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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT03817320




Registration number
NCT03817320
Ethics application status
Date submitted
22/01/2019
Date registered
25/01/2019

Titles & IDs
Public title
PO Ixazomib in Combination With Chemotherapy for Childhood Relapsed or Refractory Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma
Scientific title
A TACL Phase 1/2 Study of PO Ixazomib in Combination With Chemotherapy for Childhood Relapsed or Refractory Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma IND# 140730
Secondary ID [1] 0 0
T2017-002
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
ALL, Childhood 0 0
Lymphoblastic Lymphoma, Childhood 0 0
Lymphoblastic Leukemia, Acute, Childhood 0 0
Condition category
Condition code
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Ixazomib
Treatment: Drugs - Vincristine
Treatment: Drugs - Dexamethasone
Treatment: Drugs - Asparaginase
Treatment: Drugs - Doxorubicin
Treatment: Drugs - Methotrexate (IT)
Treatment: Drugs - Triple IT (Methotrexate, Hydrocortisone, Cytarabine)
Treatment: Drugs - Leucovorin

Experimental: Ixazomib Dose Level 1 (Stratum A) - Patients will be treated on ixazomib at 1.6 mg/m\^2/day on Days 1, 4, 8, and 11. Vincristine IV at 1.5 mg/m\^2 on Days 1, 8, 15 and 22. Pegaspargase IV/IM at 2500 IU/m\^2 on Days 2 and 15, Doxorubicin at 60 mg/m\^2 on Days 1, Dexamethasone IV/PO at 10 mg/m\^2 continuous starting on Day 1 thru Day 14, and IT chemotherapy dependent on patient's CNS status at time of enrollment. This arm is the starting Dose Level for patients being enrolled.

Experimental: Ixazomib Dose Level 2 (Stratum A) - Patients will be treated on ixazomib at 2.0 mg/m\^2/day on Days 1, 4, 8, and 11. Vincristine IV at 1.5 mg/m\^2 on Days 1, 8, 15 and 22. Pegaspargase IV/IM at 2500 IU/m\^2 on Days 2 and 15, Doxorubicin at 60 mg/m\^2 on Days 1, Dexamethasone IV/PO at 10 mg/m\^2 continuous starting on Day 1 thru Day 14, and IT chemotherapy dependent on patient's CNS status at time of enrollment. Patients will be treated at this arm Dose Level once patient accrual at Dose Level 1 has been completed and dose escalation is allowed as defined by the 3+3 design.

Experimental: Ixazomib Dose Level -1 (Stratum A) - Patients will be treated on ixazomib at 1.2 mg/m\^2/day on Days 1, 4, 8, and 11. Vincristine IV at 1.5 mg/m\^2 on Days 1, 8, 15 and 22. Pegaspargase IV/IM at 2500 IU/m\^2 on Days 2 and 15, Doxorubicin at 60 mg/m\^2 on Days 1, Dexamethasone IV/PO at 10 mg/m\^2 continuous starting on Day 1 thru Day 14, and IT chemotherapy dependent on patient's CNS status at time of enrollment. This arm Dose Level -1 is needed only if de-escalation from Dose Level 1 is required.

Experimental: Ixazomib Dose Level 1 (Stratum B) - Patients will be treated on ixazomib at 1.6 mg/m\^2/day on Days 1, 4, 8, and 11. Vincristine IV at 1.5 mg/m\^2 on Days 1, 8, 15 and 22. Pegaspargase IV/IM at 2500 IU/m\^2 on Days 2 and 15, Doxorubicin at 60 mg/m\^2 on Days 1, Dexamethasone IV/PO at 10 mg/m\^2 continuous starting on Day 1 thru Day 14, and IT chemotherapy dependent on patient's CNS status at time of enrollment. Leucovorin PO/IV at 5 mg/m\^2/dose X 2 doses given 24 and 30 hours after IT Methotrexate or Triple IT will also be given on this arm. This arm is only for patients with Down syndrome (Stratum B).


Treatment: Drugs: Ixazomib
Days 1, 4, 8, and 11. Note: at least 72 hours must have elapsed between doses

Dose Phase 1 - Assigned upon study entry.

Phase 2 - PO formulation at RP2D

Treatment: Drugs: Vincristine
IV push over 1 minute or infusion via minibag as per institutional policy

Days 1, 8, 15 and 22

Dose: = 1 year: 1.5mg/m2/dose (maximum dose 2mg)

= 6 months and \< 1 year: 1.2mg/m2/dose

\< 6 months: 1mg/m2/dose

Treatment: Drugs: Dexamethasone
Days 1-14

Dose: = 1 year: 10mg/m2/day, divided BID (i.e., 5mg/m2/dose, BID)

= 6 months and \< 1 year: 8mg/m2/day, divided BID (i.e., 4 mg/m2/dose, BID)

\< 6 months: 7mg/m2/day, divided BID (i.e., 3.5 mg/m2/dose, BID)

Treatment: Drugs: Asparaginase
Days 2, 15

Dose = 1 year: 2,500 International units (IU)/m2/dose

= 6 months and \< 1 year: 2,000 IU/m2/dose

\< 6 months: 1,750 IU/m2/dose

Patient with allergic reaction to Pegaspargase can be given Erwinase IM/IV on Mon/Wed/Fri (or every other day per institutional standard) x 6 doses for each dose of Pegaspargase.

Dosing guideline for Erwinase:

* 1 year: 25,000 IU/m2/dose
* 6 months and \< 1 year: 20,000 IU/m2/dose

\< 6 months: 17,500 IU/m2/dose

Treatment: Drugs: Doxorubicin
Day 1

Dose = 1 year: 60mg/m2/dose

= 6 months and \< 1 year: 48 mg/m2/dose

\< 6 months: 42mg/m2/dose

Treatment: Drugs: Methotrexate (IT)
For patients with CNS 1 or CNS 2, on Days 1, 15, and 29

Treatment: Drugs: Triple IT (Methotrexate, Hydrocortisone, Cytarabine)
For patients with CNS 3, on Days 1, 8, 15, 22, and 29

Treatment: Drugs: Leucovorin
For patients with Down syndrome only, on Days 2, 9, 16, 23, and 30 (based on dates when IT Methotrexate or Triple IT is given)
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Phase 1: Dose limiting toxicity (DLT) during block 1 of chemotherapy
Timepoint [1] 0 0
5 weeks

Eligibility
Key inclusion criteria
* Age Patients must be =21 years of age at the time of enrollment.

1. Phase 1 - Initial enrollment will be restricted to patients < 18 years of age until 9 such patients are enrolled
2. Phase 2 - Initial enrollment will be restricted to patients < 18 years of age until 6 such patients are enrolled (applies to Stratum A only)
* Diagnosis Patients must have a diagnosis of relapsed/refractory ALL or LLy with or without extramedullary disease (including CNS2 and CNS3). Patient with mixed phenotype ALL or mature B (Burkitt-like) leukemia are not eligible.

1. Patients with ALL must have = 5% blasts by morphology.
2. Patients with LLy must have measurable disease documented by clinical, radiologic or histologic criteria
* Performance Level Karnofsky = 50% for patients > 16 years of age and Lansky = 50% for patients = 16 years of age.
* Prior Therapy A. Prior therapeutic attempts

* Phase 1 - Any patients with relapsed/refractory ALL or LLy
* Phase 2

1. B-cell ALL/LLy: all patients must have failed two or more therapeutic attempts.
2. T-cell ALL/LLy: all patients must have failed one or more therapeutic attempts. B. Recent prior chemotherapy Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
* Myelosuppressive chemotherapy: At least 14 days must have elapsed since the completion of myelosuppressive therapy. However, patients may receive any of the following medications within 14 days without a "wash-out" period:
* Hydroxyurea: Hydroxyurea can be initiated and/or continued for up to 24 hours prior to the start of protocol therapy.

* "Maintenance-style" therapy - Therapy including vincristine (dosed at a maximum of one-time weekly), oral 6-mercaptopurine, oral methotrexate (dosed at a maximum of one-time weekly), dexamethasone (dosed at = 3 mg*/m^2/dose twice daily), and prednisone (dosed at = 20 mg*/m^2/dose twice daily) can be initiated and/or continued for up to 24 hours prior to the start of protocol therapy.

* Doses can be rounded to adjust for pill size

C. Hematopoietic stem cell transplant: Patients who have experienced their relapse after a HSCT are eligible, provided they have no evidence of acute or chronic Graft-versus-Host Disease (GVHD), are not receiving GVHD prophylaxis or treatment, and are at least 90 days post-transplant at the time of enrollment.

D. Hematopoietic growth factors: It must have been at least 7 days since the completion of therapy with G-CSF or other growth factors at the time of enrollment. It must have been at least 14 days since the completion of therapy with long-acting filgrastim (pegfilgrastim or biosimilar)

E. Biologic (anti-neoplastic agent): At least 7 days since the last dose of a biologic agent. For agents that have known adverse events occurring beyond 7 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

1. Monoclonal antibodies: At least 3 half-lives of the antibody or 21 days (whichever is shorter) must have elapsed after the last dose of monoclonal antibody. (i.e., blinatumomab half-life = 6 hours, therefore washout is 18 hours; inotuzumab half-life = 37 days therefore washout is 21 days; rituximab half-life = 66 days, therefore washout is 21 days). If steroids are being used to modify immune-related adverse events of antibody therapy, at least 14 days must have elapsed since the last dose of corticosteroid.
2. Immunotherapy: At least 30 days after the completion of any type of immunotherapy, e.g., tumor vaccines, CAR T cells. If steroids are being used to modify immune-related adverse events of immunotherapy, at least 14 days must have elapsed since the last dose of corticosteroid.

F. XRT: Craniospinal XRT is prohibited during protocol therapy. No washout period is necessary for radiation given to any extramedullary site other than CNS; =90 days must have elapsed if prior total body irradiation (TBI) or craniospinal XRT.

G. Anthracyclines: Patients must have had a lifetime exposure of <400 mg/m^2 of doxorubicin equivalents of anthracyclines.

H. Proteasome inhibitors: Patients with a prior exposure to proteasome inhibitors (e.g., bortezomib, carfilzomib) are eligible as long as the patient demonstrated at least a partial response to a proteasome inhibitor with chemotherapy combination. This criteria only applies to the Phase 2 portion of the study.

-Renal and hepatic function

Patients must have adequate renal and hepatic functions as indicated by the following laboratory values:

A. Adequate renal function defined as: Patient must have a calculated creatinine clearance or radioisotope GFR = 70ml/min/1.73m^2 OR a normal serum creatinine based on age/gender

B. Adequate Liver Function Defined as: Direct bilirubin = 1.5 x upper limit of normal (ULN) for age or normal (except in the presence of Gilbert's syndrome), AND alanine transaminase (ALT) = 5 x ULN for age. The hepatic requirements are waived for patients with known or suspected liver involvement by leukemia or lymphoma. This must be reviewed by and approved by the study chair or vice chair.

* Adequate Cardiac Function Defined as: Shortening fraction of = 27% by echocardiogram, OR ejection fraction of = 50% by radionuclide angiogram (MUGA).
* Reproductive Function A. Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed within 2 weeks prior to enrollment.

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

C. Male and female patients of child-bearing potential must agree to use an effective method of contraception approved by the investigator during the study and for a minimum of 6 months after study treatment.

* Informed Consent Patients and/or their parents or legal guardians must be capable of understanding the investigational nature, potential risks and benefits of the study. All patients and/or their parents or legal guardians must sign a written informed consent. Age appropriate assent will be obtained per institutional guidelines. To allow non-English speaking patients to participate in this study, bilingual health services will be provided in the appropriate language when feasible.
* All institutional, FDA, and OHRP requirements for human studies must be met.
Minimum age
1 Year
Maximum age
21 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients will be excluded if they have isolated CNS or testicular disease.

Patients will be excluded if they have = grade 2 peripheral sensory or motor neuropathy (defined by the Modified "Balis" Pediatric Scale of Pediatric Neuropathies) at the time of enrollment.

Patients will be excluded if they have a known allergy or intolerance to any of the drugs used in the study - except for Pegaspargase for which asparaginase Erwinia chrysanthemi (recombinant)-rywn (Rylaze®) or (if available) crisantaspase (Erwinase®), may be substituted for allergy to Pegaspargase

Patients will be excluded if they have a systemic fungal, bacterial, viral or other infection that is exhibiting ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment. The patient needs to be off pressors and have negative blood cultures for 48 hours.

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

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

Patients with DNA fragility syndromes (such as Fanconi anemia, Bloom syndrome) are excluded.

Patients will be excluded if they have had a lifetime exposure of =400 mg/m2 doxorubicin equivalents of anthracyclines (anthracycline equivalence to doxorubicin conversion see appendix iv) .

Concomitant medications Investigational drugs: Patients currently receiving another investigational drug are not eligible.

Anti-GVHD agents post transplant: patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post hematopoetic stem cell transplant are not eligible.

CYP3A4 agents: patients who are currently receiving drugs that are strong inducers of CYP3A4 are not eligible.

Patients with Ph+ALL and Ph-like ALL who are currently receiving TKI therapy

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
12/02/2019
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
30/06/2025
Actual
Sample size
Target
31
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 0 0
The Children's Hospital at Westmead - Westmead
Recruitment postcode(s) [1] 0 0
2145 - Westmead
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
District of Columbia
Country [3] 0 0
United States of America
State/province [3] 0 0
Florida
Country [4] 0 0
United States of America
State/province [4] 0 0
Georgia
Country [5] 0 0
United States of America
State/province [5] 0 0
Michigan
Country [6] 0 0
United States of America
State/province [6] 0 0
Minnesota
Country [7] 0 0
United States of America
State/province [7] 0 0
New York
Country [8] 0 0
United States of America
State/province [8] 0 0
North Carolina
Country [9] 0 0
United States of America
State/province [9] 0 0
Ohio
Country [10] 0 0
United States of America
State/province [10] 0 0
Oregon
Country [11] 0 0
United States of America
State/province [11] 0 0
Pennsylvania
Country [12] 0 0
United States of America
State/province [12] 0 0
Tennessee
Country [13] 0 0
United States of America
State/province [13] 0 0
Texas

Funding & Sponsors
Primary sponsor type
Other
Name
Therapeutic Advances in Childhood Leukemia Consortium
Address
Country
Other collaborator category [1] 0 0
Commercial sector/industry
Name [1] 0 0
Takeda
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Other
Name [2] 0 0
Children's Hospital Los Angeles
Address [2] 0 0
Country [2] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Terzah Horton, MD
Address 0 0
Baylor College of Medicine
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results not provided in https://clinicaltrials.gov/study/NCT03817320