A Study of Oral Sapacitabine in Elderly Patients With Newly Diagnosed Acute Myeloid Leukemia (SEAMLESS)

A Phase III Randomized Study of Oral Sapacitabine in Elderly Patients With Newly Diagnosed Acute Myeloid Leukemia

This Phase 3 study assesses two drug regimens as the initial treatment of patients who are at least 70 years of age and have newly diagnosed acute myeloid leukemia (AML) for whom the doctor does not recommend the use of standard intensive treatment or the patient has decided not to receive standard intensive treatment after being fully informed about its benefits and risks by his/her doctor. The two drug regimens are sapacitabine administered in alternating cycles with decitabine or decitabine alone. The purpose of the study is to learn which drug regimen is more likely to keep AML in check as long as possible.

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Sapacitabine; Drug: Decitabine

Detailed Description

This is a multicenter, randomized, Phase 3 study ("SEAMLESS") comparing two drug regimens (arms) as the front-line treatment of elderly patients aged 70 years or older with newly diagnosed acute myeloid leukemia (AML) who are not candidates for intensive induction chemotherapy. In Arm A, sapacitabine is administered in alternating cycles with decitabine, and in Arm C decitabine is administered alone. The primary efficacy endpoint is overall survival. The study is designed to demonstrate an improvement in overall survival of Arm A versus Arm C.

• Study Type: Interventional
• Enrollment (Actual): 482
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Innsbruck, Austria
    • Medizinische Universitaetsklinik
  • Linz, Austria
    • Elisabethinen Krankenhaus
  • Linz, Austria
    • Krankenhaus der Barmherzigen Schwestern
  • Salzburg, Austria
    • Univ. Klinik für Innere Medizin III LKH
  • Wels, Austria
    • Klinikum Wels-Grieskirchen GmbH
  • Wien, Austria
    • AKH Wien
  • Wien, Austria
    • Hanusch Krankenhaus
• Belgium
  • Antwerpen, Belgium
    • Ziekenhuis Netwerk Antwerpen Stuivenberg
  • Brugge, Belgium
    • AZ Sint-Jan Brugge-Oostende
  • Brussels, Belgium
    • Université Catholique de Louvain
  • La Louviere, Belgium
    • Centre Hospitalier de Jolimont-Lobbes
  • Yvoir, Belgium
    • Cliniques Universitaires UCL de Mont-Godinne
• France
  • Amiens, France
    • CHU D'amiens Hôpital Sud
  • Bayonne, France
    • Centre Hospitalier de la Côte Basque
  • Lyon, France
    • CHU De Lyon - Hôpital Edouard Herriot
  • Marseille, France
    • Institut Paoli Calmettes
  • Montpellier, France
    • CHRU De Montpellier Hopital St. Eloi
  • Mulhouse, France
    • Centre Hospitalier de Mulhouse
  • Paris, France
    • Hopital St Louis Universite Paris 7
  • Perigueux, France
    • Centre Hospitalier de Perigueux
  • Pringy, France
    • Centre Hospitalier D'annecy
  • St Brieuc, France
    • Centre Hospitalier de Saint-Brieuc Yves Ie Foll
  • Strasbourg, France
    • CHU de Strasbourg - Hôpital Civil
  • Strasbourg, France
    • Strasbourg Oncologie Liberale
  • Tours, France
    • CHU de Tours Hopital Bretonneau
• Germany
  • Berlin, Germany
    • Universitaetsklinikum Charite Berlin, Campus Benjamin Franklin
  • Dresden, Germany
    • Universitaetsklinikum Carl-Gustav-Carus Dresden
  • Duisburg, Germany
    • St. Johannes Hospital
  • Frankfurt, Germany
    • Klinikum Frankfurt Hoechst
  • Hamburg, Germany
    • Asklepios Klinik Altona
  • Hannover, Germany
    • Medizinische Hochschule Hannover
  • Heilbronn, Germany
    • SLK Kliniken Heilbronn
  • Leipzig, Germany
    • Klinikum St. Georg
  • Minden, Germany
    • Johannes Wesling Klinikum
  • Muenchen, Germany
    • TU Muenchen
  • Muenster, Germany
    • Universitaetsklinikum Muenster
• Hungary
  • Debrecen, Hungary
    • University of Debrecen
  • Győr, Hungary
    • Petz Aladár Megyei Oktató Kórház
  • Kaposvár, Hungary
    • Kaposi Mór Oktató Kórház
• Italy
  • Ancona, Italy
    • Aou Ospedali Riuniti Umberto I
  • Bergamo, Italy
    • AO Ospedali Riuniti di Bergamo
  • Bologna, Italy
    • Universita di Bologna Ist Ematologia Oncologia Medica Seragnoli
  • Brescia, Italy
    • AO Spedali Civili di Brescia
  • Campobasso, Italy
    • Università Cattolica del Sacro Cuore
  • Firenze, Italy
    • AOU Careggi
  • Genova, Italy
    • AOU San Martino IST
  • Lecce, Italy
    • PO Vito Fazzi
  • Milano, Italy
    • Ospedale San Raffaele
  • Napoli, Italy
    • AORN Antonio Cardarelli
  • Napoli, Italy
    • Uni. Napoli Ospedale Federico lI
  • Novara, Italy
    • AOU Maggiore della Carità di Novara
  • Palermo, Italy
    • AOOR Villa Sofia Cervello di Palermo
  • Pavia, Italy
    • Policlinico San Matteo di Pavia
  • Torino, Italy
    • AOU San Luigi Gonzaga
• Poland
  • Gdansk, Poland
    • Akademickie Centrum Kliniczne Szpital Akademii Medycznej w Gdansku
  • Legnica, Poland
    • Wojewodzki Szpital Specjalistyczny
  • Legnica, Poland
    • Wojewodzki Szpital Specjalistyczny w Legnicy
  • Lodz, Poland
    • University of Lodz N. Copernicus Memorial Hospital
  • Warsaw, Poland
    • IHT Instytut Hematologii I Transfuzjologii w Warszawie
  • Wroclaw, Poland
    • Samodzielny Publiczny Szpital Kliniczny Nr 1 w Wroclawiu
• Spain
  • Badalona, Spain
    • Hospital Universitari Germans Trias i Pujol ICO Badalona
  • Barcelona, Spain
    • Hospital Clinic de Barcelona
  • Barcelona, Spain
    • Hospital Universitario Vall d'Hebron
  • Barcelona, Spain
    • Hospital de la Santa Creu Sant Pau
  • La Laguna, Spain
    • Hospital Universitario de Canarias
  • Madrid, Spain
    • Hospital Universitario Ramón y Cajal
  • Madrid, Spain
    • MD Anderson Cancer Center
  • Palma de Mallorca, Spain
    • Hospital Son Llatzer
  • Palma de Mallorca, Spain
    • Hospital Universitari Son Espases
  • Pamplona, Spain
    • Clinica Universidad de Navarra
  • Pamplona, Spain
    • Complejo Hospitalario de Navarra
  • Salamanca, Spain
    • Hospital Clinico Universitario de Salamanca
  • Santiago de Compostela, Spain
    • Hospital Clinico Universitario
  • Sevilla, Spain
    • Hospital Universitario Virgen del Rocío
  • Valencia, Spain
    • Hospital Universitari "La Fe"
• Sweden
  • Luleå, Sweden
    • Sunderby Hospital
  • Lund, Sweden
    • Skåne Universitetssjukhus Univ Hospital Lund
• Switzerland
  • Bern, Switzerland
    • Inselspital Bern
• United Kingdom
  • London, United Kingdom
    • Kings College Hospital and Guys and St Thomas' Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama Comprehensive Cancer Center
  • California
    • La Jolla, California, United States, 92037
      • Scripps Cancer Center
    • Los Angeles, California, United States, 90095
      • UCLA Ronald Reagan Medical Center
  • Connecticut
    • Norwalk, Connecticut, United States, 06850
      • Norwalk Hospital
  • Florida
    • Gainesville, Florida, United States, 32608
      • Shands Cancer Hospital at University of Florida
    • Weston, Florida, United States, 33331
      • Cleveland Clinic Florida
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute, Emory University
    • Atlanta, Georgia, United States, 30342
      • Blood and Marrow Transplant Group of Georgia
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Chicago, Illinois, United States, 60611
      • Northwestern Memorial Hospital
    • Chicago, Illinois, United States, 60637
      • The University of Chicago Medical Center
  • Indiana
    • Indianapolis, Indiana, United States, 46237
      • St. Francis Medical Group Oncology and Hematology Specialists
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Greenbaum Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Saint Luke's Cancer Institute
    • Saint Louis, Missouri, United States, 63110
      • St. Louis University Cancer Center
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth - Hitchcock Medical Center
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • John Theurer Cancer Center at the Hackensack University Medical Center
  • New York
    • Hawthorne, New York, United States, 10532
      • Westchester Hematology Oncology Group, PC
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10003
      • Beth Israel Medical Center
    • Stony Brook, New York, United States, 11794
      • Stony Brook University Medical Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Canton, Ohio, United States, 44718
      • Gabrail Cancer Center Research
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Milton S. Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19104
      • Abramson Cancer Center of the University of Pennsylvania
  • South Carolina
    • Greenville, South Carolina, United States, 29601
      • Saint Francis Hospital
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Dallas, Texas, United States, 75246
      • Baylor University Medical Center
    • Houston, Texas, United States, 77030-3387
      • MD Anderson Cancer Center
    • Lubbock, Texas, United States, 79410
      • Joe Arrington Cancer Research and Treatment Center
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute at The University of Utah
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • The Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 70 years and older (Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Newly diagnosed AML based on WHO (World Health Organization) classification
• Age 70 years or older for whom the treatment of choice is low-intensity therapy by investigator assessment or who has refused intensive induction therapy recommended by investigator
• ECOG (Eastern Cooperative Oncology Group) performance status 0-2
• Adequate renal function
• Adequate liver function
• Able to swallow capsules
• Agree to practice effective contraception
• Ability to understand and willingness to sign the informed consent form

Exclusion Criteria:

• AML is of the sub-type of acute promyelocytic leukemia or extramedullary myeloid tumor without bone marrow involvement
• Having received any systemic anti-cancer therapy for AML or received treatment with hypomethylating agents or cytotoxic chemotherapy for preceding myelodysplastic syndrome (MDS) or myeloproliferative disease (MPD)
• Known or suspected central nervous system (CNS) involvement by leukemia
• Uncontrolled intercurrent illness
• Known hypersensitivity to decitabine
• Known to be HIV-positive

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sapacitabine-decitabine alternating; Arm A sapacitabine administered in alternating cycles with decitabine	Drug: Sapacitabine; Oral sapacitabine capsules; Other Names: CYC682; Drug: Decitabine; Decitabine intravenous; Other Names: Decitabine intravenous
Active Comparator: Decitabine; Arm C Decitabine	Drug: Decitabine; Decitabine intravenous; Other Names: Decitabine intravenous

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	The distribution of overall survival was estimated by the method of Kaplan and Meier. A log-rank analysis stratified by randomization stratification factors was used to compare overall survival between Arm A (decitabine/sapacitabine) versus Arm C (decitabine). Cox proportional hazards models were used to identify predictive factors for overall survival.	up to 43 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Remission (CR)	Normalization of peripheral neutrophils to >=1000 /microliter, platelet to >=100,000/microliter within 2 weeks of bone marrow biopsy/aspirate, and bone marrow to <=5 % blasts; independent of transfusions*; and no extramedullary leukemia. * independent of transfusions refer to no platelet transfusion for 1 week prior to achieving the response	up to 43 months
Complete Remission With Incomplete Platelet Count Recovery (CRp)	Normalization of bone marrow to <=5% blasts; peripheral neutrophils >=1000 /microliter, platelet <=100,000 /microliter within 2 weeks of bone marrow biopsy/aspirate; independent of transfusions*; and no extramedullary leukemia. *independent of transfusions refer to no platelet transfusion for 1 week prior to achieving the response	up to 43 months
Partial Remission (PR)	Normalization of peripheral neutrophils to >=1000 /microliter, platelet to >=100,000/microliter within 2 weeks of bone marrow biopsy/aspirate, >=50% decrease in bone marrow blasts over pre-treatment but still >5%; independent of transfusions* *independent of transfusions refer to no platelet transfusion for 1 week prior to achieving the response	up to 43 months
Hematological Improvement	HI with duration (HI); Erythroid response (HI-E) for patients with pre-treatment hemoglobin < 11 g/dL; Major response: >2 g/dL increase in hemoglobin; for RBC, transfusion independence* Minor response: 1 to 2 g/dL increase in hemoglobin; for RBC, a 50% decrease in transfusion requirements; Platelet response (HI-P) for pre-treatment platelet count <100,000/mm3; Major response: an absolute increase of platelet count by >=30,000/mm3; stabilization of platelet counts and platelet transfusion independence* Minor response: >=50% increase in platelet count with a net increase > 10,000/mm3 but <30,000/mm3; Neutrophil response (HI-N) for absolute neutrophil count (ANC) < 1,500/mm3 before therapy; Major response: >=100% increase, or an absolute increase of >500/mm3, whichever is greater Minor response: >=100% increase, but absolute increase < 500/mm3independent of transfusions refer to no platelet transfusion for 1 week prior to achieving the response	up to 43 months
Stable Disease (SD)	Failure to achieve at least hematologic improvement (HI), but no evidence of clinically significant progression for > 16 weeks.	up to 43 months
Blood Products Transfused	Number of units of packed red blood cells (PRBC) and/or platelet transfusions administered per 8-week period prior to the first dose of study drug and through the date of treatment discontinuation.	up to 43 months
Hospitalized Days	In-patient days in hospital.	up to 12 months
1-year Survival	One-year survival is the percentage of patients who are alive at 1-year measured from the date of randomization.	Percentage of patients alive at 1 year after randomization (participants were assessed up to 43 months for overall survival curve estimation but this measure presents the 1 year survival rate percentage).
Duration of Complete Remission (dCR)	Durations of normalization of peripheral neutrophils to >=1000 /microliter, platelet to >=100,000/microliter within 2 weeks of bone marrow biopsy/aspirate, and bone marrow to <=5 % blasts; independent of transfusions*; and no extramedullary leukemia. * independent of transfusions refer to no platelet transfusion for 1 week prior to achieving the response	up to 43 months
Duration of Complete Remission With Incomplete Platelet Count Recovery (dCRp)	Duration of normalization of bone marrow to <=5% blasts; peripheral neutrophils >=1000 /microliter, platelet <=100,000 /microliter within 2 weeks of bone marrow biopsy/aspirate; independent of transfusions*; and no extramedullary leukemia. *independent of transfusions refer to no platelet transfusion for 1 week prior to achieving the response	up to 43 months
Duration of Partial Remission (dPR)	Duration of normalization of peripheral neutrophils to >=1000 /microliter, platelet to >=100,000/microliter within 2 weeks of bone marrow biopsy/aspirate, >=50% decrease in bone marrow blasts over pre-treatment but still >5%; independent of transfusions* *independent of transfusions refer to no platelet transfusion for 1 week prior to achieving the response	up to 43 months
Duration of Hematological Improvement (dHI)	Duration of HI; Erythroid response (HI-E) for patients with pre-treatment hemoglobin < 11 g/dL; Major response: >2 g/dL increase in hemoglobin; for RBC, transfusion independence* Minor response: 1 to 2 g/dL increase in hemoglobin; for RBC, a 50% decrease in transfusion requirements; Platelet response (HI-P) for pre-treatment platelet count <100,000/mm3; Major response: an absolute increase of platelet count by >=30,000/mm3; stabilization of platelet counts and platelet transfusion independence* Minor response: >=50% increase in platelet count with a net increase > 10,000/mm3 but <30,000/mm3; Neutrophil response (HI-N) for absolute neutrophil count (ANC) < 1,500/mm3 before therapy; Major response: >=100% increase, or an absolute increase of >500/mm3, whichever is greater Minor response: >=100% increase, but absolute increase < 500/mm3independent of transfusions refer to no platelet transfusion for 1 week prior to achieving the response	up to 43 months
Duration of Stable Disease (dSD)	Failure to achieve at least hematologic improvement (HI), but no evidence of clinically significant progression for > 16 weeks.	up to 43 months

Collaborators and Investigators

• Sponsor: Cyclacel Pharmaceuticals, Inc.
• Investigators: Study Chair: Hagop M Kantarjian, M.D., M.D. Anderson Cancer Center

Publications and helpful links

General Publications

• Kantarjian HM, Begna KH, Altman JK, Goldberg SL, Sekeres MA, Strickland SA, Arellano ML, Claxton DF, Baer MR, Gautier M, Berman E, Seiter K, Solomon SR, Schiller GJ, Luger SM, Butrym A, Gaidano G, Thomas XG, Montesinos P, Rizzieri DA, Quick DP, Venugopal P, Gaur R, Maness LJ, Kadia TM, Ravandi F, Buyse ME, Chiao JH. Results of a randomized phase 3 study of oral sapacitabine in elderly patients with newly diagnosed acute myeloid leukemia (SEAMLESS). Cancer. 2021 Dec 1;127(23):4421-4431. doi: 10.1002/cncr.33828. Epub 2021 Aug 23.

Helpful Links

• Results of a randomized phase 3 study of oral sapacitabine in elderly patients with newly diagnosed acute myeloid leukemia (SEAMLESS)

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2011
• Primary Completion (Actual): December 15, 2016
• Study Completion (Actual): July 31, 2017

Study Registration Dates

• First Submitted: February 21, 2011
• First Submitted That Met QC Criteria: February 24, 2011
• First Posted (Estimate): February 25, 2011

Study Record Updates

• Last Update Posted (Actual): June 22, 2022
• Last Update Submitted That Met QC Criteria: May 26, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: AML
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Decitabine; Sapacitabine
• Other Study ID Numbers: CYC682-12

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No