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

Lymphoblastic Leukemia, Acute, Childhood Clinical Trial

Official title:

A Pilot Study of Vincristine Sulfate Liposome Injection (Marqibo®) in Combination With UK ALL R3 Induction Chemotherapy for Children, Adolescents, and Young Adults With Relapse of Acute Lymphoblastic Leukemia

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02879643
• Other study ID #: T2012-002
• Status: Recruiting
• Phase: Phase 1
• Start date: January 31, 2017
• Est. completion date: December 31, 2022

Study information

• Verified date: April 2020
• Source: Therapeutic Advances in Childhood Leukemia Consortium
• Contact: Ellynore Florendo
• Phone: (323) 361- 3022
• Email: eflorendo[@]chla.usc.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

Description:

This study will utilize Marqibo® as a replacement for standard vincristine in combination with chemotherapy for children with relapsed ALL. The hypothesis is that the incorporation of Marqibo® with combination chemotherapy will be safe and feasible. In the context of this pilot study, overall outcomes and efficacy will be a secondary objective. It is hypothesized that data from this combination may show improved efficacy including, complete remission (CR), minimal residual disease (MRD) negativity, and progression free survival (PFS) rates and safety (i.e., neurotoxicity) in comparison to outcomes in historical regimens, including the UK ALL R3 with standard vincristine.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 36
• Est. completion date: December 31, 2022
• Est. primary completion date: August 31, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year to 21 Years

Eligibility

Inclusion Criteria

Age

-Patients must be = 1 and = 21 years of age at the time of enrollment.

Diagnosis

• Cohort A: Patients must have a diagnosis of acute lymphoblastic leukemia (ALL) or mixed phenotypic acute leukemia with = 5% blasts in the bone marrow (M2 or M3), with or without extramedullary disease) or a diagnosis of lymphoblastic lymphoma.

• Cohorts B & C: Patients must have a diagnosis of acute lymphoblastic leukemia (ALL), lymphoblastic lymphoma, or mixed phenotypic acute leukemia with any level of detectable disease (minimal residual disease level acceptable) with or without extramedullary disease

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

Prior Therapy

• 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.

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

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

• 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.

• 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.

1. Cohort A: Patients must have less than 320 mg/m2 (or 400 mg/m2 if prior cardioprotection) lifetime exposure of anthracycline chemotherapy (See Appendix 2 for anthracycline calculation worksheet).

2. Cohorts B & C: There is no limit on prior anthracycline exposure.

• 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®).

• 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.

• 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)

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

• Recent prior chemotherapy: At least 10 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:

• 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, may substitute for the day 1 IT in cohorts A and B

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

• 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 10 days after any dose of standard vincristine.

Renal and Hepatic Function

• 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.

• Hepatic function: alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must be < 5 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

• 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.

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

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

Exclusion Criteria

Patients will be excluded if they have isolated testicular disease.

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 asparaginase are eligible. Patients unable to receive any formulation of asparaginase may only enroll on cohort C

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, 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 with Down syndrome will not be eligible for enrollment on Cohort A

Patients with a known history of human immunodeficiency virus (HIV) will 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).

Related Conditions & MeSH terms

• Acute Disease
• ALL, Childhood
• Leukemia
• Leukemia, Lymphoid
• Lymphoblastic Leukemia, Acute
• Lymphoblastic Leukemia, Acute, Childhood
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Drug:
• Marqibo
The focus of the study design and statistical analysis is to determine whether Marqibo® can be substituted for standard vincristine and successfully administered to patients with relapsed ALL in three different treatment cohorts: (A) treatment with the UK ALL R3 regimen; (B) treatment with UK ALL R3 regimen without mitoxantrone, and (C) treatment with ALL maintenance therapy. Secondary objectives include estimating rates of serious toxicities and therapy delays in each of these cohorts.

Locations

Country	Name	City	State
Australia	Royal Children's Hospital, Melbourne	Parkville,	Victoria
Australia	Sydney Children's Hospital	Randwick	New South Wales
Australia	Lady Cilento Children's Hospital	South Brisbane	Queensland
Australia	The Children's Hospital at Westmead	Westmead	New South Wales
Canada	Sainte-Justine University Hospital Center	Montréal, Québec
Canada	Hospital for Sick Children	Toronto	Ontario
Canada	British Columbia Children's Hospital	Vancouver	British Columbia
United States	CS Mott Children's Hospital, Ann Arbor	Ann Arbor	Michigan
United States	Children's Healthcare of Atlanta at Egleston	Atlanta	Georgia
United States	The Children's Hospital, University of Colorado	Aurora	Colorado
United States	Sidney Kimmel Cancer Center at Johns Hopkins	Baltimore	Maryland
United States	National Cancer Institute, Pediatric Oncology Branch	Bethesda	Maryland
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Levine Children's Hospital	Charlotte	North Carolina
United States	Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	Cincinnati Children's Hospital	Cincinnati	Ohio
United States	Rainbow Babies & Children's Hospital	Cleveland	Ohio
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Cook Children's Medical Center	Fort Worth	Texas
United States	Texas Children's Cancer Center, Baylor	Houston	Texas
United States	Childrens Hospital Los Angeles	Los Angeles	California
United States	University of Miami	Miami	Florida
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Children's Hospitals and Clinics of Minnesota	Minneapolis	Minnesota
United States	Monroe Carell Jr. Children's Hospital at Vanderbilt	Nashville	Tennessee
United States	Children's Hospital New York-Presbyterian	New York	New York
United States	Children's Hospital Orange County	Orange	California
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Oregon Health & Science University	Portland	Oregon
United States	All Children's Hospital	Saint Petersburg	Florida
United States	Primary Children's Hospital	Salt Lake City	Utah
United States	UCSF School of Medicine	San Francisco	California
United States	Seattle Children's Hospital	Seattle	Washington
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
Therapeutic Advances in Childhood Leukemia Consortium	Spectrum Pharmaceuticals, Inc

Countries where clinical trial is conducted

United States,  Australia,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants with Dose Limiting Toxicities as a Measure of Safety and Tolerability	The incidence of dose limiting toxicity (DLT) will be measured at different dose levels.	5 weeks
Secondary	The response rate after treatment.	The rate of remission will be assessed after 1 courses of therapy. A bone marrow aspirate/biopsy and CBC will be conducted to assess response.	Approx. 8 weeks