Kidger et al., “Dual-mechanism ERK1/2 inhibitors exploit a distinct binding mode to block phosphorylation and nuclear accumulation of ERK1/2”; Mol Cancer Ther, 2020
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https://clincancerres.aacrjournals.org/content/early/2020/01/03/1078-0432.CCR-19-1430.long
Abstract
Purpose: This first-in-human, phase 1 study evaluated ASTX660, an oral, small-molecule antagonist of cellular/X-linked inhibitors of apoptosis proteins in patients with advanced solid tumors or lymphoma. Experimental Design: ASTX660 was administered orally once daily on a 7-day-on/7-day-off schedule in a 28-day cycle. Dose escalation followed a standard 3+3 design to determine the maximum tolerated dose and recommended phase 2 dose (RP2D). Dose expansion was conducted at the RP2D. Results: Forty-five patients received ASTX660 (range 15-270 mg/d). Dose-limiting toxicity of grade 3 increased lipase with or without increased amylase occurred in 3 patients at 270 mg/d and 1 patient at 210 mg/d. The maximum tolerated dose was determined to be 210 mg/d and the RP2D 180 mg/d. Common treatment-related adverse events included fatigue (33%), vomiting (31%), and nausea (27%). Grade ≥3 treatment-related adverse events occurred in 7 patients, most commonly anemia (13%), increased lipase (11%), and lymphopenia (9%). ASTX660 was rapidly absorbed, with maximum concentration achieved at ~0.5‒1.0 hour. An ~2-fold accumulation in area under the curve exposures was observed on day 7 vs 1. ASTX660 suppressed cellular inhibitor of apoptosis protein-1 in peripheral blood mononuclear cells, which was maintained into the second cycle beyond the off-therapy week at the 180-mg/d RP2D and above. Clinical activity was seen in a patient with cutaneous T-cell lymphoma. Conclusions: ASTX660 demonstrated a manageable safety profile, and exhibited evidence of pharmacodynamic and preliminary clinical activity at the 180-mg/d RP2D. The phase 2 part of the study is ongoing.
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https://www.nature.com/articles/s41418-019-0465-8
Abstract
Therapeutic efficacy of first-generation hypomethylating agents (HMAs) is limited in elderly acute myeloid leukemia (AML) patients. Therefore, combination strategies with targeted therapies are urgently needed. Here, we discover that priming with SGI-110 (guadecitabine), a next-generation HMA, sensitizes AML cells to ASTX660, a novel antagonist of cellular inhibitor of apoptosis protein 1 and 2 (cIAP1/2) and X-linked IAP (XIAP). Importantly, SGI-110 and ASTX660 synergistically induced cell death in a panel of AML cell lines as well as in primary AML samples while largely sparing normal CD34+ human progenitor cells, underlining the translational relevance of this combination. Unbiased transcriptome analysis revealed that SGI-110 alone or in combination with ASTX660 upregulated the expression of key regulators of both extrinsic and intrinsic apoptosis signaling pathways such as TNFRSF10B (DR5), FAS, and BAX. Individual knockdown of the death receptors TNFR1, DR5, and FAS significantly reduced SGI-110/ASTX660-mediated cell death, whereas blocking antibodies for tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) or FAS ligand (FASLG) failed to provide protection. Also, TNFα-blocking antibody Enbrel had little protective effect on SGI-110/ASTX660-induced cell death. Further, SGI-110 and ASTX660 acted in concert to promote cleavage of caspase-8 and BID, thereby providing a link between extrinsic and intrinsic apoptotic pathways. Consistently, sequential treatment with SGI-110 and ASTX660-triggered loss of mitochondrial membrane potential (MMP) and BAX activation which contributes to cell death, as BAX silencing significantly protected from SGI-110/ASTX660-mediated apoptosis. Together, these events culminated in the activation of caspases-3/-7, nuclear fragmentation, and cell death. In conclusion, SGI-110 and ASTX660 cooperatively induced apoptosis in AML cells by engaging extrinsic and intrinsic apoptosis pathways, highlighting the therapeutic potential of this combination for AML.
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Abstract # 1376 – Oral Azacitidine and Cedazuridine Approximate Azacitidine Efficacy in a Murine Model
Authors: Haley E. Ramsey1-2, Maria P. Arrate1, Londa Fuller1, Agnieszka E. Gorska1, Kelli Boyd3-4, Melissa A. Fischer1-2, Aram Oganesian5, Mohammad Azab5, and Michael R. Savona1,2,4
1Department of Medicine, 2Cancer Biology Program, 3Department of Pathology, Microbiology and Immunology, 4Vanderbilt-Ingram Cancer Center; Vanderbilt University School of Medicine, Nashville, TN USA; 5Astex Pharmaceuticals, Inc., Pleasanton, CA
Background: DNA methyltransferase inhibitors (DNMTi) induce remissions and improve survival for patients with MDS and those with AML unable to receive standard cytotoxic chemotherapy. Accordingly, DNMTi therapy is the backbone of SOC treatment for MDS and AML. Given the inconvenience, pain, and general detriments to QOL with SQ or IV therapy daily for 5-7 days every month with azacitidine (AZA) or decitabine (DAC), many have attempted to provide the therapy orally, but encountered difficulties with this method of administration given rapid first-pass clearance via the enzyme cytidine deaminase (CDA) which is ubiquitous in the gut and liver. Recently, DAC was combined with cedazuridine (CDZ), an oral CDA inhibitor, in a fixed-dose (35mg/100mg) combination tablet (ASTX727) to approximate the pharmacokinetics of IV DAC (Savona et al Lancet Haematology 2019). To determine if a similar strategy might be feasible with AZA, we attempted to increase the bioavailability of oral AZA with CDZ in a murine tumor model.
Methods: We measured GI50 in AML cell lines treated with vehicle (DMSO), AZA, and AZA/CDZ combination. Although cancer cell lines produce CDA, total levels are negligible in comparison CDA in the gut and liver. For this reason, we then studied CDZ, AZA, and the AZA/CDZ combination in a systemic model of AML in immunocompromised mice. NSGS mice were sub-lethally irradiated and administered MOLM-13 AML cells via tail vein injection. At day seven post-transplant, engrafted mice were randomized to receive 2.5 mpk i.p. AZA(n=8), 2.5 mpk oral AZA(n=8), 3 mpk CDZ + oral AZA(n=6), or CDZ alone at 30 mpk (n=7). All oral AZA and CDZ was administered via oral gavage daily for 7 consecutive days; i.p. therapy was similarly given for 7 consecutive days. During treatment, the kinetics of MOLM-13 expansion was defined by detection of human AML in the blood as detected by flow cytometry. At approximately three weeks after transplant, CDZ-only treated mice became moribund, and all experimental groups were sacrificed for analysis of chimerism.
Results: After 72 hour of treatment, no differences were noted in viability of cell lines between AZA and AZA+ CDZ in vitro. In the xenograft model, as expected, i.p. AZA-treated mice had significant decreases in leukemic expansion in the bone marrow and spleen, whereas CDZ alone did not (AZA i.p. vs CDZ, p = 0.004 and <0.001). More importantly, whereas oral AZA alone failed to decrease AML expansion in both the bone marrow and spleen of treated mice (oral AZA vs CDZ., p = 0.677 and 0.249, respectively), the addition of CDZ to oral AZA led to significant decreases in AML in both bone marrow and spleen (Oral AZA + CDZ vs CDZ, p = 0.012 and 0.004, respectively). Likewise, addition of CDZ to oral AZA showed no significant differences in activity against AML compared to traditional AZA i.p. dosing in either bone marrow or splenic tissue (p= 0.204 and 0.224, respectively). Furthermore, in a Kaplan-Meier survival analysis, mice treated with CDZ alone die within 21 days of transplant, but both i.p. AZA and oral AZA + CDZ treated mice had a 50% extended survival with no significant difference in survival between i.p. AZA and oral AZA + CDZ treated mice (p= 0.502). H&E staining revealed no significant bone marrow toxicity in treated mice, suggesting that AZA preferentially effected transplanted MOLM-13 AML cells.
Conclusion: Consistent with previous preclinical and clinical studies with ASTX727, the oral AZA approximated AZA anti-tumor activity when co-treated with CDA-inhibitor CDZ. These preliminary data provide rationale for the development of CDZ + oral AZA therapy as a fixed dose combination (ASTX030) in myeloid disease. Clinical trials evaluating ASTX030 are being planned.
Authors: Guillermo Garcia-Manero, MD1, James McCloskey, MD2, Elizabeth A. Griffiths, MD3, Karen W.L. Yee, MD4, Amer M. Zeidan, MBBS, MHS5, Aref Al-Kali, MD6, Kim-Hien Dao, DO, PhD7, H. Joachim Deeg, MD8, Prapti A. Patel, MD9, Mitchell Sabloff, MSc, MD, FRCPC10, Mary-Margaret Keating, MD11, Nancy Zhu, MD12*, Nashat Y. Gabrail, MD13*, Salman Fazal, MD14, Joseph Maly, MD15, Olatoyosi Odenike, MD16, Aditi Shastri, MD17, Amy E. DeZern, MD18, Casey L. O’Connell, MD19, Gail J. Roboz, MD20, Aram Oganesian, PhD21*, Yong Hao, MD, PhD21*, Harold N. Keer, MD, PhD21, Mohammad Azab, MD21 and Michael R. Savona, MD22
1The University of Texas MD Anderson Cancer Center, Houston, TX; 2John Thuerer Cancer Center, Hackensack Medical Center, NJ; 3Roswell Park Comprehensive Cancer Center, Buffalo, NY; 4Princess Margaret Cancer Centre, Toronto, ON, CAN; 5Yale University and Yale Cancer Center, New Haven, CT; 6Mayo Clinic, Rochester, MN; 7Oregon Health & Science University, Portland, OR; 8Fred Hutchinson Cancer Research Center, Seattle, WA; 9University of Texas Southwestern Medical Center, Dallas, TX; 10Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada; 11Hematology/Oncology, Queen Elizabeth II Health Sciences Centre, Halifax, NS, Canada; 12University of Alberta, Edmonton, AB, Canada; 13Gabrail Cancer Center, Canton, OH; 14West Penn Hospital, Allegheny Health Network, Pittsburgh, PA; 15Norton Cancer Institute, Louisville, KY; 16University of Chicago, Chicago, IL; 17Department of Hematology and Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY; 18Johns Hopkins University Hospital, Baltimore, MD; 19USC Keck School of Medicine, University of Southern California, Los Angeles, CA; 20Weill Cornell Medicine, The New York Presbyterian Hospital, New York, NY; 21Astex Pharmaceuticals, Inc., Pleasanton, CA; 22Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN
Introduction: Hypomethylating agents (HMAs) such as decitabine (DEC) or azacitidine (AZA) are FDA approved therapies for patients with different myeloid malignancies as single agent or in combination with venetoclax. Both DEC and AZA require IV infusion for 1 hour or subcutaneous (SC) injections daily for 5-7 days of every 28-day treatment cycle. They both have limited oral bioavailability due to rapid degradation by cytidine deaminase (CDA) in the gut and liver. An orally bioavailable HMA option could reduce clinic visit frequency and reduce infusions/injections related adverse events and burden. ASTX727 is an oral tablet comprised of a fixed-dose combination (FDC) of CDA inhibitor cedazuridine (C) at 100 mg with DEC at 35 mg. In a phase 2 study, C-DEC (ASTX727) demonstrated pharmacokinetic (PK) AUC exposure similar to IV-DEC at 20mg/m2 with comparable clinical activity and safety (Garcia-Manero, et al, 15th Int’l MDS Symposium, 2019). We describe here the results of a phase 3 study designed to demonstrate exposure bioequivalence of oral C-DEC and IV-DEC and generate clinical data using C-DEC in a larger population (ASCERTAIN study).
Methods: The study used a randomized cross over design where patients were randomized 1:1 to either Sequence A: C-DEC (100 mg/35 mg respectively) in Cycle 1 followed by IV-DEC at 20 mg/m2 in Cycle 2, or Sequence B receiving IV-DEC in Cycle 1 followed by C-DEC on Cycle 2 to compare PK (primary endpoint AUC equivalence over 5 days of dosing) and pharmacodynamic (PD) of DNA demethylation using LINE-1 assay. All patients received C-DEC in all subsequent cycles from Cycle 3 onwards until treatment discontinuation to study clinical efficacy and safety of C-DEC. Patients were eligible as per the FDA-approved label (MDS IPSS Intermediate [Int]-1,-2 or high risk[HR] and CMML patients). Clinical responses were assessed by an independent expert panel according to International Working Group (IWG) 2006 response criteria. Adverse events (AEs) were graded by Common Terminology Criteria for Adverse Events (CTCAE) v 4.03.
Results: 138 patients were randomized, of whom 133 were treated with median age of 71.0 years (range 44-88), median weight was 83.1 kg (range 45-158), and median BSA was 1.99 m2 (range 1.4-2.9 m2). The IPSS status of the patients were Int-1 in 44%, Int-2 in 20%, and HR in 16%, and 12% of pts had CMML. Patients in the two arms were well balanced regarding cytogenetic risk, baseline hemoglobin, neutrophils, platelets, or red blood cell or platelet transfusion dependence. For the primary end point, the decitabine AUC0-24 (h*ng/mL) 5-Day geometric mean estimate was 856 from the C-DEC and 865 from IV-DEC resulting in an oral/IV AUC ratio of 98.9% (90% CI of 92.7-105.6%). All sensitivity and secondary exposure analyses confirmed the primary results. Comparison of hypomethylating activity as measured by LINE-1 demethylation showed difference between oral C-DEC and IV-DEC demethylation of <1% and the 95% CI of the difference included zero. Safety findings were consistent with those anticipated for IV-DEC (related Grade ≥ 3 AEs in more than 5% were thrombocytopenia, neutropenia, anemia, febrile neutropenia, and leukopenia). As of the data cutoff, median follow up was 5.2 months ( IQR 3.5-8.0) with 101 patients evaluable for response . Preliminary response analysis of all evaluable patients showed best responses of complete response (CR) in 12 patients (11.9%), marrow (m)CR in 46 (45.5%) including 14 patients (13.9%) with mCR + hematological improvement (HI), hematologic improvement (HI) in 7 (6.9%) resulting in an objective response rate (CR+mCR+ HI) in 65 patients (64%). In addition, of all 133 treated patients, 16 patients (12%) underwent hematopoietic cell transplant. Updated response data will be presented at the meeting.
Summary/Conclusions: This randomized phase 3 study demonstrates that C-DEC, the oral FDC of cedazuridine/decitabine (100 mg/35 mg) resulted in an equivalent DEC exposure to IV-DEC at 20 mg/m2 over 5 days. Safety findings are consistent with those anticipated with IV-DEC with no clinically significant GI toxicity. Preliminary clinical activity is also consistent with published data from IV-DEC. C-DEC is an oral HMA alternative to IV-DEC. Combination studies with other oral agents are being planned.
Authors: Karen W.L. Yee, MD1, Gail J. Roboz, MD2, Casey L. O’Connell, MD3, Elizabeth A. Griffiths, MD4, Raoul Tibes, MD, PhD5*, Katherine J. Walsh, MD6, Wendy Stock, MD7, Guillermo Garcia-Manero, MD8, Michael R. Savona, MD9, Farhad Ravandi, MD10, Naval G. Daver, MD11, Elias Jabbour, MD8, Todd L. Rosenblat, MD, MS12*, Jean-Pierre Issa, MD13*, Xiang Yao Su, PhD14*, Mohammad Azab, MD14 and Hagop M. Kantarjian, MD8
1Leukemia Program, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; 2Weill Cornell/NY Presbyterian Medical Center, New York, NY; 3Keck School of Medicine, University of Southern California, Los Angeles, CA; 4Roswell Park Cancer Institute, Buffalo, NY; 5Mayo Clinic Arizona, Scottsdale, AZ; 6The Ohio State University, Columbus, OH; 7University of Chicago Medical Center, Chicago, IL; 8The University of Texas MD Anderson Cancer Center, Houston, TX; 9Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN; 10Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX; 11University of Texas MD Anderson Cancer Center, Department of Leukemia, Houston, TX; 12New York-Presbyterian/Columbia University Medical Center, New York, NY; 13Fels Institute, Temple University, Philadelphia, PA; 14Astex Pharmaceuticals, Inc., Pleasanton, CA
Background: Guadecitabine is a next generation subcutaneous (SC) hypomethylating agent (HMA) resistant to degradation by cytidine deaminase which results in prolonged in vivo exposure to the active metabolite decitabine. We conducted a phase 2 study of guadecitabine in 206 AML patients. International guidelines recommend a minimum of 4 to 6 cycles of HMA treatment to gain maximum benefit, but some suggest that treatment may not be beneficial if no response was observed after 4 cycles. No prospective studies have confirmed the correlation between an HMA number of cycles with response and survival using landmark methodology. We present here the results of landmark response and survival analyses based on number of cycles and whether patients had an objective response or not.
Methods: Landmark response (CR, CRi, or CRp based on 2003 IWG criteria, grouped together as composite CR or CRc), and overall survival (OS) analyses for patients alive at or beyond month 3 and month 5 (time of planned start of cycle 4 and cycle 6 respectively) were conducted. Landmark OS was compared between patients who received at least 4 or 6 cycles and those who did not. The landmark methodology avoids the bias of early deaths before cycles 4 and 6 attributing a survival benefit in those who did not die early and were able to get more cycles. We also compared the result in responding and non-responding patients to see if survival benefit was restricted to responding patients only.
Results: The study completed enrolment with 206 AML patients: 103 patients (50%) for each of Treatment Naïve (TN) unfit for intensive chemotherapy, and relapsed/refractory (r/r) AML. Median age was 68.5y (range 22-92y), ECOG PS ≥2 in 26%, poor risk cytogenetics in 41%, secondary AML in 26%, and median baseline BM blasts % was 40% in the total AML population. 108 patients (52.4%), and 155 patients (75%) received <4 and <6 cycles respectively. The primary reasons for treatment discontinuation before 4 and 6 cycles respectively (% from the total population of 206 patients) were early progression (20.4, and 30.6%), and early death (12.6%, and 17%). However, 9.7% and 14% discontinued treatment before 4 or 6 cycles respectively as a result other less objective reasons such as patient decision, investigator decision, or adverse events which might have been manageable without treatment discontinuation. The landmark analysis population included 161 patients for 4-cycle analysis, and 133 for the 6-cycle analysis. In those patients, there were no major differences in baseline characteristics between those who received at least 4 or 6 cycles and those who did not. In the landmark analysis comparing those who received at least 4 cycles (97 patients) and those who did not (64 patients), CRc rate was 62% vs 25% (p < 0.0001) and median OS was 13.7 m vs 6.1 respectively (HR 0.53, 95% CI 0.37-0.75, p 0.0003). In the landmark analysis comparing those who received at least 6 cycles (51 patients) and those who did not (82 patients) the CRc rate was 82.4% vs 35.4% (p < 0.0001), and median OS of 19.9 m vs 8.8 m respectively (HR 0.42, 95% CI 0.27-0.64, p <0.0001). The results were consistent when TN and r/r AML patients were analyzed separately. More interestingly the landmark OS benefit in patients who received at least 4 or 6 cycles was also evident in patients who did not have an objective CRc. Patients with no CRc who received at least 4 cycles had a median OS of 8 m vs 5.4 m in those who did not (HR 0.63, 95% CI 0.40-0.98, p 0.04). Patients with no CRc who received at least 6 cycles had a median OS of 12.9 vs 8 m in those who did not (HR 0.40, 95% CI 0.17-0.94, p 0.03).
Summary/Conclusions: In a prospective phase 2 study of 206 TN and r/r AML patients treated with the HMA guadecitabine, patients who were alive at or beyond 3 and 5 months who continued treatment for at least 4 or 6 cycles respectively achieved a highly significant response and survival benefit compared to those who discontinued treatment before cycle 4 or 6. The survival benefit was evident even in patients who did not have an objective response. Reasons for treatment discontinuation should be weighed carefully before stopping HMA treatment with guadecitabine before 4 or 6 cycles in AML patients to maximize response and survival benefit. Failure to achieve an objective response after 4 cycles should not be a reason for treatment discontinuation as long as patient can still benefit.
Authors: Jean-Pierre Issa, MD1*, Marco Gobbi, MD2*, Patricia L. Kropf, MD3*, Pierre Fenaux, MD, PhD4, Gail J. Roboz, MD5, Jiri Mayer, MD6, Jürgen Krauter, MD7*, Tadeusz Robak, MD8, Hagop M. Kantarjian, MD9, Jan Novak, MD, PhD10*, Wieslaw W. Jedrzejczak, MD, PhD11*, Xavier Thomas, MD, PhD12, Mario Ojeda-Uribe, MD13*, Yasushi Miyazaki, MD, PhD14, Yoo Hong Min, MD, PhD15, Su-Peng Yeh, M.D.16*, Joseph M Brandwein, MD17, Liana Gercheva, MD18*, Judit Demeter, MD19*, Elizabeth A. Griffiths, MD20, Karen W.L. Yee, MD21, Yong Hao, MD, PhD22*, Mohammad Azab, MD22 and Hartmut Döhner, MD23
1Fels Institute, Temple University, Philadelphia, PA; 2Ospedale Policlinico San Martino, Genova, Italy; 3Fox Chase Cancer Center at Temple University Hospital, Philadelphia; 4Hôpital St Louis/Université Paris 7 / Service d’hématologie séniors, Hôpital Saint-Louis, Paris, France; 5New York-Presbyterian/Weill Cornell Medical Center, New York, NY; 6Fakultní Nemocnice Brno, Brno, Czech Republic; 7Städtisches Klinikum Braunschweig gGmbH, Braunschweig, Germany; 8Medical University of Lodz, Lodz, Poland; 9The University of Texas MD Anderson Cancer Center, Houston, TX; 10Univerzita Karlova, Praha, Czech Republic; 11MTZ Clinical Research, Medical University of Warsaw, Warsaw, Poland; 12Hematology department 1 G, Centre Hospitalier Lyon Sud, Pierre Benite, France; 13GHR Mulhouse Sud-Alsace, Mulhouse, France; 14Atomic Bomb Disease Institute, Nagasaki University Hospital, Nagasaki, Japan; 15Severance Hospital, Yonsei University Health System, Seoul, Korea, Republic of (South); 16China Medical University Hospital, Taichung, Taiwan; 17University of Alberta, Edmonton, AB, Canada; 18Clinical Hematology Clinic, Multiprofile Hospital for Active Treatment “Sveta Marina”, Varna, Bulgaria; 19Semmelweis Egyetem, Budapest, Hungary; 20Roswell Park Comprehensive Cancer Center, Buffalo, NY; 21Princess Margaret Cancer Centre, Toronto, ON, Canada; 22Astex Pharmaceuticals, Inc., Pleasanton, CA; 23University Hospital of Ulm, Ulm, Germany
Background: Guadecitabine (G) is a next generation subcutaneous hypomethylating agent (HMA) resistant to degradation by cytidine deaminase which results in prolonged in vivo exposure to the active metabolite decitabine. We conducted a large global randomized phase 3 study of G vs TC of azacitidine (AZA), decitabine (DEC), or low dose Ara-C (LDAC) in 815 TN AML patients unfit for IC (ASTRAL-1 study). The ITT results for the primary endpoints of Complete Response (CR), and Overall Survival (OS) were previously presented (Fenaux et al, EHA abstract S879, 2019). There is no consensus on definition of disease progression particularly with HMA treatment which may continue to benefit patients in the absence of objective response. EFS analysis based on end of treatment benefit (treatment discontinuation, or start of an alternative therapy, or death) regardless of progression may offer a simpler way of assessing HMA treatment benefit. We describe here the results of the study based on both PFS and EFS analyses and how they compare with OS analyses in the overall ITT population, and in subgroups of patients based on number of cycles administered.
Methods: TN-AML ineligible for IC due to age ≥ 75 y, or comorbidities, or ECOG PS 2-3 were randomized 1:1 to either G (60 mg/m2/d SC for 5-days Q28 days) or a preselected TC of AZA, DEC, or LDAC at their standard regimens. AML diagnosis, and response status by IWG 2003 criteria, were assessed by an independent central pathologist blinded to randomization assignment. CR and OS were co-primary endpoints. PFS was a secondary endpoint calculated from date of randomization to the earliest date of progression by investigators or central assessment, relapse after response, start of an alternative therapy, or death. Since progression date is sometimes difficult to ascertain under HMA treatment, an EFS analysis was conducted post hoc using the concept of time to treatment failure. EFS was therefore calculated from date of randomization to the earliest date of discontinuation of randomized treatment, start of an alternative therapy, or death. PFS, EFS, and OS data are presented for the overall ITT population, and for patients who received at least 4 cycles or 6 cycles, and patients who had an objective response.
Results: 815 patients were randomized to G (408) or TC (407). Preselected TCs prior to randomization were DEC (43%), AZA (42%), and LDAC (15%). Baseline variables were well balanced across the 2 treatment arms. The majority of patients were randomized to receive an HMA: 759 patients (93%) with only 56 patients (7%) randomized to receive LDAC. In the primary ITT analysis, CR (19.4% for G and 17.4% for TC), and OS Hazard Ratio (0.97; 95% CI 0.83-1.14) were not significantly different between G and TC. An equal proportion of patients received at least 4 cycles (57.6% for G vs 59.2% for TC), or 6 cycles (45.8% for G vs 46.2% for TC) so there was no obvious bias in terms of adherence to treatment in the 2 study arms. Table shows OS, PFS, and EFS median survival, G/TC HR with 95% CI, and p values for the primary ITT population as well as for patients who received at least 4 cycles (N=476 patients), and those who received at least 6 cycles (N=375 patients). G/TC HR for all analyses favored guadecitabine (HR <1). However only OS, and EFS seemed to significantly favor G in patients who received adequate treatment duration by number of cycles. EFS was also the only analysis to significantly favor G in the overall ITT population suggesting that it may be a better predictor of OS benefit in patients who went on to receive adequate treatment with at least 4 or 6 cycles (Table). In addition, EFS also significantly favored G in patients who achieved an objective response (CR, CRp, CRi, or PR): median EFS for G 17.4 vs 14.6 m for TC, HR 0.68, 95% CI 0.5-0.93, p 0.016.
Summary/Conclusions: In a large global 815-patient randomized study of G vs TC (composed mainly of first generation HMAs), EFS analyses that do not rely on progression date which is sometimes difficult to define favored G over TC in the ITT population, and seemed to better predict OS benefit in patients who went on to receive at least 4 or 6 cycles. EFS calculated from date of randomization to the earliest date of randomized treatment discontinuation, start of alternative therapy, or death as conducted here could be a simple surrogate for cessation of treatment benefit particularly for patients treated with HMAs.
Authors: Michael R. Savona, MD1, Hagop M. Kantarjian, MD2, Gail J. Roboz, MD3, Casey L. O’Connell, MD4, Katherine J. Walsh, MD5, Raoul Tibes, MD, PhD6*, Karen W.L. Yee, MD7, Wendy Stock, MD8, Elizabeth A. Griffiths, MD9, Elias Jabbour, MD2, Scott D. Lunin, MD10*, Todd L. Rosenblat, MD, MS11*, Nikolai A. Podoltsev, MD, PhD12, Jean-Pierre Issa, MD13*, Xiang Yao Su, PhD14*, Mohammad Azab, MD14 and Guillermo Garcia-Manero, MD2
1Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN; 2The University of Texas MD Anderson Cancer Center, Houston, TX; 3Weill Cornell/NY Presbyterian Medical Center, New York, NY; 4USC Keck School of Medicine, University of Southern California, Los Angeles, CA; 5The Ohio State University, Columbus, OH; 6Mayo Clinic Arizona, Scottsdale, AZ; 7Princess Margaret Cancer Centre, Toronto, ON, CAN; 8University of Chicago Medical Center, Chicago, IL; 9Roswell Park Cancer Institute, Buffalo, NY; 10Sarah Cannon Research Institute, Florida Cancer Specialists, Venice, FL; 11Columbia University Irving Medical Center, New York, NY; 12Yale School of Medicine, New Haven, CT; 13Fels Institute, Temple University, Philadelphia, PA; 14Astex Pharmaceuticals, Inc., Pleasanton, CA
Background: Guadecitabine is a next generation subcutaneous (SC) hypomethylating agent (HMA) resistant to degradation by cytidine deaminase which results in prolonged in vivo exposure to the active metabolite decitabine. We conducted a phase 2 study of guadecitabine in 102 Myelodysplastic Syndromes (MDS), and Chronic Myelomonocytic leukemia (CMML) patients. International guidelines recommend a minimum of 4 to 6 cycles of HMA treatment to gain maximum benefit, but some suggest that treatment may not be beneficial if no response was observed after 4 cycles. No prospective studies have confirmed the correlation between an HMA number of cycles with response and survival using landmark methodology. We present here the results of landmark response and survival analyses based on number of cycles and whether patients had an objective response or not.
Methods: Landmark response based on 2006 IWG criteria, and overall survival (OS) analyses for patients alive at or beyond month 3 and month 5 (time of planned start of cycle 4 and cycle 6 respectively) were conducted. Objective response (OR) was defined as patients who had Complete Response (CR), Partial Response (PR), marrow (m)CR, or Hematological Improvement (HI). Landmark OS was compared between patients who received at least 4 or 6 cycles and those who did not. The landmark methodology avoids the bias of early deaths before cycles 4 and 6 attributing a survival benefit in those who did not die early and were able to get more cycles. We also compared the result in responding and non-responding patients to see if survival benefit was restricted to responding patients only.
Results: The study completed enrolment with 102 patients: 53 patients after HMA failure (relapsed/refractory or r/r), and 49 HMA-naive patients (Treatment Naïve or TN) with a median follow up for the entire study of 3.2 years (IQR 2.9-3.5 years). Median age was 71 and 72 years for TN MDS/CMML and r/r MDS/CMML patients respectively. Median OS was 23.4 months (m) for TN MDS/CMML patients and 11.7 m for r/r MDS/CMML patients. Of the 102 patients treated, 37 patients (36.3%) and 58 (56.9%) received less than 4 and 6 cycles respectively. The landmark analysis population was 91 patients for the 4-cycle analysis and 87 patients for the 6-cycle analysis. In those patients, the primary reasons for treatment discontinuation before cycle 4 or 6 respectively were patient decision (9.8% and 11.8%), and investigator decision (5.9% and 9.8%) while early progression accounted for 3.9% and 10.8% of those patients. There were no major baseline characteristics difference between patients who received at least 4 and 6 cycles and those who did not in the patients included in the landmark analyses. In the landmark analysis, patients who received at least 4 cycles (65 patients) had an OR rate of 68% compared to 15% in 26 patients who received <4 cycles (p <0.0001) and median OS of 20.4 m compared to 15.2 m respectively (HR 0.78, 95% CI 0.45-1.3, p 0.36). Those who received at least 6 cycles (44 patients) had an OR rate of 82% compared to 26% in 43 patients who received < 6 cycles (p<0.0001), and median OS of 23.8 m vs 13.6 m respectively (HR 0.51, 95% CI 0.3-0.85, p 0.009). Results were consistent when r/r MDS/CMML and HMA-naïve MDS/CMML were analyzed separately. Landmark OS analysis also favored those who received guadecitabine for at least 4 or 6 cycles compared to those who received <4 and < 6 cycles even in the absence of objective response (OS HR of 0.82 and 0.42 respectively) but the sample size was small to show statistical significance (p 0.58 and 0.10 respectively)
Summary/Conclusions: In a prospective phase 2 study of 102 MDS/CMML patients treated with the HMA guadecitabine, patients who were alive at the planned start of cycle 4 and cycle 6 did not continue treatment primarily because of patient or investigator decision in addition to early progression. Those who were alive and continued treatment for at least 4 or 6 cycles achieved highly significant objective response benefit compared to those who did not. Survival benefit was highly significant for those who received at least 6 cycles and was not restricted to patients who had an objective response. It is important to weigh reasons for treatment discontinuation carefully before discontinuing guadecitabine HMA treatment in MDS/CMML patients before 6 cycles to maximize response and survival benefit.
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Authors: Authors: Gail J. Roboz, MD1, Hartmut Döhner, MD2, Marco Gobbi, MD3*, Patricia L. Kropf, MD4*, Jiri Mayer, MD5, Jürgen Krauter, MD6*, Tadeusz Robak, MD7, Hagop M. Kantarjian, MD8, Jan Novak, MD, PhD9*, Wieslaw Jedrzejczak, MD10*, Xavier Thomas, MD, PhD11, Mario Ojeda-Uribe, MD12*, Yasushi Miyazaki, MD, PhD13, Yoo Hong Min, MD, PhD14, Su-Peng Yeh, M.D.15*, Joseph M Brandwein, MD16, Liana Gercheva, MD17*, Judit Demeter, MD18*, Elizabeth A. Griffiths, MD19, Karen W.L. Yee, MD20, Jean-Pierre Issa, MD21*, Yong Hao, MD, PhD22*, Mohammad Azab, MD22 and Pierre Fenaux, MD, PhD23
1Weill Cornell Medicine and The New York Presbyterian Hospital, New York, NY; 2University Hospital of Ulm, Ulm, Germany; 3Ospedale Policlinico San Martino, Genova, Italy; 4Fox Chase Cancer Center at Temple University Hospital, Philadelphia; 5Fakultní Nemocnice Brno, Brno, Czech Republic; 6Städtisches Klinikum Braunschweig Städtisches Klinikum Braunschweig gGmbH, Braunschweig, Germany; 7Medical University of Lodz, Copernicus Memorial Hospital, Lodz, Poland; 8University of Texas MD Anderson Cancer Center, Department of Leukemia, Houston, TX; 9University Hospital Kralovske Vinohrady and Third Faculty of Medicine, Charles University, Prague, Czech Republic; 10Warsaw Medical University, Warsaw, Poland; 11Hematology Department, Lyon-Sud Hospital, Pierre Bénite, France; 12GHR Mulhouse Sud-Alsace, Mulhouse, France; 13Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan; 14Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea, Republic of (South); 15China Medical University Hospital, Taichung, Taiwan; 16University of Alberta, Edmonton, AB, Canada; 17University Hospital St. Marina, Varna, Bulgaria; 18Semmelweis University, Budapest, HUN; 19Roswell Park Comprehensive Cancer Center, Buffalo, NY; 20Princess Margaret Cancer Centre, Toronto, ON, Canada; 21Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA; 22Astex Pharmaceuticals, Inc., Pleasanton, CA; 23Hôpital St Louis/Université Paris 7 / Service d’hématologie séniors, Hôpital Saint-Louis, Paris, France
Background: Guadecitabine (G) is a next generation subcutaneous (SC) hypomethylating agent (HMA) resistant to degradation by cytidine deaminase which results in prolonged in vivo exposure to the active metabolite decitabine. We conducted a large global randomized phase 3 study of G vs Treatment Choice (TC) with azacitidine (AZA), decitabine (DEC), or low dose Ara-C (LDAC) in 815 TN AML patients unfit for IC (ASTRAL-1 study). The primary ITT results were previously presented (Fenaux et al, EHA abstract S879, 2019). Clinical guidelines for single agent HMAs recommend a minimum of 4 to 6 treatment cycles for maximum benefit. We describe here the results of the study based on number of treatment cycles administered.
Methods: TN-AML patients ineligible for IC due to age ≥ 75 y, or coexisting morbidities, or ECOG PS 2-3 were randomized 1:1 to either G (60 mg/m2/d SC for 5-days Q28 days) or a preselected TC of AZA, DEC, or LDAC at their standard dose/schedule. AML diagnosis and response status were assessed by an independent central pathologist blinded to randomization assignment. Complete response (CR) and overall survival (OS) were co-primary endpoints. We analyzed patients’ characteristics, number of treatment cycles, reasons for treatment discontinuation, CR, and OS including analyses by number of cycles received including prospective subgroups, and OS analyses of responders and non-responders.
Results: 815 patients were randomized to G (408) or TC (407). Preselected TCs prior to randomization were DEC (43%), AZA (42%), and LDAC (15%). Baseline variables were well balanced across the 2 treatment arms. For G vs TC respectively, age ≥75 y in 62% vs 62.4%, PS 2-3 in 50.5% vs 50.4% (including 10.8% vs 8.8% PS 3), and poor risk cytogenetics in 34.3% vs 34.6%. Most patients were assigned to an HMA at randomization (759, 93%) with only 56 patients (7%) randomized to receive LDAC. Both CR (19.4% for G and 17.4% for TC), and OS Hazard Ratio (0.97; 95% CI 0.83-1.14) were similar and not significantly different between G and TC. Many patients in both arms did not receive the recommended minimum of 4 cycles (42.4% vs 40.8% for G vs TC respectively), or 6 cycles (54.2% vs 53.8% for G vs TC). The proportions were well balanced between the 2 treatment arms. Characteristics of patients who received at least 4 or 6 cycles were also well balanced between the 2 treatment arms for age, PS 2-3, secondary AML, poor risk cytogenetics, BM blasts >30%, and proliferative AML (total white cell count ≥20,000/uL). The primary reasons and proportions for treatment discontinuation were similar for the 2 treatments arms. For patients with <4 and <6 cycles respectively they are, in descending order, early deaths (16.7% and 20.7% of the overall ITT population), progression (7.6% and 11.7%), adverse events (5.8% and 6.9%), and patient decision (5.5% and 7.1%). In patients who received at least 4 cycles more patients achieved CR on G (33.6%) vs TC (28.6%), and median OS was longer on G (15.6 months for G vs 13 for TC, HR 0.78, 95% CI 0.64-0.96, log-rank p 0.02, Fig 1). Similarly, in patients who received at least 6 cycles, there were more CR on G (40.1%) vs TC (36.2%) and median OS was longer on G (19.5 months for G vs 15.0 for TC, HR 0.69, 95% CI 0.54-0.88, log-rank p 0.002, Fig 2). Subgroup analyses of OS in patients who received at least 4 or 6 cycles showed that survival benefit from G over TC was consistent in all prospective subgroups including against each of the 3 TCs (AZA, DEC, and LDAC). OS analyses in patients who received at least 4 or 6 cycles also favored G vs TC in both responders (CR, CRp, CRi, or PR) and non-responders with maximum benefit in patients who received at least 6 cycles (G vs TC OS HR 0.66, 95% CI 0.45-0.96, log-rank p 0.028 for responders, and HR of 0.73, 95% CI 0.53-1.00, log-rank p 0.048 for non-responders).
Summary/Conclusions: In a large global 815-patient randomized study of G vs TC composed mainly of first generation HMAs, G was at least as effective as TC based on the primary ITT analysis of CR and the narrow 95% CI of OS HR (0.83-1.14). Analyses of patients by number of treatment cycles showed that those who received at least 4 or 6 cycles achieved longer OS in G vs TC with the largest benefit in those who received at least 6 cycles. The benefit was observed in all subgroups, and in both responders and non-responders. Treatment with single agent guadecitabine should continue as long as the patient can still benefit and for at least 6 cycles to gain the maximum survival benefit.
Background: Guadecitabine is a next generation subcutaneous (SC) hypomethylating agent (HMA) resistant to degradation by cytidine deaminase which results in prolonged in vivo exposure to the active metabolite decitabine. We conducted a phase 2 study of guadecitabine in 103 r/r AML patients. We present here duration of response and long-term survival results.
Methods: We conducted a phase 2 study of guadecitabine using different regimens and doses (randomized 5-day regimen cohorts of 60 mg/m2/d vs 90 mg/m2/d SC) and a cohort of 10-day regimen in the first 1-4 cycles at 60 mg/m2/d followed by subsequent cycles of 5-day regimen). Response and duration of response were assessed using IWG 2003 criteria: Complete Response (CR), CR with incomplete platelet recovery (CRp), and CR with incomplete count recovery (CRi). CR+CRp+CRi was defined as composite CR (CRc). Overall survival (OS) was assessed using the Kaplan-Meier (KM) method. Response status for each dose/regimen cohort and the overall treated population were assessed with analyses of duration of response and long-term survival.
Results: The study completed enrolment of 103 r/r AML patients: 50 patients received 5-day regime at 60 mg/m2/d (24 patients) or 90 mg/m2/d (26 patients), and 53 patients received the 10-day (60 mg/m2/d). Median follow up was 2.4 years (29.1 months). Patients’ characteristics for the 103 r/r AML patients enrolled included median age of 60y (range 22-82y), poor risk cytogenetics in 41%, prior hematopoietic cell transplant (HCT) in 18%, median number of prior regimens 2 (range 1-10), primary refractory to induction therapy in 47%, and 41% had a high disease burden of BM blasts >40%. There was no significant difference in CR or OS between 60 and 90 mg/m2/d 5-day regimen but the CR and CRc rates were higher on the 10-day regimen (19% and 30% respectively) vs the 5-day regimen (8% and 16%). When all regimens analyzed together, 24/103 patients (23.3%) achieved CRc. Responses (CRc) were achieved in several poor prognosis subgroups including 19% in patients with poor risk cytogenetics, 31% of refractory patients, 26% of patients who relapsed after prior HCT, and 22% in patients with early relapse (< 6 months from their prior treatment). Of the 24 CRc patients, 15 (63%) were refractory to induction, 8 (33%) had poor risk cytogenetics, and 5 (21%) had prior HCT, and 14 (58%) went on to receive HCT following response. Median overall duration of response for patients with CR, and CRc were 7 and 7.8 months respectively. After long term follow up, median OS has not been reached in patients who achieved CRc (either CR or CRp/CRi). The 2-year survival rate was 57% for CR, and 50% for CRp/CRi (Fig. 1). Median OS has not yet been reached and was similar in CRc patients who went on to receive HCT post CRc (14 patients) compared to CRc patients who did not receive HCT post treatment (10 patients) (Fig.2). The 2-year survival rate was also similar for both groups (50% for those receiving HCT vs 60% for those who did not undergo HCT). Most patients were still on guadecitabine treatment until death, progression, or HCT with no other subsequent treatment. Guadecitabine was well tolerated in all cohorts with Grade 3 or higher AEs related to the drug seen in 42% of patients predominantly myelosuppression and related infections. There was no related serious AEs leading to death. The results highlight the long survival benefit for guadecitabine responders that exceeds duration of response and seems irrespective of post treatment HCT. The results also suggest that in r/r AML patients treated with guadecitabine, CRp/CRi seem to confer a similar survival benefit to CR patients suggesting that the incomplete peripheral blood count recovery may reflect continued treatment-related myelosuppression rather than active residual disease.
Summary/Conclusions: In a phase 2 study of HMA guadecitabine in heavily pretreated r/r AML patients, 47% of whom had refractory disease, CR, CRp, and CRi all conferred long survival benefit. With a median follow up of almost 2.5 years, more than half of responding patients were still alive at 2 years and their median OS has not yet been reached. In addition, treatment with guadecitabine allowed post treatment HCT in 58% of responders.
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