Clinical trial NCT00495079: Safety and Efficacy of Marqibo in Relapsed Acute Lymphoblastic Leukemia
Official title: A Phase 2 Study to Evaluate the Safety and Efficacy of Weekly Doses of Marqibo® (Vincristine Sulfate Liposomes Injection) in Adult Patients With Philadelphia Chromosome-negative Acute Lymphoblastic Leukemia (ALL) in Second Relapse or Adult Patients With Philadelphia Chromosome-negative ALL Who Failed Two Treatment Lines of Anti-leukemia Chemotherapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Lymphoblastic Leukemia (ALL)
Keywords: acute
lymphoblastic
lymphocytic
leukemia
leukaemia
lukemia
leukimia
ALL
Marqibo
Hana Biosciences
vincristine
liposomal
liposome
optisome
hematology
malignancy
hematological
relapsed
anti-leukemia
adult
chemotherapy
Lead sponsor: Spectrum Pharmaceuticals, Inc
Sponsor class: INDUSTRY
Collaborators: name: Parexel
First posted: 2007-07-02
Enrollment: 65
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This was a Phase 2, international, multicenter, open-label, single-arm trial evaluating Marqibo (VSLI) in adult subjects with: 1) Ph- ALL or lymphoblastic lymphoma in second or greater relapse; or 2) Ph- ALL or lymphoblastic lymphoma who failed 2 or greater treatment lines of anti-leukemia chemotherapy. The original enrollment target for this study was approximately 56 subjects. Per a protocol amendment, enrollment was increased from 56 to 65.

The primary objective of this study was to evaluate:

- The efficacy of the study treatment as determined by the rate of CR plus CR with incomplete blood count recovery (CRi) in adult subjects with Philadelphia chromosome-negative (Ph-) ALL in second relapse or adult subjects with (Ph-) ALL who failed 2 treatment lines of anti-leukemia chemotherapy. Subjects must have achieved a CR to at least 1 prior anti-leukemia therapy as defined by a leukemia-free interval of ≥ 90 days.

Detailed description: The secondary objectives of this study were to evaluate:

* Duration of CR plus CRi
* Overall survival
* Safety and tolerability

Eligibility criteria: Inclusion Criteria:

* Age ≥18 years.
* Had Ph- ALL or lymphoblastic lymphoma and was in second relapse, or had failed 2 treatment lines of anti-leukemia chemotherapy.
* Had histologically or cytologically proven ALL and ≥ 10% bone marrow blasts. If \< 10% bone marrow blasts, subject must have had histologically or cytologically proven ALL and evaluable extramedullary disease. Sponsor approval was obtained prior to enrolling subjects who had \< 10% bone marrow blasts with evaluable extramedullary disease.
* Had achieved a CR to at least 1 prior anti-leukemia therapy as defined by a leukemia-free interval of ≥ 90 days.
* For subjects with a prior history of stem cell transplantation, had ≤ Grade 1 active skin graft-versus-host disease (GVHD). No active gastrointestinal or liver graft-versus-host disease.
* Had an Eastern Cooperative Oncology Group (ECOG) performance status 0 to 3.
* Had normal renal and liver function as defined below within 14 days, inclusive, prior to first dose of VSLI, unless the abnormality was considered attributable to leukemia:
* Total bilirubin ≤ 2.0 × institutional upper limit of normal, unless the subject had a known diagnosis of Gilbert's disease. If a subject had Gilbert's disease, he/she could have participated in this study, however must have been monitored closely during the study.
* Aspartate transaminase (AST) or alanine transaminase (ALT) ≤ 3 × institutional upper limit of normal.
* Serum creatinine ≤ 2.0 g/dL or calculated estimated creatinine clearance ≥ 50 mL/minute/1.73 m2 based on Cockcroft and Gault formula, unless renal dysfunction was considered due to hematologic malignancy.
* Had never received prior VSLI treatment.
* For women of childbearing potential, had a negative serum or urine pregnancy test within 14 days prior to enrollment.
* If female, the subject was postmenopausal, surgically sterilized, or willing to use acceptable methods of birth control (e.g., hormonal contraceptive, intra-uterine device, diaphragm with spermicide, and condom with spermicide or abstinence) from the Screening visit through 30 days after the last dose of VSLI.
* If male, the subject agreed to use an acceptable barrier method for contraception from the Screening visit through 30 days after the last dose of VSLI.
* Before enrollment, the subject was capable of understanding and complying with parameters as outlined in the protocol and able to sign a written informed consent according to ICH/GCP and national/local regulations.

Exclusion Criteria:

* Had Burkitt's lymphoma or Burkitt's leukemia.
* Had a history of Philadelphia chromosome-positive (Ph+) ALL and/or BCR/ABL rearrangements documented by fluorescent in situ hybridization or polymerase chain reaction.
* Had a history of Philadelphia chromosome-positive (Ph+) ALL and/or BCR/ABL rearrangements documented by fluorescent in situ hybridization or polymerase chain reaction.
* Had active CNS disease. History of treated CNS disease was allowable. The CNS disease must have resolved in order for the subject to be eligible.
* Was eligible for stem cell transplantation. This implied that a suitable donor was readily available, the subject was willing to undergo stem cell transplantation, and the Investigator believed this was a better treatment option than VSLI. This was at the Investigator's discretion.
* Was treated with any investigational agents or chemotherapy agents in the last 21 days before the first dose of VSLI, unless full recovery from side effects had occurred or the subject had rapidly progressing disease judged to be life threatening by the Investigator.
* Was receiving any other standard or investigational treatment for the subject's leukemia.
* Intrathecal chemotherapy for CNS prophylaxis was allowable.
* The use of hydroxyurea (Hydrea®) to control leukocytosis was allowable but must have been tapered off by Day 14 of Course 1. From Day 15 of Course 1 on through the end of study participation, hydroxyurea (Hydrea®) was not allowed.
* Systemic corticosteroids must have been tapered off, preferably before the start of study treatment, but no later than by Day 5 of Course 1. From Day 6 of Course 1 on through the end of study participation, systemic corticosteroids were not allowed.
* Had persistent chronic clinically significant toxicities from prior chemotherapy ≥ Grade 2 (National Cancer Institute \[NCI\] Common Terminology Criteria for Adverse Events \[CTCAE\] version 3.0).
* Had persistent ≥ Grade 2 active neuropathy (NCI CTCAE v3.0).
* Had a history of persistent ≥ Grade 2 active neurologic disorders unrelated to chemotherapy (including demyelinating form of Charcot-Marie-Tooth syndrome, acquired demyelinating disorders, or other demyelinating condition).
* Had a history of allergic reactions or sensitivity attributed to compounds of similar chemical or biologic composition to vincristine or components of study drug.
* Was female who was pregnant or breast-feeding.
* Had active serious infection not controlled by oral or intravenous antibiotics or antifungals.
* Had human immunodeficiency virus positive status.
* Had any medical condition which in the opinion of the investigator placed the subject at an unacceptably high risk for toxicities.
* Had any condition or circumstance which in the opinion of the investigator would significantly interfere with the subject's protocol compliance and put the subject at increased risk.

Primary outcomes:
measure: Complete Remission Plus Complete Remission Without Full Platelet Recovery (CR + CRi)
timeFrame: Response assessment performed at the end of each 28 day course.
measure: Clinical Response Assessment Per Independent Response Review Committee (IRRC) Evaluation
timeFrame: Response assessment at the end of each 28 days course
Secondary outcomes:
measure: Duration of CR + CRi
timeFrame: CR + CRi duration was calculated from the date the subject first met the definition of CR or CRi until the date of relapse
measure: Overall Survival
timeFrame: unlimited
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: USC - Norris Cancer Center
state: California
city: Los Angeles
country: United States
facility: UCLA Medical Center
state: California
city: San Francisco
country: United States
facility: University of California Medical Center
state: California
city: Stanford
country: United States
facility: Stanford Hospitals and Clinics
state: California
city: Denver
country: United States
facility: Rocky Mountain Cancer Center
state: Colorado
city: Atlanta
country: United States
facility: Emory University - Winship Cancer Institute
state: Georgia
city: Chicago
country: United States
facility: Loyola University Medical Center
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: Iowa City
country: United States
facility: Univesity of Iowa - Hospitals and Clinica
state: Iowa
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Valhalla
country: United States
facility: New York Medical College
state: New York
city: Pittsburgh
country: United States
facility: Western Pennsylvania Allegheny Health System
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Houston
country: United States
facility: University of Texas M.D. Anderson Cancer Center
state: Texas
city: Toronto
country: Canada
facility: Princess Margaret Hospital
state: Ontario
city: Dresden
country: Germany
facility: Dresden University Hospital
city: Essen
country: Germany
facility: University of Essen
city: Frankfurt
country: Germany
facility: J.W. Goethe University
city: Leipzig
country: Germany
facility: University of Leipzig
city: Muenster
country: Germany
facility: University of Muenster
city: Rostock
country: Germany
facility: University of Rostock
city: Stuttgart
country: Germany
facility: Diakonie-Klinikum Stuttgart
city: Stuttgart
country: Germany
facility: Robert Bosch Hospital
city: Ulm
country: Germany
facility: University of Ulm
city: Haifa
country: Israel
facility: Rambam Medical Center
city: Jerusalem
country: Israel
facility: Hadassah Medical Center - Ein Karem
city: Petah-Tikva
country: Israel
facility: Rabin Medical Center Campus
city: Tel Hashomer
country: Israel
facility: The Chaim Sheba Medical Center
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
Study officials:
affiliation: M.D. Anderson Cancer Center
name: Susan O'Brien, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Schiller GJ, Damon LE, Coutre SE, Hsu P, Bhat G, Douer D. High-Dose Vincristine Sulfate Liposome Injection, for Advanced, Relapsed, or Refractory Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia in an Adolescent and Young Adult Subgroup of a Phase 2 Clinical Trial. J Adolesc Young Adult Oncol. 2018 Oct;7(5):546-552. doi: 10.1089/jayao.2018.0041. Epub 2018 Sep 21.
citation: Silverman JA, Reynolds L, Deitcher SR. Pharmacokinetics and pharmacodynamics of vincristine sulfate liposome injection (VSLI) in adults with acute lymphoblastic leukemia. J Clin Pharmacol. 2013 Nov;53(11):1139-45. doi: 10.1002/jcph.155. Epub 2013 Aug 17.
citation: O'Brien S, Schiller G, Lister J, Damon L, Goldberg S, Aulitzky W, Ben-Yehuda D, Stock W, Coutre S, Douer D, Heffner LT, Larson M, Seiter K, Smith S, Assouline S, Kuriakose P, Maness L, Nagler A, Rowe J, Schaich M, Shpilberg O, Yee K, Schmieder G, Silverman JA, Thomas D, Deitcher SR, Kantarjian H. High-dose vincristine sulfate liposome injection for advanced, relapsed, and refractory adult Philadelphia chromosome-negative acute lymphoblastic leukemia. J Clin Oncol. 2013 Feb 20;31(6):676-83. doi: 10.1200/JCO.2012.46.2309. Epub 2012 Nov 19.