Safety and Efficacy of Marqibo in Relapsed Acute Lymphoblastic Leukemia
Condition: Acute Lymphoblastic Leukemia (ALL)
MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid
Intervention: Marqibo® (vincristine sulfate liposomes injection)
Intervention description: Dosing was done every 7 days (± 3 days) on Days 1, 8, 15, and 22 with no less than 4 days between dosing days. Dose calculations were based on body surface area using the subject's height (from Screening) and actual weight for each course.
Intervention MeSH terms: Vincristine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 65.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: acute; lymphoblastic; lymphocytic; leukemia; leukaemia; lukemia; leukimia; ALL; Marqibo; Hana Biosciences; vincristine; liposomal; liposome; optisome; hematology; malignancy; hematological; relapsed; anti-leukemia; adult; chemotherapy

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.
    

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.