scholarly journals Phase I Pharmacokinetic and Pharmacodynamic Study of 17-Allylamino, 17-Demethoxygeldanamycin in Patients With Advanced Malignancies

2005 ◽  
Vol 23 (18) ◽  
pp. 4152-4161 ◽  
Author(s):  
Udai Banerji ◽  
Anne O'Donnell ◽  
Michelle Scurr ◽  
Simon Pacey ◽  
Sarah Stapleton ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Dose Range ◽  
Plasma Concentrations ◽  
Clinical Activity ◽  
Phase Ii Trials ◽  
Pharmacodynamic Profile ◽  
Advanced Malignancies ◽  
Grade 3

Purpose To study the toxicity and pharmacokinetic-pharmacodynamic profile of 17-allylamino, 17- demethoxygeldanamycin (17-AAG) and to recommend a dose for phase II trials. Patients and Methods This was a phase I study examining a once-weekly dosing schedule of 17-AAG. Thirty patients with advanced malignancies were treated. Results The highest dose level reached was 450 mg/m2/week. The dose-limiting toxicities (DLTs) encountered were grade 3 diarrhea in three patients (one at 320 mg/m2/week and two at 450 mg/m2/week) and grade 3 to 4 hepatotoxicity (AST/ALT) in one patient at 450 mg/m2/week. Two of nine DLTs were at the highest dose level. Two patients with metastatic melanoma had stable disease and were treated for 15 and 41 months, respectively. The dose versus area under the curve-relationship for 17-AAG was linear (r2 = .71) over the dose range 10 to 450 mg/m2/week, with peak plasma concentrations of 8,998 μg/L (standard deviation, 2,881) at the highest dose level. After the demonstration of pharmacodynamic changes in peripheral blood leukocytes, pre- and 24 hours post-treatment, tumor biopsies were performed and demonstrated target inhibition (c-RAF-1 inhibition in four of six patients, CDK4 depletion in eight of nine patients and HSP70 induction in eight of nine patients) at the dose levels 320 and 450 mg/m2/week. It was not possible to reproducibly demonstrate these changes in biopsies taken 5 days after treatment. Conclusion It has been possible to demonstrate that 17-AAG exhibits a tolerable toxicity profile with therapeutic plasma concentrations and target inhibition for 24 hours after treatment and some indications of clinical activity at the dose level 450 mg/m2/week. We recommend this dose for phase II clinical trials.

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.

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]

Phase I study of topotecan and cisplatin in patients with advanced solid tumors: a cancer and leukemia group B study.

1994 ◽  
Vol 12 (12) ◽  
pp. 2743-2750 ◽  
Author(s):  
A A Miller ◽  
J B Hargis ◽  
R C Lilenbaum ◽  
S Z Fields ◽  
G L Rosner ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase Ii ◽  
Dose Escalation ◽  
Topoisomerase I ◽  
Advanced Solid Tumors ◽  
Phase Ii Trials ◽  
Grade 3 ◽  
Dose Levels

PURPOSE The objectives of this phase I trial were to determine the dose-limiting toxicities (DLTs) of the novel topoisomerase I inhibitor topotecan combined with cisplatin, to define the maximum-tolerated doses (MTDs) of the combination without and with the use of filgrastim, and to define recommended doses for phase II trials. PATIENTS AND METHODS Patients with advanced solid tumors were eligible if they had normal bone marrow, renal, and hepatic function and had not previously been treated with platinum compounds. Topotecan was administered intravenously on days 1 through 5 and cisplatin was administered intravenously on day 1 of a 21-day cycle. The topotecan dose was fixed at 1.0 mg/m2/d on the first four dose levels, and cisplatin was escalated in 25-mg/m2 increments from 25 to 100 mg/m2 without filgrastim. After encountering DLT, the dose of cisplatin was decreased by one level and topotecan dose escalation was attempted. After defining the MTD without growth factor, the study proceeded with escalating cisplatin doses to define the MTD with filgrastim 5 micrograms/kg subcutaneously (SC) daily starting on day 6 of treatment. Priming with filgrastim 5 micrograms/kg SC on days -6 to -2 before the first course was explored last. RESULTS Of 38 patients entered, 37 were eligible, 35 assessable for toxicity in the first course, and 28 assessable for response. The principal toxicity was grade 4 neutropenia, which had to last more than 7 days to be considered dose-limiting. No DLT was observed at the starting cisplatin dose of 25 mg/m2 (dose level 1). On level 2 (cisplatin 50 mg/m2, one patient had dose-limiting neutropenia and one patient had grade 3 renal toxicity. On level 3 (cisplatin 75 mg/m2), two patients had dose-limiting neutropenia. Therefore, cisplatin dose escalation was stopped. On dose level 5 (cisplatin 50 mg/m2 and topotecan 1.25 mg/m2/d), one patient had grade 4 neutropenia that lasted more than 7 days and one patient died of neutropenic sepsis. The remaining dose levels used topotecan 1.0 mg/m2/d plus cisplatin 75 mg/m2 (level 6) and 100 mg/m2 (levels 7 and 8) with filgrastim. No DLT was observed on level 6. On level 7, two patients had dose-limiting neutropenia and one patient had grade 3 hyperbilirubinemia. Priming with filgrastim on level 8 demonstrated no obvious advantage over level 7, and one patient had grade 4 thrombocytopenia that lasted more than 7 days. Three patients with non-small-cell lung cancer achieved a partial response and one patient with breast cancer had a complete response. CONCLUSION Topotecan and cisplatin in combination cause more neutropenia than expected from either drug given alone at the same dosage. The recommended phase II doses are topotecan 1.0 mg/m2/d for 5 days in combination with cisplatin 50 mg/m2 on day 1 without filgrastim or cisplatin 75 mg/m2 on day 1 with filgrastim support.

A Phase I Trial of the Small Molecule Pan-Bcl-2 Family Inhibitor Obatoclax Mesylate (GX15-070) Administered by Continuous Infusion for up to Four Days to Patients with Hematological Malignancies.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 892-892 ◽  
Author(s):  
Aaron D. Schimmer ◽  
Joseph Brandwein ◽  
Susan M. O’Brien ◽  
Hagop Kantarjian ◽  
Bruce D. Cheson ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Dose Level ◽  
Phase Ii ◽  
Plasma Concentrations ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Gait Disturbance ◽  
Myelogenous Leukemia ◽  
Clinical Activity ◽  
Grade 3

Obatoclax antagonizes the BH3-binding groove of the bcl-2 family of anti apoptotic proteins. It is active in chronic lymphocytic leukemia(CLL; O’Brien et al, ASH 2005) with a recommended phase II dose of 28 mg/m2 given over 3 h every 3 weeks with DLT of grade 3 infusional CNS toxicities. We evaluated prolonged infusions to minimize these toxicities while maintaining clinical activity. An initial trial established a Phase II dose of 28 mg/m2 over 24 h every 2 weeks with dose limiting toxicities (DLTs) at 40 mg/m2 and responses in 4/8 MDS patients (Borthakur et al., ASH 2006). We report on 21 patients who received obatoclax 20–28 mg/m2/24 h weekly (n=9) or 20 mg/m2/24 h for 2, 3 or 4 consecutive days every 2–3 weeks (n=12). The final dose level of 28 mg/m2/24 h for 4 days is now open. Median age was 61 (range 26–75) and 11 patients were male. Diagnoses included: acute myelogenous leukemia (AML; 13), myelodysplastic syndromes (MDS; 6), acute lymphocytic leukemia (ALL; 1) and CLL (1). A total of 180 infusions of 24 h were administered. The most common adverse events (AE) were euphoric mood (57%), fatigue (57%), febrile neutropenia (43%), gait disturbance (43%), chills (33%), diarrhea (33%), nausea (33%), somnolence (33%), dizziness (29%). All were of Grades 1–2 with the exception of 7 grade 3 AEs of febrile neutropenia (unrelated to obatoclax administration) and 1 each of diarrhea, fatigue and gait disturbance. There were no DLTs. Multiple day infusions were well tolerated; for the 20 mg/m2/24 h x 4days dose level, 4/6 patients received ≥ 4 cycles, with two ongoing at this time. Plasma concentrations of obatoclax reached a steady state before end of infusion. Mean Cmax values at 20 mg/m2/24 h during1x24, 2x24, 3x24,4x24 h, and 28 mg/m2/24 h during 1x24 h infusions was 15.3, 8.4, 10.1, 15.7 and 10.8 ng/mL, respectively. The mean AUC(0–tlast) values at 20 mg/m2/24 h associated with 1x24, 2x24, 3x24, 4x24 h, and 28 mg/m2/24 h associated with 1x24 h infusions were 264.3, 396.9, 624.3, 1109.3 and 211.1 ng · hr/mL, respectively, increasing as expected with the duration of the infusion. One patient with treatment-related AML with a t(9;11)(p22;q23) translocation achieved a cytogenetic complete response (CR) with complete hematological recovery and transfusion independence on Day 9 following the start of weekly 24 h infusions of obatoclax. This CR was sustained > 8 months while the patient received a total of 35 weekly infusions of 20 mg/m2 without cumulative toxicities. Conclusions: obatoclax can be administered by prolonged infusions without eliciting novel or cumulative toxicities. The dramatic response observed in a patient with AML with immediate recovery of peripheral blood counts supports that the cytotoxic effects of obatoclax are specific to malignant cells while sparing normal bone marrow, as did our earlier reports of improvement in cytopenias in patients with MDS and CLL. The infusional schedules described here will be attractive to combine with standard chemotherapy regimens for AML and other indications to improve treatment outcomes where they may be limited by overexpression of Bcl-2 family members.

Phase I trial of D2C7 immunotoxin (D2C7-IT) administered intratumorally via convection-enhanced delivery (CED) for recurrent malignant glioma (MG).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 2566-2566
Author(s):  
Annick Desjardins ◽  
Dina Randazzo ◽  
Vidyalakshmi Chandramohan ◽  
Katherine B. Peters ◽  
Margaret O Johnson ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Cerebral Edema ◽  
Phase I Trial ◽  
Dose Range ◽  
Antibody Fragment ◽  
Who Grade ◽  
Recombinant Immunotoxin ◽  
Grade 3

2566 Background: D2C7-IT is a recombinant immunotoxin comprised of a dual-specific antibody fragment targeting EGFRwt and EGFRvIII and a genetically engineered form of the Pseudomonas exotoxin, PE38-KDEL. We report the results of a phase I trial evaluating D2C7-IT delivered intratumorally by CED. Methods: Eligible patients were adults with recurrent supratentorial WHO grade III or IV MG; solitary tumor; ≥4 weeks after chemotherapy, bevacizumab or study drug; adequate organ function; and KPS>70%. Two patients per dose level (DL) were to enroll in the dose escalation portion (dose range: 40ng/mL to 23,354ng/mL). Results: From May 2015 to May 2018, 43 patients enrolled on study. Observed dose limiting toxicities include: grade 4 seizure (n=1) on DL3, grade 3 confusion and pyramidal tract syndrome (n=1) on DL13, and grade 4 cerebral edema (n=1) and grade 3 dysphasia (n=1) on DL17. Grade 3 or higher adverse events possibly related to D2C7-IT include: seizure (grade 4, n=2; grade 3, n=3), cerebral edema (grade 4, n=1), hydrocephalus (grade 3, n=5), headache (grade 3, n=4), hemiparesis (grade 3, n=4), dysphasia (grade 3, n=3), lymphopenia (grade 3, n=4), thromboembolic event (grade 3, n=3); and one each of grade 3 elevated ALT, urinary tract infection, fall, wound complication, generalized muscle weakness, confusion, encephalopathy, and somnolence. As of February 2020, four patients remain alive, with three patients demonstrating persistent radiographic partial response more than 54, 34 and 28 months after a single infusion of D2C7-IT. Conclusions: Dose level 13 (6,920ng/mL) was selected as the optimal phase II dose. Accrual in a dose expansion phase II trial is ongoing, and we are initiating a combination trial of D2C7-IT with checkpoint inhibitior. Clinical trial information: NCT02303678 .

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.

Phase I Study of XK469R (NSC 698215), a Quinoxaline Phenoxypropionic Acid Derivative, in Patients with Refractory Hematological Malignancies.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1952-1952
Author(s):  
Wendy Stock ◽  
Samir D. Undevia ◽  
Stefan Faderl ◽  
Olotoyosi Odenike ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Phase I ◽  
Acid Derivative ◽  
Dose Level ◽  
Phase I Study ◽  
Plasma Concentrations ◽  
Hematologic Malignancies ◽  
Median Number ◽  
Fixed Dose ◽  
Pharmacokinetic Analysis ◽  
Clinical Activity

Abstract XK469R is a quinoxaline phenoxypropionic acid derivative which possesses broad activity against murine and human tumors (including leukemia) and high activity against multidrug-resistant tumors. COMPARE analysis of cytotoxicity data from the NCI cell line screen suggested a unique mechanism. Phase I studies in patients with advanced solid tumors indicated that the dose-limiting toxicity (DLT) was myelosuppression, without other significant toxicities noted, at a fixed dose of 1400 mg/dose when given on a day 1,3,5 schedule every 21 days. Therefore, we conducted a phase I study to establish the DLT and maximally tolerated dose (MTD) of XK469R in patients with refractory hematologic malignancies, as well as to study the pharmacokinetics of XK469R in this patient population. XK469R was given as a straight dose as an IV infusion over 30 minutes-1 hour on days 1, 3, and 5 of a 21 day cycle. Because significant interpatient variability in drug clearance (associated with toxicity) was noted in prior studies, each dose cohort included a minimum of six patients. The dose levels studied were 1400 mg (n=6), 1750 mg (n=12), 2200 mg (n=14), and 2750mg (n=14). A total of 46 patients with relapsed/refractory leukemia have been treated and are evaluable for toxicity; 41 patients with AML, 4 ALL, and 1 CML-BC. The group consists of 26 males and 20 females with a median age of 53 (range 20–85). ECOG PS included 0 (n=19), 1 (n=21), and 2 (n=6). Median number of cycles received was 1; 10 patients received 2 cycles and 2 patients received 3 cycles. DLT was defined as any clinically significant grade 3 or 4 adverse nonhematologic toxicity other than prolonged myelosuppression, as defined by NCI criteria specific for leukemia. DLTs of colitis and mucositis were observed at the 2200 mg dose level, and mucositis and elevated bilirubin at the 2750 mg dose level. Other possibly related grade 1 and 2 toxicities noted were SGOT/PT elevations, nausea/vomiting, diarrhea, anorexia, indigestion, rash, and alopecia. The MTD, defined as the dose level at which <2/6 patients experience a DLT, was 2200 mg. Forty-two patients were evaluable for response and include CR (n=1, in 1750 mg cohort), HI (n=5), SD (n=21), and PD (n=15). Preliminary pharmacokinetic analysis revealed that plasma concentrations of XK469R decline in a biphasic manner. Half-life was long with a mean value of 48 h. Mean clearance was 206 ml/h with a coefficient of variation of 32%. Patients with lower clearance did not appear to be at greater risk of DLT. In conclusion, the recommended phase II dose of XK469R in patients with advanced leukemia is 1750 mg (day 1,3,5). Due to its novel mechanism of action, reasonable toxicity profile, and clinical activity in these high-risk patients, further exploration of XK469R, possibly in combination with other established agents, is warranted in patients with relapsed/refractory acute leukemia.

Phase I Study of AVE9633, an AntiCD33-Maytansinoid Immunoconjugate, Administered as an Intravenous Infusion in Patients with Refractory/Relapsed CD33-Positive Acute Myeloid Leukemia (AML).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4548-4548 ◽  
Author(s):  
Francis Giles ◽  
Rodica Morariu-Zamfir ◽  
John Lambert ◽  
Srdan Verstovsek ◽  
Deborah Thomas ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Disulfide Bonds ◽  
Phase I Study ◽  
Dose Range ◽  
Microtubule Assembly ◽  
Treatment Schedule ◽  
Specific Tumor ◽  
M Phase ◽  
Grade 3

Abstract AVE9633 is an immunoconjugate created by conjugation of the cytotoxic maytansinoid, DM4, to the monoclonal IgG1 antibody, huMy9-6 (average of 3.5 molecules of DM4 per antibody). The huMy9-6 antibody is a humanized version of a murine monoclonal antibody, My9-6, which is specific for the CD33 antigen expressed on the surface of myeloid cells, including the majority of cases of AML. Because CD33 has little expression outside the hematopoietic system, it represents an attractive target for antibody-based therapy in patients with AML. The humanized antibody, huMy9-6, binds to the CD33 antigen with an apparent KD in the range of 10−10 M. Maytansinoids are anti-mitotics that inhibit tubulin polymerization and microtubule assembly, inhibiting cells during the G2/M phase of the mitotic cycle. In order to link maytansinoids to antibodies via disulfide bonds, a new thiol-containing maytansinoid (DM4) was synthesized. Attachment of potent maytansinoids to an antibody via disulfide bonds provides a satisfactory stability in the bloodstream. After the conjugate is bound at the specific tumor site it is internalized and the cytotoxic agent is released within the target cell. A phase I study of AVE9633 is being conducted in patients with refractory/relapsed CD33+ AML. The study regimen consists of AVE9633 IV infusion on Day 1 of a 3 weeks cycle. To date dose levels of 15 (N=3), 30 (N=5), 50 (N=4), 75 (N=4), 105 (N=2), 200 (N=3) and 260 (N=1) mg/m2 have been investigated. Hypersensitivity reactions during perfusion were noted, requiring prophylaxis with steroids. No other AVE9633- attributable extramedullary Grade 3 AE has been observed to date. Free DM4, measured by LC/MS/MS was detectable from the 75 mg/m2 dose level; its Cmax (at the end of infusion) increased from 10 ng/mL at the 75 mg/m2 dose level to 70 ng/mL at 200 mg/m2. Neither AVE9633-associated myelosuppression nor responses have been noted. Using Flow Cytometry Assay on peripheral blasts and monocytes, total saturation and down regulation of CD33 were observed following administration of doses ≥ 30 mg/m2. AVE9633 exposure (measuring, by ELISA method, all antibodies containing at lease one molecule of DM4) increased proportionally with the administered dose in the dose range 15 to 200 mg/m2. Updated PK results and potential explanations for the lack of efficacy using this treatment schedule will be presented.

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.

Phase I-II Study of Clofarabine-Melphalan-Alemtuzumab (CMA) Conditioning for Allogeneic Hematopoietic Cell Transplantation (HCT) in Patients with Advanced Hematologic Malignancies: Determination of MTD and Outcomes.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 197-197 ◽  
Author(s):  
Koen van Besien ◽  
Justin Kline ◽  
Lucy A Godley ◽  
Richard A. Larson ◽  
Vu H. Nguyen ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Dose Level ◽  
Phase Ii ◽  
Renal Toxicity ◽  
Phase Ii Study ◽  
Hematologic Malignancies ◽  
Advisory Committees ◽  
Grade 3 ◽  
One Year

Abstract Abstract 197 Supported by an unrestricted grant from Genzyme Corporation. Fludarabine (Flu) melphalan-alemtuzumab is a well tolerated, reduced intensity conditioning regimen for HCT. Clofarabine (Clo), a second generation nucleoside analog with excellent activity in acute leukemia, might enhance disease control over Flu. We report outcomes of a completed phase I and ongoing phase II study of CMA conditioning for allogeneic peripheral blood HCT. Tacrolimus was administered as GVHD prophylaxis. For the phase I cohort, one pt was enrolled per dose level, until the first DLT or until 2 had grade 3 toxicity. Dose level 1 consisted of: clo 10 mg/m2/day on d −7 to −3 and melphalan 100 mg/m2 on day −2. Clo was increased by 10 mg/m2/day per cohort until 40 mg/m2/day. Then, melphalan was increased by 20 mg/m2 until 140 mg/m2. Alemtuzumab was given at a fixed dose of 20 mg/day on d −7 to −3. Twelve pts were accrued in the phase I portion of whom three remain in remission at 26, 22 and 21 months. Forty pts, median age 53 (24–69), have been accrued in the phase II study of whom 16 had related and 24 unrelated donors. 20 had AML/MDS (6 refractory, 4 CR2, 9 CR1, 1 untreated MDS), 16 NHL (6 refractory, 9 chemosensitive relapse, 1 CR1) 2 CLL, 2 MPD. ASBMT risk score was high in 14, intermediate in 14, and low in 12. Performance score was 0 in 19, 1 in 17, 2 in 2, and not documented in 2 patients. The phase II dose was initiated at Clo 40 mg/m2/day x 5 days and melphalan 140 mg/m2. Twenty-four pts received this dose. Grade 3 renal toxicity occurred between day −7 and day +7 in 4 of 24 (17%) pts receiving this dose. The phase II dose was then reduced to Clo 30 mg/m2/day x 5 days and melphalan 140 mg/m2, and used to treat 16 pts. One pt with preexisting cardiomyopathy and refractory AML died during conditioning from cardiovascular failure. No grade 3 renal toxicity has been observed in this cohort and 3 pts had reversible grade 2 renal failure. Other toxicities included: gr 2–3 reversible ALT elevation between day −2 and day +5 in 8 pts; gr 2 reversible bilirubin elevation in 1 pt. No grade 3–4 hand foot syndrome or VOD occurred in this cohort. All evaluable pts engrafted. Twenty of 24 pts had full donor CD3 chimerism on day 30 and 2 had mixed donor chimerism. 11 pts had gr II aGVHD, and 3 had gr IIII/IV aGVHD. 7 have cGVHD.With a median follow-up of 313 days (19–607), 24 of 40 pts (60%) in the phase II portion of the study remain in remission. Eight have relapsed, 4 of whom have died. Eight others have died of treatment-related causes (7 after Clo 40 and 1 after Clo 30). Estimated one year survival is 72% (95%CI, 56–88) and PFS is 63% (45–81%). Neither dose of Clo (40 vs 30), donor type (MUD vs related), age (< 50 vs >50) affected outcomes. One year PFS was 56% (28–84) for NHL and 68% (46–90) for AML/MDS (P=NS). One year PFS was 43% (15–71%) for ASBMT high risk pts vs 70% (50–90%) for ASBMT low/intermediate risk pts (P=0.01; Figure 1). Conclusions: Clofarabine - melphalan - alemtuzumab conditioning induces durable remissions in a substantial fraction of patients with advanced hematologic malignancies. Clo 30/Mel 140 has an excellent safety profile. Disclosures: Off Label Use: clofarabine for transplant conditioning. Kline:Genzyme corporation: Membership on an entity's Board of Directors or advisory committees. Odenike:Genzyme corporation: Membership on an entity's Board of Directors or advisory committees. Stock:Genzyme: Research Funding.

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