Safety and Efficacy of Marqibo in Relapsed Acute Lymphoblastic Leukemia

• Complete Remission Plus Complete Remission Without Full Platelet Recovery (CR + CRi) [ Time Frame: Response assessment performed at the end of each 28 day course. ] [ Designated as safety issue: No ]
  CR is defined as no evidence of ALL: ANC>or=1x10^9/L or platelet count>100x10^9/L, absence of leukemia blast cells in blood and marrow (<5% blasts), resolution of all sites of extramedullary disease (EMD). CR with incomplete blood count recovery (CRi): As per CR but platelet count< 100x10^9/L or ANC< 1x10^9/L. Partial remission(PR):CR with>5-25% abnormal cells in the marrow or 50% decrease in bone marrow blasts. Reduction in EMD by at least 50%. Hematologic Improvement. Bone marrow blast(BMB) response: BMB<5% in the absence of HI. Stable disease(SD):No significant hematological and extramedullary change from baseline.
• Clinical Response Assessment Per Independent Response Review Committee (IRRC) Evaluation [ Time Frame: Response assessment at the end of each 28 days course ] [ Designated as safety issue: No ]
  Number of subjects who achieved Complete Remission (CR)as assessed by the IRRC. CR is defined as no evidence of ALL. ANC>=1X10^9/L or Platelet count>=100x10^9/L, absence of blasts in blood and morrow (<5%), resolution of all sites of extramedullary disease (EMD). CR with incomplete blood count recovery(CRi)is defined as per CR but platelet count <100x10^9/L or ANC<1x10^9/L.

• Duration of CR + CRi [ Time Frame: CR + CRi duration was calculated from the date the subject first met the definition of CR or CRi until the date of relapse ] [ Designated as safety issue: No ]
  Duration of response for those subjects who achieved CR or CRi
• Overall Survival [ Time Frame: unlimited ] [ Designated as safety issue: No ]
  Time, in days, from informed consent date until the date of death or date of last contact

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.

The secondary objectives of this study were to evaluate:

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

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.