A phase I trial of bexarotene, a retinoid X receptor agonist, in non-M3 acute myeloid leukemia

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7061-7061
Author(s):  
D. E. Tsai ◽  
S. Luger ◽  
A. Kemner ◽  
C. Andreadis ◽  
A. Loren ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Median Number ◽  
Clinical Activity ◽  
Cell Transplant ◽  
Platelet Counts ◽  
Cytotoxic Treatment ◽  
Dose Levels ◽  
Bone Marrow Blasts

7061 Background: In vitro, bexarotene inhibits the proliferation of non-M3 AML cell lines and induces differentiation of leukemic blasts. This phase I study was designed to evaluate the safety of escalating doses of bexarotene in patients with non-M3 AML and has completed enrollment. Methods: Bexarotene was administered daily until disease progression occurred. Dose escalation occurred in cohorts of 3–6 patients through 6 dose levels ranging from 100–400mg/m2. Results: 27 patients were enrolled: 19M/8F, median age 69 (range 51–82), 13 prior MDS, 12 primary refractory, median number of induction attempts 2, no prior chemotherapy 3, prior autologous stem cell transplant 5, 26 blood transfusion dependent, 18 platelet transfusion dependent, and 20 neutropenic. Despite prophylactic use of antihyperlipidemic agents, 4 patients developed grade ≥3 hypertriglyceridemia. Two patients developed a syndrome reminiscent of retinoic acid syndrome, consisting of dyspnea, pleural/pericardial effusions, and edema in the setting of a rising neutrophil count. This syndrome resolved with stopping bexarotene and initiating steroids. Evidence of activity was noted with bone marrow blasts decreasing to ≤5% in 4 patients. Seven patients showed evidence of neutrophil response (pretreatment median ANC 364/μL, range 28–1,242/μL, treatment ANC 3,540/μL, range 1,200–26,207/μL). Flow sorted peripheral blood neutrophils were collected from 3 of these patients and examined by FISH. Between 92–100% of neutrophils contained the patient's leukemic cytogenetic abnormality suggesting differentiation of the leukemic blasts. Eleven patients with platelet counts <100,000/μL had increases in their platelet counts >20,000/μL (peak range 40- 292x103/μL). Five of these patients with platelet counts <20,000/μL had improvement to 40–91,000/μL and became transfusion independent. Conclusions: Bexarotene is well tolerated at the dose levels studied. Evidence for clinical activity has been seen as exemplified by improvement in platelet counts, increased neutrophil counts and decreased bone marrow blasts. We postulate that bexarotene may induce leukemic blast differentiation in non-M3 AML and represent a novel non-cytotoxic treatment. No significant financial relationships to disclose.

A Phase I Trial of Bexarotene, a Retinoid X Receptor Agonist, in non-M3 Acute Myeloid Leukemia: Evidence of Myeloid Differentiation and Clinical Activity.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1955-1955
Author(s):  
Donald E. Tsai ◽  
Selina Luger ◽  
Allison Kemner ◽  
Alison W. Loren ◽  
Cezary Swider ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Cytogenetic Analysis ◽  
Clonal Evolution ◽  
Clinical Activity ◽  
Cell Transplant ◽  
Platelet Counts ◽  
Cytotoxic Treatment ◽  
Dose Levels

Abstract In vitro, bexarotene has been shown to inhibit the proliferation of non-M3 AML cell lines and induce differentiation of leukemic blasts. This phase I study was designed to evaluate the safety of escalating doses of bexarotene in patients with non-M3 AML. Bexarotene was administered orally daily until disease progression occurred. Prophylactic antihyperlipidemic agents were used in all patients. Six dose levels ranging from 100 to 400mg/m2 are planned. Dose escalation occurred in cohorts of 3–6 patients based on dose-limiting toxicity. Twenty patients have been enrolled in 5 dose cohorts (100–300mg/m2) with enrollment demographics: 13M/7F, median age 69 (range 51–82), 11 prior MDS, 8 primary refractory, median number of induction attempts 2, no prior induction chemotherapy 2, prior autologous stem cell transplant 4, 19 blood transfusion dependent, 13 platelet transfusion dependent, and 16 neutropenic. Consistent with reported toxicity, 2 patients developed hypothyroidism, 7 patients developed grade 2–4 hypertriglyceridemia and 1 patient developed grade 2 pancreatitis. Two patients developed a syndrome reminiscent of retinoic acid syndrome, consisting of dyspnea/hypoxia, pleural/pericardial effusions, weight gain/edema and dry cough in the setting of a rapidly rising neutrophil count. This syndrome resolved within 48 hours of stopping bexarotene and initiating steroids. No CR’s were noted, however significant evidence of drug activity were seen. Six patients showed evidence of neutrophil response (pretreatment median ANC 286/μL, range 28–1,037/μL, posttreatment ANC 3,150/μL, range 1,100–27,207/μL). Flow sorted peripheral blood neutrophils were collected from three of these patients and examined by FISH. Between 92–100% of purified neutrophils contained the patient’s leukemic cytogenetic abnormality suggesting differentiation of the leukemic blasts. Bone marrow blasts decreased to <6% in 3 patients. Nine patients with platelet counts <100,000/μL had increases in their platelet counts >30,000/μL (peak range 40–292x103/μL). Four of these patients with platelet counts <20,000/μL had improvement in their counts to 40–91,000/μL and became transfusion independent. One patient, with sustained clinical response, had 2 independent leukemic clones (7- and 7q- respectively) and no normal metaphases on bone marrow cytogenetic analysis prior to treatment. After 2 months of treatment, cytogenetic analysis showed 93% normal metaphases and no evidence of the original clones. However, 7% of metaphases consisted of 2 new leukemic clones with multiple cytogenetic abnormalities derived from his original clones. This is suggestive of partial eradication of the original leukemic clones and reestablishment of normal hematopoesis but with clonal evolution of the leukemic clones. Daily oral bexarotene is well tolerated at the dose levels studied to date. Early evidence for clinical activity has been seen as exemplified by improvement in platelet counts, increased neutrophil counts, cytogenetic effects, and decreased bone marrow blast counts. We postulate that bexarotene may work by inducing leukemic blast differentiation in non-M3 AML and may represent a novel non-cytotoxic treatment modality. Patient enrollment is ongoing.

A phase I trial of bexarotene, a retinoid X receptor agonist, in relapsed or refractory non-M3 acute myeloid leukemia (AML)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6567-6567
Author(s):  
D. E. Tsai ◽  
S. M. Luger ◽  
A. W. Loren ◽  
A. Kemner ◽  
J. Thompson ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Retinoic Acid ◽  
Phase I ◽  
Platelet Transfusion ◽  
Median Number ◽  
Cell Transplant ◽  
Platelet Counts ◽  
Dose Levels ◽  
Retinoic Acid Syndrome

6567 Background: In vitro, bexarotene inhibits the proliferation of non-M3 AML cell lines and induces differentiation of leukemic blasts. This phase I study was designed to evaluate the safety of escalating doses of bexarotene in patients with relapsed or refractory non-M3 AML. Methods: Bexarotene was administered orally daily until disease progression occurred. Five dose levels ranging from 100 to 300 mg/m2 were planned. Dose escalation occurred in cohorts of 3–6 patients based on dose-limiting toxicity. Results: Fourteen patients have been enrolled in 4 dose cohorts (100–250 mg/m2) with enrollment demographics: 8M/6F, median age 63 (range 51–76), 6 prior MDS, 6 primary refractory, median number of induction attempts 2, prior autologous stem cell transplant 4, 14 blood transfusion dependent, 12 platelet transfusion dependent, and 12 neutropenic. Two patients developed hypothyroidism. Despite prophylactic use of antihyperlipidemic agents, 4 patients developed grade 2 or 3 hypertriglyceridemia. Two patients developed a syndrome reminiscent of retinoic acid syndrome, consisting of dyspnea/hypoxia, pleural/pericardial effusions, weight gain/edema and dry cough in the setting of a rapidly rising neutrophil count. This syndrome resolved within 48 hours of stopping bexarotene and initiating steroids. One patient had a WBC rise from 1.7×103/μL (ANC 1,037/μL, 18% blasts) pre-bexarotene to 23.9×103/μL (ANC 19,368/μL, 3% blasts) during this syndrome. Flow cell sorted peripheral blood neutrophils all contained this patient’s original t(8;21) by FISH, suggesting differentiation of the leukemic blasts. Bone marrow blasts decreased to ≤5% in two patients. Three platelet transfusion dependent patients had increases in their platelet counts to a peak count of 40–292×103/μL on bexarotene. Conclusion: Daily oral bexarotene is well tolerated at the dose levels studied to date. Early evidence for activity has been seen as exemplified by improvement in platelet counts, decreased bone marrow blast counts, blast differentiation and possible retinoic acid syndrome. Patient enrollment is ongoing. [Table: see text]

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.

Final results of phase I and pharmacokinetic study of SJG-136 administered on a daily x 5 schedule

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e13506-e13506 ◽  
Author(s):  
T. M. Kadia ◽  
S. Faderl ◽  
Z. Estrov ◽  
M. Konopleva ◽  
S. George ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Performance Status ◽  
Median Number ◽  
Clinical Activity ◽  
Vascular Leak ◽  
Ecog Performance Status ◽  
Acute Leukemias ◽  
Number Of Patients ◽  
Dose Levels

e13506 Background: SJG-136 is a pyrrolobenzodiazepine dimer that forms covalent DNA crosslinks in a sequence-specific manner in the minor groove. In vitro testing demonstrated a broad pattern of antitumor activity in sub-nmol concentrations. A phase I study in patients (pts) with solid tumors revealed clinical activity, defined MTD as 30 mg/m2/d administered on daily x 3 schedule, and confirmed manageable toxicity. Here we report the results of a CTEP-sponsored phase I trial of SJG-136 administered on a daily x 5 schedule in pts with relapsed or refractory (R/R) leukemias. Methods: Previously treated pts with R/R acute leukemias (AML, ALL, high risk MDS, CML blast phase) or R/R CLL with adequate organ function and ECOG performance status of ≤ 2 were eligible for the study. The starting dose level was 6 mcg/m2 given intravenously daily x 5 days on a 21 day cycle. Pts were sequentially enrolled in cohorts of 3 and the dose was escalated in a classic 3+3 schema at the dose levels: 6, 12, 24, and 36 mcg/m2. Repeat courses and intrapatient dose escalation were allowed. Results: Sixteen pts (11M, 5 F) were enrolled on the study. The median age of the patients was 53 (21–84). Thirteen (81%) pts had R/R AML, and 3 (19%) had R/R ALL of which 5 (31%) had diploid and 6 (38%) had adverse cytogenetics. Median number of prior therapies was 3 (2–6). Pts enrolled at each dose level (mcg/m2) were: 6 (3 pts), 12 (5 pts), 24 (4 pts), 36 (4 pts). The median number of cycles delivered was 1 (0–5). The dose of 36 mcg/m2 was found to be above the MTD, with the DLT being grade 3 soft tissue edema. Other manifestations of vascular leak including grade I, II hypoalbuminemia, edema, and pleural effusions were seen in a number of patients starting at dose level 24 mcg/m2 and above. Other non-dose limiting toxicities included nausea, dyspnea, fatigue, bloating, and insomnia. One pt had a PR, 8 pts had stable disease, and 6 had progression. Pharmacokinetic characteristics in this population will be reported. Conclusions: SJG-136 is safe and active in patients with advanced leukemias. Edema and other vascular leak syndromes are characteristic toxicities of the agent at higher dose levels. 24 mcg/m2 is the recommended phase II dose for the daily x 5 schedule. No significant financial relationships to disclose.

A phase I dose-escalation study of the novel KSP inhibitor ARRY-520 in advanced leukemias

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 7022-7022
Author(s):  
Z. Estrov ◽  
J. Cortes ◽  
G. Borthakur ◽  
S. Faderl ◽  
G. Garcia Manero ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Single Dose ◽  
Phase I ◽  
Peripheral Blood ◽  
Dose Schedule ◽  
Clinical Activity ◽  
Dose Escalation Study ◽  
Hematological Cancers ◽  
Bone Marrow Blasts ◽  
Ksp Inhibitor

7022 ARRY-520 is a potent, selective KSP inhibitor that arrests cells in mitosis with the subsequent onset of apoptosis. ARRY-520 has shown potent activity in preclinical models of hematological cancers and is being evaluated in a phase I trial in patients with advanced or refractory leukemias. The primary objectives of this study are to establish the safety and the MTD of ARRY-520 given as a single dose each cycle. Secondary objectives are to characterize the pharmacokinetics (PK) of ARRY-520, to assess evidence of preliminary clinical activity, and to explore biomarkers of KSP inhibition. ARRY-520 is administered as a 1-h IV infusion as a single dose per cycle in a “3 + 3 phase I design”. Dose escalations are following a prespecified schema. PK analyses for ARRY-520 are performed on plasma samples collected during cycle 1 and cycle 2. Pretreatment and post-treatment peripheral blood samples are collected for analysis of markers of KSP activity. To date, 15 patients, with a median age of 69 yrs (range 44–84 yrs), have been enrolled in the single dose schedule, 3 patients each at doses of 2.5 mg/m2, 3.75 mg/m2, and 5.6 mg/m2 and 6 patients at 4.5 mg/m2 per cycle. All patients had disease refractory to, and/or relapsed from, 1 or more prior therapies with a median of 3 prior regimens (range 1–10). Two patients at 5.6 mg/m2 experienced a DLT of gr3 mucositis. ARRY-520 was well tolerated at doses below 5.6 mg/m2. 4.5 mg/m2 has been determined to be the MTD. ARRY-520 has shown promising signs of clinical activity at doses of 3.75 mg/m2 and above. 2 patients had a complete reduction in their peripheral blasts on day 5 of cycle 1. Of these, one patient experienced a 70% reduction in bone marrow blasts while on study. One patient without peripheral blood blasts at baseline had a 43% reduction in bone marrow blasts and four additional patients had marked reductions in WBC counts. This is the first reported use of a KSP inhibitor in refractory and/or relapsed leukemias. ARRY-520 has been well tolerated in patients on a single dose schedule. Mucositis was observed as the DLT at 5.6 mg/m2. At doses 3.75 mg/m2 and above, ARRY-520 has shown signs of clinical activity. Based on these data, an alternative dose schedule is being explored. Updated data including safety, PK, PD, and preliminary activity of ARRY 520 from this study will be presented. [Table: see text]

Phase I study of TH-302, an investigational hypoxia-targeted drug, and dexamethasone in patients with relapsed/refractory multiple myeloma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8602-8602
Author(s):  
Irene M. Ghobrial ◽  
Jacob Laubach ◽  
Philippe Armand ◽  
Erica Boswell ◽  
Courtney Hanlon ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Phase I ◽  
Clinical Activity ◽  
Heavily Pretreated ◽  
Hepatorenal Function ◽  
Definition Of ◽  
Ecog Ps

8602 Background: TH-302 is an investigational 2-nitroimidazole prodrug of the DNA alkylator Br-IPM designed to be selectively activated in hypoxia. In multiple myeloma (MM) mouse models, diseased animals demonstrate a marked expansion of areas of hypoxia in the bone marrow. TH-302 exhibited anti-tumor activity against MM in vitro and in vivo and synergism was seen when combined with bortezomib (Hu et al, Blood 2010; Chesi et al, Blood 2012). Based on these findings, a phase I/II study of TH-302 plus dexamethasone (dex) was initiated for patients (pts) with relapsed/refractory MM. Methods: Eligible pts in the study (NCT01522872) had ECOG PS ≤ 2, receipt of at least two prior therapies, and acceptable hepatorenal function and hematologic status. A standard 3+3 dose escalation design was used with a fixed oral 40 mg dose of dex and 40% dose increments of TH-302. TH-302 was administered IV with dex on days 1, 4, 8, and 11 of a 21-day cycle. The objectives were to determine DLTs and the MTD; assess the safety, tolerability and preliminary clinical activity of TH-302 plus dex; and study the relationship between hypoxia within the bone marrow and response to TH-302. Results: Eleven pts have been treated: 7M/4F with a median age 61 years (range: 53 – 86) and 6 prior therapies (range: 3 – 10). All received both bortezomib and lenalidomide/thalidomide containing regimens. TH-302 was dosed at 240 (n=5), 340 (n=4), and 480 (n=2) mg/m² for a median of 5 cycles. No DLTs were reported at 240 or 340 mg/m². Two pts treated at 480 mg/m² had DLTs of grade 3 mucositis, exceeding the definition of MTD. A dose expansion is thus ongoing at 340 mg/m2. Two patients had SAEs related to TH-302 (pneumonia). Five pts continue on study after a median of 7 cycles (range: 2–11). Nine pts have had efficacy evaluations: 2 pts with partial responses, 2 pts with minimal responses, and 5 pts with stable disease, for an overall response rate (of MR or better) of 44%. Conclusions: TH-302 can be administered at 340 mg/m2 biweekly + dex, with dose limiting mucositis seen at higher doses. Initial clinical activity has been noted with an ORR of 44% in heavily pretreated MM pts who are relapsed/refractory to both bortezomib and lenalidomide. Clinical trial information: NCT01522872.

Phase I Trial of the Targeted Alpha-Particle Nano-Generator Actinium-225 (225Ac)-Lintuzumab (Anti-CD33; HuM195) in Acute Myeloid Leukemia (AML)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 768-768 ◽  
Author(s):  
Joseph G. Jurcic ◽  
Todd L. Rosenblat ◽  
Michael R. McDevitt ◽  
Neeta Pandit-Taskar ◽  
Jorge A. Carrasquillo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Clinical Activity ◽  
Bone Marrow Blast ◽  
Elimination Kinetics ◽  
Advisory Committees ◽  
Dose Levels

Abstract Abstract 768 Background: Lintuzumab, a humanized anti-CD33 antibody, targets myeloid leukemia cells and has modest activity against AML. To increase the antibody's potency yet avoid nonspecific cytotoxicity seen with β-emitting isotopes, the α-emitter bismuth-213 (213Bi) was conjugated to lintuzumab. Substantial clinical activity was seen in phase I and II trials, but the use of 213Bi is limited by its 46-min half-life. The isotope generator, 225Ac (t½=10 days), yields 4 α-emitting isotopes and can be conjugated to a variety of antibodies using DOTA-SCN. 225Ac-labeled immunoconjugates kill in vitro at radioactivity doses at least 1,000 times lower than 213Bi analogs and prolong survival in mouse xenograft models of several cancers (McDevitt et al. Science 2001). Methods: We are conducting a first-in-man phase I dose escalation trial to determine the safety, pharmacology, and biological activity of 225Ac-lintuzumab in AML. Results: Fifteen patients (median age, 62 yrs; range, 45–80 yrs) with relapsed (n=10) or refractory (n=5) AML were treated to date. Patients received a single infusion of 225Ac-lintuzumab at doses of 0.5 (n=3), 1 (n=4), 2 (n=3), 3 (n=3), or 4 (n=2) μCi/kg (total administered activity, 23–402 μCi). No acute toxicities were seen. Myelosuppression was the most common toxicity; the median time to resolution of grade 4 leukopenia was 26 days (range, 0–71 days). DLT was seen in 3 patients, including myelosuppression lasting >35 days in 1 patient receiving 4 μCi/kg and death due to sepsis in 2 patients treated at the 3 and 4 μCi/kg dose levels. Febrile neutropenia was seen in 4 patients, and 4 patients had grade 3/4 bacteremia. Extramedullary toxicities were limited to transient grade 2/3 liver function abnormalities in 4 patients. With a median follow-up of 2 mos (range, 1–24 mos), no evidence of radiation nephritis was seen. We analyzed plasma pharmacokinetics by gamma counting at energy windows for 2 daughters of 225Ac, francium-221 (221Fr) and 213Bi. Two-phase elimination kinetics were seen with mean plasma t½-α and t½-β of 1.9 and 35 hours, respectively. These results are similar to other lintuzumab constructs labeled with long-lived radioisotopes. Peripheral blood blasts were eliminated in 9 of 14 evaluable patients (64%), but only at doses of ≥1 μCi/kg. Bone marrow blast reductions were seen in 8 of 12 evaluable patients (67%) at 4 weeks, including 6 patients (50%) who had a blast reduction of ≥50%. Three patients treated with 1, 3, and 4 μCi/kg achieved bone marrow blast reductions to ≤5%. Conclusions: This is the first study to show that therapy with a targeted α-particle generator is feasible in humans. 225Ac-lintuzumab has antileukemic activity across all dose levels. Accrual to this trial continues to define the MTD. Disclosures: Jurcic: Actinium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. McDevitt:Actinium Pharmaceuticals, Inc.: Consultancy, Research Funding. Cicic:Actinium Pharmaceuticals, Inc.: Employment, Equity Ownership, Patents & Royalties. Scheinberg:Actinium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

Combination Therapy With Mocetinostat, An Oral, Spectrum-Selective Histone Deacetylase (HDAC) Inhibitor, and 5-Azaciditine: Indication Of Clinical Activity In MDS

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1550-1550 ◽  
Author(s):  
Guillermo Garcia Manero ◽  
Luger Selina ◽  
Klimek Virginia ◽  
Cooper Maureen ◽  
Emmanuel C. Besa ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Histone Deacetylase ◽  
Hdac Inhibitor ◽  
Hodgkin's Lymphoma ◽  
Clinical Activity ◽  
Bone Marrow Blast ◽  
Monosomy 7 ◽  
Previously Treated ◽  
Bone Marrow Blasts

Abstract Background Mocetinostat (MGCD0103) is an orally available, spectrum-selective, non-hydroxamate histone deacetylase (HDAC) inhibitor targeting HDACs 1, 2, 3 and 11. Single-agent activity has been observed in Myelodysplastic Syndromes (MDS), Acute Myelogenous Leukemia (AML), Hodgkin’s lymphoma, and non-Hodgkin’s lymphoma. Preclinical studies demonstrating potential synergy between hypomethylating agents and HDAC inhibitors in relieving transcriptional repression support the evaluation of mocetinostat in combination with 5-azacitidine (AZA) in MDS and AML. Methods The objectives of this open-label, Phase I/II trial of patients with MDS or AML were to determine the MTD of mocetinostat when combined with AZA (75 mg/m2 SC; days 1-7 every 28 days) and to estimate the overall response rate of this combination. In addition, we conducted an ad hoc, independent response assessment for all patients in this study (ASCO 2013) and performed a retrospective, subset analysis on those patients entering this study with 5-20% bone marrow blasts at screening to represent a population with RAEB-1 and RAEB-2. Results A total of 66 subjects with AML and intermediate and high-risk MDS were enrolled in this phase I/II trial. In the Phase I component, 24 patients were treated at 5 dose levels of mocetinostat that ranged from 35 to 135 mg administered 3x/wk starting on Day 5 of treatment with AZA, and in the Phase II component, 42 patients were treated at 90 mg or 110 mg of mocetinostat 3x/wk with AZA. We were interested in analyzing the responses of MDS patients enrolled in this study to gauge the potential for improved activity compared to AZA monotherapy. Therefore, the subset of interest for the current analysis included 22 with baseline bone marrow blast counts of 5-20%, including 8 with 5-9% and 14 with 10-20% bone marrow blasts. The median age was 73 (range 41-82) with 13M and 9F. Thirteen pts received no prior treatment with chemotherapy or other agents for MDS, and 9 were previously treated. Cytogenetic analyses were available for 7 patients: diploid, 2; monosomy 7, 3 (all with other anomalies); complex, 1; and trisomy 8, 1. Chromosome 5 abnormalities occurred in the presence of other abnormalities (2 with monosomy 7). Eighteen patients initiated dosing at 90 mg, 3 at 110 mg, and 1 at 135 mg. The most common ≥ Grade 3 drug-related adverse events were diarrhea (23%), fatigue (18%), thrombocytopenia (18%), and anemia (14%). The CR+CRi rate was 13/22 (59%), with 1 additional patient demonstrating hematologic improvement. The CR+CRi rate appeared similar regardless of line of therapy and the percentage of blasts at baseline (5-9% vs. 10-20%). Most patients (68%) demonstrated decreases in bone marrow blast counts on at least one post-treatment assessment. Of 17 patients who were either RBC or platelet transfusion dependent at baseline, 6 patients (35%) became transfusion-free of both red cells and platelets. Conclusions The combination of mocetinostat and AZA is active in patients with MDS, including some patients who were previously treated and is associated with a 59% rate of CR+CRi in a subset of patients with 5-20% bone marrow blasts at screening, and with 35% of transfusion-dependent patients becoming transfusion independent. A randomized study is planned to further evaluate the clinical activity of mocetinostat plus AZA in MDS. Disclosures: Chao: Mirati Therapeutics: Employment. Humphrey:Mirati Therapeutics Inc.: Employment.

KB004, a Novel Non-Fucosylated Humaneered® Antibody, Targeting EphA3, Is Active and Well Tolerated in a Phase I/II Study of Advanced Hematologic Malignancies

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3756-3756 ◽  
Author(s):  
Ronan T Swords ◽  
Andrew H Wei ◽  
Simon Durrant ◽  
Anjali S. Advani ◽  
Mark S Hertzberg ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Dose Level ◽  
Research Funding ◽  
Hematologic Malignancies ◽  
Clinical Activity ◽  
Bone Marrow Biopsies ◽  
Infusion Reactions ◽  
Equity Ownership ◽  
Dose Levels

Abstract Background: EphA3 is a novel drug target involved in cell positioning in fetal development. In adults it is an oncofetal antigen, that is re-expressed in hematologic malignancies (blood and bone marrow, leukemic stem cells) and solid tumors. It is also upregulated in diseases characterized by abnormal proliferation and fibrosis, such as idiopathic pulmonary fibrosis and diabetic kidney disease. KB004 is a Humaneered® high affinity antibody (KD = 610 pM) targeting EphA3 with at least 3 possible mechanisms of action: direct apoptosis in tumor cells, activation of ADCC and disruption of tumor vasculature. Objectives: The primary objectives of the Phase I study component are to determine safety and MTD for KB004 in patients with hematologic malignancies, refractory to or unfit for chemotherapy. Secondary objectives are to characterize PK, immunogenicity, and preliminary clinical activity of KB004. Exploratory objectives include evaluation of EphA3 expression on tumor, stromal, and endothelial cells. Methods: Multicenter Phase I/II study. Key eligibility criteria: unsuitable for standard of care or relapsed or refractory hematologic malignancy, ECOG PS 0-1, adequate organ function, platelets ≥ 10,000/uL (untransfused for 7 days) and normal coagulation times. KB004 was administered as a 1-2 hr intravenous infusion on days 1, 8, and 15 of each 21-day cycle, at incremental doses of 20, 40, 70, 100, 140, 190, 250 and 330 mg. At 70 mg and above infusion reaction prophylaxis included H1 and H2 blockers, acetaminophen and IV steroids. Safety and activity by IWG response criteria were assessed. Peripheral blood and bone marrow biopsies for PK analysis and EphA3 expression were also collected. Results: A total of 50 patients (AML 39, MDS 7, DLBCL 1, MF 3) received KB004 in the phase I/dose finding component of the study, which has been completed. The most common toxicities were transient grade 1 and grade 2 transient infusion reactions (IRs) in 79% of patients. IRs were characterized by chills, elevated temperature, fever, rigors, back pain, nausea, vomiting, hypotension, hypertension and transient hypoxia (in 2 cases). No other significant KB004 related toxicity was observed. Two patients discontinued KB004 due to an IR. One of these (grade 3) defined a DLT at the 330mg dose level. A second patient at 330mg had grade 2 infusion reactions associated with multiple infusion delays. These observations prompted expansion of the next lowest dose cohort, 250mg. Six evaluable patients were treated at this dose level. No clinically significant IRs or DLTs were observed. This is therefore the recommended phase 2 dose (RP2D). At all dose levels observed Cmax for KB004 was approximately dose proportional. Sustained exposure above the predicted effective concentration (1ug/mL) to cover the 7-day interval between doses was achieved above 190mg. Responses according to IWG criteria were observed in patients with AML, MF and MDS at the 20 mg, 140g and 250mg dose levels, respectively. At 20mg, a 78 yr-old patient with relapsed AML achieved CRp. Remission was sustained for over 18 months and relapse was preceded by a rise in EphA3 expression. Serial bone marrow biopsies with KB004 treatment show decreased reticulin and collagen fibrosis. At 140mg, a 67 yr old patient with JAK2 V617F mutant previously untreated myelofibrosis whose predominant clinical problem at diagnosis was anemia achieved Clinical Improvement [CI]. Transfusion independency (both RBC and platelets) has been sustained for 8+ months with improvement in constitutional symptoms and improved splenomegaly. At 250 mg an 84 yr-old patient with MDS/MPN (intermediate risk) achieved a Hematologic Improvement [HI, erythroid]. A > 50% reduction in marrow blast percentage was seen in 8 patients. Bone marrow biopsies positive for EphA3 expression with a cut-off of 10% of nucleated cells were obtained in greater than 70% of AML patients. Of 20 patients for whom EphA3 expression data exists with time, 7 (35%) had at least a 50% reduction in expression with treatment. Conclusion: KB004 is a novel agent targeted against EphA3 that is well tolerated when given as a weekly 2 hour infusion. The promising clinical activity profile is postulated to be consistent with the antifibrotic mechanism. The Phase II component of the study is ongoing in which the activity of KB004 will be characterized in disease specific cohorts including AML, MDS and MF at the RP2D of 250mg. Disclosures Durrant: KaloBios: Research Funding. Advani:KaloBios: Research Funding. Greenberg:Celgene: Research Funding; Novartis: Research Funding; GSK: Research Funding; Onconova: Research Funding; KaloBios: Research Funding. Cortes:KaloBios: Research Funding. Yarranton:KaloBios: Employment; Glaxo: Equity Ownership; EnGen: Equity Ownership, Science Advisor, Science Advisor Other; Stemline Therapeutics: Equity Ownership. Walling:KaloBios, Corcept Therapeutics, Prothena, NewGen Therapeutics, Valent Technologies, LBC Pharmaceuticals: Consultancy, Equity Ownership; Amgen, BioMarin: Equity Ownership; Crown BioScience: Membership on an entity's Board of Directors or advisory committees.

A Phase I Trial of AT9283, a Multitargeted Kinase Inhibitor, in Patients with Refractory Hematological Malignancies.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 904-904 ◽  
Author(s):  
Farhad Ravandi ◽  
James Foran ◽  
Srdan Verstovsek ◽  
Jorge Cortes ◽  
William Wierda ◽  
...  
Keyword(s):  
Phase I ◽  
Hematological Malignancies ◽  
Kinase Inhibitor ◽  
Tumor Lysis Syndrome ◽  
Median Number ◽  
Linear Increase ◽  
Pharmacokinetic Data ◽  
Early Results ◽  
Dose Levels

Abstract AT9283 is a small molecule inhibitor of aurora kinases A and B, JAK2, and JAK3 (IC50 <5nM in each case). AT9283 was administered as a 72-hour continuous intravenous infusion to patients with refractory hematological malignancies at 6 different dose levels: 3, 6, 12, 24 and 48 mg/m2 daily x 3. Inclusion/exclusion criteria, and definitions of DLT and MTD were standard. A 3+3 dose escalation phase I design was implemented. To date, 20 patients have been treated: 3 at 3, 3 at 6, 7 at 12, 3 at 24 and 4 at 48 mg/m2/daily x 3. Seven were females; median age was 58 years (range 22 to 86); 19 patients had previously treated acute myeloid leukemia (AML); 15 were in second or subsequent salvage; abnormal cytogenetics were present in 15. Two patients had undergone prior matched unrelated allografts. The median number of prior chemotherapy regimens was 2 (range 1 to 5). Pharmacokinetic data is available for patients treated at early dose levels only. Median systemic clearance varied up to two-fold between patients with some suggestion of a non-linear increase in exposure at higher dose levels. At the completion of the infusion, the plasma concentration of AT9283 decreased rapidly exhibiting a multiphasic elimination and a terminal half-life of 6 to 13 hours. At doses of 3 to 48 mg/m2/D x 3, no MTD has been defined; 2 patients treated at 12 mg/m2/D x 3 developed tumor lysis syndrome which resolved spontaneously in one case and required hemodialysis in the second. This dose level was expanded to treat 6 patients. Patients received a median of two cycles of treatment (range 1 to 3). So far, 6 of 20 patients (30%) exhibited evidence of anti-leukemia activity, with significant reductions in bone marrow blasts (≥ 50%) observed at all dose levels: In summary, AT9283 shows good early results and continues to accrue patients to define the DLT and MTD with the 72-hour infusion schedule. In vitro studies suggest that prolonging the duration of infusion will increase the drug’s biological effect. This will be explored following the identification of the MTD for a 72-hour infusion.

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