Saleh, Mansoor N.

e14537 Background: Over-expression of Bcl-2 family proteins is common in human cancers. Initial trials of the oral, pan-Bcl-2 inhibitor AT-101 showed acute dose limiting toxicity of Gr 3–4 AST/ALT (MTD 40 mg/d) and ileus with prolonged dosing daily (QD) for 21/28 days per cycle (Saleh, NCI/EORTC, 2005; James, ASCO, 2006 and Saleh, ASCO, 2007). MTD in the QD schedule has been previously reported. In this study different dosing schedules of AT-101 were tested in adults with advanced cancers and final results for the pulse dosing schedule of twice a day for three days every other week (b.i.d. x 3d EOW) are being reported. Methods: Serial patient (pt) cohorts received AT-101 at escalating doses of 30–80 mg b.i.d. x 3d EOW. Adverse events (AEs) were graded by the NCI CTCAE v3.0. Efficacy was determined by RECIST. Results: 37 pts have been enrolled. Safety data is available on 34/37 pts. In this b.i.d. x 3d EOW dosing schedule, ileus/small bowel obstruction (SBO) occurred in 3 pts (one at each dose level of 30, 40 and 50 mg) and was the dose limiting toxicity for this schedule. Of note, the SBO that occurred at 30 mg was felt to be unrelated to study agent therefore, 30 mg b.i.d. x 3d EOW was the MTD determined for this schedule. The most common (>50%) grade 1–2 AEs included: nausea, vomiting, diarrhea, fatigue and anorexia. Grade 3–4 AEs occurring in > 2 pts include: nausea, abdominal pain, elevated AST (3 pts each), vomiting, fatigue, dehydration (4 pts each), hypokalemia (5 pts). Stable disease was reported in 13/37 (35%) pts. One pt with NSCLC continues on study with stable disease for 33 cycles and 2 additional pts were on study with stable disease for 18 and 9 cycles. The mean Plasma Cmax was 301 ng/ml (+ 477 ng/ml SD) and mean AUC for 30 mg b.i.d.x3d EOW was 1080 ng*hr/ml (+ 1990 ng/ml SD) with a median peak concentration at 4 hours post dose. Conclusions: Pulse dosing of AT-101 achieved an MTD of 30mg b.i.d. x 3d EOW and is associated with reduced toxicity than continuous daily dosing, and may be preferable in combination regimens. [Table: see text]

3583 Background: Over-expression of Bcl-2 family proteins is common in human cancers. Initial trials of the oral pan-Bcl-2 inhibitor AT-101 showed acute dose limiting toxicity of Gr 3–4 AST/ALT (MTD 40 mg/d), and ileus with prolonged dosing daily (QD) for 21/28 days per cycle (Saleh, NCI_EORTC, 2005; James, ASCO, 2006). Our ongoing Phase 1 study tests different dosing schedules of AT-101 in adults with advanced cancers. Methods: Serial patient (pt) cohorts received AT-101 at escalating doses twice a day for three days every other week (BIDx3dEOW) or once weekly (QW). Adverse events (AEs) were graded by the NCI CTCAE v. 3.0. Results: 24 pts have received pulse dosing; safety data are available for 20 pts (30–70 mg BIDx3dEOW, N=13; 80–160 mg QW, N=7). For comparison, 38 pts received 5–60 mg QD. Median number of cycles (range): BIDx3dEOW_2(1–9); QW_3(1–3), QD_2(1–12). AST/ALT is not yet dose limiting, nor the MTD reached, at 70 mg BIDx3dEOW or 160 mg QW. Ileus occurred in 4/38 pts dosed daily but in no pts on either pulse schedule. Other potentially related Gr 3–4 AEs were: BIDx3dEOW (6 pts)–AST (1 pt), abdominal pain (2 pts), elevated CK/right ventricular dysfunction (1 pt w/history of COPD/doxil therapy), hypokalemia (1 pt);QW: none; QD: AST/ALT (5 pts), nausea/vomiting/diarrhea (3 pts each) fatigue (2 pts), hypocalcemia (2 pts), hypokalaemia/anorexia/dehydration/hypophosphatemia (1 pt), elevated GGT (1 pt). The most common Gr 1–2 AEs_nausea/vomiting/fatigue_occurred in over 50% of QD and BIDx3dEOW pts but only 1/7 QW pts. Plasma Cmax (mean ± SD, μM): 70 mg BIDx3d EOW, 2.4 ± 0.9; 160 mg QW, 3.5 ± 1.3; 40 mg/d (MTD, 21/28 d), 2.6 ± 2.0. T ½ was approx. 3 hours on all schedules. Conclusions: Pulse dosing of AT-101 appears associated with reduced toxicity than more continuous daily dosing, and may be preferable in combination regimens. No significant financial relationships to disclose.

Purpose To evaluate the efficacy and safety of arsenic trioxide monotherapy in patients with myelodysplastic syndromes (MDS). Patients and Methods Patients received arsenic trioxide (0.25 mg/kg/d) on 5 consecutive days per week for 2 weeks, followed by 2 weeks’ rest (one cycle). Two patient cohorts were established according to International Prognostic Scoring System risk category: lower-risk (low or intermediate-1) or higher-risk MDS (intermediate-2 or high). For lower-risk MDS, hematologic improvement (HI) was the primary response end point. For higher-risk MDS, additional end points included complete or partial remission. Based on the expected time to response, patients receiving two or more cycles were prospectively evaluated. Results Hematologic adverse events included neutropenia, thrombocytopenia, and febrile neutropenia. Two patients died during the study due to treatment-related toxicities. Most common grade 3/4 nonhematologic events were pneumonia, fatigue, hemorrhage, pain, and dyspnea. Among patients who received one or more doses (n = 70) or completed two or more cycles (n = 51), the HI rates were 34% and 39% in lower-risk patients, and 6% and 9% in higher-risk patients, respectively; the overall major HI rates were 20% and 22%. One higher-risk patient achieved a complete remission (3%). Major HIs were observed in all hematologic lineages; erythroid responses were the most common. Transfusion independence or reduction by ≥ 50% occurred in 33% of patients dependent on RBC transfusions. The overall median duration of HI was 6.8 months (range, 2 to 40 months). Conclusion Arsenic trioxide monotherapy has moderate activity against MDS, with a manageable adverse effect profile. The further study of arsenic trioxide in MDS, particularly in combination with other agents, is warranted.

PURPOSE: Rituximab is commonly used as a single agent or in combination therapy for non-Hodgkin’s lymphoma (NHL). Ibritumomab tiuxetan radioimmunotherapy targets the same antigen as rituximab and has demonstrated efficacy in rituximab-naïve NHL. This study evaluated ibritumomab tiuxetan in the treatment of rituximab-refractory follicular NHL. PATIENTS AND METHODS: Eligible patients were refractory to rituximab; this was defined as no objective response to rituximab (375 mg/m2 weekly for 4 weeks) or time to progression (TTP) of ≤ 6 months. The ibritumomab tiuxetan treatment regimen consisted of pretreatment with rituximab (250 mg/m2 intravenously on days 1 and 8) to deplete peripheral blood B cells, then yttrium-90 ibritumomab tiuxetan (0.4 mCi/kg; maximum, 32 mCi) intravenously on day 8, administered on an outpatient basis. An imaging/dosimetry dose of indium-111 ibritumomab tiuxetan (5 mCi) was injected after rituximab (day 1) in 28 patients. RESULTS: Fifty-seven patients were treated. The median age was 54 years, 74% had tumors ≥ 5 cm, and all were extensively pretreated (median, four prior therapies; range, one to nine). The estimated radiation-absorbed doses to healthy organs were below the study-defined limit in all patients studied with dosimetry. The overall response rate for the 54 patients with follicular NHL was 74% (15% complete responses and 59% partial responses). The Kaplan-Meier–estimated TTP was 6.8 months (range, 1.1 to ≥ 25.9 months) for all patients and 8.7 months for responders. Adverse events were primarily hematologic; the incidence of grade 4 neutropenia, thrombocytopenia, and anemia was 35%, 9%, and 4%, respectively. CONCLUSION: Ibritumomab tiuxetan radioimmunotherapy is effective in rituximab-refractory patients. The only significant toxicity is hematologic.

Mildly thrombocytopenic patients with relapsed or refractory low-grade non-Hodgkin lymphoma (NHL) have an increased risk of chemotherapy-induced myelosuppression following treatment. The safety and efficacy of radioimmunotherapy with a reduced dose of90Y ibritumomab tiuxetan (0.3 mCi/kg [11 MBq/kg]; maximum 32 mCi [1.2 GBq]) was evaluated in 30 patients with mild thrombocytopenia (100-149 × 109 platelets/L) who had advanced, relapsed or refractory, low-grade, follicular, or transformed B-cell NHL. The ibritumomab tiuxetan regimen included an infusion of rituximab (250 mg/m2) and injection of 111In ibritumomab tiuxetan (5 mCi [185 MBq]) for dosimetry evaluation, followed 1 week later with rituximab (250 mg/m2) and90Y ibritumomab tiuxetan (0.3 mCi/kg [11 MBq/kg]). Patients (median age, 61 years; 90% stage III/IV at study entry; 83% follicular lymphoma; and 67% with bone marrow involvement) had a median of 2 prior therapy regimens (range, 1-9). Estimated radiation-absorbed doses were well below the study-defined maximum allowable for all 30 patients. With the use of the International Workshop criteria for NHL response assessment, the overall response rate was 83% (37% complete response, 6.7% complete response unconfirmed, and 40% partial response). Kaplan-Meier estimated median time to progression (TTP) was 9.4 months (range, 1.7-24.6). In responders, Kaplan-Meier estimated median TTP was 12.6 months (range, 4.9-24.6), with 35% of data censored. Toxicity was primarily hematologic, transient, and reversible. The incidence of grade 4 neutropenia, thrombocytopenia, and anemia was 33%, 13%, and 3%, respectively. Reduced-dose ibritumomab tiuxetan is safe and well tolerated and has significant clinical activity in this patient population.