Vincristine Sulfate Liposome Injection (Marqibo®) in Combination With UK ALL R3 Induction Chemotherapy for Children, Adolescents, and Young Adults With Relapsed ALL

Status: Recruiting
Phase: Phase 1
DFCI Protocol ID: 16-568

This is a pilot study utilizing Marqibo® (vincristine sulfate liposome injection) combined with dexamethasone, mitoxantrone and asparaginase (UK ALL R3) for relapsed acute lymphoblastic leukemia (ALL).

Conducting Institutions:

Dana-Farber Cancer Institute, Children's Hospital Boston

Overall PI:

Andrew Place, MD, PhD, Dana Farber Cancer Institute

Site-responsible Investigators:

Contacts:

Dana-Farber Cancer Institute: Childrens Hospital Pediatric Clinical Translation Investigation Program CTIP, ctip@partners.org

Eligibility Criteria

Inclusion Eligibility Criteria

Age Patients must be ≥ 1 and ≤ 21 years of age at the time of enrollment.

Diagnosis Patients must have a diagnosis of acute lymphoblastic leukemia (ALL) with ≥ 5%
blasts in the bone marrow (M2 or M3), with or without extramedullary disease (excluding
active Central Nervous System 3 involvement).

Subjects with first relapse must have an M3 marrow to be eligible.

Performance Level Karnofsky > 50% for patients > 16 years of age and Lansky > 50% for
patients ≤ 16 years of age.

Prior Therapy

  1. Patients must have recovered from the acute toxic effects (≤ Grade 2 or baseline) of
     all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study,
     unless otherwise specified. Subjects with disease related cytopenias will be
     eligible.

  2. Patients must have relapsed disease after attaining at least a first remission. They
     may be in first to third relapse.

  3. Patients with Philadelphia chromosome t(9;22) positive disease must have received at
     least two prior tyrosine kinase inhibitors.

  4. Patients who have experienced their relapse after a Hematopoietic stem cell
     transplantation (HSCT) are eligible, provided they have no evidence of
     graft-versus-host disease (GVHD) and are at least 100 days post-transplant at the
     time of enrollment.

  5. Prior anthracycline lifetime cumulative exposure: Patients must have less than 320
     mg/m2 (or 400 mg/m2 if prior cardioprotection) lifetime exposure of anthracycline
     chemotherapy.

  6. Hematopoietic growth factors: It must have been at least seven days since the
     completion of therapy with granulocyte colony-stimulating factor (GCSF) or other
     growth factors at the time of enrollment. It must have been at least 14 days since
     the completion of therapy with pegfilgrastim (Neulasta®).

  7. Biologic anti-neoplastic agents: At least seven days after the last dose of a
     biologic agent. For agents that have known adverse events occurring beyond seven days
     after administration, this period must be extended beyond the time during which
     adverse events are known to occur. The duration of this interval must be discussed
     with the study chair or vice chair.

  8. Monoclonal antibodies: At least three half-lives (or 30 days—whichever is longer) of
     the antibody must have elapsed after the last dose of monoclonal antibody. (e.g.,
     Rituximab = 66 days, Epratuzumab = 69 days)

  9. Immunotherapy: At least 30 days after the completion of any type of immunotherapy,
     e.g. tumor vaccines, chimeric antigen receptor T-cells.

 10. Recent prior chemotherapy: At least 14 days after standard vincristine and the
     completion of any type of chemotherapy induction regimen. At least 3 weeks after
     radiation therapy. At least 30 days after the completion of any investigational
     neoplastic agent is also required. An investigational agent is defined as any drug
     that is not approved and licensed for sale by the FDA for institutions in the United
     States, by Health Canada for institutions in Canada and by The Therapeutic Goods
     Administration for institutions in Australia.

Exceptions:

  1. There is no time restriction in regard to prior intrathecal chemotherapy provided
     there is complete recovery from any acute toxic effects of such; it is allowable to
     enroll a patient that has received IT Cytarabine (ARA-C), IT Methotrexate (MTX) or
     triple IT therapy within 14 days of enrollment as part of their evaluation to
     diagnose disease relapse. The IT therapy given within 14 days of initiation of
     protocol specified chemotherapy, will substitute for the day 1 IT.

  2. Subjects with rapidly progressive disease may receive hydroxyurea until they begin
     study therapy;

  3. Patients who relapse while on maintenance-type ALL therapy or are receiving
     maintenance therapy for disease stabilization will not require a wash-out period
     before entry into this study. However, there must be at least 14 days after any dose
     of standard vincristine.

Renal and Hepatic Function

  1. Renal function: Patient's serum creatinine must be ≤ 1.5 x institutional upper limit
     of normal (ULN) according to age. If the serum creatinine is greater than 1.5 times
     normal, the patient must have a calculated creatinine clearance or radioisotope
     glomerular filtration rate (GFR) ≥ 70milliliter/min/1.73m2. Alternatively, a 24-hour
     creatinine clearance may also be used.

  2. Hepatic function: alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
     must be < 3 x institutional upper limit of norm ULN. Total bilirubin must be ≤ 1.5 x
     ULN (except in the case of subjects with documented Gilbert's disease ≤ 5 × ULN).

Cardiac Function Patients must have a shortening fraction ≥ 27% or an ejection fraction ≥
55% by echocardiogram, cardiac MRI or multigated acquisition scan (MUGA).

Reproductive Function

  1. Female patients must not be pregnant and those of childbearing potential must have a
     negative urine or serum pregnancy test confirmed within one week prior to enrollment.

  2. Female patients with infants must agree not to breastfeed their infants while on this
     study.

  3. Male and female patients of childbearing potential must agree to use an effective
     method of contraception during the study.

Exclusion Eligibility Criteria

Patients will be excluded if they have active Central Nervous System (CNS) 3 status.

Patients will be excluded if they have isolated testicular disease.

Patients with biphenotypic leukemia will be excluded.

Patients will be excluded if they have refractory disease or fourth relapse and beyond,
defined as any of the following:

  1. Patients with four or more prior induction attempts,

  2. Refractory disease after first or greater relapse and a re-induction attempt,

  3. Failing to go into remission from original diagnosis after two previous induction
     attempts.

Patients will be excluded if they have previously received Marqibo®.

Patients will be excluded if they have a known allergy to any of the drugs used in the
study, with the exception that patients with an allergy to PEG-asparaginase who can
receive Erwinia are eligible.

Patients will be excluded if they have active, uncontrolled systemic fungal, bacterial,
viral or other infection despite appropriate antibiotics or other treatment.

Patients who require azole antifungal agents will be excluded. Azoles must be discontinued
at least one week prior to the start of Marqibo®.

Patients will be excluded if there is a plan to administer non-protocol chemotherapy,
radiation therapy, another investigational agent or immunotherapy during the study period.

Patients with pre-existing, persistent grade 2 or greater sensory or motor neuropathy from
any cause will be excluded.

Patients will be excluded if they have Down syndrome, significant concurrent disease,
illness, psychiatric disorder or social issue that would compromise patient safety or
adherence with the protocol treatment or procedures or interfere with consent, study
participation, follow up, or interpretation of study results.

Patients positive for human immunodeficiency virus (HIV) will be excluded due to the
increased risk of complications such as severe infection and unknown interaction of
Marqibo® with antiretroviral drugs.

Active hepatitis B or C infection as defined by seropositive for hepatitis B (hepatitis B
surface antigen (HBsAg)) or hepatitis C and elevated liver transaminases (defined as above
the ULN per the institution normal ranges).

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