Abstract CT103: Clinical safety and activity in a phase I trial of AG-221, a first in class, potent inhibitor of the IDH2-mutant protein, in patients with IDH2 mutant positive advanced hematologic malignancies

13007 Background: 4-HPR is a retinoid cytotoxic for cancer cell lines. In clinical trials, oral capsule 4-HPR had limited bioavailability and activity. An intravenous intralipid emulsion formulation of 4-HPR (ILE 4-HPR) was developed to increase bioavailability. The objectives of this phase I trial were to determine a maximally tolerated dose (MTD) of ILE 4-HPR, and to assess toxicities, pharmacokinetics (PK), and preliminary response data. Methods: We used an accelerated titration Simon design 2 dose escalation schema with 100% increase in ILE 4-HPR per dose level tested until moderate toxicity was observed in 2 patients or DLT in one. Ten dose levels were planned with a starting dose of 80 mg/m2/day (continuous i.v. x 5 days q 3 weekly), increasing until Dose level 10 at 1,810 mg/m2. A De-escalation to 1,240 mg/m2/day Dose level 9 was added when DLT was observed in 2 patients at 1,810 mg/m2 dose level 10. Results: To date, 11 patients have been enrolled. At dose level 10 (1,810 mg/m2/day), 2 pts experienced a DLT of grade IV hypertriglyceridemia with grade 2 pancreatitis. A de-escalation to dose level 9 (1,280 mg/m2/day) has enrolled 4 pts, 1 had grade IV hypertriglyceridemia; enrollment is ongoing. We observed a transient response in a patient with NHL at 320 mg/m2 and a continued partial response in one patient with NHL on dose level 10 (1,810 mg/m2). PK showed a linear relationship of dose to plasma level, with steady-state levels of 54 μM (1,280 mg/m2)and 62 μM (1,810 mg/m2). Conclusions: ILE 4-HPR was given via continuous infusion to a dose of 1,810 mg/m2/day x 5 days. 1 patient with NHL had a transient partial response and a second patient with chemotherapy-refractory NHL had a partial response sustained on treatment for > 6 months. The DLT of hypertriglyceridemia is likely related to the intralipids delivered. Enrollment continues at a dose of 1,280 mg/m2/day. ILE 4- HPR can be safely administered and obtained plasma levels 6 to 7 times higher than previously obtained by oral capsule 4-HPR, with clinical activity in hematologic malignancies. No significant financial relationships to disclose.

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Phase I Evaluation of Prolonged-Infusion Gemcitabine With Irinotecan for Relapsed or Refractory Leukemia or Lymphoma

Journal of Clinical Oncology ◽

10.1200/jco.2002.08.166 ◽

2002 ◽

Vol 20 (13) ◽

pp. 2995-3000 ◽

Cited By ~ 20

Author(s):

Adam J. Bass ◽

Jon P. Gockerman ◽

Eve Hammett ◽

Carlos M. DeCastro ◽

David J. Adams ◽

...

Keyword(s):

Confidence Interval ◽

Acute Leukemia ◽

Phase I ◽

Phase I Trial ◽

Overall Response Rate ◽

Response Rate ◽

Total Duration ◽

Hematologic Malignancies ◽

Prolonged Infusion ◽

Induction Regimen

PURPOSE: To estimate the maximum-tolerated duration of infusion of gemcitabine at 10 mg/m2/min in combination with irinotecan at 40 mg/m2 daily for 3 days in the treatment of relapsed or refractory acute leukemia or lymphoma. PATIENTS AND METHODS: Patients with leukemia or lymphoma were escalated in separate strata. Stratum I consisted of 11 patients, median age of 47 years (range, 18 to 68 years), with relapsed or refractory leukemia. Stratum II contained nine patients, median age of 48 years (range, 39 to 68 years), who had refractory non-Hodgkin’s lymphoma. Patients received irinotecan at 40 mg/m2 daily for 3 days, beginning just before the first dose of gemcitabine. Gemcitabine was given at 10 mg/m2/min, with the total duration adjusted following a modified continuous reassessment model. RESULTS: Severe myelosuppression and stomatitis/esophagitis were the most serious hematologic and nonhematologic toxicities. Several patients developed febrile neutropenia, nausea, or vomiting. In both strata, the maximum recommended duration of infusion of gemcitabine was 12 hours delivered at 10 mg/m2/min (7,200 mg/m2). The overall response rate for one cycle of this therapy in this phase I trial for patients with leukemia was 18% (95% confidence interval, 8% to 45%), and for those with lymphoma, 33% (95% confidence interval, 17% to 66%). CONCLUSION: A prolonged infusion of gemcitabine at 10 mg/m2/min for 12 hours with 3 days of irinotecan at 40 mg/m2/d is a tolerable induction regimen for patients with acute leukemia or lymphoma. Stomatitis/esophagitis should be anticipated; however, this regimen may induce responses in patients with difficult-to-treat hematologic malignancies.

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Phase I trial of an interleukin-2 (IL-2) fusion toxin (DAB486IL-2) in hematologic malignancies expressing the IL-2 receptor

Blood ◽

10.1182/blood.v79.10.2547.2547 ◽

1992 ◽

Vol 79 (10) ◽

pp. 2547-2554 ◽

Cited By ~ 4

Author(s):

CF LeMaistre ◽

C Meneghetti ◽

M Rosenblum ◽

J Reuben ◽

K Parker ◽

...

Keyword(s):

Phase I ◽

Diphtheria Toxin ◽

Phase I Trial ◽

Interleukin 2 ◽

Hematologic Malignancies ◽

Genetically Engineered ◽

Pharmacokinetic Analysis ◽

Fusion Toxin ◽

High Affinity Receptor ◽

Elevated Creatinine

Abstract DAB486IL-2 is a recombinant fusion toxin in which the native receptor binding domain of diphtheria toxin has been replaced with human interleukin-2 (IL-2). It selectively binds and intoxicates only cells that bear the high-affinity receptor for IL-2. In the first clinical trial of a genetically engineered ligand fusion-toxin, we have treated 18 patients with chemotherapy-resistant IL-2 receptor expressing hematologic malignancies with escalating doses of DAB486IL-2. The maximal tolerated dose of a daily intravenous bolus of DAB486IL-2 was 0.1 mg/kg per day for 10 doses, established by asymptomatic, reversible elevations of hepatic transaminases without changes in other tests of liver function. Other mild reversible side effects noted were rash, nausea, elevated creatinine, chest tightness, and fever. Pharmacokinetic analysis showed a monophasic clearance of 5.8 +/- 0.7 minutes with peak levels of 3,549 +/- 1,041 mg/mL at the 0.1 mg/kg dose. Approximately 50% of patients developed an antibody response to diphtheria toxin or DAB486IL-2. The presence of such antibodies did not preclude patients from experiencing an antitumor response as four of the six patients with antitumor effect had detectable antibody titers. Although this was a phase I trial designed to define the safety of DAB486IL-2, remissions were observed in three patients lasting from 5 to over 18 months. The ability to achieve significant tumor reductions in this group of heavily treated patients is encouraging and suggests additional trials are warranted in hematologic malignancies.

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