Guadecitabine (SGI-110) vs Treatment Choice in Adults With MDS or CMML Previously Treated With HMAs

Sponsor

Astex Pharmaceuticals, Inc. (Industry)

Overall Status

Completed

CT.gov ID

NCT02907359

Collaborator

(none)

408

Enrollment

Locations

Arms

Actual Duration (Months)

4.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

A Phase 3, randomized, open-label, parallel-group, multicenter study designed to evaluate the efficacy and safety of guadecitabine in subjects with MDS or CMML who failed or relapsed after adequate prior treatment with azacitidine, decitabine, or both. This global study will be conducted in approximately 15 countries. Approximately 408 subjects from approximately 100 study centers will be randomly assigned in a 2:1 ratio to either guadecitabine (approximately 272 subjects) or Treatment Choice (approximately 136 subjects). The study consists of a 14-day screening period, a treatment period, a safety follow-up visit, and a long-term follow-up period. The study is expected to last more than 2 years, and the duration of individual subject participation will vary. Subjects may continue to receive treatment for as long as they continue to benefit.

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndromes Leukemia, Myelomonocytic, Chronic	Drug: Guadecitabine Other: Treatment Choice	Phase 3

Detailed Description

Multicenter, randomized, open-label, parallel-group study of guadecitabine vs Treatment Choice (TC). Approximately 408 subjects will be randomly assigned 2:1 to either guadecitabine or TC.

Guadecitabine: approximately 272 subjects.
TC: approximately 136 subjects.

Before randomization, the investigator will assign each subject to one of the following TC options:

Low dose cytarabine (LDAC).
Standard Intensive Chemotherapy (IC) of a 7+3 regimen.
Best Supportive Care (BSC) only. BSC will be provided to all subjects as per standard and institutional practice. Subjects randomized to TC will not be allowed to cross over to guadecitabine. Data will be reviewed by an independent Data Monitoring Committee at regular intervals, primarily to evaluate safety during study conduct. Randomization will be stratified by disease category (MDS vs CMML), bone marrow (BM) blasts (BM blasts >10% vs BM blasts ≤10%), TC option (LDAC vs IC vs BSC), and study center region.

Guadecitabine: 60 mg/m2 given SC daily on Days 1-5 in 28-day cycles (delayed as needed to allow blood count recovery). Treatment should be given for at least 6 total cycles in the absence of unacceptable toxicity or disease progression requiring alternative therapy. Beyond 6 cycles, treatment should continue as long as the subject continues to benefit. BSC should be given according to standard and institutional practice.

Treatment Choice (TC): Before randomization, the investigator will assign each subject to one of the following TC options:

Low dose cytarabine (LDAC) given as 20 mg/m2 SC or IV once daily for 14 days in 28-day cycles (delayed as needed to allow blood count recovery). Treatment should be given for at least 4 cycles in the absence of disease progression or unacceptable toxicity.
Standard Intensive Chemotherapy (IC) of a 7+3 regimen: given as cytarabine 100-200 mg/m2/day given as continuous infusion for 7 days and an anthracycline given as per institutional standard practice such as daunorubicin (45-60 mg/m2/day), or idarubicin (9-12 mg/m2/day), or mitoxantrone (8-12 mg/m2/day) by intravenous infusion for 3 days.
Best Supportive Care (BSC) only: given according to standard and institutional practice. BSC includes, but is not limited to blood transfusions (RBCs or platelets), growth factors including erythropoiesis stimulating agents (ESA), granulocyte stimulating factors (GSFs), iron chelating therapy, and broad spectrum antibiotics and/or antifungals.

Study Design

Study Type:

Interventional

Actual Enrollment :

408 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 3, Multicenter, Randomized, Open-Label Study of Guadecitabine (SGI-110) Versus Treatment Choice in Adults With Myelodysplastic Syndromes (MDS) or Chronic Myelomonocytic Leukemia (CMML) Previously Treated With Hypomethylating Agents

Actual Study Start Date :

Oct 1, 2016

Actual Primary Completion Date :

Mar 31, 2020

Actual Study Completion Date :

Nov 30, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Guadecitabine Guadecitabine 60 mg/m2 given subcutaneously daily on Days 1-5 in 28-day cycles. The total amount (in mg) of guadecitabine to be administered is determined by body surface area.	Drug: Guadecitabine Guadecitabine regimen is 60 mg/m2 given SC daily on Days 1-5 in 28-day cycles (delayed as needed to allow blood count recovery). Treatment should be given for at least 6 total cycles in absence of unacceptable toxicity or disease progression requiring alternative therapy. Other Names: SGI-110
Active Comparator: Treatment Choice Best Supportive Care. Low dose cytarabine. Standard Intensive Chemotherapy.	Other: Treatment Choice BSC: according to standard/institutional practice; includes RBC or platelet transfusions; growth factors, ie, erythropoiesis stimulating agents, granulocyte stimulating factors, iron chelating therapy; broad spectrum antibiotics and/or antifungals. Low dose cytarabine: 20 mg/m2 SC or IV QD for 14 days in 28-day cycles. Other schedules allowed per institutional practice. Treatment for ≥4 cycles absent disease progression/toxicity. BSC per institutional/standard practice. Standard Intensive Chemotherapy: recommended 7+3 given as cytarabine 100-200 mg/m2/day continuous infusion for 7 days and an anthracycline for 3 days. Anthracyclines per institutional practice include daunorubicin (45-60 mg/m2/day) or idarubicin (9-12 mg/m2/day) or mitoxantrone (8-12 mg/m2/day) by IV infusion. Subjects with complete or partial response after IC induction should receive ≥1 additional cycles with reduced cytotoxic doses then BSC per standard /institutional practice.

Arm

Intervention/Treatment

Experimental: Guadecitabine

Guadecitabine 60 mg/m2 given subcutaneously daily on Days 1-5 in 28-day cycles. The total amount (in mg) of guadecitabine to be administered is determined by body surface area.

Drug: Guadecitabine

Guadecitabine regimen is 60 mg/m2 given SC daily on Days 1-5 in 28-day cycles (delayed as needed to allow blood count recovery). Treatment should be given for at least 6 total cycles in absence of unacceptable toxicity or disease progression requiring alternative therapy.

Other Names:

SGI-110

Active Comparator: Treatment Choice

Best Supportive Care. Low dose cytarabine. Standard Intensive Chemotherapy.

Other: Treatment Choice

BSC: according to standard/institutional practice; includes RBC or platelet transfusions; growth factors, ie, erythropoiesis stimulating agents, granulocyte stimulating factors, iron chelating therapy; broad spectrum antibiotics and/or antifungals. Low dose cytarabine: 20 mg/m2 SC or IV QD for 14 days in 28-day cycles. Other schedules allowed per institutional practice. Treatment for ≥4 cycles absent disease progression/toxicity. BSC per institutional/standard practice. Standard Intensive Chemotherapy: recommended 7+3 given as cytarabine 100-200 mg/m2/day continuous infusion for 7 days and an anthracycline for 3 days. Anthracyclines per institutional practice include daunorubicin (45-60 mg/m2/day) or idarubicin (9-12 mg/m2/day) or mitoxantrone (8-12 mg/m2/day) by IV infusion. Subjects with complete or partial response after IC induction should receive ≥1 additional cycles with reduced cytotoxic doses then BSC per standard /institutional practice.

Outcome Measures

Primary Outcome Measures

Overall survival [18 Months]

Secondary Outcome Measures

Transfusion independence [18 months]
Marrow complete response [18 months]
Survival rate [18 months]
Leukemia-free survival [18 months]
As described in Time Frame.
Number of days alive and out of the hospital (NDAOH). [18 months]
Disease response [18 months]
Duration of response [18 months]
Number of transfusions [18 months]
Health-related quality of life [18 months]
Incidence and severity of adverse events. [18 months]
30-day and 60-day all-cause mortality [18 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Adult subjects ≥18 years of age who are able to understand and comply with study procedures, and provide written informed consent before any study-specific procedure.
Cytologically or histologically confirmed diagnosis of MDS or CMML according to the 2008 World Health Organization (WHO) classification.
Performance status (ECOG) of 0-2.
Previously treated MDS or CMML, defined as prior treatment with at least one hypomethylating agent (HMA; azacitidine and/or decitabine) for intermediate or high risk MDS or CMML whose disease progressed or relapsed as follows:

Subject received HMA for at least 6 cycles and was still transfusion dependent (as defined in 5b below).
Subject had disease progression prior to Cycle 6 defined as ≥50% increase in bone marrow blasts from pretreatment levels to >5%, or ≥2 g/dL reduction of Hgb from pretreatment levels with transfusion dependence after at least 2 cycles of HMA.

Other prior treatments for MDS such as lenalidomide, cytarabine, intensive chemotherapy, hydroxyurea, erythropoietin and other growth factors, or hematopoietic cell transplant (HCT) are allowed.

Subjects must have either:

Bone marrow blasts >5% at randomization, OR
Transfusion dependence, defined as having had transfusion (in the setting of active disease) of 2 or more units of RBC or platelets within 8 weeks prior to randomization.

Creatinine clearance or glomerular filtration rate ≥30 mL/min estimated by the Cockroft-Gault (C-G) or other medically acceptable formulas such as MDRD (Modification of Diet in Renal Disease) or CKD-EPI (the Chronic Kidney Disease Epidemiology Collaboration).
Women of childbearing potential must not be pregnant or breastfeeding and must have a negative pregnancy test at screening. Women of childbearing potential and men with female partners of childbearing potential must agree to practice 2 highly effective contraceptive measures of birth control and must agree not to become pregnant or father a child while receiving treatment with guadecitabine, LDAC, or IC and for at least 3 months after completing treatment.

Exclusion criteria:

Subjects who have been diagnosed as having AML with peripheral blood or bone marrow blasts of ≥20%.
Subjects who may still be sensitive to repeated treatment with decitabine or azacitidine such as subjects who had response to prior decitabine or azacitidine treatment, but relapsed >6 months after stopping treatment with these agents.
Prior treatment with guadecitabine.
Hypersensitivity to decitabine, guadecitabine, or any of their excipients.
Second malignancy currently requiring active therapy, except breast or prostate cancer stable on or responding to endocrine therapy.
Treated with any investigational drug within 2 weeks of the first dose of study treatment.
Total serum bilirubin >2.5 ULN (except for subjects with Gilbert's Syndrome for whom direct bilirubin is <2.5×ULN), or liver cirrhosis or chronic liver disease Child-Pugh Class B or C.
Known active HIV, HBV, or HCV infection. Inactive hepatitis carrier status or low viral hepatitis titer on antivirals is allowed.
Known significant mental illness or other condition such as active alcohol or other substance abuse or addiction that, in the opinion of the investigator, predisposes the subject to high risk of noncompliance with the protocol.
Refractory congestive heart failure unresponsive to medical treatment, active infection resistant to all antibiotics, or advanced non-MDS associated pulmonary disease requiring >2 liters per minute oxygen.
Life expectancy of less than one month
subjects with TP53 mutations

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope	Duarte	California	United States	91010
2	Desert Hematology Oncology Medical Group, Inc.	Rancho Mirage	California	United States	92270
3	Cancer Specialists of North Florida	Fleming Island	Florida	United States	32003
4	Mount Sinai Medical Center	Miami Beach	Florida	United States	33140
5	Rush University Medical Center	Chicago	Illinois	United States	60612
6	North Shore Medical Center	Evanston	Illinois	United States	60201
7	Franciscan Health Indianapolis	Indianapolis	Indiana	United States	46237
8	University of Maryland	Baltimore	Maryland	United States	21201
9	University of Michigan Cancer Center	Ann Arbor	Michigan	United States	48109
10	John Theurer Cancer Center	Hackensack	New Jersey	United States	07601
11	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
12	Weill Cornell Medical College	New York	New York	United States	10065
13	Stony Brook University Medical Center	Stony Brook	New York	United States	11794
14	Duke Cancer Center	Durham	North Carolina	United States	27705
15	Penn State Milton S. Hershey Medical Center	Hershey	Pennsylvania	United States	17033
16	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111
17	Medical University of South Carolina	Charleston	South Carolina	United States	29425
18	Bon Secours Saint Francis Hospital	Greenville	South Carolina	United States	29607
19	University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030
20	Swedish Cancer Institute	Seattle	Washington	United States	98104
21	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109
22	West Virginia University Mary Babb Randolph Cancer Center	Morgantown	West Virginia	United States	26506
23	Ziekenhuis Netwerk Antwerpen Stuivenberg	Antwerp		Belgium
24	Algemeen Ziekenhuis Sint-Jan Brugge-Oostende	Brugge		Belgium
25	Grand Hôpital de Charleroi - Notre Dame	Charleroi		Belgium
26	Tom Baker Cancer Center	Calgary	Alberta	Canada	T2N 4N2
27	University of Alberta Hospital	Edmonton	Alberta	Canada	T6G 2B7
28	Royal Victoria Regional Health Centre	Barrie	Ontario	Canada	L4M 6M2
29	Juravinski Cancer Centre	Hamilton	Ontario	Canada	L8V 1C3
30	Princess Margaret Hospital	Toronto	Ontario	Canada	M5G 2C1
31	Burnaby Hospital	Burnaby		Canada
32	Moncton Hospital	Moncton		Canada
33	Maisonneuve-Rosemont Hôpital Service d'Hematologie et d'Oncologie Medicale	Montréal		Canada
34	Saskatchewan Cancer Agency	Regina		Canada
35	Fakultní nemocnice Brno	Brno		Czechia
36	Fakultni Nemocnice Hradec Králové	Hradec Králové		Czechia
37	Fakultní nemocnice Ostrava	Ostrava		Czechia
38	Onkologická klinika Všeobecná fakultní nemocnice v Praze a 1	Praha 2		Czechia
39	Fakultní Nemocnice Královské Vinohrady	Praha		Czechia
40	Aalborg Universitetshospital	Aalborg		Denmark
41	Aarhus Universitetshospital	Aarhus		Denmark
42	Rigshospitalet	Copenhagen		Denmark
43	Odense University Hospital	Odense		Denmark
44	Centre Hospitalier Universitaire	La Tronche		France
45	Hôpital Dupuytren	Limoges		France
46	GHR Mulhouse Sud-Alsace	Mulhouse Cedex		France
47	Hôpital Hôtel-Dieu	Nantes		France
48	Centre Antoine Lacassagne	Nice		France
49	Hôpital Saint Louis	Paris		France
50	Centre Hospitalier Lyon Sud	Pierre-Bénite		France
51	Centre Hospitalier Universitaire de Toulouse	Toulouse		France
52	Städtisches Klinikum Braunschweig	Braunschweig		Germany
53	Marien Hospital Düsseldorf	Düsseldorf		Germany
54	Universitaetsklinikum Freiburg	Freiburg		Germany
55	Universitätsklinikum Halle	Halle		Germany
56	Universitätsklinikum Ulm	Ulm		Germany
57	Azienda Ospedaliera SS. Antonio E. Biagio E. Cesare Arrigo di Alessandria	Alessandria		Italy
58	Azienda Ospedaliero Universitaria Careggi	Firenze		Italy
59	Azienda Ospedaliera Universitaria San Martino	Genova		Italy
60	Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico	Milano		Italy
61	AORN A. Cardarelli	Napoli		Italy
62	Azienda Ospedaliera Universitaria-Maggiore della Carità di Novara	Novara		Italy
63	Azienda Ospedaliera Ospedali Riuniti Marche Nord	Pesaro		Italy
64	Ospedale S. Eugenio	Roma		Italy
65		Chubu		Japan
66		Chugoku		Japan
67		Kanto		Japan
68		Kinki		Japan
69		Kyushu		Japan
70		Tohoku		Japan
71	Seoul National University Hospital	Seoul		Korea, Republic of	03080
72	Severance Hospital, Yonsei University Health System	Seoul		Korea, Republic of	03722
73	Asan Medical Center	Seoul		Korea, Republic of	05505
74	Samsung Medical Center	Seoul		Korea, Republic of	06351
75	Seoul Saint Mary's Hospital	Seoul		Korea, Republic of	137-701
76	Ulsan University Hospital	Ulsan		Korea, Republic of	44033
77	Samodzielny Publiczny Szpital Kliniczny nr 1 w Lublinie	Lublin		Poland
78	Instytut Hematologii i Transfuzjologii	Warszawa		Poland
79	Samodzielny Publiczny Centralny Szpital Kliniczny	Warszawa		Poland
80	Hospital General Universitario de Alicante	Alicante		Spain
81	Hospital Universitari Germans Trias i Pujol	Badalona		Spain
82	Fundació Hospital de la Santa Creu i Sant Pau	Barcelona		Spain
83	Hospital Universitario Vall d'Hebron	Barcelona		Spain
84	Hospital San Pedro de Alcantara	Cáceres		Spain
85	Hospital de León	León		Spain
86	Hospital General Universitario Gregorio Marañon	Madrid		Spain
87	Hospital Universitario 12 de Octubre	Madrid		Spain
88	Hospital Universitario Ramón Y Cajal	Madrid		Spain
89	Hospital Universitario de Salamanca	Salamanca		Spain
90	Hospital Universitari i Politecnic La Fe de Valencia	Valencia		Spain
91	Sahlgrenska Universitetssjukhuset, Östra sjukhuset	Göteborg		Sweden
92	Universitetssjukhuset Örebro	Örebro		Sweden
93	Medway NHS Foundation Trust	Gillingham		United Kingdom
94	The Leeds Teaching Hospitals NHS Trust	Leeds		United Kingdom
95	Chelsea and Westminster Hospital NHS Foundation Trust	London		United Kingdom
96	Nottingham University Hospitals NHS Trust	Nottingham		United Kingdom