Clinical Trials What are they?

Transcription

1 Newer Agents And Combinations in Myelodysplastic Syndromes Ruben A. Mesa, MD Mayo Clinic Arizona David P. Steensma, MD Dana-Farber Cancer Institute What are they? Biomedical or health-related related research studies in human beings that follow a predeterminded protocol (document detailing uniform treatment) Two major types Interventional-when patients are assigned a treatment Observational-when patients are observed Why participate? Patients play an active role in their own health care, they become engaged Patients can gain access to new treatments that may not be otherwise available, before formal governmental (FDA) approval Patients can help others by contributing to medical research and helping establish new and better treatments for future patients 1

2 Who can or should participate? Patients with a disease where treatment is not curative Clinical trials have inclusion and exclusion criteria to Protect the safety of the patient from the new treatment being tested Help produce reliable results which will make sure the trial really determines if the new treatment is effective Inclusion/exclusion criteria include age, type and stage of disease, prior treatment history, organ function (heart, lung, kidneys) to make sure the treatment is safe Informed consent Process of learning the facts of the clinical trial before deciding whether or not to participate Details are explained by the treating physician, nurse and other professionals Document must be signed which includes purpose of the clinical trial and treatment, duration, required procedures, risks and potential benefits Benefits Patients play an active role in their health care Patients can gain access to new treatments before they are approved by the government (FDA) and widely available Patients can help others by contributing to medical research to identify new and better treatment 2

3 Risks There may be side effects, some lifethreatening Treatment under study in the clinical trial may not be effective Treatment on the clinical trial may require more time and tests than required by what we call standard (routine or nonprotocol or nonclinical trial) treatment Phases Phase I-designed to determine the best and safest dose and identify side effects Phase II-designed to determine the effectiveness of the new treatment Phase III-designed to compare the effectiveness of the new treatment to the commonly used treatment Phase IV-postmarketing (after FDA approval) trial to further refine the risks and benefits and identify new side effects once the new treatment is widely used Sponsors and funding (financial support) University medical centers, cancer centers Foundations Pharmaceutical industry Federal agencies such as the National Institutes of Health, Cooperative oncology groups 3

4 Outline Combination approaches Azacitidine + MS275 Azacitidine + SAHA (vorinostat) Newer agents Oral azacitidine Oral TLK199 (ezatiostat) IV and oral clofarabine IV ON01910.Na Alemtuzumab (IV) Combination Approaches Azacitidine Combination Studies Combination Patient Population Response Azacitidine + lenalidomide Azacitidine + etanercept Azacitidine + vorinostat Azacitidine + MGCD0103 Azacitidine + gemtuzumab Azacitidine + romiplostim High-risk MDS (n = 18) MDS (low to high risk) (n = 18) MDS, elderly AML (n = 18) MDS, R/R AML (n = 52) AML/high-risk MDS (n = 15) Low/int-1 MDS azacitidine or decitabine Overall RR: 67% CR: 44% CR: 72% (13/18) CR: 50% (9/18) CR/CRi: 35%; PR: n = 1 (18/52) CR + CRp: 72% (11/15) Platelet response CR = complete response, R/R = relapsed/refratory, RR = response rate 4

5 ECOG E1905 study schema Eligible patients (no prior azacitidine): MDS (higher risk; if IPSS low/int-1 risk, then platelets <50 x 10 9 /L or ANC<500) CMML with WBC <12 x 10 9 /L AML with multilineage dysplasia and WBC 30 x 10 9 /L for 4 weeks Azacitidine SC 50 mg/m 2 x 10 days every 28 days Randomize 1:1 Primary Endpoint: IWG 2000 responses with hematological normalization (CR+PR+trilineage HI) Azacitidine SC 50 mg/m 2 x 10 days every 28 days, plus Entinostat (MS-275) 4 mg/m2 PO days 3 and 10 each cycle E1905 enrolled patients Number enrolled Median age Diagnosis: 150 (137 eligible, 136 evaluable) 72 years MDS n=88 CMML n=5 AML n=43 IPSS Int-2/High 72% Poor risk cytogenetics 31% Prebet T et al, ASH 2010, Abstract #601 Response / AE E1905 study results Comparator -- CALGB 9221 study: CR + PR + trilineage HI rate = 15% Arm A (azacitidine monotherapy) Arm B (combination therapy) Complete response (CR) 12% 7% Partial response (PR) 9% 7% Trilineage hematological improvement (thi) Qualifying Response (CR+PR+tHI) Other hematological improvement 10% 10% 31% 24% (p=ns) 12% 19% Any response 43% 44% Grade IV thrombocytopenia 44% 63% (p=0.07) Grade III/IV fatigue 13% 23% (p=0.13) Prebet T et al, ASH 2010, Abstract #601 5

6 ASH 2010 Abstract #604 Phase II Study of 5-azacytidine and vorinostat in patients with newly diagnosed MDS or AML not eligible for clinical trials because poor performance or presence of other comorbidities Guillermo Garcia-Manero, Elihu Estey, Elias Jabbour, Tapan Kadia, Zeev Estrov, Jorge Cortes, Ross Levine, Hui Yang, Pat Boone and Hagop Kantarjian Department of Leukemia, University of Texas MD Anderson Cancer Center; Fred Hutchinson Cancer Research Center, and Memorial Sloan Kettering Cancer Center AZA + SAHA: Patient eligibility Untreated MDS ( Int-1) or AML And any of the following: Total bilirubin 2 mg/dl Creatinine 2 mg/dl ECOG performance status > 2 Excluded from any other clinical trial Dose and schedule: AZA 75 mg/m2 IV QD days 1 to 5 SAHA 200 mg PO TID days 1 to 5 Cycles repeated every 28 days 6

7 AZA+ SAHA: Patient Characteristics Characteristic Total N=27 Median age (range) Median % BM blasts (range) Diagnosis (%) AML MDS Median (range) Total bilirubin Creatinine 69 (44-83) 20 (2-62) 9 (33) 18 (66) 1.1 ( ) 1.2 ( ) WBC 14 ( ) Cytogenetics (%) Diploid Unfavorable N eligible for creatinine N eligible for Total Bili N eligible for malignancy * N eligible other* 7 (25) 20 (75) 4 (14) 3 (11) 10 (37) 10 (37) *Metastatic sarcoma, met ovarian, met breast ca (3), prostate ca, CLL(2), NHL (2), GBM, liver cirrhosis (2), CHF (2), COPD, bone dx Toxicity (Any Grade) AZA + SAHA Non-Hematological Toxicity (N=24, courses= 48) N o Pts Course 1 Course 2 Diarrhea 7 3 Nausea/Vomiting 6 4 Constipation 4 Fatigue 3 2 Hepatic 3 Rash 1 AZA+ SAHA: Complete Responses N CR OR % Median Courses to Response (range) Evaluated: (1-9) Stopping rule for CR: 4 CR in 30 achieved by patient # 8 7

8 Novel Agents 23 Evaluation of Oral Azacitidine Using Extended Treatment Schedules: A Phase I Study (Abstract 603) G. Garcia-Manero, S.D. Gore, C.R. Cogle, E.J. Jabbour, M.R. Ward, K.J. MacBeth, E. Laille, H. Giordano, H.M. Kantarjian, and B.S. Skikne Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX, USA; The Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD, USA; University of Florida, Gainesville, FL, USA; Celgene Corporation, Summit, NJ, USA Extended dosing oral azacitidine in MDS: phase I Design and patients Eligibility: Age 18 with MDS, CMML, or AML Hb 9 g/dl or platelets <50 x 10 9 /L No prior azanucleoside therapy Starting dose: 300 mg QD or 200 mg BID for 14/28 or 21/28 days Cohorts of 6, DLT assessment after Cycle 1 Enrolled patients thus far: 25 (14 M : 11 F), median age 68 (range 44-87) MDS (n=13) AML (de novo, n=7; post-mds, n=3) CMM: (n=2) Garcia-Manero et al, ASH 2010 Abstract #603 8

9 Extended dosing oral azacitidine in MDS: phase I Results Adverse events: 2 DLTs (grade 3 N/V) in patients on 14 days QD dosing No DLTs yet on 21 days QD, 14 day BID, 21 day BID No dose escalation/mtd definition yet Rate of febrile neutropenia highest with 21-day QD cohort PK: mean first/last day drug exposure 26-58% of historically expected SC drug exposure (AUC) Updated response data at meeting on 15 MDS patients: CR in 2/15 (IWG 2006 criteria) Any HI in 6/14 RBC transfusion freedom in 3/5 Garcia-Manero et al, ASH 2010 Abstract #603 Townsend DM et al Oncogene 2003; Steensma D Hem/Onc Clin N America 2010 Phase I/II Study of Intravenous Liposomal TLK199 in MDS Liposome n=54 Responses: Trilineage responses in 4/16 pts (25%) with pancytopenia HI-E in 9/38 (24%) anemic pts HI-N in 11/26 (42%) neutropenic pts HI-P in 12/24 (50%) thrombocytopenic pts Adverse events: Most mild & attributable to liposomal preparation (e.g. back pain, chills, nausea, bone pain, and diarrhea) Raza A et al J Hematol Oncol 2:20,

10 Phase I Study of Oral TLK199 (Ezatiostat) in MDS n=45, IPSS Low to INT-2, median age 71 Starting dose 200 mg Up to 6,000 mg/day ezatiostat divided into 2 doses days 1-7 out of 21-day cycle was tolerated, without a DLT 17/45 (38%) had His by IWG 2000, most (11) at higher end of dose range ( 4 g/day) 6/29 HI-E, 4/19 HI-N, 7/21 HI-P Adverse events (all grade ½): nausea (65%) diarrhea (43%) vomiting (31%) constipation (13%) abdominal pain (9%) Raza A et al Blood 113:6533, 2009 Ongoing Phase II TLK199 Study n=86, 36 participating centers Eligible: De novo IPSS Low/Int-1 MDS Endpoint: HI-E (primary) Schedule 1: Ezatiostat 4500 mg/day in 2 divided doses PO for 2 weeks on, 1 week off Schedule 2: Ezatiostat 4500 mg/day in 2 divided doses PO for 3 weeks on, 1 week off Clinicaltrials.gov identifier NCT 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 2910a) Azra Raza, Naomi Galili, Scott Smith, John E. Godwin, Ralph Boccia, Han Myint, Daruka Mahadevan, Deborah Mulford, Mark Rarick, Mary Ann Allison, Ostap Melnyk, Lisa Meng, Marsha Jones, Gail Brown, Shelby A Young, and Mikkael A. Sekeres 10

11 Phase 2 Oral Ezatiostat Response Type 3000 mg/day 2 wks on/1 wk off (n=30) 2000 mg/day 3 wks on/1 wk off (n=31) Total (n=61) HI E (%) (95% CI) 7 (24) (10 44) 6 (19) (8 38) 13 (22) (12 34) HI N (%) (95% CI) 1 (10) (0 45) 3 (27) (6 61) 4 (19) (5 42) HI P (%) (95% CI) 1 (7) (0 34) 0 (0) (0 25) 1 (4) (0 19) Bilineage (HI-E and HI-N) (%) (95% CI) 1 (11) (0 48) 3 (27) (6 61) 4 (20) (6 44) Trilineage (HI-E, HI-N, and HI-P) (%) (95% CI) 1 (17) (0 64) 0 (0) (0 52) 1 (9) (0 41) Median Time (Weeks) to HI-E Response (Range) 8 (8 10) 8 (8 11) 8 (8 11) Median Duration (Weeks) of HI-E Response (Range) 18 (2 51) 46 (2 63) 34 (2 63) # of RBC Transfusion Dependent Patients (%) 20 (69) 18 (58) 38 (63) RBC Transfusions Reduced by 4U/8wks (%) (95% CI) 6 (30) (12 54) 5 (28) (10 54) 11 (29) (15 46) RBC Transfusion Independence (%) (95% CI) 1 (5) (0 25) 3 (17) (4 41) 4 (11) (3 25) Raza et al. Blood 2010;116:2910a Steensma HemOncClin NA 2010 IV Clofarabine MDS Study Eligible: MDS or CMML with either >5% blasts or IPSS Int-2/High risk Treatment: Clofarabine, either 15 or 30 mg/m2/day IV for 5 consecutive days, repeat every 4-6 wks Patients: 58 patients enrolled 40% >70 years old 74% with IPSS Int-2/High risk disease 60% had tried azacitidine or decitabine or both 26% had a prior malignancy 1 RA, 15 RAEB-1, 26 RAEB-2, 9 CMML,7 RAEB-t Jabbour E et al ASCO 2010; abstract

12 IV Clofarabine in MDS: Results Any response Overall (n=58) 15 mg/m2 dose (n=37) 30 mg/m2 dose (n=21) 21 (36%) 15 (41%) 6 (29%) CR (%) 15 (26%) 10 (27%) 5 (24%) HI (%) 6 (10%) 5 (14%) 1 (5%) Died by 8 weeks Alive at one year 11 (19%) 5 (14%) 6 (29%) 37% 37% 38% Jabbour E et al ASCO 2010; abstract 6504 IV Clofarabine in MDS: Adverse Effects Common: Nausea/vomiting Diarrhea Skin rash Liver test abnormalities Serious (grade 3 or 4): Infections (45%, more common with higher dose) Renal failure (6 patients, 4 with higher dose) Preliminary Results of Fixed-Dose Oral Clofarabine (CLO) In Patients Who Have Failed Hypomethylating Agents for the Treatment of Myelodysplastic Syndromes (MDS) (Abstract 1869) Mikkael A. Sekeres, Gail J. Roboz, Olatoyosi Odenike, Edward Agura, Bayard L. Powell, Reginald Ewesuedo, Michael J. Vasconcelles, Stefan Faderl, and Hagop Kantarjian 12

13 Oral Clo for Patients Failing Hypomethylating Agents Sekeres et al. Blood 2010;116:1869a. Oral Clo for Patients Failing Hypomethylating Agents Sekeres et al. Blood 2010;116:1869a. ON Na - Multikinase Inhibitor Cell-cycle functions and localizations of Plk1 ON Na Multikinase inhibitor Polo-like kinase 1 modulator? PI3K/Akt/ERK pathway inhibitor Induces Bim, inhibits Mcl-1 activation Reduces cyclin D1 levels Barr F et al Nature Reviews Molecular Cell Biology 2004; 5:

14 % aneuploidy % aneuploidy 3/21/2011 ON Na Development History = Ongoing MDS/AML study recruiting pts per clinicaltrials.gov Source: ON Na Suppresses Cyclin D1 Accumulation in trisomy 8 Myelodysplastic Syndromes Patients While Decreasing Bone Marrow CD34+ Blast Counts and Aneuploid Clone Size Ongoing studies NIH (9) and St Vincents (6) 15 pts with treatment-refractory IPSS Int-1 to High risk MDS or AML (2 AML; 7 with trisomy 8) (13 pts at St Vincents reported in another abstract) Escalating doses: 800 mg/m2/day over 48 hours continuous IV 3 weeks out of 4 up to 1500 mg/m2/day over 48 hours continuous IV 3 weeks out of 4 Most common AEs: cytopenias, nausea, fatigue Responses: StV: One patient RBC transfusion-independent x 14 mos, one patient with neutrophil response; 2/6 pts with increased blasts reduced (2 progressed, 2 stable) NIH: 1 HI-E, 2 HI-N, 2 bilineage responses Sloand E et al ASH 2009 Abstract #120 Raza A et al ASH 2009 Abstract # Aneuploidy During ON Na Treatment Baseline After 4-8 weeks of treatment Blast Proportion During ON Na Treatment Baseline After 4-8 weeks of treatment Sloand E et al ASH 2009 Abstract #120 Raza A et al ASH 2009 Abstract #

15 Predicted Probability of Response (PPR) to Immunosuppressive Therapy in MDS Age of the patient (years) + Duration of transfusion dependence (months) HLA DRB15 - HLA DRB15 + PPR >57 >71 Low (0-40%) High (41-100%) Validation Cohort (n=23) PPR Total Response No Response Low (0-40%) 14 1 (7%) 13 (93%) High (41-100%) 9 6 (67%) 3 (33%) Saunthararajah Y et al Blood (8): Phase II: Alemtuzumab in IPSS Int-1/Int-2 MDS With High PPR For Immunosuppressive Therapy Key Eligibility (goal n=39): De novo MDS with cytopenias and <5% blasts High likelihood (PPR) of IST response (using 2003 formula) No prior ATG/CSA Regimen: Alemtuzumab (anti-cd52) test dose, then 10 mg IV/day x 10 days TMP/SMX and valgancyclovir prophylaxis Results: Enrolled patients younger (median ~53 years old) and more hypocellular (45%) than a typical MDS population IWG responses in 15/16 (93%) with Int-1 MDS, 2/5 (40%) with Int-2 Cytogenetic remission in 5/7 Transient EBV positivity in 4/22 Sloand EM et al Abstract #116 - ASH