Study of Vosaroxin or Placebo in Combination With Cytarabine in Patients With First Relapsed or Refractory AML (VALOR)

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)

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

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: vosaroxin + cytarabine; Drug: placebo + 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.

• Study Type: Interventional
• Enrollment (Actual): 711
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Australian Capital Territory
    • Garran, Australian Capital Territory, Australia, 2605
      • The Canberra Hospital
  • New South Wales
    • Concord, New South Wales, Australia, 2139
      • Concord Repatriation General Hospital
    • Gosford, New South Wales, Australia, 2250
      • Haematology Department, Gosford Hospital
    • Westmead, New South Wales, Australia, 2145
      • Westmead Hospital
  • Queensland
    • Brisbane, Queensland, Australia, 4029
      • Royal Brisbane and Women's Hospital
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Haematology and Bone Marrow Transplant Unit, Royal Adelaide Hospital
    • Bedford Park, South Australia, Australia, 5042
      • Flinders Medical Centre
  • Victoria
    • Geelong, Victoria, Australia, 3220
      • Andrew Love Cancer Center, Geelong Hospital, Barwon Health
    • Melbourne, Victoria, Australia, 3004
      • The Alfred Hospital
    • Parkville, Victoria, Australia, 3050
      • Department of Clinical Haematology and BMT Service, Royal Melbourne Hospital
  • Western Australia
    • Perth, Western Australia, Australia, 6000
      • Royal Perth Hospital
• Austria
  • Graz, Austria, 8036
    • Universitatsklinik Graz, Universitatsklinik fur Innere Medizin, Abteilung fur Hamatologie
  • Innsbruck, Austria, 6020
    • University Hospital for Internal Medicine V, Innsbruck Medical University
  • Salzburg, Austria, 5020
    • Landeskrankenhaus Salzburg, Universitaetsklinik fur innere Medizin lll, Universitaetsklinikum der PMU
  • Wien, Austria, 1090
    • AKH Wien / MedUniWien Universtatsklinik fur Innere Medizin 1
• Belgium
  • Antwerpen, Belgium, 2020
    • ZNA Middleheim Lindendreef 1
  • Antwerpen, Belgium
    • ZNA Stuivenberg, Lange Beeldekensstraat 267
  • Brugge, Belgium, 8000
    • AZ St.-Jan Brugge-Oostende AV
  • Brussels, Belgium, 1200
    • Cliniques Universitaires Saint Luc
  • Leuven, Belgium, B 3000
    • UZ Leuven, campus Gasthuisberg, Department of Haematology
  • Roeselare, Belgium, 8800
    • H.-Hartziekenhuis Roeselare - Menen vzw
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • Division of Hematology, Vancouver General Hospital
  • New Brunswick
    • Saint John, New Brunswick, Canada, E2L 4L2
      • Saint John Regional Hospital
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 2Y9
      • Queen Elizabeth II Health Sciences Centre
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • University Health Network, Princess Margaret Hospital
  • Quebec
    • Greenfield Park, Quebec, Canada, J4V 2H1
      • Charles Lemoyne Hospital
• Czechia
  • Brno, Czechia, 625 00
    • Fakultni nemocnice Brno, Interni hematoonkologicka klinika
  • Hradec Kralove, Czechia, 500 05
    • Fakultni nemocnice Hradec Kralove, 2. Interni klinika-oddeleni klinicke hematologie
  • Srobarova
    • Praha, Srobarova, Czechia, 100 34 Praha 10
      • Fakultni nemocnice Kralovske Vinohrady, Oddeleni klinicke hematologie
• France
  • Angers Cedex 01, France, 49033
    • CHU Angers, Service des maladies du sang
  • Bobigny, France, 93000
    • Hopital Avicenne- Departement Onco-hematologie
  • Le Chesnay, France, 78157
    • Hopital Mignot
  • Marseille, France, 13009
    • Institut Paoli Calmettes
  • Nantes, France, 44093
    • CHU Nantes Hotel Dieu, Service d'hematologie clinique
  • Pessac, France, 33604
    • CHU de Bordeaux- Hopital Haut-Leveque, Centre Francois Magendle
  • Pierre Benite, France, 69495
    • Centre Hospitalier Lyon Sud - Service d'Hematologie - Pavillon Marcel Berard - Bat. 1G - 1er etage, 165 Chemin du grand Revoyet
  • Toulouse, France, 31059
    • Service d'hematologie- Hopital Purpan- CHU de Toulouse
  • Lille Cedex
    • Lille, Lille Cedex, France, 59037
      • CHU Lille, Service des maladies du sang, Hopital Huriez
• Germany
  • Duisburg, Germany, 47166
    • St. Johannes-Hospital
  • Frankfurt, Germany, 65929
    • Klinikum Frankfurt am Main-Hochst, Department of Hematology and Oncology, Klinikum Frankfurt Academic Hospital of the University of Frankfurt
  • Hamburg, Germany, 20246
    • Universitatsklinikum Hamburg-Eppendorf; ll. Medizinische Klinik und Poliklinik; Onkologie, Hamatologie und Knochenmarktransplantation
  • Hannover, Germany, 30625
    • Medizinische Hochschule Hannover, Abteilung Hamatologie
  • Heilbronn, Germany, 74078
    • SLK-Kliniken Heilbronn GmbH, Medizinische Klinik
  • Kiel, Germany, 24116
    • Staedtisches Krankenhaus Kiel GmbH, Infektionsambulanz der 2. Medizinischen Klinik
  • Leipzig, Germany, 04129
    • Klinikum St. Georg gGmbH; Klinik fur Internistische Onkologie/Hamatologie
  • Muenster, Germany, 48149
    • University Hospital of Muenster
  • Munich, Germany, 81675
    • Klinikum rechts der Isar der Technischen Universitat Munchen lll, Medizinische Klinik
• Hungary
  • Debrecen, Hungary, H-4030
    • University of Debrecen Medical and Health Sciences Center
  • Gyor, Hungary, H-9024
    • Petz Aladar County Hospital
  • Kaposvar, Hungary, H-7400
    • kaposi Mor Oktato Korhaz Belgyogyaszati Osztaly
  • Szeged, Hungary, H-6720
    • Szegedi Tudomanyegyetem, 11. Belgyogyaszati Klinika
• Italy
  • Brindisi, Italy, 72100
    • Ospedale "A. Perrino", U.O. Compessa di Ematologia
  • Ferrara, Italy, 44121
    • Azienda Ospedaliero-Universitaria Sant'Anna, Sezione di Ematologia, Dipartmento di Science Biomediche e Terapie Avanzate
  • Genova, Italy, 16132
    • Ospedaliera Universitaria San Martino di Genova
  • Lecce, Italy, 73100
    • Ospedale "Vito Fazzi", U.O Ematologia
  • Napoli, Italy, 80131
    • AORN "A. Cardarelli", U.O.S.C. Ematologia con TMO
  • Novara, Italy, 28100
    • Azienda Ospedaliero-Universitaria Maggiore Della Carita, Struttura Complessa Direzione Universitaria Ematologia
  • Pavia, Italy, 27100
    • Fondazione IRCCS, Policlinico S. Matteo - Dipartimento di Ematologia
• Korea, Republic of
  • Seoul, Korea, Republic of, 110-744
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 137-701
    • Seoul St. Mary's Hospital
  • Seoul, Korea, Republic of, 135-710
    • Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine
  • Seoul, Korea, Republic of, 138-736
    • Dept. of Hematology, Asan Medical Center
• New Zealand
  • Christchurch, New Zealand, 8011
    • Canterbury Health Laboratories
  • Hamilton, New Zealand, 3240
    • Department of Haematology, Waikato Hospital
  • Palmerston North, New Zealand, 4414
    • Regional Cancer Treatment Service, Palmerston North Hospital
  • Auckland
    • Grafton, Auckland, New Zealand, 1023
      • Haematology Research, Auckland District Health Board, Auckland City Hospital
• Poland
  • Gdansk, Poland, 80-952
    • Uniwersyteckle Centrum Kliniczne
  • Poznan, Poland, 60-569
    • Klinika Hematologii i Chorob Rozrostowych Ukladu Krwiotworczego, Szpital Kliniczny Przemiemienia Panskiego Uniwersytetu Medycznego im. Karola Marcinkowskiego w Poznaniu
  • Wroclaw, Poland, 50-369
    • Samodzielny Publiczny Szpital Kliniczny Nr 1 we Wroclawiu
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d'Hebron
  • Barcelona, Spain, 08025
    • Hospital de la Santa Creu I Sant Pau
  • Barcelona, Spain
    • Hospital del Mar
  • Barcelona, Spain, 08916
    • Hospital Universitari Germans Trias i Pujol
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Madrid, Spain, 28033
    • Centro Oncologico MD Anderson International Espana
  • Palma de Mallorca, Spain, 07198
    • Hospital Sont Llatzer
  • Salamanca, Spain, 37007
    • Hospital Universitario de Salamanca
  • Valencia, Spain, 46026
    • Hospital Universitari Politecnic la Fe Hematology Department
• United Kingdom
  • Blackpool, United Kingdom, FY3 8NR
    • Blackpool Victoria Hospital, Blackpool Teaching Hospitals NHS Foundation Trust
  • Cambridge, United Kingdom, CB2 0QQ
    • Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital
  • Cardiff, United Kingdom, CF14 4XW
    • Department of Haematology, University Hospital of Wales
  • Cottingham, United Kingdom, GY16 5JQ
    • Queen's Centre for Oncology and Hematology, Castle Hill Hospital
  • Leicester, United Kingdom, LE1 5WW
    • Leicester Royal Infirmary, University Hospitals of Leicester, NHS Trust
  • Liverpool, United Kingdom, L7 8XP
    • Department of Haematology, Royal Liverpool University Hospital
  • London, United Kingdom, SE1 9RT
    • Department of Haematology, Guy's Hospital
  • Manchester, United Kingdom, M13 9WL
    • Central Manchester University Hospitals NHS Trust, Manchester Royal Infirmary
• United States
  • California
    • La Jolla, California, United States, 92093
      • Moores UCSD Cancer Center
    • Los Angeles, California, United States, 90095
      • UCLA Division of Hematology/Oncology
    • San Diego, California, United States, 92123
      • Sharp Clinical Oncology Research
    • San Francisco, California, United States, 94143
      • University of California San Francisco
  • Colorado
    • Denver, Colorado, United States, 80218
      • HCA HealthONE - Rocky Mountain Blood and Marrow Transplant Program
  • District of Columbia
    • Washington, District of Columbia, United States, 20037
      • George Washington University-Medical Faculty Associates
  • Florida
    • Fort Lauderdale, Florida, United States, 33308
      • Holy Cross Hospital
    • Jacksonville, Florida, United States, 32207
      • Baptist Cancer Institute
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center & Research Institute
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Georgia Health Sciences University
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center, Division of Hematology/Oncology
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Melvin and Bren Simon Cancer Center
    • 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
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Clinic Foundation
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
  • Missouri
    • Columbia, Missouri, United States, 65203
      • Ellis Fischel Cancer Center, University of Missouri Health Care
  • 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 Hackensack University Medical Center
  • New York
    • Lake Success, New York, United States, 11042
      • North Shore Long Island Jewish Health System
    • New York, New York, United States, 10065
      • Weill Cornell Medical College
    • New York, New York, United States, 100065
      • Memorial Sloan-Kettering Cancer Center
    • Stony Brook, New York, United States, 11794
      • Stony Brook University Medical Center
    • Valhalla, New York, United States, 10595
      • New York Medical College, Division of Oncology/Hematology
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Mecklenburg Medical Group
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health Sciences
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals fo Cleveland
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Tennessee
    • Memphis, Tennessee, United States, 38119
      • Family Cancer Center
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology, PLLC
    • Nashville, Tennessee, United States, 37232
      • Henry-Joyce Cancer Clinic
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern Medical Center at Dallas
    • Houston, Texas, United States, 77030
      • The University of Texas, M.D. Anderson Cancer Center, Department of Leukemia
    • San Antonio, Texas, United States, 78229
      • Cancer Care Centers of South Texas
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • Department of Medicine Section of Hematology/Oncology, West Virginia University Hospitals, Mary Babb Randolph Cancer Center, West Virginia University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Group A: vosaroxin + cytarabine; vosaroxin (short IV infusion within 10 minutes) on days 1 and 4: cytarabine on days 1 through 5; a maximum of 2 cycles of Induction and 2 cycles for Consolidation	Drug: vosaroxin + cytarabine; Vosaroxin days 1 and 4: 90 mg/m2 for induction 1; 70 mg/m2 for all other cycles Cytarabine 1 g/m2 daily on days 1-5 (IDAC)
PLACEBO_COMPARATOR: Group B: placebo + cytarabine; placebo (short IV infusion within 10 minutes and volume matched to vosaroxin) on days 1 and 4: cytarabine on days 1 through 5; a maximum of 2 cycles of Induction and 2 cycles for Consolidation	Drug: placebo + cytarabine; Placebo days 1 and 4: volume matched to vosaroxin Cytarabine 1 g/m2 daily on days 1-5 (IDAC); Other Names: control

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Vosaroxin + cytarabine patient survival versus placebo + cytarabine patient survival	Up to 5 years or duration of study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Remission (CR) Rate Based on Modified International Working Group (IWG) Criteria.	Group A (Vosaroxin + cytarabine) patient CR as compared to Group B (placebo + cytarabine) patient CR. Complete remission (CR) is typically defined using IWG criteria as bone marrow blast count of less than 5% with adequate recovery of peripheral blood counts.	Up to 5 years or duration of study
All Cause Mortality	Vosaroxin + cytarabine mortality versus placebo + cytarabine mortality	30 Days
All Cause Mortality	Vosaroxin + cytarabine mortality versus placebo + cytarabine mortality	60 Days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Remission (OR) Rate Based on the IWG Response Criteria	Group A patient OR compared to Group B patient OR Overall Remission includes Complete Remission (CR), Complete Remission with incomplete platelet recovery (CRp), Complete Remission with incomplete blood count recovery (CRi), and Partial Remission (PR). Complete remission means bone marrow blast count of less than 5% with adequate recovery of peripheral blood counts as typically defined by the IWG. Both CRi and CRp refer complete remission but with incomplete blood count and platelet recovery, respectively. PR, or partial remission, refers to remission in which bone marrow contains blast counts between 5 and 25 percent.	Up to 5 years or the duration of the study
Event Free Survival (EFS)		Up to 5 years or duration of study
Leukemia-Free Survival (LFS)	Durability of remission (CR) assessed by LFS	Up to 5 years or the duration of the study

Collaborators and Investigators

• Sponsor: Sunesis Pharmaceuticals
• Investigators: Study Director: Linda Neuman, MD, Sunesis Pharmaceuticals

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: December 17, 2010
• Primary Completion (ACTUAL): September 26, 2014
• Study Completion (ACTUAL): March 1, 2017

Study Registration Dates

• First Submitted: August 27, 2010
• First Submitted That Met QC Criteria: August 30, 2010
• First Posted (ESTIMATE): August 31, 2010

Study Record Updates

• Last Update Posted (ACTUAL): August 22, 2018
• Last Update Submitted That Met QC Criteria: July 25, 2018
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: Cancer; Acute Myeloid Leukemia; Leukemia; Cytarabine; Blood; Malignancy; Hematologic; Vosaroxin; Refractory AML; Hematologic diseases; SNS-595; Sunesis; First Relapsed AML; VALOR; Voreloxin
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Cytarabine
• Other Study ID Numbers: VOS-AML-301; 2010-021961-61 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified data of individual participants experiencing Serious Adverse Events