Warsi, Ghulam

8028 Background: Effective treatment for relapsed/refractory cHL is lacking. The oral mammalian target of rapamycin inhibitor EVE showed promising efficacy and acceptable toxicity in cHL. We conducted a study to confirm EVE safety and efficacy in relapsed/refractory cHL. Methods: In this multicenter, open-label, 2-step, phase 2 study, adults with cHL that progressed after high-dose chemotherapy with autologous hematopoietic stem cell transplant (AHSCT) or a gemcitabine-, vinorelbine-, or vinblastine-containing regimen received EVE 10 mg/d until disease progression or unacceptable toxicity. Response was assessed every 12 wk via integrated positron emission tomography/computed tomography (CT) with contrast or CT with contrast. Primary endpoint was overall response rate (ORR) per modified response criteria for malignant lymphoma. Adverse events (AEs) were assessed during, and for ≥4 wk after, EVE treatment. Results: 55 patients were enrolled. Of the 38 currently evaluable patients, 37% were men, median age was 32.5 y, 53% were pretreated with AHSCT, and 95% were pretreated with gemcitabine, vinorelbine, or vinblastine; 71% had disease progression during previous therapies or discontinued previous treatment due to progression. 23 patients discontinued treatment, most commonly due to disease progression (n = 11). ORR was 37% (Table). Median progression-free survival (PFS) was 7.2 mo. The most common hematologic AEs were thrombocytopenia (39%) and anemia (24%); the most common nonhematologic AEs were fatigue (47%), cough (29%), dyspnea (26%), headache (21%), and rash (21%). Grade 3/4 AEs, most commonly thrombocytopenia (18%), were observed in 45% of patients. Conclusions: EVE showed a favorable ORR and median PFS in the first 38 evaluable patients with highly pretreated, relapsed/refractory cHL. The AE profile was consistent with that previously observed for EVE. These preliminary results confirm those of an earlier study and support further evaluation of EVE in cHL. [Table: see text]

Abstract Abstract 2717 Background: Dysregulation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signal transduction pathway, which is central to cellular growth, proliferation, metabolism, survival, and angiogenesis, is implicated in Hodgkin lymphoma (HL) pathogenesis. In a previous phase II study of patients with relapsed/refractory lymphomas, the oral mTOR inhibitor everolimus showed promising clinical activity and acceptable toxicity in a subgroup of 19 heavily pretreated patients with HL (Johnston et al. Am J Hematol 2010;85:320–4). The purpose of this study was to confirm the safety and efficacy of everolimus 10 mg/day in patients with relapsed/refractory classical HL. Methods: In this multicenter, US, phase II study, patients aged ≥18 years with classical HL whose disease progressed after high-dose chemotherapy with autologous hematopoietic stem cell transplant (AHSCT) and/or a gemcitabine-, vinorelbine-, or vinblastine-containing regimen were treated with oral everolimus 10 mg/day until disease progression or unacceptable toxicity. Radiological response was assessed every 12 weeks using integrated positron emission tomography/computed tomography with contrast or computed tomography with contrast. The primary endpoint was the overall response rate (ORR) evaluated using modified response criteria for malignant lymphoma (Cheson et al. J Clin Oncol 2007;25:579–86). Secondary endpoints included median progression-free survival (PFS). Adverse events (AEs) were assessed throughout the study and for ≥4 weeks after the last everolimus dose. Results: The results from 37 patients in the safety population with evaluable data are reported in this abstract. Among these 37 patients, 35% were male, and the median age was 32 years. The median times from initial diagnosis to the first and most recent recurrence/relapse were 9 and 38 months, respectively. Of the 37 patients, 54% were pretreated with AHSCT and 95% were pretreated with a gemcitabine-, vinorelbine-, or vinblastine-containing regimen. The percentage of patients who experienced disease progression during prior therapies or discontinued their previous treatment due to disease progression was 73%. The median number of prior medication regimens was 4.5. Twenty-two patients discontinued treatment, including 11 due to disease progression and 8 due to AEs. The ORR was 35%, and an additional 27% of patients had stable disease (Table). The median PFS was 7.2 months (Figure). The most common hematologic AEs were thrombocytopenia (38%) and anemia (22%), and the most common nonhematologic AEs were fatigue (43%), cough (27%), headache (22%), dyspnea (22%), and rash (22%). Grade 3 or 4 drug-related AEs were noted in 12 (32%) patients and most commonly included thrombocytopenia (16%), neutropenia (8%), and anemia (8%). Serious AEs were experienced by 19% of patients; no serious AE occurred in more than 1 patient. Conclusion: Everolimus was associated with a favorable ORR and median PFS duration in highly pretreated patients with relapsed/refractory classical HL, confirming results of a previous study. The AE profile was consistent with that previously observed for everolimus; most AEs were grade 1 or 2 and manageable. These results suggest that further study evaluating everolimus in HL is warranted. Disclosures: Pinter-Brown: Genentech: Speakers Bureau; Spectrum: Honoraria; Celgene: Consultancy; Merck: Consultancy; Allos: Consultancy. Rogerio:Novartis Pharmaceuticals Corporation: Employment. Warsi:Novartis Pharmaceuticals Corporation: Employment. Graham:Novartis Pharmaceuticals Corporation: Employment. Ramchandren:Seattle Genetics: Research Funding; Novartis: Research Funding; Millennium: Research Funding; Celgene: Research Funding; Pfizer: Research Funding.

Abstract Abstract 2740 Background: Historically, treatment options for the approximately 30% of patients with Hodgkin lymphoma (HL) who have primary refractory disease or relapse after experiencing initial response have been limited to high-dose chemotherapy with autologous hematopoietic stem cell transplant (AHSCT). Development of novel therapeutic options is needed to improve outcomes in patients whose disease is refractory to or relapses after initial chemotherapy or subsequent high-dose chemotherapy with AHSCT. The oral mammalian target of rapamycin inhibitor everolimus showed promising efficacy and acceptable toxicity in 19 patients with heavily pretreated HL enrolled in a phase 2 study of everolimus monotherapy for relapsed, rare lymphomas (Johnston et al. Am J Hematol 2010;85:320-4). To confirm the efficacy and safety of everolimus monotherapy in patients with relapsed/refractory classical HL, we conducted a multicenter, open-label, 2-step, phase 2 study. Methods: Adults with classical HL that progressed after high-dose chemotherapy with AHSCT or a gemcitabine-, vinorelbine-, or vinblastine-containing regimen received everolimus 10 mg/day until disease progression or unacceptable toxicity. Response was assessed every 12 weeks via computed tomography with contrast or integrated positron emission tomography/computed tomography with contrast. The primary study endpoint was the overall response rate (ORR) evaluated according to the modified response criteria for malignant lymphoma (Cheson et al. J Clin Oncol 2007;25:579-86). Secondary endpoints included the disease control rate (DCR), duration of overall response, duration of disease control, progression-free survival (PFS), and safety. Results: A total of 57 patients were enrolled in this study; 57.9% were women, the median age was 32.0 years, 57.9% were pretreated with AHSCT, and 100% were pretreated with gemcitabine, vinorelbine, or vinblastine. Overall, 66.7% of patients experienced disease progression during previous therapies or discontinued previous treatment due to progression. At the time of analysis, 48 patients discontinued study treatment, most commonly due to disease progression (n = 25). The ORR and DCR were 42.1% and 77.2%, respectively (Table). The median time to response was 57 days. Median PFS was 9.0 months. Adverse events experienced by >25% of patients were fatigue (56.1%), thrombocytopenia (47.4%), cough (38.6%), rash (38.6%), pyrexia (31.6%), anemia (29.8%), dyspnea (28.1%), back pain (26.3%), and diarrhea (26.3%). Grade 3/4 adverse events were observed in 33 patients (57.9%); the most common were thrombocytopenia (21.1%) and anemia (12.3%). Stomatitis was experienced by 14 patients (24.6%) and was of grade 3 severity in 2 patients (3.5%). Pneumonitis was observed in 6 patients (10.5%) and was of grade 1 severity in 2 patients (3.5%) and grade 2 severity in 4 patients (7.0%). Conclusions: In this phase 2 study, everolimus monotherapy demonstrated favorable efficacy and a short time to response in patients with heavily pretreated, relapsed/refractory classical HL. The overall safety profile was consistent with that previously observed for everolimus in patients with HL and other cancers. The results of this study confirm previous results and support the further evaluation of everolimus in patients with classical HL. Disclosures: Johnston: Novartis: Consultancy. Off Label Use: Everolimus is an mTOR inhibitor indicated in the US for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer in combination with letrozole after failure of letrozole or anastrozole; adults with progressive pancreatic neuroendocrine tumors that are unresectable, locally advanced, or metastatic; adults with advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib; adults with renal angiomyolipoma and tuberous sclerosis complex not requiring immediate surgery; and adults and children aged 3 years or greater with subependymal giant cell astrocytoma associated with tuberous sclerosis complex who require therapeutic intervention but are not candidates for curative surgical resection. Pinter-Brown:Millennium: Consultancy. Rogerio:Novartis: Employment; Novartis: Equity Ownership. Warsi:Novartis: Employment; Novartis: Equity Ownership. Chau:Novartis: Employment. Ramchandren:Seattle Genetics: Honoraria.

Background: The phase II, exploratory, open-label Exploring Nilotinib BCR-ABL Effects (ENABL) study [ ClinicalTrials.gov identifier: NCT00644878] assessed the impact of switching to nilotinib therapy in patients with chronic myeloid leukemia in chronic phase (CML-CP) who had a suboptimal molecular response with imatinib. Methods: Patients with CML-CP who had previously achieved a complete cytogenetic response (CCyR), but had a suboptimal molecular response, with frontline imatinib therapy ( N = 18) were assigned to receive nilotinib 300 mg twice daily. The primary endpoint was the change in BCR-ABL1 transcript levels from baseline after 12 months; rates of major molecular response (MMR) and safety were also assessed. Results: At 3 months after switching to nilotinib, 10 of 17 (59%) evaluable patients had achieved MMR. At 12 months, 9 of 12 (75%) evaluable patients had achieved MMR, and the median BCR-ABL1 level among all patients remaining in the study was 0.020% on the International Scale (IS), equivalent to a 3.7-log reduction from the standardized IS baseline (primary endpoint). Adverse events (AEs) were typically grade 1/2 and manageable with dose interruptions. A total of three patients experienced serious study drug-related AEs, including pancreatitis, bradycardia, and vertigo. No deaths were reported. Conclusions: Overall, results from this exploratory study suggest that switching to nilotinib due to suboptimal molecular response with imatinib can result in improved molecular response for patients with CML-CP.

Abstract Background: Aromatase inhibitor (AI) therapy effectively increases disease-free survival in postmenopausal women (PMW) with ER+ and/or PR+ breast cancer (BCa). However, the use of AIs results in nearly complete ablation of estrogen production which can lead to accelerated bone loss and increased fracture risk. The Z-FAST study evaluated the efficacy and safety of zoledronic acid (ZOL) in preventing AI associated bone loss in PMW with early breast cancer (EBC) who received adjuvant letrozole (LET).Material and Methods: 602 PMW with stage I-IIIa ER+ and/or PR+ BCa starting LET (2.5 mg qd x 5 yrs) were randomized (1:1) to upfront ZOL (4 mg IV q 6 mos) vs delayed ZOL. The delayed arm (D) received ZOL when either the post-baseline T-score decreased to <-2 or a clinical fracture occurred. All patients (pts) were treated with calcium and vitamin D. The primary endpoint, the percent change in lumbar spine (LS) bone mineral density (BMD) at 12 mos, was previously reported (JCO; 25:829, 2007). The 5 year (5y) final study results are reported here.Discussion: Baseline characteristics were similar between groups. 180 pts in upfront ZOL arm (U) and 175 pts in D completed full 5y study. Of pts with BMD data available, U (n=140) showed a mean increase of 6.2% in LS BMD while D (n=132) showed a mean decrease of 2.4%, resulting in an absolute difference of 8.6% (p<0.001). U (n=141) showed a mean increase of 2.6% in total hip (TH) BMD while D (n=132) showed a mean decrease of 4.1%, resulting in an absolute difference of 6.7% (p<0.001). When BMD data in D was excluded after pts started ZOL (censored analysis), the absolute difference in LS and TH BMD between the two arms was 11.3% and 8.7%, respectively. Among pts with baseline LS T-score between -1 and -2, 27.9% (19) U pts [8.6% (7) D pts] returned to normal T-score (T-score >-1), and no U pts as compared to 4.9%(4) D pts became severely osteopenic (T <-2). 17.7% (53) D pts met criteria that required initiation of ZOL. Although the study was not designed to detect a significant difference in the fracture rate between treatment arms, fractures occurred in 10.7% (29) U pts and 12.4% (33) D pts. Administration of ZOL q 6 mos for up to 5y was safe and well tolerated. No serious renal adverse events suspected related to ZOL and no confirmed osteonecrosis of the jaw cases (ONJ) were reported. Disease recurrence including death due to disease progression was reported in 7.0%, 95% C.I. (3.7%-10.3%) from K-M (16) pts in U, and 8.8%, 95% C.I. (5.2%-12.5%) (21) pts in D.Conclusion: The 5y follow-up of the Z-FAST trial show that the overall difference in the percentage change in BMD between U and D, at both LS and TH, progressively increased from baseline through 5y. These data demonstrate that ZOL 4mg IV q 6 mos is effective in preventing bone loss associated with adjuvant AI therapy in PMW with EBC. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4083.