nab-Paclitaxel–Based Therapy in Underserved Patient Populations: The ABOUND.PS2 Study in Patients With NSCLC and a Performance Status of 2

IntroductionThe phase II ABOUND.PS2 study (NCT02289456) assessed safety/tolerability of a first-line modified nab-paclitaxel/carboplatin regimen for patients with advanced non-small cell lung cancer (NSCLC) and Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2.MethodsChemotherapy-naive patients with stage IIIB/IV NSCLC and ECOG PS 2 received four cycles of nab-paclitaxel 100 mg/m2 days 1 and 8 plus carboplatin area under the curve 5 day 1 q3w (induction). Patients without progression received nab-paclitaxel monotherapy (100 mg/m2 days 1 and 8 q3w) until progression/unacceptable toxicity. Primary endpoint: percentage of patients discontinuing induction due to treatment-emergent adverse events (TEAEs).Results11/40 treated patients (27.5%; 95% CI, 14.60–43.89) discontinued chemotherapy induction due to TEAEs; 16/40 (40.0%) continued nab-paclitaxel monotherapy. Median progression-free and overall survival were 4.4 (95% CI, 2.99–7.00) and 7.7 (95% CI, 4.93–13.17) months. Grade 3/4 TEAEs during induction included neutropenia (22.5%), anemia (17.5%), thrombocytopenia (5.0%), and peripheral neuropathy (2.5%).ConclusionThis nab-paclitaxel–based regimen was tolerable in patients with advanced NSCLC and ECOG PS 2, with efficacy comparable to historical chemotherapy data

SWOG S0919: A phase II study of idarubicin and cytarabine in combination with pravastatin for relapsed acute myeloid leukemia (AML)

7028 Background: Inhibition of cholesterol synthesis and uptake sensitizes AML blasts to chemotherapy (Blood 104: 1816, 2004). A prior Phase 1 study demonstrated the safety of high dose pravastatin given with idarubicin and cytarabine in patients with AML and also reported an encouraging response rate (Blood 109: 2999, 2007). SWOG S0919 therefore evaluated the complete remission (CR) rate in a larger number of pts with relapsed AML treated with the pravastatin dose arrived at in the Phase 1 trial. Methods: Pts were treated at SWOG institutions from Aug 2009 through Nov 2012. Pravastatin was supplied by Bristol-Meyers Squibb. The protocol was approved by each institution’s review board. Eligibility: age ≥ 18 yrs, relapsed AML, cardiac ejection fraction ≥ 45%, CR/ CR with incomplete count recovery (CRi) following most recent chemotherapy lasting ≥ 3 months, no prior hematopoietic cell transplant. Treatment: oral pravastatin 1280 mg Days 1-8, idarubicin 12 mg/m 2 /d IV Days 4-6, and cytarabine 1.5 g/m 2 /d continuous IV infusion Days 4-7. Pts achieving a CR could receive 2 cycles of consolidation. CR and CRi were defined by IWG criteria. Fifty eligible pts were to be accrued. If ≥ 21 pts achieved CR or CRi, the regimen would be considered sufficiently effective (critical level = 4.8% if true CR rate = 30% and power of 90% if true CR rate = 50%). Results: The study closed to accrual on Nov 1, 2012 after meeting the defined criterion for a positive study. Thirty-six pts with a median age of 59 yr (range 23-78) were enrolled. Seventeen pts (47%) were male and the median WBC was 2800/ uL (range 700-110,600). The median time from initial dx to registration was 18 mo (range 5-136). Relapse status: 1 st : 17 pts (47%), 2 nd : 15 (42%), 3 rd : 2 (5.5%), and 4 th : 2 (5.5%). Eighteen pts have died, 3 during treatment. The response rate was 75% (95% CI 58-88%; 20 CR, 7 CRi); and the median overall survival was 10 mo. The p-value comparing 75% to 30% (null response rate) is 3.356 x 10 -8 . Duration of last CR (≤ 6 months) and prior high dose cytarabine exposure did not affect response to protocol treatment. Conclusions: The CR/ CRi in this relapsed population is encouraging. We plan to evaluate the efficacy of this regimen in higher-risk patients. Clinical trial information: NCT00840177

A phase 2 study of lenalidomide monotherapy in patients with deletion 5q acute myeloid leukemia: Southwest Oncology Group Study S0605

Older acute myeloid leukemia (AML) patients with a chromosome 5q deletion have poor outcomes with conventional chemotherapy. This phase 2 study explored the safety and efficacy of single-agent lenalidomide in previously untreated older AML patients with del(5q) who declined standard chemotherapy. Patients were treated with lenalidomide 50 mg daily for 28 days as induction therapy and 10 mg daily for 21 days of a 28-day cycle as maintenance until disease progression or unacceptable toxicity. Among 37 evaluable patients, the median age was 74 years (range, 60-94), 21 (57%) were female, 19 (51%) had prior myelodysplastic syndrome, and 30 (81%) had pretreatment cytogenetic studies evaluated centrally. Six had isolated del(5q), 1 had del(5q) and +8, 23 had complex cytogenetics, and 7 others had del(5q) identified locally. Fourteen patients (38%) completed induction therapy: 7 patients died during induction therapy, 8 had disease progression, 7 had nonfatal adverse events, and 1 entered hospice. Eight patients started maintenance therapy. Five patients (14%) achieved a partial or complete response, 2 with isolated del(5q) and 3 with complex cytogenetics. Relapse-free survival was 5 months (range, 0-19). Median overall survival was 2 months for the entire population. In conclusion, lenalidomide as a single agent has modest activity in older del(5q) AML patients. Southwest Oncology Group Study S0605 is registered at www.clinicaltrials.gov as NCT00352365

A Phase II Study of Lenalidomide for Previously Untreated Deletion (del) 5q Acute Myeloid Leukemia (AML) Patients Age 60 or Older Who Are Not Candidates for Remission Induction Chemotherapy (Southwest Oncology Group Study S0605)

Abstract Abstract 332 Background: Older patients (pts, ≥60 years [yrs]) with AML have a dismal prognosis; the majority are not treated with any type of chemotherapy. Many have antecedent myelodysplastic syndromes (MDS), and 20–30% harbor chromosome 5 abnormalities. Lenalidomide (LEN) yields hematologic responses in 67% of lower-risk MDS pts with the del(5q) cytogenetic lesion, and complete responses (CRs) in 20% of higher-risk del(5q) MDS pts, all with isolated lesions. This Phase II study explores the safety and efficacy of single agent LEN in previously untreated older pts with AML and the del(5q) abnormality. Method: Untreated older pts with AML defined by 2001 World Health Organization criteria (without t(15;17)) who harbored a del(5q) cytogenetic abnormality (alone or in combination with other abnormalities) and who declined or were felt to be poor candidates for intensive induction chemotherapy were eligible. Pts were treated with LEN 50mg daily for up to 28 days as induction therapy. Concomitant cytotoxic or growth factor therapies were not allowed. Pts achieving stable disease or better per day 28 bone marrow assessment received post-remission LEN 10mg daily for 21 days of a 28-day cycle until disease progression or unacceptable toxicities. Enrollment from October 2006 through June 2010 was in 2 stages: 20 pts were registered; if at least 1 CR/CRi was observed using International Working Group response criteria, another 20 pts were to be enrolled. The study was designed with a critical level of 4.7% (erroneously concluding the regimen warrants further study if the true response rate is 5% or less) and power of 92% (probability of concluding that a response rate of 20% warrants further study). Result: Of 41 patients enrolled, 4 were excluded (2 without AML, 1 without del(5q), and 1 died prior to receiving therapy), leaving 37 for toxicity and efficacy analyses. Median age was 74 yrs (range, 60–94), 21 (57%) were female, 33 (89%) white, and 19 (51%) had prior MDS. Median presenting white blood cell count was 2,600 mcl (range, 600–658,000), and 30 (81%) had a performance status of 1. Of the 37 evaluable pts, 29 had pretreatment cytogenetic studies evaluated centrally. Two pts displayed no demonstrable abnormalities (but had del(5q) by fluorescence in situ hybridization); 5 had isolated del (5q); and 22 (76%) had complex karyotypes (≥3 abnormalities). Seven patients were removed from protocol therapy due to toxicities (infection, renal, respiratory, gastrointestinal, and rash), and 4 deaths occurred that were at least possibly related to therapy: 2 respiratory, 1 cardiac, and 1 febrile neutropenia. Five additional patients had grade 4 non-hematologic toxicities: hypocalcemia (2), fatigue (2), infection (1). Fourteen pts (38%) completed protocol induction therapy. Four pts (11%) of the 37 evaluable pts achieved CR/CRi following induction therapy, all of whom had complex karyotypes; 3 of the 4 relapsed after 1, 2, and 4 months, and the 4th died 13 months after CR without a report of relapse. Thirteen (35%) pts had stable disease following induction therapy; 8 went on to protocol post-remission therapy. Thirty-three of the 37 pts have died and the median overall survival was 2 months (95% CI, 1 to 4 months). The follow-up time of the 4 survivors was between 6 and 23 months. Conclusion: LEN as a single agent has modest activity and expected toxicity in older del(5q) AML pts, particularly when compared to other single-agent molecularly-targeted approaches, such as FLT3 inhibitors. Future trials will combine LEN with cytoxic or hypomethylator therapies in older del(5q) AML pts. Disclosures: Sekeres: Celgene: Honoraria. Off Label Use: Lenalidomide in (del)5q AML. Lancet:Celgene: Research Funding. List:Celgene: Research Funding

Phase 1 Dose-Ranging Study of Oral Ezatiostat Hydrochloride (Telintra®, TLK199) in Combination with Lenalidomide (Revlimid®) in Patients with Non-Deletion(5q) Low to Intermediate-1 Risk Myelodysplastic Syndrome (MDS)

Abstract Abstract 2778 Introduction: Lenalidomide is approved for the treatment of del(5q) MDS in US and Japan. In Low to Intermediate-1 (Int-1) risk non-del(5q) MDS, lenalidomide treatment is less effective with a lower response rate (25%) and shorter response duration [Raza A. et al, Blood, 2008.111,1]. Ezatiostat, a glutathione S-transferase P1-1 (GST P1-1) inhibitor, activates Jun kinase, promoting the growth and maturation of hematopoietic progenitors while inducing apoptosis in malignant cells. Based on the novel mechanism of action, response rates, non-overlapping toxicities, and tolerability observed in a single agent ezatiostat Phase 2 study in MDS, a study of the combination of ezatiostat and lenalidomide was conducted to determine the safety and efficacy of ezatiostat with lenalidomide in non-del(5q) Low to Int-1 risk MDS. Methods: In this multicenter Phase 1 dose-ranging study, ezatiostat was given at a starting dose of 2000 mg in combination with lenalidomide at 10 mg, days 1–21 of a 28-day cycle. In stage 1, 3–6 patients in a standard 3+3 design were treated before escalation to the ezatiostat/lenalidomide 2500/10 mg dose level. Treatment was given until lack of MDS response or unacceptable toxicity. Hematologic improvement-erythroid (HI-E) rates were determined by the MDS International Working Group (IWG; 2006) criteria. Results: Eighteen pts (median age 73 yrs; range 57–82; 72% male), with World Health Organization classifications: 4 refractory anemia (RA), 2 RA with excess blasts-1, 4 refractory cytopenia with multilineage dysplasia (RCMD), 5 RCMD with ring sideroblasts, 2 MDS-unclassified, 1 MDS/myeloproliferative disorder-U were enrolled. Thirteen pts (72%) were Int-1 risk, 5 (28%) Low risk; 4 pts (22%) had abnormal cytogenetics. Twelve RBC transfusion-dependent pts (67%) required a median of 6 units (range 4–10)/8-weeks. Two pts (11%) were platelet transfusion dependent. A total of 67 treatment cycles were given (median 3.5 cycles/pt [range 1–11]) and only 6 cycles (9%) required dose reductions and 8 (12%) dose delays. Two of 6 pts reported DLTs (Grade 3 diarrhea and Grade 3 rash) at 2500/10 mg, with 9 additional pts receiving the recommended combination dose of 2000/10 mg. Eleven of 18 pts were evaluable (4 at 2500/10 mg and 7 at 2000/10 mg), and 3 pts are still on therapy with insufficient treatment duration to be evaluable. The HI-E rate was 43% (3/7; 95% CI, 10%–82%) for pts at the recommended 2000/10 mg dose and 6 pts are continuing therapy at the time of analysis. Three of 8 (38%; 95% CI, 9%–76%) RBC transfusion-dependent evaluable pts achieved transfusion independence including 1 responder who did not respond to prior lenalidomide. In responders, the median increase in hemoglobin level was 3.4 g/dL (from 7.9 g/dL). In 2 of 4 thrombocytopenic pts, a HI-platelet (HI-P) response was observed. A bilineage (HI-E and HI-P) response in 2 of 4 pts with anemia and thrombocytopenia was reported. One RBC and platelet transfusion-dependent pt who had a poor response to prior anti-thymocyte globulin treatment achieved complete RBC and platelet transfusion independence. The combination was generally well tolerated with no unexpected toxicities. Most common treatment-related non-hematologic adverse events (AEs) were Grades 1 and 2 including: fatigue (6%, 28%), swelling (0%, 11%), anorexia (11%, 6%), rash (0%, 6%), skin odor (11%, 6%), nausea (39%, 11%), diarrhea (22%,17%), vomiting (28%,17%), upper abdominal pain (5.6%, 5.6%), and constipation (11%, 0%). Grade 3 events were rash (11%), nausea (6%), diarrhea (17%), and vomiting (6%). Most common hematologic-related AEs were Grades 1 and 2 thrombocytopenia (11%, 6%) and neutropenia (0%, 11%). Grade 3–4 AEs were thrombocytopenia (11%, 17%), neutropenia (17%, 11%), anemia (6%, 6%), and febrile neutropenia (11%, 0%). Conclusions: Ezatiostat is the first GST P1-1 inhibitor to cause clinically significant reductions in RBC and platelet transfusions, including RBC and platelet transfusion independence. Since ezatiostat is non-myelosuppressive, it is a good candidate for combination with lenalidomide and in this study, the combination was well tolerated. Interestingly, ezatiostat may also have the potential to enhance lenalidomide's efficacy. The recommended doses of this combination regimen for future studies is the ezatiostat/lenalidomide 2000/10 mg. Disclosures: Off Label Use: Lenalidomide was used off-label in patients with non-del5q MDS. Mulford:Celgene: Speakers Bureau. Brown:Telik, Inc.: Employment, Equity Ownership. Meng:Telik, Inc.: Employment, Equity Ownership. Lyons:Incyte: Research Funding; Telik: Research Funding; Alexion: Consultancy, Honoraria; Novartis: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Sekeres:Celgene: Consultancy, Honoraria, Speakers Bureau. Mesa:NS Pharma: Research Funding; Astra Zeneca: Research Funding; SBio: Research Funding; Lilly: Research Funding; Incyte: Research Funding; Celgene: Research Funding

Nab-paclitaxel-based therapy in underserved patient populations: The aboundPs2 study in patients with nsclc and a performance status of 2

Introduction: The phase II ABOUND.PS2 study (NCT02289456) assessed safety/tolerability of a first-line modified Methods: Chemotherapy-naive patients with stage IIIB/IV NSCLC and ECOG PS 2 received four cycles of Results: 11/40 treated patients (27.5%; 95% CI, 14.60-43.89) discontinued chemotherapy induction due to TEAEs; 16/40 (40.0%) continued Conclusion: Thi

Phase 2 Randomized Multicenter Study of Extended Dosing Schedules of Oral Ezatiostat HCl (Telintra), a Glutathione Analog Prodrug GSTP1-1 Inhibitor, In Low to Intermediate-1 Risk Myelodysplastic Syndrome (MDS)

Abstract Abstract 2910 Introduction: MDS is characterized by defects in hematopoietic cell growth, differentiation and apoptosis. Ezatiostat, a glutathione S-transferase inhibitor, activates Jun kinase, promoting the growth and maturation of hematopoietic progenitors while inducing apoptosis in leukemic blasts. The purpose of this Phase 2 study was to determine the efficacy and safety of ezatiostat on extended dose schedules in MDS. Methods: Patients (pts) with International Prognostic Scoring System Low or Int-1 risk MDS were enrolled. After initial dose-ranging in 14 pts, subsequent pts were randomized to 2 selected dose schedules: 37 pts at 3 gm daily for 2 weeks followed by a 1-week rest period and 36 pts at 2 gm daily for 3 weeks followed by a 1-week rest period. Treatment was given until lack of MDS response or unacceptable toxicity. A logistic regression analysis was conducted to identify significant MDS disease factors associated with hematologic improvement-erythroid (HI-E) rates as determined by the MDS International Working Group (2006) criteria. Results: Seventy-three pts were median age 73 years (range 48–89) 70% male, and with World Health Organization classification as follows: 11 refractory anemia (RA), 15 RA with ring sideroblasts, 5 RA with excess blasts-1, 24 refractory cytopenia with multilineage dysplasia, 9 MDS-unclassified, 3 MDS/Myeloproliferative disorder-U, 4 MDS-del 5q, and 2 Unknown. Fifty pts (68%) were INT-1 risk, 23 (32%) were Low risk; 27 pts (37%) had abnormal karyotypes with 23 (85%) complex/poor prognostic types. RBC transfusion-dependent pts required a median of 6 (range 4–19) U/8 weeks prior to study entry. Prior treatments included: 34 (47%) DNA methyltransferase (DMTI), 28 (38%) lenalidomide, 56 (77%) erythropoietin, and 32 (44%) growth factors. The HI-E response rate was similar for evaluable pts on the 2 schedules, therefore the data were pooled. The overall HI-E rate was 22% (13/60) [95% CI, 12.1%–34.2%]. The median duration of response was 34 weeks. Eleven of 38 (29%) RBC transfusion-dependent pts had transfusion reductions (reduction of 4U/8weeks) with 4 pts (11%) achieving transfusion independence. A 40% HI-E rate (6/15 pts) [95% CI, 16.3%–67.7%], was observed in pts who had prior lenalidomide, but no prior DMTI, with 5/11 pts (45%) achieving significant RBC transfusion reduction and 3/11 pts (27%) achieving transfusion independence. A 28% HI-E rate (5/18 pts) [95% CI, 9.7%–53.5%] was observed in pts who were lenalidomide and DMTI naive, with 4/8 pts (50%) achieving clinically significant RBC transfusion reduction. Sixteen pts had received prior DMTI but no prior lenalidomide treatment, a 0% HI-E rate (95%CI: 0%-20.6%) was reported. Prior DMTI treatment predicts a 6-fold decrease in the odds for HI-E response to ezatiostat (p=0.027). A 19% HI-Neutrophil (HI-N) rate was observed in 4/21 pts with neutropenia (95% CI, 5.4%–41.9%) and a bilineage (HI-E and HI-N) rate of 20% (95% CI, 5.7%–43.7%) in 4/20 pts with anemia and neutropenia. A 3.7% (95% CI, 0.1%–19%) HI-P rate was observed in 1/27 thrombocytopenic pts and a trilineage (HI-E, HI-N, HI-P) rate of 9.1% (95% CI, 0.2%–41.3%) in 1/11 pts with trilineage cytopenia. There were 2 cytogenetic complete responses, 1 with 45X,-Y[4], 46, XY [16] and 1 with del5q. A total of 431 ezatiostat cycles were given, median 4.0 (range 1–14). Only 15 cycles (3.5%) required dose reduction and 37 cycles (8.6%) dose delays. Most common ezatiostat-related adverse events (AEs) were non-hematologic Grade 1 and 2 gastrointestinal (GI) including: nausea (45%, 17%), diarrhea (25%, 8%), and vomiting (30%, 12%). Grade 3 events were: nausea (1%), diarrhea (3%), and vomiting (2%). Prior DMTI treatment was associated with an increased incidence of GI AEs. Pts with prior DMTI use had GI AEs (Grades 1, 2, 3): nausea (51%, 20%, 2%), vomiting (34%, 7%, 2%), diarrhea (22%, 10%, 5%). DMTI-naive pts had fewer GI AEs (Grades 1, 2, 3): nausea (39%, 15%, 0%), vomiting (26%, 15%, 2%), diarrhea (28%, 7%, 2%). Conclusions: Ezatiostat is the first GSTP1-1 inhibitor shown to cause clinically significant reduction in RBC transfusions, including transfusion independence, as well as HI-N and HI-P. Ezatiostat has shown clinically significant efficacy in lenalidomide naive and lenaliomide treated pts. The tolerability and activity profile of ezatiostat may offer an important treatment option for pts with low to INT-1 risk MDS. Disclosures: Raza: Telik, Inc.: Research Funding. Galili:Telik, Inc.: Research Funding. Godwin:Scripps Health: Honoraria. Boccia:Telik, Inc.: Research Funding. Rarick:Telik, Inc.: Research Funding. Meng:Telik, Inc.: Employment, Equity Ownership. Jones:Telik, Inc.: Employment, Equity Ownership. Brown:Telik, Inc.: Employment, Equity Ownership, Patents & Royalties. Young:Telik, Inc.: Employment, Equity Ownership. Sekeres:Celgene Corp: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees

image_3_nab-Paclitaxel–Based Therapy in Underserved Patient Populations: The ABOUND.PS2 Study in Patients With NSCLC and a Performance Status of 2.jpg

Introduction<p>The phase II ABOUND.PS2 study (NCT02289456) assessed safety/tolerability of a first-line modified nab-paclitaxel/carboplatin regimen for patients with advanced non-small cell lung cancer (NSCLC) and Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2.</p>Methods<p>Chemotherapy-naive patients with stage IIIB/IV NSCLC and ECOG PS 2 received four cycles of nab-paclitaxel 100 mg/m² days 1 and 8 plus carboplatin area under the curve 5 day 1 q3w (induction). Patients without progression received nab-paclitaxel monotherapy (100 mg/m² days 1 and 8 q3w) until progression/unacceptable toxicity. Primary endpoint: percentage of patients discontinuing induction due to treatment-emergent adverse events (TEAEs).</p>Results<p>11/40 treated patients (27.5%; 95% CI, 14.60–43.89) discontinued chemotherapy induction due to TEAEs; 16/40 (40.0%) continued nab-paclitaxel monotherapy. Median progression-free and overall survival were 4.4 (95% CI, 2.99–7.00) and 7.7 (95% CI, 4.93–13.17) months. Grade 3/4 TEAEs during induction included neutropenia (22.5%), anemia (17.5%), thrombocytopenia (5.0%), and peripheral neuropathy (2.5%).</p>Conclusion<p>This nab-paclitaxel–based regimen was tolerable in patients with advanced NSCLC and ECOG PS 2, with efficacy comparable to historical chemotherapy data.</p

image_4_nab-Paclitaxel–Based Therapy in Underserved Patient Populations: The ABOUND.PS2 Study in Patients With NSCLC and a Performance Status of 2.jpeg

Introduction<p>The phase II ABOUND.PS2 study (NCT02289456) assessed safety/tolerability of a first-line modified nab-paclitaxel/carboplatin regimen for patients with advanced non-small cell lung cancer (NSCLC) and Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2.</p>Methods<p>Chemotherapy-naive patients with stage IIIB/IV NSCLC and ECOG PS 2 received four cycles of nab-paclitaxel 100 mg/m² days 1 and 8 plus carboplatin area under the curve 5 day 1 q3w (induction). Patients without progression received nab-paclitaxel monotherapy (100 mg/m² days 1 and 8 q3w) until progression/unacceptable toxicity. Primary endpoint: percentage of patients discontinuing induction due to treatment-emergent adverse events (TEAEs).</p>Results<p>11/40 treated patients (27.5%; 95% CI, 14.60–43.89) discontinued chemotherapy induction due to TEAEs; 16/40 (40.0%) continued nab-paclitaxel monotherapy. Median progression-free and overall survival were 4.4 (95% CI, 2.99–7.00) and 7.7 (95% CI, 4.93–13.17) months. Grade 3/4 TEAEs during induction included neutropenia (22.5%), anemia (17.5%), thrombocytopenia (5.0%), and peripheral neuropathy (2.5%).</p>Conclusion<p>This nab-paclitaxel–based regimen was tolerable in patients with advanced NSCLC and ECOG PS 2, with efficacy comparable to historical chemotherapy data.</p