Phase I trial of bevacizumab plus sunitinib in patients (pts) with metastatic renal cell carcinoma (mRCC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5099-5099 ◽  
Author(s):  
D. R. Feldman ◽  
G. V. Kondagunta ◽  
E. A. Ronnen ◽  
P. Fischer ◽  
R. Chang ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase I Trial ◽  
Kinase Inhibitor ◽  
Maximum Tolerated Dose ◽  
Fixed Dose ◽  
Rapid Progression ◽  
Hematologic Toxicity ◽  
Phase Ii Trials ◽  
Dose Levels

5099 Background: Bevacizumab, an intravenous monoclonal antibody against VEGF, and sunitinib, an oral multi-targeted tyrosine kinase inhibitor of VEGF and PDGF receptors, both have activity in mRCC [NEJM 349:427–434; JAMA 295:2516–2524]. Combining bevacizumab and sunitinib may increase antitumor efficacy by maximizing inhibition of the VEGF pathway. The safety and maximum tolerated dose (MTD) of sunitinib in combination with bevacizumab was assessed in this Phase I trial. Methods: Cohorts of 3–6 pts with mRCC received escalating doses of sunitinib (dose levels: 25, 37.5, and 50 mg po) daily for 4 weeks (wks) followed by 2 wks off with fixed- dose bevacizumab (10 mg/kg iv) every 2 wks continuously. Pre-determined dose-limiting toxicities (DLTs) in the first 6-wk cycle included Grade (Gr) 4 neutropenia, ≥Gr 3 thrombocytopenia of ≥7 days, Gr 4 hypertension or proteinuria, and other Gr 3 non-hematologic toxicity of ≥7 days. Pts who came off study prior to completion of cycle 1 for any reason other than a DLT were replaced. Serum VEGF levels were measured before and during cycles 1 and 2. Results: 16 pts (11 male, 5 female, median age 57) were enrolled. Of 8 patients entered at the first dose level (sunitinib 25 mg, bevacizumab 10 mg/kg), 2 were replaced; 1 never received treatment and 1 did not complete cycle 1 due to rapid progression of disease (PD). No DLTs occurred in the remaining 6 evaluable pts in this cohort. At the 2nd dose level (n =6, sunitinib 37.5 mg, bevacizumab 10 mg/kg), 1 pt receiving low molecular weight heparin had a DLT of Gr 4 hemorrhage. 2 pts have enrolled in the 3rd dose level (sunitinib 50 mg, bevacizumab 10 mg/kg) but are not yet evaluable for toxicity or response. Gr 3/4 toxicities over all cycles included Gr 3 hypertension (n=4), Gr 3 proteinuria (n=2), Gr 3 abdominal pain (n=2), Gr 4 hemorrhage (n=1), and Gr 3 hand/foot syndrome (n=1). 13 pts were evaluated for best response–4 had partial responses, 7 had stable disease, and 2 had PD. Serum VEGF levels decreased during cycle 1 in all pts. Conclusions: The combination of sunitinib and bevacizumab in mRCC pts was tolerable at the first 2 dose levels. Once the MTD is identified, further testing of this combination in phase II trials may be indicated for mRCC as well as other malignancies. [Table: see text]

A phase I study of sunitinib malate (SU11248) in combination with gefitinib in patients with metastatic renal cell carcinoma (mRCC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4537-4537 ◽  
Author(s):  
E. A. Ronnen ◽  
G. V. Kondagunta ◽  
C. Lau ◽  
P. Fischer ◽  
M. S. Ginsberg ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Fixed Dose ◽  
Hematologic Toxicity ◽  
Phase Ii Trials ◽  
Sunitinib Malate ◽  
Grade 3

4537 Background: Sunitinib malate (SU11248) is an oral multitargeted tyrosine kinase inhibitor of VEGF and PDGF receptors. Two phase II trials with sunitinib given as second line therapy in patients with mRCC showed a ≥40% response rate (JCO 2006;24:16–24; Proc ASCO 23,380s). Combining sunitinib and gefitinib (an EGFR inhibitor) may enhance antitumor activity by providing a broader spectrum of tyrosine kinase inhibition. The maximum tolerated dose (MTD) of sunitinib in combination with gefitinib was assessed in this Phase I trial. Methods: Patients with mRCC previously treated with cytokine therapy were enrolled in the study. Cohorts of 4–6 patients received escalating doses of sunitinib and a fixed dose of gefitinib. Dose levels of sunitinib were 37.5 mg and 50 mg. Dose limiting toxicity (DLT) was defined as Grade 4 hematologic toxicity, Grade 3 nonhematologic toxicity of ≥7 days or a Grade 2 cardiac toxicity. Six-week treatment cycles comprised of sunitinib daily for 4 weeks followed by 2 weeks off and continuous gefitinib at 250 mg daily except in Cycle 1 where gefitinib was begun on Day 10. Results: In the first dose level (n=4, 37.5 mg of sunitinib and 250 mg of gefitinib), no DLTs were observed. In the second dose level (50 mg of sunitinib and 250 mg of gefitinib), there were 7 patients enrolled, but 1 patient had dose reduction for hypertension during the sunitinib monotherapy part of the study and was not included in the cohort defining MTD. 2 of 6 patients experienced a DLT (Grade 2 decline in ejection fraction, persistent Grade 3 fatigue) and the MTD was determined as 37.5 mg of sunitinib with 250 mg of gefitinib. Grade 3 adverse events included: diarrhea (n = 2) and hand/foot syndrome (n = 2). Laboratory abnormalities included grade 4 neutropenia (n = 1), grade 3 neutropenia (n = 2), and grade 3 thrombocytopenia (n = 2). Overall, 5 of 11 patients demonstrated a partial response and patient accrual to the phase 2 portion of the study is underway. Conclusions: The combination of sunitinib and gefitinib in mRCC patients was well tolerated and MTD was determined. The efficacy and toxicity of this combination is being assessed in a phase II component of this trial. [Table: see text]

Final Results of a Phase I Study of the Fc Engineered CD19 Antibody XmAb®5574 (MOR00208) in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL).

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2894-2894 ◽  
Author(s):  
Jennifer A. Woyach ◽  
Farrukh Awan ◽  
Ian W. Flinn ◽  
Rolondo Enoch ◽  
Paul A. Foster ◽  
...  
Keyword(s):  
High Risk ◽  
Febrile Neutropenia ◽  
Adverse Events ◽  
Phase I ◽  
B Cell ◽  
Dose Level ◽  
Phase I Trial ◽  
Hematologic Toxicity ◽  
B Cell Malignancies ◽  
Dose Levels

Abstract Abstract 2894 Antibody (Ab) therapies such as the CD20 monoclonal abs rituximab and ofatumumab are commonly used in CLL alone and in combination with chemotherapy, however, CD20 density is low on CLL cells, suggesting this may not be the ideal target. CD19, which is ubiquitously expressed on CLL cells and those of other B cell malignancies is a reasonable candidate for ab targeting. XmAb5574 is a novel humanized IgG1 CD19 monoclonal ab with an engineered Fc region to enhance Fc gamma receptor binding affinity. In vitro, this ab demonstrates direct cytotoxicity and antibody dependent cellular phagocytosis similar to rituximab, however, shows enhanced natural killer antibody dependent cellular cytotoxicity compared to other therapeutic abs used in CLL (Awan, FT Blood 2009). We have performed a first in human trial of this ab as a single agent in relapsed or refractory (R/R) CLL, and present the results in this report. This study is a multi-institutional phase I trial of XmAb5574 in patients (pts) with R/R CLL. Eligible pts were those with CLL who had at least 1 prior therapy and required treatment by International Working Group on CLL (IWCLL) 2008 Guidelines (Hallek, M Blood 2008), had Eastern Cooperative Oncology Group Performance Status <3, had platelets ≥50,000/mm3, and had adequate organ function. Primary endpoints were to determine maximal tolerated dose (MTD), describe toxicity, and characterize pharmacokinetics (PK). A secondary endpoint was to explore efficacy. An accelerated titration design was used in which 1 pt was accrued to the first two dose levels provided there were no dose limiting toxicities (DLT) or ≥ grade 2 adverse events (AE), and then a standard 3×3 design was employed from dose level 3 forward. Dose levels included 0.3, 1, 3, 6, 9, and 12 mg/kg with an expansion to a total of 16 pts at the MTD. XmAb5574 was administered as an intravenous infusion on days 1, 4, 8, 15, and 22 of cycle (C) 1, and on days 1, 8, 15, and 22 of C2. Toxicity was assessed using the National Cancer Institute's Common Criteria for Adverse Events v4.0 for non-hematologic toxicity, and IWCLL 2008 guidelines for hematologic toxicity. Disease response assessment by physical exam was performed on C1D28, C2D28, and 4, 8, and 12 weeks after the end of C2. Radiographic assessment was performed C2D28. 27 pts were enrolled to this phase I trial. The median age of all pts was 66 years (range 40–84). The pts were generally high risk: 14 (52%) had high-risk disease by Rai stage, 8 (30%) had del(11q22.3) and 10 (37%) had del(17p13.1) by FISH, and 24 (89%) had IgVH unmutated disease. The median number of prior therapies was 4 (range 1–14). Toxicity with this agent was modest. Dose escalation continued without dose limiting toxicity (DLT) until the highest dose level, in which one patient experienced grade 4 neutropenia associated with febrile neutropenia which required dose discontinuation. 100% of patients experienced any AE, with the majority of AE being grade 1–2. The most common AEs were infusion reactions in 18 patients (67%), all of which were grade 1 or 2. Treatment-related Grade 3 or 4 AEs occurred in 5 pts (19%), and included neutropenia (n=3), thrombocytopenia (n=2), increased aspartate aminotransferase (AST) (n=1), febrile neutropenia (n=1), and tumor lysis syndrome (n=1). All were on the 12 mg/kg dose level except one pt receiving 1mg/kg who experienced neutropenia. Overall response rate by IWCLL 2008 criteria is 11%, all of which have been partial responses (PR). Using IWCLL 1996 response criteria which does not include CT scan assessment of disease resulted in a PR in 13 pts (42%). Only 2 pts had PD at the 8 week evaluation point. Responses occurred at the 6, 9, and 12 mg/kg dose levels. All objective responses were in pts categorized as CLL as opposed to SLL, and no patients with lymph nodes >5cm responded. PK was best modeled by a two-compartment model. Half-life was 14 days, with clearance 5mL/day/kg that was not dose-dependent. Across the dose range, area under the curve increased in a dose-proportional manner, while maximum concentration increased in a less than proportional manner. A steady-state was reached at or before infusion 9. XmAb5574 shows acceptable toxicity and signs of preliminary efficacy in patients with high-risk, heavily pretreated CLL. These results justify movement into phase II study in CLL as well as other B cell malignancies. Modest toxicity, in particular infectious toxicity, will potentially allow combinations with other active agents in CLL. Disclosures: Enoch: Xencor, Inc.: Employment. Foster:Xencor, Inc: Consultancy.

Phase I Trial of the Novel Mammalian Target of Rapamycin Inhibitor Deforolimus (AP23573; MK-8669) Administered Intravenously Daily for 5 Days Every 2 Weeks to Patients With Advanced Malignancies

2008 ◽  
Vol 26 (3) ◽  
pp. 361-367 ◽  
Author(s):  
Monica M. Mita ◽  
Alain C. Mita ◽  
Quincy S. Chu ◽  
Eric K. Rowinsky ◽  
Gerald J. Fetterly ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Mammalian Target Of Rapamycin ◽  
Maximum Tolerated Dose ◽  
Target Of Rapamycin ◽  
Phase Ii Trials ◽  
Solid Malignancies ◽  
Advanced Malignancies ◽  
Grade 3 ◽  
Dose Levels

Purpose This phase I trial was conducted to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of deforolimus (previously known as AP23573; MK-8669), a nonprodrug rapamycin analog, in patients with advanced solid malignancies. Patients and Methods Patients were treated using an accelerated titration design with sequential escalating flat doses of deforolimus administered as a 30-minute intravenous infusion once daily for 5 consecutive days every 2 weeks (QD×5) in a 28-day cycle. Safety, pharmacokinetic, pharmacodynamic, and tumor response assessments were performed. Results Thirty-two patients received at least one dose of deforolimus (3 to 28 mg/d). Three dose-limiting toxicity events of grade 3 mouth sores were reported. The maximum-tolerated dose (MTD) was 18.75 mg/d. Common treatment-related adverse events included reversible mouth sores and rash. Whole-blood clearance increased with dose. Pharmacodynamic analyses demonstrated mammalian target of rapamycin inhibition at all dose levels. Four patients (one each with non–small-cell lung cancer, mixed müllerian tumor [carcinosarcoma], renal cell carcinoma, and Ewing sarcoma) experienced confirmed partial responses, and three additional patients had minor tumor regressions. Conclusion The MTD of this phase I trial using an accelerated titration design was determined to be 18.75 mg/d. Deforolimus was well tolerated and showed encouraging antitumor activity across a broad range of malignancies when administered intravenously on the QD×5 schedule. On the basis of these overall results, a dose of 12.5 mg/d is being evaluated in phase II trials.

scholarly journals Phase I Trial of Rituximab, Cladribine and Temsirolimus (RCT) for Initial Therapy of Mantle Cell Lymphoma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3661-3661 ◽  
Author(s):  
David J. Inwards ◽  
Paul Fishkin ◽  
Betsy R. LaPlant ◽  
Matthew T. Drake ◽  
Paul Kurtin ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Mantle Cell Lymphoma ◽  
Dose Level ◽  
Cell Lymphoma ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Mantle Cell ◽  
Grade 3 ◽  
Dose Levels

Abstract Abstract 3661 Objective: We conducted this trial to determine the maximum tolerated dose (MTD) and schedule of temsirolimus added to an established regimen comprised of rituximab and cladribine for the initial treatment of mantle cell lymphoma and to generate preliminary information on the toxicity and efficacy of this combination. Methods: A standard phase I cohort of 3 study design was utilized. MTD was defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) in at least one-third of patients (at least 2 of a maximum of 6 new patients). DLT was defined as grade 4 ANC (<500) for ≥5 days, grade 4 ANC (<500) associated with fever (>100.5 F) and/or active infection, PLT <25,000, grade 4 infection, or ≥grade 3 non-hematologic toxicity during the first cycle of therapy as per NCI Common Terminology Criteria for Adverse Events v3.0. The fixed doses of rituximab and cladribine were 375 mg/m2 IV day 1 and 5 mg/m2/d IV days 1–5 of a 28 day cycle, respectively, as previously published. There were 5 planned temsirolimus IV dose levels: 15 mg day 1; 25 mg day 1; 25 mg days 1 and 15; 25 mg days 1,8 and 15; and 25 mg days 1,8,15, and 22. The fifth dose level is as previously published in combination with rituximab. Results: A total of 17 patients were treated: 3 each at dose levels 1–4 and 5 at dose level 5 (25 mg temsirolimus days 1,8,15, and 22). The median age was 75 years (52–86). There were 11 males and 6 females. At presentation 88% had stage IV disease, and 94% had extranodal disease. MIPI scores were low in 6% (1 patient), intermediate in 59% (10 patients), and high in 35% (6 patients). There was a single DLT recorded at dose level 3 based on the initial DLT criteria, though this cytokine release syndrome was clearly rituximab related, and occurred prior to the first dose of temsirolimus. Five patients were treated at the highest planned temsirolimus dose level (25 mg days 1,8,15, and 22) with no DLT observed. No further dose escalation was planned, and this level was determined to be tolerated, though higher levels may be tolerable. All patients were evaluable for adverse events. Hematologic toxicity was frequent, with grade 3 anemia in 12% of patients, grade 3 thrombocytopenia in 35%, grade 4 thrombocytopenia in 30%, grade 4 lymphopenia in 47%, grade 3 neutropenia in 24%, and grade 4 neutropenia in 18% of patients. There were 3 thrombotic episodes, 2 of which were attributed to therapy, and 3 episodes of pneumonitis. The overall response rate was 94% with 53% CR and 41% PR. The median progression free survival was 18.7 months. Conclusions: Temsirolimus 25 mg IV weekly may be safely added to rituximab and cladribine at 375 mg/m2 IV day 1 and 5 mg/m2/d IV days 1–5 of a 28 day cycle, respectively. This regimen had promising preliminary activity in an elderly cohort of patients with mantle cell lymphoma. Disclosures: Off Label Use: Temsirolimus for mantle cell lymphoma.

scholarly journals Phase I Trial and Pharmacokinetic Study of Ixabepilone Administered Daily for 5 Days in Children and Adolescents With Refractory Solid Tumors

2009 ◽  
Vol 27 (4) ◽  
pp. 550-556 ◽  
Author(s):  
Brigitte C. Widemann ◽  
Wendy Goodspeed ◽  
Anne Goodwin ◽  
Tito Fojo ◽  
Frank M. Balis ◽  
...  
Keyword(s):  
Phase I ◽  
Children And Adolescents ◽  
Solid Tumors ◽  
Phase I Trial ◽  
Maximum Tolerated Dose ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Phase Ii Trials ◽  
Eligibility Criteria ◽  
Dose Levels

PurposeThe objectives of this phase I trial were to determine the maximum-tolerated dose (MTD), toxicity profile, dose-limiting toxicities (DLTs), pharmacokinetics, and preliminary response rate for ixabepilone, a microtubule-stabilizing agent, administered intravenously daily for 5 days in children and adolescents.Patients and MethodsPatients ≥ 2 and ≤ 18 years with relapsed or refractory solid tumors were enrolled onto sequential cohorts to the following five dose levels: 3.0 (n = 3), 4.5 (n = 4), 6.0 (n = 3), 8.0 (n = 6), and 10 (n = 3) mg/m2/d. Eligibility criteria, dose levels, definitions of DLT and MTD, and pharmacokinetic sampling times were designed to be as similar as possible to the adult phase I trial of ixabepilone on the same schedule.ResultsNineteen children (median age, 10 years; range, 2 to 18 years) were enrolled, and 18 (12 with sarcomas) were assessable for toxicity. DLTs (grade 4 neutropenia for > 5 days and grade 3 fatigue) were observed in two of three patients receiving 10 mg/m2/d. The MTD of ixabepilone administered daily for 5 days every 21 days was 8 mg/m2/d. Myelosuppression, GI, and hepatic toxicities were common non-DLTs. Peripheral neuropathy was uncommon. Ixabepilone clearance was 475 ± 247 mL/min/m2, volume of distribution at steady-state was 12.2 ± 5.4 L/kg, and half-life was 14 hours.ConclusionThe recommended dose of ixabepilone for phase II trials in solid tumors is 8 mg/m2/d daily for 5 days every 21 days. This dose is 33% higher than the MTD in adults receiving the same dosing schedule. Pharmacokinetic parameters in children and adolescents were highly variable but similar to adults.

Preliminary results of a phase I trial of sorafenib combined with cisplatin/etoposide (CE) or carboplatin/pemetrexed (CbP) in solid tumor patients (pts)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e13521-e13521
Author(s):  
N. S. Dhruva ◽  
T. E. Stinchcombe ◽  
C. M. Walko ◽  
M. A. Socinski ◽  
S. Bernard ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Dose Level ◽  
Phase I Trial ◽  
Single Agent ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Small Cell ◽  
Hematologic Toxicity ◽  
Level 1

e13521 Background: Sorafenib had demonstrated single agent activity in non-small cell and small cell lung cancer. Methods: A non-comparative, two arm phase I trial escalating sorafenib in combination with fixed doses of CE or CbP was performed. A 3-patient cohort design was utilized to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT). Dose level 0 for all pts was a sorafenib dose of 200 mg po BID continuously. Pts on arm A received C (60 mg/m2) on day 1 and E 120 mg/m2 on days 1,2,3 every 3 weeks with escalating doses of sorafenib. On arm B, pts received treatment with Cb (AUC=6) and P 500 mg/m2 every 3 weeks with escalating doses of sorafenib. However, excessive toxicity was observed on arm B, therefore the trial was amended such that Cb dose was lowered to AUC=5 (arm C). DLT were assessed in the 1st cycle and defined as grade (gr.) 4 anemia or thrombocytopenia, gr. 4 neutropenia lasting > 7 days, gr. ≥ 3 non-hematologic toxicity (except nausea, vomiting, and alopecia) and > 2 week dose delay. Response was assessed every 2 cycles according to RECIST, and best response was recorded. Results: Between 9/2007 and 9/2008, 20 pts were treated on the trial; median age 62 (range 47–73), male/female: 12/8, PS of 0/1: 6/14, and median number of prior therapies 2 (range 1–4). The most common tumor types were NSCLC (n=8), SCLC (n=4) and head/neck (n=2). At dose level 0 arm A (200 mg BID), 2 of 4 patients experienced DLT (gr.4 thrombocytopenia, gr.3 fatigue, febrile neutropenia and gr.4 neutropenia for > 7 days, gr.3 febrile neutropenia, diarrhea, hypokalemia, hyponatremia); 2 pts have been enrolled at dose level -1 (200 mg po QD) without DLT. Two of 3 patients enrolled on arm B at dose level 0 had gr.4 thrombocytopenia. On arm C at dose level 0 (200 mg po BID), 1/6 pts experienced DLT (gr.3 hyponatremia, dehydration, hypoglycemia). Enrollment continued at dose level 1 (400 mg po BID), but 2/5 pts experienced a DLT (both gr. 3 fatigue/anorexia). Responses observed were: PR (n=3) (all arm C), and SD (n=6). Conclusions: The MTD of sorafenib in combination with carboplatin (AUC=5) and pemetrexed 500 mg every 3 weeks is 200 mg po BID. The MTD of sorafenib in combination with cisplatin/etoposide has yet to be determined and is currently accruing at dose level -1. [Table: see text]

Phase I trial sunitinib plus everolimus in patients with metastatic renal cell carcinoma (mRCC).

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 311-311 ◽  
Author(s):  
A. M. Molina ◽  
D. R. Feldman ◽  
M. S. Ginsberg ◽  
P. Fischer ◽  
M. J. Trinos ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Phase I ◽  
Cell Carcinoma ◽  
Dose Level ◽  
Renal Cell ◽  
Phase I Trial ◽  
Kinase Inhibitor ◽  
Clear Cell ◽  
Maximum Tolerated Dose ◽  
Grade 3

311 Background: Sunitinib a targeted tyrosine kinase inhibitor and everolimus an mTOR inhibitor both inhibit hypoxia-induced factor-dependent signaling and have activity in advanced renal cell carcinoma (RCC). The safety and maximum tolerated dose (MTD) of sunitinib in combination with everolimus was assessed in this phase I trial. Methods: Cohorts of 3–6 patients with mRCC received sunitinib at 37.5 or 50 mg daily for 4 weeks followed by 2 weeks off with everolimus administered either daily (2.5 or 5 mg) or weekly (20 or 30 mg). Dose-limiting toxicities (DLTs) were assessed in the first 6-week cycle to determine MTD. Results: 20 patients (13 clear cell and 7 non-clear cell RCC) were enrolled in five cohorts. Both patients in the 2nd dose level (everolimus 5 mg daily, sunitinib 37.5mg) experienced grade 3 DLT (thrombocytopenia and mucositis; vomiting). With weekly everolimus dosing, the MTD was everolimus 30 mg /sunitinib 37.5 mg (4th dose level). However, only one of six patients at this dose level tolerated treatment beyond 4 cycles. Grades 3 and 4 toxicities observed with chronic treatment included infection, gastrointestinal hemorrhage, and pulmonary embolism. A total of six patients were treated with everolimus 20b mg weekly/37.5 mg sunitinib (3rd dose level) with better tolerance as chronic therapy. Overall, 5 out of 20 patients achieved a partial response including 3 patients with non-clear cell histology. Conclusions: Partial responses were observed in both clear cell and non-clear cell histologies. However, due to toxicity the combination of sunitinib and everolimus could not be administered at full doses. [Table: see text]

scholarly journals A Safety Study of the Addition of Omacetaxine to the Standard-of-Care Induction Regimen of Cytarabine and Idarubicin in Newly-Diagnosed AML Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5218-5218
Author(s):  
Sonia Christian ◽  
Kelley E. Kozma ◽  
Stephanie Barath ◽  
Ardaman Shergill ◽  
Damiano Rondelli ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
De Novo ◽  
Standard Of Care ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Induction Regimen ◽  
Dose Levels

Abstract Background: Omacetaxine mepesuccinate (OM) is a semi-synthetic form of Homoharringtonine (HH), a cephalotaxine alkaloid. OM induces cell apoptosis by inhibiting peptide bond formation during mRNA translation, with rapid loss of short-lived proteins, such as MCL-1, c-MYC, and Cyclin D1 (Lu, J Hematol Oncol. 2014, 7: 2). Notably, cytarabine synergizes with HH in causing apoptosis of leukemia cells in vitro. A phase III RCT in China of 620 patients with de novo AML demonstrated superior CR and 3-yr survival rates upon addition of HH to a standard 2-drug AML induction therapy ('7 + 3'; Jin, Lancet Oncol. 2013, 14:599). Thus, we hypothesized that OM, at an appropriate dose, would similarly enhance the efficacy of a 7 + 3 regimen. OM is FDA-approved for the treatment of TKI-resistant CML. The MTD of 1.25 mg/m2/d SQ for 14 days every 28 days, as determined in a phase I/II CML trial of OM (Quintás-Cardama, Cancer 2007, 109: 248), served as a basis for the dose escalation used in this study. Methods: The primary endpoint of this phase I safety trial was to determine the optimally safe and active dose (OD) of OM when added to a standard 7 + 3 induction regimen, cytarabine and idarubicin. OM was administered SQ q12h d1-7 with cytarabine (100mg/m2 CIV) d1-7 and idarubicin (12mg/m2 IV) d1-3. Four dose levels were tested, starting with OM 0.625 mg/m2 q12h (further dose levels: 1.25, 2.0, 3.0, and 4.2 mg/m2 q12h). All newly diagnosed, untreated de novo or secondary AML patients, aged 18-70y with ECOG PS of 0-3 were eligible for this study. Secondary endpoints included overall response rate (ORR) and overall and event free survival (OS, EFS). Hematologic toxicity (HT) was defined as incomplete hematologic recovery; ANC < 1.0 x 109/L or platelet count < 100 x 109/L present at d49, with the bone marrow documented to be free of leukemic infiltration. Dose escalation was based on the EffTox design (Biometrics 2004, 60:684), a Bayesian adaptive design which considers the trade-off between efficacy and toxicity in determining the OD for Phase II trials. Results: Twenty-two patients, median age 58 (range 25-69) years were enrolled from June 2015 to June 2018. 12 patients (54.5%) had adverse cytogenetics, 6 (27%) intermediate risk, 3 (13.7%) favorable risk and 1 patient's cytogenetic risk was unknown (fibrotic BM). Eight patients demonstrated disease evolution from myelodysplastic syndrome (MDS). Altogether 16 of the 22 patients (73%) were deemed high risk based on cytogenetics or MDS-AML evolution. The EffTox design was implemented until cohort 4 (3 mg/m2 q12h), where 2 of 3 patients experienced a grade 5 non-hematologic toxicity (NHT), resulting in a dose-limiting toxicity (DLT). Since no DLTs were observed in cohort 3, an additional 5 patients were thus enrolled at this dose level to ensure safety. The OD was determined to be the dose level used in cohort 3: OM 2 mg/m2. No HTs were observed in 21 of 22 patients, (one patient not evaluable). The most common non-hematologic treatment emergent adverse events (TEAEs) of any grade were fever (68%), nausea (64%), vomiting (55%), hyperglycemia (41%), diarrhea (41%), mucositis (36%), headache (36%), sinus tachycardia (32%), rash/dermatitis (32%), and abdominal pain (32%). The most prevalent non-hematologic grade 3/4 TEAEs were febrile neutropenia (23%), hypoxia (18%), hyperglycemia (18%), and dyspnea (18%). ORR (CR and CRi) was 45.5%. Median OS was 605 days and EFS was 100 days. Conclusion: In this population with predominantly high-risk AML, the combination of OM with a standard 7 + 3 regimen demonstrates a manageable safety profile with acceptable efficacy. As ~ 25% of patients achieving CR with '7 + 3' do so after a second induction (based on meta-analysis of 6 trials, n = 1980, see Cancer 2010, 116: 5012), the ORR here is comparable to those receiving a single standard of care induction. The results in this high-risk group are therefore promising and warrant further investigation in a phase II trial. At present, we are assessing leukemic blast MCL protein expression in stored pre-treatment samples to determine if this predicts OM efficacy. NCT02440568. Teva has performed a Medical Accuracy Review of this abstract. Figure. Figure. Disclosures Khan: Teva: Speakers Bureau. Patel:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Honoraria.

Phase I trial of the somatostatin analog octreotide acetate in the treatment of fluoropyrimidine-induced diarrhea.

1995 ◽  
Vol 13 (1) ◽  
pp. 222-226 ◽  
Author(s):  
S Wadler ◽  
H Haynes ◽  
P H Wiernik
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase I Trial ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Response To Therapy ◽  
Somatostatin Analog ◽  
Watery Diarrhea ◽  
Gastrointestinal Malignancies ◽  
Octreotide Acetate

PURPOSE Diarrhea is one of the dose-limiting toxicities for administration of fluorouracil (5FU) in patients with gastrointestinal malignancies and can result in severe morbidities or mortality. The somatostatin analog octreotide acetate has been used in the treatment of 5FU-induced diarrhea with promising results. A phase I trial was initiated to determine the maximum-tolerated dose of octreotide acetate that could be administered in this setting. PATIENTS AND METHODS Patients were required to have National Cancer Institute Common Toxicity Criteria > or = grade 2 diarrhea or watery diarrhea secondary to treatment with 5FU or a modulated 5FU regimen. At least three patients were treated at each dose level; after satisfactory completion of this dose level (zero of three or one of six patients with < or = grade 2 toxicity), additional patients were added at the next dose level. Doses of octreotide acetate studied were 50 to 2,500 micrograms subcutaneously three times daily for 5 days. RESULTS A total of 35 patients received 49 courses of therapy. The only significant toxicities occurred at 2,500 micrograms. At this dose level, one patient developed an allergic reaction with flushing, nausea, and dizziness after each of the first two injections. A second patient developed asymptomatic hypoglycemia with a serum glucose level of 26 mg/dL. The maximum-tolerated dose was 2,000 micrograms. The efficacy of the treatment correlated significantly (P = .01) with the dose of octreotide administered, and more patients completed the course of therapy at the higher doses. CONCLUSION Octreotide acetate can be safely administered for the treatment of fluoropyrimidine-induced diarrhea in patients with gastrointestinal malignancies. The dose-limiting toxicities were allergic (nausea, rash, and light-headedness) and endocrine (hypoglycemia). There was a significant correlation between complete response to therapy and octreotide dose.

Phase I trial of subcutaneous interleukin-6 in patients with advanced malignancies.

1993 ◽  
Vol 11 (3) ◽  
pp. 499-506 ◽  
Author(s):  
J Weber ◽  
J C Yang ◽  
S L Topalian ◽  
D R Parkinson ◽  
D S Schwartzentruber ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Interleukin 6 ◽  
Phase Ii Trials ◽  
Organ Toxicity ◽  
Advanced Malignancies ◽  
Major Organ ◽  
Dose Levels ◽  
Grade Iii

PURPOSE Based on preclinical evidence in murine models that interleukin-6 (IL-6) mediates regression of metastatic tumors, we performed a phase I study of recombinant human IL-6 in patients with refractory advanced malignancies to determine its pharmacokinetics, toxicities, and possible immunologic and antitumor effects. PATIENTS AND METHODS Recombinant IL-6 was administered as a single subcutaneous dose daily for 7 days, with 7 days off therapy followed by another 7 days of IL-6. Doses were escalated in cohorts of three patients starting at 3 micrograms/kg/d, provided that toxicity at the preceding dose level was not dose-limiting. Dose-limiting toxicity was defined as grade III or IV major organ toxicity that did not resolve to grade II or less in 24 hours after stopping IL-6, using the National Cancer Institute Common Toxicity Criteria. Patients were treated with 3, 10, and 30 micrograms/kg/d IL-6 subcutaneously. RESULTS Three patients each were treated at the 3- and 10-micrograms dose levels. Two of five patients treated with 30 micrograms/kg/d IL-6 subcutaneously had grade III major organ toxicity that required IL-6 therapy to be discontinued. All patients experienced fever, chills, and minor fatigue. Significant increases in C-reactive protein (CRP), fibrinogen, platelet counts, and lymphocyte IL-2 receptor levels were seen in patients at the 10- and 30-micrograms/kg dose levels. Decreases in albumin and hemoglobin were observed, particularly at the 30-micrograms/kg dose level. The half-life (T1/2 beta) was 4.2 hours, with a peak IL-6 level at 5 hours. No antitumor responses were seen. CONCLUSION A safely tolerated dose of daily subcutaneous IL-6 is 10 micrograms/kg, with hepatotoxicity and cardiac arrhythmia being the dose-limiting toxicities at 30 micrograms/kg. Phase II trials of IL-6 administered subcutaneously daily for at least 7 days for two cycles with an intervening week of rest are recommended for phase II trials. However, patients with extensive replacement of liver by tumor and abnormal liver functions should receive IL-6 therapy with caution.

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