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

Acute Myeloid Leukemia Clinical Trial

— VALOR  

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01191801
• Other study ID #: VOS-AML-301
• Secondary ID: 2010-021961-61
• Status: Completed
• Phase: Phase 3
• Start date: December 17, 2010
• Est. completion date: March 1, 2017

Study information

• Verified date: March 2017
• Source: Sunesis Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 711
• Est. completion date: March 1, 2017
• Est. primary completion date: September 26, 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

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 + cytarabine
Placebo days 1 and 4: volume matched to vosaroxin Cytarabine 1 g/m2 daily on days 1-5 (IDAC)

Locations

Country	Name	City	State
Australia	Haematology and Bone Marrow Transplant Unit, Royal Adelaide Hospital	Adelaide	South Australia
Australia	Flinders Medical Centre	Bedford Park	South Australia
Australia	Royal Brisbane and Women's Hospital	Brisbane	Queensland
Australia	Concord Repatriation General Hospital	Concord	New South Wales
Australia	The Canberra Hospital	Garran	Australian Capital Territory
Australia	Andrew Love Cancer Center, Geelong Hospital, Barwon Health	Geelong	Victoria
Australia	Haematology Department, Gosford Hospital	Gosford	New South Wales
Australia	The Alfred Hospital	Melbourne	Victoria
Australia	Department of Clinical Haematology and BMT Service, Royal Melbourne Hospital	Parkville	Victoria
Australia	Royal Perth Hospital	Perth	Western Australia
Australia	Westmead Hospital	Westmead	New South Wales
Austria	Universitatsklinik Graz, Universitatsklinik fur Innere Medizin, Abteilung fur Hamatologie	Graz
Austria	University Hospital for Internal Medicine V, Innsbruck Medical University	Innsbruck
Austria	Landeskrankenhaus Salzburg, Universitaetsklinik fur innere Medizin lll, Universitaetsklinikum der PMU	Salzburg
Austria	AKH Wien / MedUniWien Universtatsklinik fur Innere Medizin 1	Wien
Belgium	ZNA Middleheim Lindendreef 1	Antwerpen
Belgium	ZNA Stuivenberg, Lange Beeldekensstraat 267	Antwerpen
Belgium	AZ St.-Jan Brugge-Oostende AV	Brugge
Belgium	Cliniques Universitaires Saint Luc	Brussels
Belgium	UZ Leuven, campus Gasthuisberg, Department of Haematology	Leuven
Belgium	H.-Hartziekenhuis Roeselare - Menen vzw	Roeselare
Canada	Charles LeMoyne Hospital	Greenfield Park	Quebec
Canada	Queen Elizabeth II Health Sciences Centre	Halifax	Nova Scotia
Canada	Saint John Regional Hospital	Saint John	New Brunswick
Canada	University Health Network, Princess Margaret Hospital	Toronto	Ontario
Canada	Division of Hematology, Vancouver General Hospital	Vancouver	British Columbia
Czechia	Fakultni nemocnice Brno, Interni hematoonkologicka klinika	Brno
Czechia	Fakultni nemocnice Hradec Kralove, 2. Interni klinika-oddeleni klinicke hematologie	Hradec Kralove
Czechia	Fakultni nemocnice Kralovske Vinohrady, Oddeleni klinicke hematologie	Praha	Srobarova
France	CHU Angers, Service des maladies du sang	Angers Cedex 01
France	Hopital Avicenne- Departement Onco-hematologie	Bobigny
France	Hopital Mignot	Le Chesnay
France	CHU Lille, Service des maladies du sang, Hopital Huriez	Lille	Lille Cedex
France	Institut Paoli Calmettes	Marseille
France	CHU Nantes Hotel Dieu, Service d'hematologie clinique	Nantes
France	CHU de Bordeaux- Hopital Haut-Leveque, Centre Francois Magendle	Pessac
France	Centre Hospitalier Lyon Sud - Service d'Hematologie - Pavillon Marcel Berard - Bat. 1G - 1er etage, 165 Chemin du grand Revoyet	Pierre Benite
France	Service d'hematologie- Hopital Purpan- CHU de Toulouse	Toulouse
Germany	St. Johannes-Hospital	Duisburg
Germany	Klinikum Frankfurt am Main-Hochst, Department of Hematology and Oncology, Klinikum Frankfurt Academic Hospital of the University of Frankfurt	Frankfurt
Germany	Universitatsklinikum Hamburg-Eppendorf; ll. Medizinische Klinik und Poliklinik; Onkologie, Hamatologie und Knochenmarktransplantation	Hamburg
Germany	Medizinische Hochschule Hannover, Abteilung Hamatologie	Hannover
Germany	SLK-Kliniken Heilbronn GmbH, Medizinische Klinik	Heilbronn
Germany	Staedtisches Krankenhaus Kiel GmbH, Infektionsambulanz der 2. Medizinischen Klinik	Kiel
Germany	Klinikum St. Georg gGmbH; Klinik fur Internistische Onkologie/Hamatologie	Leipzig
Germany	University Hospital of Muenster	Muenster
Germany	Klinikum rechts der Isar der Technischen Universitat Munchen lll, Medizinische Klinik	Munich
Hungary	University of Debrecen Medical and Health Sciences Center	Debrecen
Hungary	Petz Aladar County Hospital	Gyor
Hungary	kaposi Mor Oktato Korhaz Belgyogyaszati Osztaly	Kaposvar
Hungary	Szegedi Tudomanyegyetem, 11. Belgyogyaszati Klinika	Szeged
Italy	Ospedale "A. Perrino", U.O. Compessa di Ematologia	Brindisi
Italy	Azienda Ospedaliero-Universitaria Sant'Anna, Sezione di Ematologia, Dipartmento di Science Biomediche e Terapie Avanzate	Ferrara
Italy	Ospedaliera Universitaria San Martino di Genova	Genova
Italy	Ospedale "Vito Fazzi", U.O Ematologia	Lecce
Italy	AORN "A. Cardarelli", U.O.S.C. Ematologia con TMO	Napoli
Italy	Azienda Ospedaliero-Universitaria Maggiore Della Carita, Struttura Complessa Direzione Universitaria Ematologia	Novara
Italy	Fondazione IRCCS, Policlinico S. Matteo - Dipartimento di Ematologia	Pavia
Korea, Republic of	Dept. of Hematology, Asan Medical Center	Seoul
Korea, Republic of	Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Seoul St. Mary's Hospital	Seoul
New Zealand	Canterbury Health Laboratories	Christchurch
New Zealand	Haematology Research, Auckland District Health Board, Auckland City Hospital	Grafton	Auckland
New Zealand	Department of Haematology, Waikato Hospital	Hamilton
New Zealand	Regional Cancer Treatment Service, Palmerston North Hospital	Palmerston North
Poland	Uniwersyteckle Centrum Kliniczne	Gdansk
Poland	Klinika Hematologii i Chorob Rozrostowych Ukladu Krwiotworczego, Szpital Kliniczny Przemiemienia Panskiego Uniwersytetu Medycznego im. Karola Marcinkowskiego w Poznaniu	Poznan
Poland	Samodzielny Publiczny Szpital Kliniczny Nr 1 we Wroclawiu	Wroclaw
Spain	Hospital de la Santa Creu i Sant Pau	Barcelona
Spain	Hospital del Mar	Barcelona
Spain	Hospital Universitari Germans Trias i Pujol	Barcelona
Spain	Hospital Universitario Vall d'Hebron	Barcelona
Spain	Centro Oncologico MD Anderson International Espana	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Sont Llatzer	Palma de Mallorca
Spain	Hospital Universitario de Salamanca	Salamanca
Spain	Hospital Universitari Politecnic la Fe Hematology Department	Valencia
United Kingdom	Blackpool Victoria Hospital, Blackpool Teaching Hospitals NHS Foundation Trust	Blackpool
United Kingdom	Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital	Cambridge
United Kingdom	Department of Haematology, University Hospital of Wales	Cardiff
United Kingdom	Queen's Centre for Oncology and Hematology, Castle Hill Hospital	Cottingham
United Kingdom	Leicester Royal Infirmary, University Hospitals of Leicester, NHS Trust	Leicester
United Kingdom	Department of Haematology, Royal Liverpool University Hospital	Liverpool
United Kingdom	Department of Haematology, Guy's Hospital	London
United Kingdom	Central Manchester University Hospitals NHS Trust, Manchester Royal Infirmary	Manchester
United States	University of Michigan	Ann Arbor	Michigan
United States	Georgia Health Sciences University	Augusta	Georgia
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Mecklenburg Medical Group	Charlotte	North Carolina
United States	Rush University Medical Center, Division of Hematology/Oncology	Chicago	Illinois
United States	University of Chicago	Chicago	Illinois
United States	University Hospitals fo Cleveland	Cleveland	Ohio
United States	Ellis Fischel Cancer Center, University of Missouri Health Care	Columbia	Missouri
United States	UT Southwestern Medical Center at Dallas	Dallas	Texas
United States	HCA HealthONE - Rocky Mountain Blood and Marrow Transplant Program	Denver	Colorado
United States	Henry Ford Health System	Detroit	Michigan
United States	Duke University Medical Center	Durham	North Carolina
United States	Holy Cross Hospital	Fort Lauderdale	Florida
United States	John Theurer Cancer Center at Hackensack University Medical Center	Hackensack	New Jersey
United States	The University of Texas, M.D. Anderson Cancer Center, Department of Leukemia	Houston	Texas
United States	Indiana University Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	St. Francis Medical Group Oncology and Hematology Specialists	Indianapolis	Indiana
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	Baptist Cancer Institute	Jacksonville	Florida
United States	Moores UCSD Cancer Center	La Jolla	California
United States	North Shore Long Island Jewish Health System	Lake Success	New York
United States	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire
United States	UCLA Division of Hematology/Oncology	Los Angeles	California
United States	Family Cancer Center	Memphis	Tennessee
United States	Department of Medicine Section of Hematology/Oncology, West Virginia University Hospitals, Mary Babb Randolph Cancer Center, West Virginia University	Morgantown	West Virginia
United States	Henry-Joyce Cancer Clinic	Nashville	Tennessee
United States	Tennessee Oncology, PLLC	Nashville	Tennessee
United States	Ochsner Clinic Foundation	New Orleans	Louisiana
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	Weill Cornell Medical College	New York	New York
United States	Cancer Care Centers of South Texas	San Antonio	Texas
United States	Sharp Clinical Oncology Research	San Diego	California
United States	University of California San Francisco	San Francisco	California
United States	Stony Brook University Medical Center	Stony Brook	New York
United States	H. Lee Moffitt Cancer Center & Research Institute	Tampa	Florida
United States	New York Medical College, Division of Oncology/Hematology	Valhalla	New York
United States	George Washington University-Medical Faculty Associates	Washington	District of Columbia
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Sunesis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  Czechia,  France,  Germany,  Hungary,  Italy,  Korea, Republic of,  New Zealand,  Poland,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	Event Free Survival (EFS)		Up to 5 years or duration of study
Other	Leukemia-Free Survival (LFS)	Durability of remission (CR) assessed by LFS	Up to 5 years or the duration of the study
Primary	Overall Survival	Vosaroxin + cytarabine patient survival versus placebo + cytarabine patient survival	Up to 5 years or duration of study
Secondary	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
Secondary	All Cause Mortality	Vosaroxin + cytarabine mortality versus placebo + cytarabine mortality	30 Days
Secondary	All Cause Mortality	Vosaroxin + cytarabine mortality versus placebo + cytarabine mortality	60 Days