-28.9). One additional PR was observed by ir-RC but was not confirmed within the data cut-off date of 11/11/19. In pts with prior immune checkpoint inhibitors (ICIs) (5) ORR was 20% (95% CI 0.5-71.6) and median PFS was 7.6 months (95% CI 1.3-NR). Preliminary data show a statistically significant lower % of circulating monocytic MDSC (HLADR−1CD11b+CD33highCD14+CD15−) and exhausted T cells (CD45+CD3+CD8+TIM3+) following treatment in pts (4) with objective responses as compared to pts (4) with progressive disease. Conclusions: The results from this phase I suggest that the combination of entinostat, atezolizumab and bevacizumab is relatively well tolerated and is active in renal cell carcinoma patients, in both ICIs naïve and resistant disease. A phase II portion of this study is currently accruing patients. Clinical trial information: NCT03024437 .

Phase I study (A8471004) in Asian patients of PF-03446962, a fully human mab against ALK-1 receptor involved in tumor angiogenesis: Safety, pharmacokinetics (PK), and pharmacodynamics (PD).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 11031-11031
Author(s):  
Kyung-Hun Lee ◽  
Toshihiko Doi ◽  
Tae Min Kim ◽  
Atsushi Ohtsu ◽  
Tae Yong Kim ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Drug Exposure ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Clinical Activity ◽  
Vegf Inhibitors ◽  
Study Results ◽  
Dose Levels

11031 Background: Activin receptor like kinase 1 (ALK-1) is a member of the TGF-βRI family selectively expressed in proliferating endothelial cells, and plays an important role in regulating tumor initiation and metastasis. PF-03446962 is a fully human IgG2 mAb anti ALK-1 evaluated within two phase 1 studies in Western and Asian pts. Herein we report the preliminary safety, PK and PD data of the Phase I study. Methods: Primary objective is to identify the maximum tolerated dose (MTD) in Asian cancer pts; secondary objectives include the safety profile, PK, antitumor activity, and potential PD markers in blood and tumor samples. PF-03446962 is administered IV on Day 1, 29 and then q 2 weeks. Results: Study A8471004 consists of two parts: a 3+3 dose escalation (Part 1) and a dose expansion (Part 2) at 2 dose levels. In Part 1, 16 pts have been enrolled at 3 dose levels (4 pts at 4.5 mg/kg, 3 pts at 7.0 mg/kg, and 9 pts at 10 mg/kg). No DLTs occurred in Part 1 and 10 mg/kg was confirmed as MTD in the Asian population. The observed AUC0-28day for the 4.5, 7 and 10 mg/kg doses, were 12960, 22190 and 28030 μg·h/mL and Cmax were 97.1, 131.5 and 179.8 μg/mL, respectively. Drug exposure (mean Cmax and AUC) increased in a nearly dose proportional manner in Asians. In Part 2, expansion cohorts at doses of 7.0 mg/kg (10pts) and 10.0 mg/kg (8pts) of pts previously treated with VEGF inhibitors (VEGFi) have been enrolled, and the most common drug related adverse events observed (>10%) being thrombocytopenia, pyrexia, epistaxis, and telangiectasia (an anti-ALK-1 mediated toxicity) similarly in the 2 dose levels. Telangiectasia was observed in 1 CRC and 3 HCC patients. 4 patients who progressed after VEGFi treatment (RCC, sarcoma, 2 HCC patients) presented a SD lasting for 290, 248, 247 and 208 days, respectively, suggesting the ALK-1 could serve as mechanism of escape for VEGF. Conclusions: PF-03446962 is a first in class mAb targeting ALK-1. Treatment with PF-03446962 is well tolerated in the Asian pts and preliminary observation of clinical activity supports ALK-1 as a viable target. Update of study results and potential PD effects obtained on blood and tumor samples will be presented. Clinical trial information: NCT01337050.

CTNI-47. INTERIM RESULTS OF NCT03011671: A MULTI-INSTITUTIONAL PHASE I STUDY OF ACETAZOLAMIDE WITH TEMOZOLOMIDE IN ADULTS WITH NEWLY DIAGNOSED MGMT-METHYLATED MALIGNANT GLIOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi70-vi70
Author(s):  
Bakhtiar Yamini ◽  
Seán Lyne ◽  
Riley Driscoll ◽  
Giovanna Bernal ◽  
Longtao Wu ◽  
...  
Keyword(s):  
Phase I ◽  
Malignant Glioma ◽  
Phase I Study ◽  
Objective Response ◽  
Controlled Study ◽  
Current Phase ◽  
Newly Diagnosed ◽  
Biomarker Analysis ◽  
Secondary Endpoints ◽  
Grade Iii

Abstract Preclinical studies indicate that up-regulation of carbonic anhydrase (CA) by temozolomide (TMZ), via a mechanism requiring the proto-oncogene BCL-3, promotes resistance to therapy in glioblastoma (GBM) cells. Moreover, the CA inhibitor, acetazolamide (ACZ), sensitizes patient-derived GBM cells and xenografts to TMZ. These findings led to the current Phase I study investigating the safety and efficacy of adding ACZ to adjuvant TMZ in patients with newly diagnosed, MGMT-methylated malignant glioma. 24 patients were enrolled (23 GBM and one Grade III IDH-mutant astrocytoma), median age was 53.5 and mean KPS 91. ACZ was given on days 1-21 of each adjuvant TMZ cycle (250 mg BID days 1-7, increased to 500 mg BID days 8-21). No patient experienced the primary outcome of regimen limiting toxicity (RLT) and there were only three grade III adverse events deemed likely unrelated to ACZ. For the secondary endpoints of overall and progression free survival (OS and PFS, respectively), only the 23 GBM patients were included (22 IDH-wildtype and 1 IDH-mutant). From diagnosis, median PFS was 18.8 months (95% CI: 10.4-23.0) and median OS was 25.0 months (95% CI: 19.9-28.4). Median time from diagnosis to consent was 2.9 months. As of April 2021, only 7 of 23 deaths had occurred. 2-year OS% was 68.2%. Further analysis of secondary endpoints including 6-month objective response rate (ORR) and biomarker analysis of BCL-3 by IHC will be available in the coming months. In sum, the data indicate that addition of ACZ to TMZ is safe and does not lead to reduced TMZ dosing. Also, compared to historical data, interim outcomes suggest that addition of ACZ may substantially improve PFS and 2-year overall survival. These findings support the hypothesis that ACZ acts as a chemosensitizer of alkylating chemotherapy in GBM and support examination of this regimen in a randomized, placebo-controlled study.

scholarly journals Phase I Study of Ficlatuzumab and Cetuximab in Cetuximab-Resistant, Recurrent/Metastatic Head and Neck Cancer

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1537 ◽  
Author(s):  
Julie E. Bauman ◽  
James Ohr ◽  
William E. Gooding ◽  
Robert L. Ferris ◽  
Umamaheswar Duvvuri ◽  
...  
Keyword(s):  
Phase I ◽  
Head And Neck ◽  
Phase I Study ◽  
Resistance Mechanism ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Intrinsic Resistance ◽  
Immune Biomarkers ◽  
Pathway Inhibition ◽  
Recommended Phase Ii Dose

Cetuximab, an anti-EGFR monoclonal antibody (mAb), is approved for advanced head and neck squamous cell carcinoma (HNSCC) but benefits a minority. An established tumor-intrinsic resistance mechanism is cross-talk between the EGFR and hepatocyte growth factor (HGF)/cMet pathways. Dual pathway inhibition may overcome cetuximab resistance. This Phase I study evaluated the combination of cetuximab and ficlatuzumab, an anti-HGF mAb, in patients with recurrent/metastatic HNSCC. The primary objective was to establish the recommended Phase II dose (RP2D). Secondary objectives included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Mechanistic tumor-intrinsic and immune biomarkers were explored. Thirteen patients enrolled with no dose-limiting toxicities observed at any dose tier. Three evaluable patients were treated at Tier 1 and nine at Tier 2, which was determined to be the RP2D (cetuximab 500 mg/m2 and ficlatuzumab 20 mg/kg every 2 weeks). Median PFS and OS were 5.4 (90% CI = 1.9–11.4) and 8.9 (90% CI = 2.7–15.2) months, respectively, with a confirmed ORR of 2 of 12 (17%; 90% CI = 6–40%). High circulating soluble cMet levels correlated with poor survival. An increase in peripheral T cells, particularly the CD8+ subset, was associated with treatment response whereas progression was associated with expansion of a distinct myeloid population. This well-tolerated combination demonstrated promising activity in cetuximab-resistant, advanced HNSCC.

Phase I Study of a Weekly Schedule of Irinotecan, High-Dose Leucovorin, and Infusional Fluorouracil as First-Line Chemotherapy in Patients With Advanced Colorectal Cancer

1999 ◽  
Vol 17 (3) ◽  
pp. 907-907 ◽  
Author(s):  
Udo Vanhoefer ◽  
Andreas Harstrick ◽  
Claus-Henning Köhne ◽  
Wolf Achterrath ◽  
Youcef M. Rustum ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Phase I ◽  
Dose Level ◽  
Phase I Study ◽  
Advanced Colorectal Cancer ◽  
High Dose ◽  
Weekly Schedule ◽  
First Line ◽  
Dose Levels ◽  
Line Chemotherapy

PURPOSE: To determine the maximum-tolerated dose (MTD) of a weekly schedule of irinotecan (CPT-11), leucovorin (LV), and a 24-hour infusion of fluorouracil (5-FU24h) as first-line chemotherapy in advanced colorectal cancer and to assess preliminary data on the antitumor activity. PATIENTS AND METHODS: Twenty-six patients with measurable metastatic colorectal cancer were entered onto this phase I study. In the first six dose levels, fixed doses of CPT-11 (80 mg/m2) and LV (500 mg/m2) in combination with escalated doses of 5-FU24h ranging from 1.8 to 2.6 g/m2 were administered on a weekly-times-four (dose levels 1 to 4) or weekly-times-six (dose levels 5 to 6) schedule. The dose of CPT-11 was then increased to 100 mg/m2 (dose level 7). RESULTS: Seventy-nine cycles of 5-FU24h/LV with CPT-11 were administered in an outpatient setting. No dose-limiting toxicities were observed during the first cycle at dose levels 1 to 6, but diarrhea of grade 4 (National Cancer Institute common toxicity criteria) was observed in three patients after multiple treatment cycles. Other nonhematologic and hematologic side effects, specifically alopecia and neutropenia, did not exceed grade 2. With the escalation of CPT-11 to 100 mg/m2 (dose level 7), diarrhea of grade 3 or higher was observed in four of six patients during the first cycle; thus, the MTD was achieved. Sixteen of 25 response-assessable patients (64%; 95% confidence interval, 45% to 83%) achieved an objective response. CONCLUSION: The recommended doses for further studies are CPT-11 80 mg/m2, LV 500 mg/m2, and 5-FU24h 2.6 g/m2 given on a weekly-times-six schedule followed by a 1-week rest period. The addition of CPT-11 to 5-FU24h/LV seems to improve the therapeutic efficacy in terms of tumor response with manageable toxicity.

ERK1/2 phosphorylation: a biomarker analysis within a phase I study with the new Raf kinase inhibitor BAY43-9006

2002 ◽  
Vol 40 (12) ◽  
pp. 567-568 ◽  
Author(s):  
R.A. Hilger ◽  
S. Kredke ◽  
D. Hedley ◽  
J.G. Moeller ◽  
R.J. Bauer ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Kinase Inhibitor ◽  
Raf Kinase ◽  
Biomarker Analysis

Phase I Study of a Liposomal Carrier (CPX-351) Containing a Synergistic, Fixed Molar Ratio of Cytarabine (Ara-C) and Daunorubicin (DNR) in Advanced Leukemias

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2984-2984 ◽  
Author(s):  
Eric J. Feldman ◽  
Jeffrey Lancet ◽  
Jonathan E. Kolitz ◽  
Ellen Ritchie ◽  
Alan F. List ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Dose Escalation ◽  
Phase I Study ◽  
Molar Ratio ◽  
Phase 2 ◽  
Phase 2 Study ◽  
Grade 3 ◽  
Refractory Aml

Abstract Background: CPX-351 is a liposomal formulation of Ara-C and DNR which fixes the synergistic 5:1 molar ratio found to enhance efficacy in both in vitro and in vivo preclinical leukemia models. CPX-351 overcomes the pharmacokinetic (PK) differences of each drug, enabling the maintenance of the 5:1 molar ratio for extended periods of time after IV administration and the delivery of this ratio to bone marrow. Preclinical data from in vitro models show that CPX-351 is actively internalized by leukemic cells within vacuoles and subsequently releases DNR intracellularly. A Phase I study was performed with CPX-351 in patients with acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), and myelodysplastic syndrome (MDS). Objectives: to determine safety, tolerability, and pharmacokinetics of a 90 min IV infusion of CPX-351 given on days 1, 3, 5 to patients with advanced leukemia and MDS, and to seek preliminary evidence of antitumor activity. Methods: Patients with relapsed/refractory AML/ALL and MDS were eligible. A second induction course was permitted if the day 14 bone marrow showed evidence of antileukemic effect and persistent leukemia. Dosing started at 3 units/m2 (1 u = 1 mg Ara-C and 0.44 mg DNR) using single patient cohorts and dose doublings. Three patient cohorts and 33% dose increments began after evidence of antileukemic activity and continued until limiting toxicities (DLTs) completed dose escalation. PK samples were collected after each dose. Results: Forty-seven subjects received 69 courses of CPX-351: Male/Female = 31/16, median age = 62 years (range 23–81); 44 patients had AML and 3 patients had ALL; median number of prior regimens = 2 (1–7). Thirty-seven patients entered the escalation phase of the study and ten subjects, most in first relapse, were treated after completion of dose escalation to confirm safety. At 24 u/m2 antileukemic effects were observed leading to increased cohort size to 3 and decreased escalation rate to 33%. The MTD and recommended Phase 2 dose was 101 u (101 mg Ara-C + 44 mg DNR)/m2 after observing 3 DLTs (decreased LVEF, hypertensive crisis, prolonged aplasia) at 134 u/m2. Adverse events data are available for 36 of 37 patients from the escalation phase of the study. Nonhematologic grade 3–5 toxicities occurring in more than one patient included: infections (58%), dyspnea (11%), fever (11%), hypophosphatemia (8%), hypokalemia (6%), renal failure (6%), skin rash (6%), headache (6%) hyperglycemia (6%) hypoxia (6%) and respiratory failure (6%). Mucositis of any grade was observed in 42% of patients with 3% having grade 3 mucositis. Diarrhea of grade 1 and 2 severity occurred in 39% of patients. Interim analysis of PK data demonstrates maintenance of the 5:1 molar ratio and detectable encapsulated drug persisting up to 24 hours. The average half-lives were 35 hr for total Ara-C and 23 hr for DNR, significantly longer than reported for the conventional drugs. Overall, 11 patients achieved CR/CRp. Among the 19 patients treated at the MTD, 5 of the 13 patients evaluable for response achieved CR. Six patients were treated above the MTD (134 u/m2) and 2 achieved CR. Median time to CR was 43 days. Conclusions: The recommended phase 2 dose is 101 u/m2. CPX-351 was well tolerated, with no unexpected toxicities noted up to the MTD. GI toxicities and mucositis were transient and nearly always of mild to moderate severity. Reduced LV function was observed in two patients both with substantial prior anthracycline exposure. CRs were observed in heavily pre-treated patients with relapsed/refractory AML. Future plans include a randomized Phase 2 study comparing CPX-351 versus Cytarabine + Daunorubicin (“7 + 3”) in older (>60 yo) subjects with previously untreated AML, and a phase 2 study in patients with AML in 1st relapse.

Phase I study of bortezomib and oxaliplatin (BOX) in solid tumors: Improved neurotoxicity (NT) profile with lower bortezomib (B) dose

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12007-12007
Author(s):  
R. A. Kosloff ◽  
J. Wright ◽  
P. Ivy ◽  
J. Escalon ◽  
B. Norwood ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Study ◽  
Major Contributor ◽  
Organ Function ◽  
Dose Escalation Study ◽  
Adequate Organ Function ◽  
Dose Levels ◽  
Platinum Agents

12007 Background: B inhibits proteasome function and may be synergistic in causing apoptotic death with platinum agents. We were interested in combining B with OX but concerned with dose limiting (DL) NT based on our prior B phase I study [Hamilton et al., JCO 2005]: therefore this Phase I dose-escalation study (alternating increases of B and OX) focusing on NT was planned. Methods: Patients (pts) with metastatic solid tumors, PS 0–2, platinum or taxane naive, no peripheral neuropathy and adequate organ function, received B (D1, 4, 15, 18) and OX (D1, 15) every 28 days in a dose escalation design (see table ). Baseline and monthly assessments were performed by an independent neurologist. Results: 27 (18 gastrointestinal, 3 melanoma, 3 ovarian, 3 others) were accrued; pt characteristics: 14 male/13 female; median age 55 years (range 35–75); 2 median cycles (range 1–10). NT was not DL because it did not occur within the first cycle. Late and limiting NT was observed in levels 2–5 after 2–9 cycles, but serial neurologic evaluations showed reversible NT. With an amended new dose level to lower B to 1.0 mg/m2 (level 6) to avoid late NT, NT was not observed. Of 22 evaluable pts, there were 3 partial responses (ampullary, GE junction, biliary), 6 stable disease, and 13 disease progression by RECIST criteria. Conclusions: biweekly BOX is tolerable at B 1.0 mg/m2 and OX 85 mg/m2 with no DL NT. Additional observations on late NT are ongoing. This suggests B is a major contributor to NT observed in dose levels 2–5 and may potentiate the effects of OX. [Table: see text] [Table: see text]

A phase I study of the VEGF receptor tyrosine kinase inhibitor vatalanib (PTK787/ZK 222584) and gemcitabine in patients with advanced pancreatic cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4122-4122 ◽  
Author(s):  
T. Kuo ◽  
A. Fitzgerald ◽  
H. Kaiser ◽  
B. I. Sikic ◽  
G. A. Fisher
Keyword(s):  
Pancreatic Cancer ◽  
Tyrosine Kinase ◽  
Phase I ◽  
Tyrosine Kinase Inhibitor ◽  
Phase I Study ◽  
Kinase Inhibitor ◽  
Advanced Pancreatic Cancer ◽  
Patient Cohort ◽  
Grade 3 ◽  
Dose Levels

4122 Background: The VEGF pathway is the predominant mediator of angiogenesis in pancreatic cancer. Vatalanib (PTK787/ZK 222584) is a small molecule tyrosine kinase inhibitor of all known VEGF receptors. We initiated a phase I study of vatalanib and gemcitabine for advanced pancreatic cancer. Methods: Patients with newly diagnosed unresectable or metastatic pancreatic adenocarcinoma were enrolled. Previous adjuvant chemoradiotherapy with fluorouracil was allowed. Gemcitabine was given by fixed-dose rate infusion weekly x 3 in a 28-day cycle, and vatalanib was given orally daily. Dose-limiting toxicities (DLT) are defined as any grade 3/4 toxicity during the first cycle. The dose levels are as follows: Results: To date, 11 patients are evaluable for toxicity (5M/6F; median age 62 years, range 40–82 years; median KPS 90%). Thus far, 42 cycles have been given, with a median of four cycles per patient. Two patients have experienced DLT. The first patient (cohort 1) experienced grade 3 diarrhea and hypokalemia and grade 4 neutropenia occurring simultaneously and treated without sequelae. The second patient (cohort 3) developed grade 3 deep vein thrombosis. Beyond the first cycle, grade 3 toxicities included neutropenia (1), anemia (3), thrombocytopenia (1), hypertension (2), diarrhea (1), hypokalemia (1), thrombosis (1), and proteinuria (1). Three of eleven patients (27%) did not complete treatment to the first evaluation timepoint (2 cycles); two discontinued due to toxicity and one discontinued due to disease progression. Two of eleven patients (18%) had a partial response by RECIST. Six of eleven patients (55%) had stable disease as the best response ranging from 2–6 months. Conclusions: The combination of gemcitabine and vatalanib is generally well-tolerated with most grade 3/4 toxicities occurring late in the treatment course. Antitumor responses have been observed at initial dose levels and accrual to the final cohort with BID dosing of vatalanib continues. [Table: see text] No significant financial relationships to disclose.

Phase I study of sapacitabine, an oral nucleoside analogue, in patients with advanced leukemias or myelodysplastic syndromes

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7063-7063 ◽  
Author(s):  
W. Plunkett ◽  
G. Garcia-Manero ◽  
S. Faderl ◽  
J. Cortes ◽  
P. Boone ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Nucleoside Analogue ◽  
Phase I Study ◽  
Performance Status ◽  
Median Number ◽  
Primary Objective ◽  
Dna Breaks ◽  
Platelet Recovery ◽  
Refractory Aml

7063 Background: Sapacitabine, a 2′-deoxycytidine nucleoside analogue with unique ability to induce G2 cell cycle arrest and cause irreparable single-strand DNA breaks, is undergoing clinical evaluation for the treatment of cancer. The recommended Phase II dose (RD) in patients with advanced solid tumors was 75 mg b.i.d.×7 days orally every 21 days. The major DLT was myelosuppression. Here, we present the initial results of a Phase I study of sapacitabine in patients with advanced leukemias or MDS. The primary objective was to define the MTD of the above dosing schedule and the secondary objectives were to characterize the PK/PD effects of sapacitabine and its major metabolite CNDAC. Methods: Eligible patients had relapsed/refractory leukemias or MDS, or untreated disease if not willing to proceed with conventional systemic chemotherapy, adequate organ functions and performance status of 0–2. At least 3 patients were enrolled at each dose level. The MTD was the highest dose level at which =2/6 patients experienced a DLT during the first treatment cycle. Results: Twenty- nine patients received sapacitabine. Median age was 64 (range: 36 - 91). The majority of patients had AML (n=24) or MDS (n=4). Median number of prior chemotherapies was 2 (range: 0 - 6). MTD was reached at the dose level of 375 mg b.i.d. with 2/7 patients experienced the DLT of small bowel obstruction (n=1) or neutropenic colitis (n=1). One patient died from complications of neutropenic colitis. Common non-hematologic adverse events (all grades, regardless of causality) included nausea, vomiting, diarrhea, anorexia, alopecia, and fatigue, most of which were mild to moderate in intensity. PK and PD data are being analyzed. To date, 7 patients (5 AML, 2 MDS) had a reduction in bone marrow blast counts to = 5% including 1 CR in refractory AML with incomplete platelet recovery and 1 CR in relapsed MDS. In addition, 2 AML patients with relapsed leukemia cutis had a significant reduction in leukemia infiltrates in skin. Conclusion: The RD of sapacitabine for the b.i.d.×7 days every 21 days schedule is 325 mg b.i.d. The DLT is gastrointestinal toxicity. Sapacitabine is well tolerated and has promising antileukemic activity in patients with relapsed or refractory AML and MDS. No significant financial relationships to disclose.

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