Clinical trial NCT01191801: Study of Vosaroxin or Placebo in Combination With Cytarabine in Patients With First Relapsed or Refractory AML
Official title: A Phase 3, Randomized, Controlled, Double-Blind, Multinational Clinical Study of the Efficacy and Safety of Vosaroxin and Cytarabine Versus Placebo and Cytarabine in Patients With First Relapsed or Refractory Acute Myeloid Leukemia (VALOR)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Acute Myeloid Leukemia
Keywords: Leukemia
Acute Myeloid Leukemia
Hematologic
Hematologic diseases
Blood
Cancer
Malignancy
Vosaroxin
Cytarabine
First Relapsed AML
Refractory AML
VALOR
Sunesis
Voreloxin
SNS-595
Lead sponsor: Sunesis Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2010-08-31
Enrollment: 711
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study compared treatment groups of patients treated with vosaroxin and cytarabine versus patients treated with placebo and cytarabine.

Detailed description: The study includes additional objectives to ones listed above as Outcome Measures. These additional objectives also compared treatment groups in the following:

CR + CRp rate, defined as CR + CRp based on modified IWG response criteria.

Combined CR rate (CR+CRp+CRi).

Percentage of patients who have post-treatment (subsequent) transplantation.

Percentage of patients who received subsequent non-protocol therapy (including transplantation).

Safety and tolerability.

In keeping with FDA guidance for adaptive trial designs, the study incorporated an independent DSMB (Drug Safety Monitoring Board) to address potential uncertainty concerning the true treatment affect between the treatment groups and to address a deterioration of power from a small difference. Sunesis remained blinded and had no involvement in the interim data analysis, interpretation, or adaptive design. Based on the results of the interim data analysis the DSMB recommended an increase in the target number of deaths from 375 in 450 patients to 562 in 675 patients which based on a 5% dropout rate increased enrollment from 475 to 712.

The primary analysis was performed when the target number of deaths had been achieved based on a permuted block randomization procedure, stratified by disease status (refractory, first relapse with duration of first CR or CRp ≥ 90 days and \< 12 months, or first relapse with duration of first CR or CRp ≥ 12 months and ≤ 24 months), age (\< 60 years or ≥ 60 years), and geographic location (US or outside US). The study included periods of screening, treatment / hematologic recovery, post-treatment follow-up, and long-term follow-up for survival.

Follow-up was monthly during the first year, every 2 months during the second year, and every 3 months thereafter until death, withdrawal of consent, or loss to follow-up, whichever occurred first. Long-term follow-up began for all patients when the required number of deaths for primary analysis had been met; thereafter, survival data were collected every 4 months until death, withdrawal of consent, or loss to follow-up, whichever occurred first.

The long term follow-up for this study continues at this time and the September 2014 date reflects database lock for primary analyses reflected in the Results Section. During long term follow-up Sunesis is not collecting Adverse Events.

Eligibility criteria: Inclusion Criteria:

* Provided signed, written informed consent
* At least 18 years of age
* Had a diagnosis of AML according to World Health Organization (WHO) classification
* First relapsed or refractory AML (refractory to initial induction therapy) with at least 5% blasts by bone marrow or aspirate or 1% blasts in peripheral blood with additional requirements for relapsed or refractory
* Had an ECOG score of 0-2
* Had adequate liver and renal function as indicated by certain laboratory values
* Had adequate cardiac function (left ventricular ejection fraction at least 40% by multiple gated acquisition scan or ECG)
* Nonfertile or agreed to use an adequate method of contraception until 30 days after the last treatment
* Had any clinically significant nonhematologic toxicity after prior chemotherapy recovered to Grade 1 per NCI-CTCAE

Exclusion Criteria:

* Had acute promyelocytic leukemia
* Had more than 2 cycles of induction therapy for AML
* Had completed a single cycle of treatment containing a total dose of 5 g/m2 or more of cytarabine within 90 days before randomization
* Refractory to or relapsed within the previous 3 months after therapy with an IDAC- or HIDAC-containing regimen
* Had received a hematopoietic stem cell transplant (HSCT) within the previous 90 days
* Had received active immunosuppressive therapy for graft-versus-host disease (GVHD) within 2 weeks before study start
* Had any other severe concurrent disease, or have a history of serious disease involving the heart, kidney, liver, or other organ system
* Had evidence of central nervous system involvement of active AML
* Had other active malignancies (including other hematologic malignancies) or been diagnosed with other malignancies within the last 12 months, except nonmelanoma skin cancer or cervical intraepithelial neoplasia
* Had an active, uncontrolled infection
* Had received any other investigational therapy within 14 days or not recovered from acute affects of the other investigational therapy
* Had received prior or current hydroxyurea or medications to reduce blast count within 24 hours before randomization
* Had received previous treatment with vosaroxin
* Pregnant or lactating
* Had any other medical, psychological, or social condition that may interfere with consent, study participation, or follow-up
* Had known HIV seropositivity

Primary outcomes:
measure: Overall Survival
timeFrame: Up to 5 years or duration of study
Secondary outcomes:
measure: Complete Remission (CR) Rate Based on Modified International Working Group (IWG) Criteria.
timeFrame: Up to 5 years or duration of study
measure: All Cause Mortality
timeFrame: 30 Days
measure: All Cause Mortality
timeFrame: 60 Days
Other outcomes:
measure: Overall Remission (OR) Rate Based on the IWG Response Criteria
timeFrame: Up to 5 years or the duration of the study
measure: Event Free Survival (EFS)
timeFrame: Up to 5 years or duration of study
measure: Leukemia-Free Survival (LFS)
timeFrame: Up to 5 years or the duration of the study
Locations:
city: La Jolla
country: United States
facility: Moores UCSD Cancer Center
state: California
city: Los Angeles
country: United States
facility: UCLA Division of Hematology/Oncology
state: California
city: San Diego
country: United States
facility: Sharp Clinical Oncology Research
state: California
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Denver
country: United States
facility: HCA HealthONE - Rocky Mountain Blood and Marrow Transplant Program
state: Colorado
city: Washington
country: United States
facility: George Washington University-Medical Faculty Associates
state: District of Columbia
city: Fort Lauderdale
country: United States
facility: Holy Cross Hospital
state: Florida
city: Jacksonville
country: United States
facility: Baptist Cancer Institute
state: Florida
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center & Research Institute
state: Florida
city: Augusta
country: United States
facility: Georgia Health Sciences University
state: Georgia
city: Chicago
country: United States
facility: Rush University Medical Center, Division of Hematology/Oncology
state: Illinois
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Melvin and Bren Simon Cancer Center
state: Indiana
city: Indianapolis
country: United States
facility: St. Francis Medical Group Oncology and Hematology Specialists
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: New Orleans
country: United States
facility: Ochsner Clinic Foundation
state: Louisiana
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Columbia
country: United States
facility: Ellis Fischel Cancer Center, University of Missouri Health Care
state: Missouri
city: Lebanon
country: United States
facility: Dartmouth-Hitchcock Medical Center
state: New Hampshire
city: Hackensack
country: United States
facility: John Theurer Cancer Center at Hackensack University Medical Center
state: New Jersey
city: Lake Success
country: United States
facility: North Shore Long Island Jewish Health System
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: Stony Brook
country: United States
facility: Stony Brook University Medical Center
state: New York
city: Valhalla
country: United States
facility: New York Medical College, Division of Oncology/Hematology
state: New York
city: Charlotte
country: United States
facility: Mecklenburg Medical Group
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Cleveland
country: United States
facility: University Hospitals fo Cleveland
state: Ohio
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Memphis
country: United States
facility: Family Cancer Center
state: Tennessee
city: Nashville
country: United States
facility: Tennessee Oncology, PLLC
state: Tennessee
city: Nashville
country: United States
facility: Henry-Joyce Cancer Clinic
state: Tennessee
city: Dallas
country: United States
facility: UT Southwestern Medical Center at Dallas
state: Texas
city: Houston
country: United States
facility: The University of Texas, M.D. Anderson Cancer Center, Department of Leukemia
state: Texas
city: San Antonio
country: United States
facility: Cancer Care Centers of South Texas
state: Texas
city: Morgantown
country: United States
facility: Department of Medicine Section of Hematology/Oncology, West Virginia University Hospitals, Mary Babb Randolph Cancer Center, West Virginia University
state: West Virginia
city: Garran
country: Australia
facility: The Canberra Hospital
state: Australian Capital Territory
city: Concord
country: Australia
facility: Concord Repatriation General Hospital
state: New South Wales
city: Gosford
country: Australia
facility: Haematology Department, Gosford Hospital
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Brisbane
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Haematology and Bone Marrow Transplant Unit, Royal Adelaide Hospital
state: South Australia
city: Bedford Park
country: Australia
facility: Flinders Medical Centre
state: South Australia
city: Geelong
country: Australia
facility: Andrew Love Cancer Center, Geelong Hospital, Barwon Health
state: Victoria
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Parkville
country: Australia
facility: Department of Clinical Haematology and BMT Service, Royal Melbourne Hospital
state: Victoria
city: Perth
country: Australia
facility: Royal Perth Hospital
state: Western Australia
city: Graz
country: Austria
facility: Universitatsklinik Graz, Universitatsklinik fur Innere Medizin, Abteilung fur Hamatologie
city: Innsbruck
country: Austria
facility: University Hospital for Internal Medicine V, Innsbruck Medical University
city: Salzburg
country: Austria
facility: Landeskrankenhaus Salzburg, Universitaetsklinik fur innere Medizin lll, Universitaetsklinikum der PMU
city: Wien
country: Austria
facility: AKH Wien / MedUniWien Universtatsklinik fur Innere Medizin 1
city: Antwerpen
country: Belgium
facility: ZNA Middleheim Lindendreef 1
city: Antwerpen
country: Belgium
facility: ZNA Stuivenberg, Lange Beeldekensstraat 267
city: Brugge
country: Belgium
facility: AZ St.-Jan Brugge-Oostende AV
city: Brussels
country: Belgium
facility: Cliniques Universitaires Saint Luc
city: Leuven
country: Belgium
facility: UZ Leuven, campus Gasthuisberg, Department of Haematology
city: Roeselare
country: Belgium
facility: H.-Hartziekenhuis Roeselare - Menen vzw
city: Vancouver
country: Canada
facility: Division of Hematology, Vancouver General Hospital
state: British Columbia
city: Saint John
country: Canada
facility: Saint John Regional Hospital
state: New Brunswick
city: Halifax
country: Canada
facility: Queen Elizabeth II Health Sciences Centre
state: Nova Scotia
city: Toronto
country: Canada
facility: University Health Network, Princess Margaret Hospital
state: Ontario
city: Greenfield Park
country: Canada
facility: Charles LeMoyne Hospital
state: Quebec
city: Praha
country: Czechia
facility: Fakultni nemocnice Kralovske Vinohrady, Oddeleni klinicke hematologie
state: Srobarova
city: Brno
country: Czechia
facility: Fakultni nemocnice Brno, Interni hematoonkologicka klinika
city: Hradec Kralove
country: Czechia
facility: Fakultni nemocnice Hradec Kralove, 2. Interni klinika-oddeleni klinicke hematologie
city: Lille
country: France
facility: CHU Lille, Service des maladies du sang, Hopital Huriez
state: Lille Cedex
city: Angers Cedex 01
country: France
facility: CHU Angers, Service des maladies du sang
city: Bobigny
country: France
facility: Hopital Avicenne- Departement Onco-hematologie
city: Le Chesnay
country: France
facility: Hopital Mignot
city: Marseille
country: France
facility: Institut Paoli Calmettes
city: Nantes
country: France
facility: CHU Nantes Hotel Dieu, Service d'hematologie clinique
city: Pessac
country: France
facility: CHU de Bordeaux- Hopital Haut-Leveque, Centre Francois Magendle
city: Pierre Benite
country: France
facility: Centre Hospitalier Lyon Sud - Service d'Hematologie - Pavillon Marcel Berard - Bat. 1G - 1er etage, 165 Chemin du grand Revoyet
city: Toulouse
country: France
facility: Service d'hematologie- Hopital Purpan- CHU de Toulouse
city: Duisburg
country: Germany
facility: St. Johannes-Hospital
city: Frankfurt
country: Germany
facility: Klinikum Frankfurt am Main-Hochst, Department of Hematology and Oncology, Klinikum Frankfurt Academic Hospital of the University of Frankfurt
city: Hamburg
country: Germany
facility: Universitatsklinikum Hamburg-Eppendorf; ll. Medizinische Klinik und Poliklinik; Onkologie, Hamatologie und Knochenmarktransplantation
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover, Abteilung Hamatologie
city: Heilbronn
country: Germany
facility: SLK-Kliniken Heilbronn GmbH, Medizinische Klinik
city: Kiel
country: Germany
facility: Staedtisches Krankenhaus Kiel GmbH, Infektionsambulanz der 2. Medizinischen Klinik
city: Leipzig
country: Germany
facility: Klinikum St. Georg gGmbH; Klinik fur Internistische Onkologie/Hamatologie
city: Muenster
country: Germany
facility: University Hospital of Muenster
city: Munich
country: Germany
facility: Klinikum rechts der Isar der Technischen Universitat Munchen lll, Medizinische Klinik
city: Debrecen
country: Hungary
facility: University of Debrecen Medical and Health Sciences Center
city: Gyor
country: Hungary
facility: Petz Aladar County Hospital
city: Kaposvar
country: Hungary
facility: kaposi Mor Oktato Korhaz Belgyogyaszati Osztaly
city: Szeged
country: Hungary
facility: Szegedi Tudomanyegyetem, 11. Belgyogyaszati Klinika
city: Brindisi
country: Italy
facility: Ospedale "A. Perrino", U.O. Compessa di Ematologia
city: Ferrara
country: Italy
facility: Azienda Ospedaliero-Universitaria Sant'Anna, Sezione di Ematologia, Dipartmento di Science Biomediche e Terapie Avanzate
city: Genova
country: Italy
facility: Ospedaliera Universitaria San Martino di Genova
city: Lecce
country: Italy
facility: Ospedale "Vito Fazzi", U.O Ematologia
city: Napoli
country: Italy
facility: AORN "A. Cardarelli", U.O.S.C. Ematologia con TMO
city: Novara
country: Italy
facility: Azienda Ospedaliero-Universitaria Maggiore Della Carita, Struttura Complessa Direzione Universitaria Ematologia
city: Pavia
country: Italy
facility: Fondazione IRCCS, Policlinico S. Matteo - Dipartimento di Ematologia
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine
city: Seoul
country: Korea, Republic of
facility: Seoul St. Mary's Hospital
city: Seoul
country: Korea, Republic of
facility: Dept. of Hematology, Asan Medical Center
city: Grafton
country: New Zealand
facility: Haematology Research, Auckland District Health Board, Auckland City Hospital
state: Auckland
city: Christchurch
country: New Zealand
facility: Canterbury Health Laboratories
city: Hamilton
country: New Zealand
facility: Department of Haematology, Waikato Hospital
city: Palmerston North
country: New Zealand
facility: Regional Cancer Treatment Service, Palmerston North Hospital
city: Gdansk
country: Poland
facility: Uniwersyteckle Centrum Kliniczne
city: Poznan
country: Poland
facility: Klinika Hematologii i Chorob Rozrostowych Ukladu Krwiotworczego, Szpital Kliniczny Przemiemienia Panskiego Uniwersytetu Medycznego im. Karola Marcinkowskiego w Poznaniu
city: Wroclaw
country: Poland
facility: Samodzielny Publiczny Szpital Kliniczny Nr 1 we Wroclawiu
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Universitari Germans Trias i Pujol
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Madrid
country: Spain
facility: Centro Oncologico MD Anderson International Espana
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Palma de Mallorca
country: Spain
facility: Hospital Sont Llatzer
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: Valencia
country: Spain
facility: Hospital Universitari Politecnic la Fe Hematology Department
city: Blackpool
country: United Kingdom
facility: Blackpool Victoria Hospital, Blackpool Teaching Hospitals NHS Foundation Trust
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital
city: Cardiff
country: United Kingdom
facility: Department of Haematology, University Hospital of Wales
city: Cottingham
country: United Kingdom
facility: Queen's Centre for Oncology and Hematology, Castle Hill Hospital
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary, University Hospitals of Leicester, NHS Trust
city: Liverpool
country: United Kingdom
facility: Department of Haematology, Royal Liverpool University Hospital
city: London
country: United Kingdom
facility: Department of Haematology, Guy's Hospital
city: Manchester
country: United Kingdom
facility: Central Manchester University Hospitals NHS Trust, Manchester Royal Infirmary
Study officials:
affiliation: Sunesis Pharmaceuticals
name: Linda Neuman, MD
role: STUDY_DIRECTOR
References:
citation: Ravandi F, Ritchie EK, Sayar H, Lancet JE, Craig MD, Vey N, Strickland SA, Schiller GJ, Jabbour E, Erba HP, Pigneux A, Horst HA, Recher C, Klimek VM, Cortes J, Roboz GJ, Odenike O, Thomas X, Havelange V, Maertens J, Derigs HG, Heuser M, Damon L, Powell BL, Gaidano G, Carella AM, Wei A, Hogge D, Craig AR, Fox JA, Ward R, Smith JA, Acton G, Mehta C, Stuart RK, Kantarjian HM. Vosaroxin plus cytarabine versus placebo plus cytarabine in patients with first relapsed or refractory acute myeloid leukaemia (VALOR): a randomised, controlled, double-blind, multinational, phase 3 study. Lancet Oncol. 2015 Sep;16(9):1025-1036. doi: 10.1016/S1470-2045(15)00201-6. Epub 2015 Jul 30.