Phase I/II study of a novel oral isotype-selective histone deacetylase (HDAC) inhibitor MGCD0103 in combination with azacitidine in patients (pts) with high-risk myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7062-7062 ◽  
Author(s):  
G. Garcia-Manero ◽  
A. S. Yang ◽  
V. Klimek ◽  
S. Luger ◽  
W. M. Newsome ◽  
...  
Keyword(s):  
Phase I ◽  
Hdac Inhibitor ◽  
Dna Methyltransferase ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Myelogenous Leukemia ◽  
Clinical Activity ◽  
Relevant Dose ◽  
Aberrant Dna Methylation ◽  
Dose Levels

7062 Background: Aberrant DNA methylation and histone acetylation are common in leukemia. The HDAC inhibitor MGCD0103 (0103) and the DNA methyltransferase inhibitor azacitidine (aza); which is approved for all FAB subtypes of MDS, synergize preclinically and both have single-agent activity in MDS and AML. Based on these data, we developed a Phase I/II study of combination aza + 0103 in pts with AML and MDS. Phase I data is presented. Methods: Pts with advanced MDS (=10% marrow blasts), relapsed/refractory or untreated elderly patients with AML were treated with aza 75 mg/m2 SC daily for 7d of each 28-day cycle and 0103 110mg 3x/week starting on day 5. The primary endpoint was determination of the maximum tolerated dose (MTD) of the combination. The phase I portion followed “3+3” model; only 0103 was escalated. Results: Dose levels of 0103 explored were 35, 60, 90, 110 and 135 mg. 24 pts (those having received =1 dose of MGCD0103) have been evaluated; AML=22, MDS=2. Median age 67 (40–85), total cycles=56 (mean=2.3, range=1–11). Dose limiting toxicities observed: vomiting (1/8 pts at 90 mg), nausea & anorexia (2/3 pts at 135 mg), and anorexia (1/6 pts at 110 mg). The MTD of 0103 in the combination was determined to be110 mg. PK characteristics of neither drug was altered by co-administration. 7/9 pts had significant reduction of whole cell HDAC activity during treatment with the combination. Antileukemia activity was documented in 7 pts; 6 of which were among 14 at the 2 most relevant dose levels (90 & 110 mg): 3 CR, 1 PR, and 3 CR without platelet or neutrophil recovery (required for per- protocol response). Of these 7, 4 are ongoing and 3 have been discontinued: 1 to transplant and 2 for SAEs. Conclusions: The Phase I portion of the trial demonstrates that the 0103+aza combination is safe in pts with advanced AML/MDS, and has encouraging biologic & clinical activity. Phase II portion of the study is ongoing at MTD. Molecular studies are ongoing. No significant financial relationships to disclose.

Phase I/II Study of the Oral Isotype-Selective Histone Deacetylase (HDAC) Inhibitor MGCD0103 in Combination with Azacitidine in Patients (pts) with High-Risk Myelodysplastic Syndrome (MDS) or Acute Myelogenous Leukemia (AML).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1954-1954 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Allen S. Yang ◽  
Francis Giles ◽  
Stefan Faderl ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Phase I ◽  
Hdac Inhibitor ◽  
Dna Methyltransferase ◽  
Performance Status ◽  
Single Agent ◽  
Substantial Reduction ◽  
Myelogenous Leukemia ◽  
Clinical Activity ◽  
Older Patient

Abstract Aberrant DNA methylation and histone code alterations are common in leukemia. The oral isotype-selective HDAC inhibitor MGCD0103 and the DNA methyltransferase inhibitor azacitidine have been shown to have synergistic antileukemia activity in preclinical models. Both agents have single-agent clinical activity in MDS and AML (Garcia-Manero, ASCO, 2006 & Silverman, JCO, 2002). Based on this, we have developed a Phase I/II study of the combination in leukemia. Patients with relapsed/refractory MDS (10% or more marrow blasts) or AML, or untreated older patients with AML are eligible. Adequate performance status, renal and hepatic functions are required. Azacitidine is administered at its approved dose/schedule: 75 mg/m2 SC daily x 7 every 28 days. MGCD0103 was started on day 5 of azacitidine and was given as an oral dose 3 times a week without adjusting for body weight, without interruption. The phase I portion of the study design followed a classic “3+3” model and only MGCD0103 was dose escalated. Three dose levels of MGCD0103 have been studied so far: 35, 60 and 90 mg. Twelve patients have been registered in this study. The median age is 61 (range 45–85). All, but 1 patient with MDS, had AML. All patients had relapsed or refractory disease. A total of 24 cycles have been administered, mean = 2.0 (range 1–4). Only 1 patient has experienced dose limiting toxicity: grade 3 vomiting at a dose of 90 mg of MGCD0103. Otherwise, the combination has been very well tolerated and the MTD has not yet been defined, with dosing currently ongoing at the approximate MTD of single agent MGCD0103: 110 mg orally three times a week without interruption. Preliminary PK data indicate that the t1/2 for azacitidine is less than 2 h, and does not appear to be affected by MGCD0103. Likewise, MGCD0103 pharmacokinetic characteristics do not appear to be affected by azacitidine. The majority of patients exhibited substantial reduction in HDAC activity during treatment with the combination. Analysis of DNA methylation is ongoing. Two patients have achieved response: 1 complete remission after 4 courses of therapy (in an older patient in first relapsed AML with an initial CR duration of 11 months and multiple cytogenetic abnormalities). A second older patient with refractory AML achieved a complete marrow CR (marrow blasts less than 5%) but died from pneumonia (not drug-related) after the second course of therapy on day 28 before peripheral count recovery. In conclusion, the combination of azacitidine with MGCD0103 is safe in patients with advanced AML/MDS. The combination has encouraging safety, PK, and clinical activity profiles. The study continues at the MTD of single agent MGCD013 in combination with azacitidine. Once the MTD of the combination is documented, the study will continue as a phase II study in this patient population.

Phase I/II Study of MGCD0103, an Oral Isotype-Selective Histone Deacetylase (HDAC) Inhibitor, in Combination with 5-Azacitidine in Higher-Risk Myelodysplastic Syndrome (MDS) and Acute Myelogenous Leukemia (AML).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 444-444 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Allen S. Yang ◽  
Virginia Klimek ◽  
Jorge Cortes ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Hdac Inhibitor ◽  
Response Rate ◽  
Single Agent ◽  
Substantial Reduction ◽  
Myelogenous Leukemia ◽  
Clinical Activity ◽  
Flat Dose ◽  
Dose Levels

Abstract Epigenetic alterations are common in leukemia. MGCD0103 in an oral isotype-selective HDAC inhibitor that synergizes in vitro with the DNA methyltransferase inhibitor 5-azacitidine (Vidaza, Pharmion). Both agents have single-agent clinical activity in MDS and AML (Garcia-Manero, ASCO, 2006 & Silverman, JCO, 2002). We have developed a Phase I/II study of 5-azacitidine in combination with MGCD0103 in patients with AML and MDS. Patients with MDS (≥10% marrow blasts), relapsed/refractory AML, or untreated elderly patients with AML were eligible. Adequate performance status, renal and hepatic functions were required. 5-azacitidine was administered at its approved dose/schedule: 75 mg/m2 SC daily for the first 7 days of a 28 day cycle. MGCD0103 was administered as a flat dose orally three-times a week starting on the 5th day of 5-azacitidine administration. The phase I portion of the study design followed a classic “3+3” model and only MGCD0103 was dose escalated. The phase II portion targeted a 30% response rate. Final data from the Phase I and II portions of the study will be presented at the Meeting. Five dose levels of MGCD0103 have been evaluated: 35, 60, 90, 110 and 135 mg. At current data cut-off, 37 patients registered in the study were fully evaluable: median age was 67 (range 27–85); 31 patients had AML and 6 MDS. A total of 97 cycles were administered to date, mean = 2.6 (range 1–12). Dose limiting toxicities included nausea, vomiting, anorexia, diarrhea and dehydration which appear similar to dose limiting toxicities for MGCD0103 alone. The MTD of MGCD0103 was initially determined to be 110 mg, however, upon cohort expansion, this dose level was associated with excess toxicity and the starting dose was decreased to 90 mg. Eleven (30%) patients have achieved response: 4 CR, 5 CR-i, and 2 PR. Of these 11 patients, 6 continue on study with mean duration on study of 7 cycles. Of the 5 patients discontinued, 3 discontinued due to SAEs, 1 due to progressive disease and 1 to undergo transplantation. Of the 27 patients at the phase II dose levels of 90 and 110mg, 10 achieved a response (37%; same rate at both doses). Preliminary response data are available at the time of abstract preparation for 13 additional patients, revealing 4 with CR (one of which had 1% residual peripheral blast) and 3 with CR-I for a response rate of 53% in this subset. MGCD0103 pharmacokinetics were not affected by 5-azacitidine. Likewise, co-administration of MGCD0103 had no impact on the pharmacokinetics of 5-azacitidine. A majority of patients exhibited a substantial reduction in PBMC HDAC activity during treatment with the combination. Analysis of DNA methylation is ongoing. In conclusion, the combination of 5-azacitidine with MGCD0103 is safe in patients with advanced AML/MDS and has clinical activity potentially superior to that expected with 5-azacitidine alone in this patient population. These results form the bases of a planned randomized study of 5-azacitidine with or without MGCD0103 in AML and MDS.

Clinical activity and safety of the histone deacetylase inhibitor MGCD0103: Results of a phase I study in patients with leukemia or myelodysplastic syndromes (MDS)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6500-6500 ◽  
Author(s):  
G. Garcia-Manero ◽  
M. Minden ◽  
Z. Estrov ◽  
S. Verstovsek ◽  
W. M. Newsome ◽  
...  
Keyword(s):  
Phase I ◽  
Performance Status ◽  
Single Agent ◽  
Median Number ◽  
Myelogenous Leukemia ◽  
Clinical Activity ◽  
Tumour Suppressor Genes ◽  
Dependent Manner ◽  
Hdac Inhibition ◽  
Dose Dependent

6500 Background: MGCD0103 is a novel inhibitor of human histone deacetylases (HDACs), with selectivity for the cancer-associated isoforms of class I HDACs. Deacetylation of histones by HDACs is postulated to inactivate tumour suppressor genes leading to neoplastic transformation, and therefore inhibition of this enzyme may result in antineoplastic activity. Methods: To study the safety and activity of MGCD0103, we have developed a phase I open-label dose escalation study of MGCD0103 administered orally, three-times weekly in patients with leukemia or MDS, with the primary endpoints being the determination of the maximum tolerated dose (MTD) and the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of MGCD0103. Eligibility criteria included appropriate performance status and renal and hepatic functions. Patients with relapsed/refractory leukemia or MDS and older patients with untreated AML/MDS were eligible. Results: Twenty patients have been enrolled at four dose levels (20, 40, 80 and 60 mg/m2) so far. Their characteristics are: median age 60 years (range 33–76); the majority of patients so far treated have AML; median number of prior therapies is 1 (range 0–3). Most patients had complex cytogenetics. MGCD0103 has been well tolerated at doses below 80 mg/m2. The MTD has been reached, with 3 out of 4 patients at a dose of 80 mg/m2 developing grade 3 toxicity, mainly fatigue, nausea, vomiting or diarrhea. Grade 2 toxicities include anorexia, constipation, dehydration. The median number of courses is 1 (range 1 to 6). As of January 2006, 7 patients are on study. PK evaluations show dose-dependent exposure. Analysis of peripheral blood cell HDAC activity indicates that HDAC inhibition occurs in all patients in a dose-dependent manner. Two patients with multiple relapsed/refractory acute myelogenous leukemia, and one with MDS have achieved a complete marrow response (blasts less than 6%). Of importance, maximal HDAC inhibition was observed in those patients at the time of best response. Conclusions: Single-agent MGCD0103 has clinical activity and is well tolerated at doses below 80 mg/m2 orally three times a week in patients with advanced leukemia. No significant financial relationships to disclose.

A first-in-human phase I study of the oral p38 MAPK inhibitor LY2228820 dimesylate in patients with advanced cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3001-3001 ◽  
Author(s):  
Matthew P. Goetz ◽  
Anthony W. Tolcher ◽  
Paul Haluska ◽  
Kyriakos P. Papadopoulos ◽  
Charles Erlichman ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
P38 Mapk ◽  
Advanced Cancer ◽  
Phase I Study ◽  
Single Agent ◽  
Clinical Activity ◽  
Dependent Manner ◽  
Dose Levels ◽  
Dose Dependent

3001 Background: p38 MAPK regulates production of cytokines by the tumor microenvironment and its activation enables cancer cells to survive in the presence of oncogenic stress, radiation, chemotherapy, and targeted therapies. LY2228820 is a selective small-molecule inhibitor of p38 MAPK and preclinical studies demonstrate antitumor activity as a single agent and in combination with standard agents. We performed a phase I study to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of LY2228820 and to characterize its pharmacokinetics and pharmacodynamics. Methods: Dose escalation was performed in a 3+3 design. LY2228820 was taken orally every 12 hours on days 1-14 of a 28-day cycle. Results: 54 patients received either capsules at 8 dose levels (10, 20, 40, 65, 90, 120, 160, and 200mg) or tablets at 5 dose levels (160, 200, 300, 420, and 560mg). For both formulations, Cmax and AUC increased in a dose-dependent manner. LY2228820 inhibited p38 MAPK induced phosphorylation of MAPKAP-K2 in peripheral blood with dose-dependent maximum inhibition from 10 to 70% across the dose range 10-200mg. The most common drug-related adverse events included fatigue, nausea, rash, constipation, vomiting, and pruritus. 1 patient (200mg) had DLT of erythema multiforme (Gr3) and 2 patients (560mg) had DLT of ataxia (Gr3) and dizziness (Gr2), respectively. Although the MTD was 420mg, the frequency of Gr1/2 adverse events (mainly rash, dizziness, and tremor) and observation of clinical activity at lower dose levels led to a recommended dose of 300mg (mean AUC0-24 = 11.7ug-hr/ml at steady state). Early clinical activity has been observed in ovary, breast, and kidney cancers. One patient with metastatic clear cell carcinoma of the kidney refractory to sorafenib, sunitinib, and temsirolimus had confirmed near partial response (29% decrease) after 8 cycles and remains on therapy. 15 patients (28%) achieved best overall response of stable disease, which in 12 patients (22%) was prolonged (≥4 cycles). Conclusions: LY2228820 demonstrates acceptable pharmacokinetics, safety, and early clinical activity as a single agent in advanced cancer. A phase II study for patients with ovary cancer is planned.

A Phase I, Multi-Center, Dose Escalation Study of Atiprimod in Patients with Refractory or Relapsed Multiple Myeloma (MM).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 111-111 ◽  
Author(s):  
Michael Wang ◽  
Moshe Talpaz ◽  
Sundar Jagannath ◽  
Asher Alban Chanan-Khan ◽  
Raymond Alexanian ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Treated Group ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Dose Escalation Study ◽  
M Proteins ◽  
Dose Levels

Abstract Atiprimod (N-N-diethl-8, 8-dipropyl-2-azaspiro [4,5] decane-2-propanamine) is an orally bioavailable cationic amphilic compound that inhibited STAT 3 activation in MM cells. It effectively blocked the signaling pathway of interleukin-6, resulting in activation of caspase 3 and apoptosis (Amit-Vazina et al, Br J Cancer, 2005). Atiprimod has also induced cytotoxicity in dexamethasone, doxorubicin, and melphalan resistant MM cell lines (Hamasaki et al, Blood, 2005). Based on these encouraging in vitro data, we initiated a multi-center, phase I trial of atiprimod for patients (pts) with refractory or relapsed MM who had 2 prior lines of therapy and serum creatinine less than 2 mg/dl. Primary objectives were to evaluate the safety of atiprimod in MM pts and to identify the maximum tolerated dose (MTD). Each cycle of treatment consisted of 14 consecutive days of oral atiprimod followed by 14 consecutive days without treatment. A standard phase I dose escalation was used to determine MTD with atiprimod dose levels at 30 mg, 60 mg, 90 mg, 120 mg, and 180 mg. To date, 14 pts from 4 centers have been enrolled with evaluable data in 12 patients. Median age was 60 (range 44–64); median prior lines of therapy were 4 (range 3–7); median duration from initial treatment to registration to this trial was 36 months (range 19–76). Cohorts of 3 patients have been treated at 30, 60, 90,120 mg/day and 2 patients have been enrolled at the 180 mg/day level; no cohorts have been expanded because of dose-limiting toxicity. Median number of cycles received by MM pts was 2 (range 1–5). Common Grade 1 toxicity events included diarrhea, liver enzyme elevation and dyspepsia. There were two Grade 2 toxicity events with 1 neutropenia at the 90 mg/day level and 1 diarrhea at the 120 mg/day level. One pt had Grade 3 transaminase elevation (peak AST 402, ALT 469 units/L, bilirubin 0.5 mg/dl) during the second cycle that resolved on its own during the 14 day period off treatment. Two patients with rapidly rising serum M proteins prior to enrollment had a transient but clear reduction of their M proteins (30% and 80%) after the first 14 days of atiprimod. Two pts at higher dose levels noted subjective improvement in their bone pain. Atiprimod was generally well tolerated in this heavily treated group of MM pts. The MTD has not been reached. Although there has been no response to date, clinical activity is not expected until higher dose levels are evaluated (240 mg/day, 300 mg/day, and 360 mg/day). After the MTD has been established, the study of atiprimod combinations should be considered based on the in vitro assessment of synergy with other active agents.

Phase I and pharmacologic study of docetaxel and cisplatin in patients with advanced solid tumors.

1997 ◽  
Vol 15 (3) ◽  
pp. 1071-1079 ◽  
Author(s):  
L C Pronk ◽  
J H Schellens ◽  
A S Planting ◽  
M J van den Bent ◽  
P H Hilkens ◽  
...  
Keyword(s):  
Side Effects ◽  
Phase I ◽  
Single Agent ◽  
Dose Intensity ◽  
Complete Response ◽  
Dose Schedule ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Parameters ◽  
Infusion Schedule ◽  
Dose Levels

PURPOSE This phase I study was performed to assess the feasibility of the combination of docetaxel and cisplatin and to determine the maximum-tolerated dose (MTD) and the side effects with an emphasis on sequence-dependent side effects. MATERIALS AND METHODS Patients who were not pretreated with taxanes or cisplatin derivatives and who had received no more than one prior combination chemotherapy regimen or two single-agent regimens were entered. Treatment consisted of docetaxel given as a 1-hour infusion followed by cisplatin as a 3-hour infusion (schedule A), or cisplatin followed by docetaxel (schedule B). Docetaxel doses ranged from 55 to 100 mg/m2 and cisplatin doses from 50 to 100 mg/m2. RESULTS Leukocytopenia and granulocytopenia were common (overall, 90%; grade 3 or 4, 87%), short-lasting, and docetaxel dose-dependent. Infections and neutropenic fever occurred in 10% and 4.5% of courses, respectively. Nonhematologic toxicities were mild to moderate and included alopecia, nausea, vomiting, diarrhea, mucositis, neurotoxicity, fluid retention, and skin and nail toxicity. There were no significant differences in pharmacokinetic parameters between schedules A and B. Tumor responses included one complete response (CR) and nine partial responses (PRs). CONCLUSION The dose levels docetaxel 100 mg/m2 plus cisplatin 75 mg/m2 and docetaxel 85 mg/m2 plus cisplatin 100 mg/m2 appeared to be manageable. At these dose levels, the median relative dose-intensity was high and 81% and 88% of all cycles, respectively, could be given at full dose. Schedule A is advocated for further treatment.

Clofarabine Combinations in Acute Myeloid Leukemia (AML) Salvage: A Dose-Finding Phase I Study of Clofarabine Plus Idarubicin and Clofarabine/Idarubicin Plus Cytarabine (ara-C).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2803-2803
Author(s):  
Stefan Faderl ◽  
Alessandra Ferrajoli ◽  
William Wierda ◽  
Farhad Ravandi ◽  
Zeev Estrov ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Single Agent ◽  
Response Rates ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Unrelated Donor ◽  
Acute Leukemias ◽  
First Relapse ◽  
Dose Levels

Abstract Clofarabine is a second-generation nucleoside analog with single agent activity in acute leukemias. To try and improve efficacy, various combination trials are being conducted. In studies of clofarabine plus ara-C we reported overall response rates of 41% (CR 24%) in AML salvage and 60% (CR 52%) in untreated elderly AML with acceptable toxicity profile. To explore additional clofarabine combinations in AML we conducted a phase I study of clofarabine (C) with idarubicin (I) [CI] alone and with ara-C (A) [CIA] in pts with relapsed AML and high-grade MDS. Dose-limiting toxicities (DLT) were defined as ≥ grade 3 drug-related toxicities. Maximum tolerated dose (MTD) was determined by “3+3” method. Thirty-three patients (18 on CI and 15 on CIA) have been treated and are evaluable. Of 18 pts on CI, 6 were primary refractory and 12 in first relapse (median first remission duration [CRD1] 2 mos. [range 0–9]. Eleven pts had abnormal cytogenetics. Fourteen pts received prior ara-C-based regimens, 2 relapsed from allogeneic transplant (SCT). Median age: 57 yrs (range 24–71). Four dose levels have been explored. When C was given at 22.5mg/m2 i.v. daily x 5d and I at 12mg/m2 i.v. daily x 3d, 2 ≥ gr. 3 toxicities (diarrhea, rash, ↑ bili) occurred necessitating dose de-escalation. Subsequent levels included C at 15mg/m2 x 5d/I at 8mg/m2 x 3d (6 pts, 1 ≥ gr.3 toxicity [↑ bili]), C at 18 mg/m2 x 5d, I at 10mg/m2 x 3 d (3 pts, no DLT), and C at 22.5mg/m2 x 5d, I at 10mg/m2 x 3d (3 pts, no DLT). Three (17%) responses (2 CRp, 1 CR) occurred. Of 15 pts on CIA, 4 were primary refractory and 11 in first relapse. Median CRD1 was 9 mos (0–24). Eight pts had an abnormal karyotype. Seven pts received prior ara-C-based regimens and 2 failed unrelated donor SCT. Median age: 58 yrs (23–78). Three dose levels were evaluated. At 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, 2 of 3 pts developed ≥ gr.3 toxicities (↑ bili, diarrhea) necessitating dose de-escalation. Subsequent levels included C at 15mg/m2 x 5d, I at 6mg/m2 x 3d, A at 0.75g/m2 x 5d (6 pts, 1 with ≥ gr. 3 rash, ↑ bili), and C at 22.5mg/m2 x 5d, I at 6mg/m2 x 3d, and A at 0.75g/m2 x 5d (6 pts, 1 with ≥ gr. 3 ↑ bili). Nine (60%) responses (8 CR, 1 CRp) occurred. Further dose escalation of clofarabine is planned in both trials. The preliminary results indicate feasibility of the combinations. The higher response rates with CIA need to be evaluated in view of different pt. characteristics between the two trials.

Phase I study of a novel, pharmacokinetically derived schedule of flavopiridol in acute leukemias: Clinical efficacy including hyperacute tumor lysis, pharmacokinetics, and pharmacodynamics

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6568-6568
Author(s):  
W. Blum ◽  
R. B. Klisovic ◽  
C. Kefauver ◽  
A. Johnson ◽  
M. Phelps ◽  
...  
Keyword(s):  
Phase I ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Calf Serum ◽  
Clinical Activity ◽  
Acute Leukemias ◽  
Tumor Lysis ◽  
Optimal Dosing ◽  
Dose Levels

6568 Background: Flavopiridol is a cyclin dependent kinase inhibitor with in vitro activity in many cancer cell lines. However, phase I/II studies of either 24 or 72-hour continuous infusion schedules demonstrated no significant clinical activity. Discordant binding of flavopiridol to human plasma proteins as compared to fetal calf serum prompted us to perform pharmacokinetic modeling studies which suggested that optimal dosing would be a 30 min IV bolus followed by 4 hr IV infusion. With this schedule, our group has observed impressive clinical activity in refractory CLL. Methods: We intensified this schedule for relapsed or refractory adult AML and ALL patients (pts) to administer an IV bolus over 30 min followed by an infusion over 4 hrs on 3 consecutive days in a phase I trial. Results: To date, 10 pts have been treated at 2 dose levels. Pts had relapsed/refractory AML (N=6) or ALL (N=4) and were 25–77 yrs old. 4 pts received flavopiridol at 20 mg/m2 IV bolus and 30 mg/m2 infusion; 6 received 30 mg/m2 bolus followed by 35 mg/m2 infusion. The most significant toxicity was tumor lysis; treatment was well tolerated, and toxicities were similar to those previously reported by our group with the single day dosing schedule used in CLL. Plasma levels were 1–2 μM during the infusion (N=7) and declined with a terminal half life comparable to that previously reported with a 72 hr infusion. Significant anti-leukemic activity was seen in 5/7 evaluable pts at both dose levels. Tumor lysis was seen in both ALL and AML (see table ). Downregulation of Mcl-1 protein by immunoblotting was seen in 2/3 pts tested to date. Conclusions: Single agent flavopiridol given with this novel, pharmacologically modeled schedule has clinical activity in pts with relapsed/refractory ALL and AML. Further study in acute leukemia using this schedule is warranted; dose escalation to the current trial is ongoing. (NCI U01 CA 76576–05) [Table: see text] No significant financial relationships to disclose.

Novel phase I design for oncology research

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2517-2517
Author(s):  
L. Lupinacci ◽  
K. Anderson ◽  
L. Sun ◽  
Y. Tymofyeyev
Keyword(s):  
Phase I ◽  
Dose Range ◽  
Single Agent ◽  
Adaptive Method ◽  
Maximum Tolerated Dose ◽  
Target Dose ◽  
Regulatory Review ◽  
Stage Design ◽  
Oncology Research ◽  
Dose Levels

2517 Background: Phase I studies in oncology patients seek to identify a dose of a new investigational agent that is tolerable and has the potential to be effective. Toxicity data are the key to defining dose levels of the new agent that are acceptable for further study. Several Phase I designs are available to researchers. Some are practical and easy to implement. Others are complex but yield better information on the toxicity of studied doses. We sought a Phase I design that had a high probability of selecting a dose with acceptable toxicity, allowed adaptation based on observed dose-limiting toxicity (DLT) data and did not create considerable enrollment delays. Methods: We compared the 3+3 design, an algorithmically-determined adaptive method proposed by Ji, et al. (2007), and variations on Ji's design including a 2-stage design combining a 3+3 with a modified Ji design. We simulated Phase I trials with 6 dose levels and 12 dose response relationships and studied the properties of the designs including how often the dose with the target toxicity level was selected, the expected percentage of patients with a DLT and the expected sample size. We also implemented operational conventions on top of the preferred design to enhance the practicality and clinical usefulness of the design. Results: In general, the adaptive, Ji-based designs outperformed the 3+3, selecting the target dose up to 18% more often. The 2- stage and other Ji-based designs were comparable in most scenarios and performed the best when the target dose was among the middle doses in the dose range tested. When the target dose was the highest dose or higher than all of the doses tested, the 3+3 and 2-stage designs outperformed some of the other Ji-based designs. Conclusions: For single agent studies, we prefer a 2-stage design in which a 3+3 is implemented until a preliminary maximum tolerated dose (MTD) is identified. Then, a modified Ji design (target toxicity rate = 20%) is used to confirm the MTD and allow further dose refinement. While this design may underperform slightly compared with the complex continuous reassessment methods, this design is easier to implement and more intuitive to investigators and ethical and regulatory review boards. In addition, it maximizes enrollment continuity while ensuring appropriate patient safety. [Table: see text]

Results of a Phase I/II Study of the Combination of 5-aza-2′-Deoxycytidine (DAC) and Valproic Acid (VPA) in Patients (pts) with Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 263-263 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Hagop Kantarjian ◽  
Blanca Sanchez-Gonzalez ◽  
Stefan Faderl ◽  
Srdan Verstovsek ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Myelogenous Leukemia ◽  
Clinical Activity ◽  
Antiepileptic Agent ◽  
Level 3 ◽  
Level 1 ◽  
Dose Levels ◽  
Level 2 ◽  
Grade Iii

Abstract DAC is a potent hypomethylating agent with clinical activity in patients with myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML). VPA is a histone deacetylase inhibitor used as an antiepileptic agent. In vitro, the combination of DAC with VPA results in synergistic antileukemia activity at doses of VPA above 1mM. Based on this data, we have developed a phase I/II study of this combination for pts with leukemia. The phase I of the study followed a classic 3+3 design. The dose of DAC was fixed: 15 mg/m2 iv daily for 10 days. This was based on a previous phase I study (Blood2004;103:1635) that indicated that this schedule had an optimal toxicity-response profile in this population. Three dose levels of VPA were selected: 20, 35 and 50 mg/kg. VPA was given orally for 10 days concomitantly with DAC. 22 pts have completed the phase I portion of the study (median age 56 years, range 4–78, 20 pts AML, 2 MDS). At dose level 1 (20 mg/kg of VPA) no grade III-IV toxicity was observed. At dose level 2 (VPA 35 mg/kg), 2 out 6 pts developed grade III neurotoxicity. Both pts were receiving high doses of other neurotropic agents. After IRB approval, 3 mores pts were treated at this dose level with no significant toxicity. Subsequently, 3 pts were treated at the highest planned dose level (50 mg/kg) with no toxicity observed. This cohort was then expanded to a total of 10 pts. One pt developed grade III neurotoxicity. No other severe drug-related toxicities were observed, but 5 patients at all dose levels developed grade II sedation/somnolence. Pancytopenia was induced in all pts. At dose level 1, one pt with refractory AML achieved complete remission (CR) after the second course of therapy. This is now maintained for 5 courses. At dose level 2, a patient with HIV disease and relapsed AML achieved CR after the third course of therapy, and 2 pts with relapsed AML achieved complete marrow responses (marrow blasts less then 5%, no recovery of peripheral counts). Of 3 pts evaluable for response at dose level 3, 1 pt with MDS has achieved CR after 1 course, and 1 with relapsed AML a complete marrow response. Median free VPA levels pretreatment were 0, and 25 mg/L on both days 5 and 10 and returned to 0 prior to next course. Histone acetylation measured by Western blot was observed in 3 pts (25%), all at doses above 20 mg/kg of VPA. Reactivation of p21 expression was induced in 4 out 11 pts analyzed. Global hypomethylation measured using a bisulfite PCR LINE assay was induced in 1 out 3 pts so far studied. Based on the toxicity observed, the phase II portion of the study was initiated. This is restricted to pts with AML/MDS. Seven pts have been accrued to this phase, and 8 out the 10 pts at dose level 3 of the phase I are also evaluable. The response data of this pts will be updated at the meeting. In summary, the combination of low dose DAC and VPA up to doses of 50 mg/kg can be safely administered to pts with leukemia although it may be complicated by neurotoxicity. Clinical and biological activity was observed at all dose levels.

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