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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT05476770




Registration number
NCT05476770
Ethics application status
Date submitted
25/07/2022
Date registered
27/07/2022

Titles & IDs
Public title
Tagraxofusp in Pediatric Patients With Relapsed or Refractory CD123 Expressing Hematologic Malignancies
Scientific title
A Phase I Study of Tagraxofusp With or Without Chemotherapy in Pediatric Patients With Relapsed or Refractory CD123 Expressing Hematologic Malignancies
Secondary ID [1] 0 0
T2020-006
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hematologic Malignancy 0 0
AML 0 0
ALL 0 0
BPDCN 0 0
MDS 0 0
Lymphoblastic Lymphoma 0 0
Lymphoma, B-Cell 0 0
Lymphoma, T-Cell 0 0
Hodgkin Lymphoma 0 0
Mixed Phenotype Acute Leukemia 0 0
Acute Undifferentiated Leukemia 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 - Tagraxofusp
Treatment: Drugs - Fludarabine
Treatment: Drugs - Cytarabine
Treatment: Drugs - Dexamethasone
Treatment: Drugs - Vincristine
Treatment: Drugs - Azacitidine
Treatment: Drugs - Methotrexate
Treatment: Drugs - Cytarabine IT
Treatment: Drugs - Hydrocortisone

Experimental: Part 1 - Tagraxofusp

-Days 1-5

IT Therapy (may include methotrexate, cytarabine, or triple IT)

* Day 1
* Patients may receive additional IT therapy with their end-of-cycle disease re-evaluation at the discretion of the treating investigator

Experimental: Part 2 - Cohort A - Tagraxofsup

-Days 4-8

Fludarabine -Days 1-5

Cytarabine

-Days 1-5

IT Therapy (may include methotrexate, cytarabine, or triple IT) CNS1 IT Therapy

* Day 1
* Patients may receive additional IT therapy with their end-of-cycle disease re-evaluation at the discretion of the treating investigator

CNS2/3 IT Therapy

* Days 1, 8, 15, and 22
* Patients may receive additional IT therapy with their end-of-cycle disease re-evaluation at the discretion of the treating investigator

Experimental: Part 2 - Cohort B - Tagraxofsup

-Days 8-12

Dexamethasone -Days 1-5

Vincristine

-Days 1, 8, 15, and 22

IT Therapy (may include methotrexate, cytarabine, or triple IT) CNS1 IT Therapy

* Day 1
* Patients may receive additional IT therapy with their end-of-cycle disease re-evaluation at the discretion of the treating investigator

CNS2/3 IT Therapy

* Days 1, 8, 15, and 22
* Patients may receive additional IT therapy with their end-of-cycle disease re-evaluation at the discretion of the treating investigator

Experimental: Part 2 - Cohort C - Tagraxofsup -Days 1-5

Azacitidine

-Days 1-5

IT Therapy (may include methotrexate, cytarabine, or triple IT) CNS1 IT Therapy

* Day 1
* Patients may receive additional IT therapy with their end-of-cycle disease re-evaluation at the discretion of the treating investigator

CNS2/3 IT Therapy

* Days 1, 8, 15, and 22
* Patients may receive additional IT therapy with their end-of-cycle disease re-evaluation at the discretion of the treating investigator


Treatment: Drugs: Tagraxofusp
Dose will be assigned at study entry. Give IV over 15 minutes.

Treatment: Drugs: Fludarabine
30 mg/m\^2 will be given IV over 30 minutes on days 1-5.

Infusion will start 30 minutes after start of tagraxofusp on days 4 and 5.

Treatment: Drugs: Cytarabine
2000 mg/m2 intravenously will be given daily over 1-3 hours for 5 days on days 1 through 5. Infusion will begin 4 hours after start of fludarabine. Because of an increased risk of neurotoxicity, it is recommended that IT cytarabine be separated from high dose IV cytarabine administration by at least 24 hours on C1D1.

Treatment: Drugs: Dexamethasone
* 20 mg/m2/day divided BID (max 40 mg/day) given orally on days 1 through 5 and 15 through 19. The two doses should be separated by at least 8 hours.
* Any oral formulation of dexamethasone is acceptable.
* IV may be given if oral formulation is not tolerated

Treatment: Drugs: Vincristine
* 1.5 mg/m2 (maximum dose 2 mg) given intravenously as an IV push over 1-5 minutes or infusion via minibag as per institutional policy on days 1, 8, 15, and 22.
* Infusion will start 30 minutes after start of tagraxofusp on day 8.

Treatment: Drugs: Azacitidine
* 75 mg/m2 subcutaneously or intravenously will be given daily over 15 minutes for 5 days on days 1 through 5.
* Azacitidine will be given 30-60 minutes before beginning the tagraxofusp infusion.

Treatment: Drugs: Methotrexate
Give intrathecally:

* 8 mg for patients age 1-1.99
* 10 mg for patients age 2-2.99
* 12 mg for patients 3-8.99 years of age
* 15 mg for patients =9 years of age

Treatment: Drugs: Cytarabine IT
Give intrathecally:

* 30 mg for patients age 1-1.99
* 50 mg for patients age 2-2.99
* 70 mg for patients =3 years of age

If given as part of Triple IT Therapy:

AML Patients:

Age 1-1.99 - 24 mg Age 2-2.99 - 30 mg Age =3 years of age - 36 mg

AML Patients:

Age 1-1.99 - 16 mg Age 2-2.99 - 20 mg Age 3-8.99 - 24 mg Age =9 years of age - 30 mg

Treatment: Drugs: Hydrocortisone
Given intrathecally.

AML Patients:

Age 1-1.99 - 16 mg Age 2-2.99 - 20 mg Age =3 years of age - 24 mg

AML Patients:

Age 1-1.99 - 8 mg Age 2-2.99 - 10 mg Age 3-8.99 - 12 mg Age =9 years of age - 15 mg
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Occurrence of dose limiting toxicity (DLT) during cycle 1 of therapy
Timepoint [1] 0 0
At the end of Cycle 1 (21 days for Part 1, and 28 days for Part 2)

Eligibility
Key inclusion criteria
Age

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

Diagnosis

* Relapsed and/or refractory hematologic malignancy (including, but not limited to, acute lymphoblastic leukemia, acute myeloid leukemia, myelodysplastic syndrome, mixed phenotype acute leukemia, acute undifferentiated leukemia, blastic plasmacytoid dendritic cell neoplasm, Hodgkin lymphoma, and non-Hodgkin lymphoma).
* Tumor cells must demonstrate surface expression of CD123 at the time of enrollment by flow cytometry or immunohistochemistry, as defined by the local institution.

Disease Status:

Monotherapy, Part 1

* Second or greater relapse; or
* Refractory after 2 or more chemotherapy cycles; or
* First relapse after primary chemotherapy-refractory disease; or
* BPDCN in first relapse or refractory after 1 or more chemotherapy cycles

Combination therapy, Part 2

* First or greater relapse; or
* Refractory after 2 or more chemotherapy cycles; or
* BPDCN in first relapse or refractory after 1 or more chemotherapy cycles

For relapsed/refractory leukemia, patients must have:

* >5% blasts in the bone marrow aspirate or biopsy by morphology or flow cytometry
* Patients with 1% - 5% blasts are eligible for Part 2, Cohort C (only), if A single bone marrow sample with flow cytometry and at least one other test (e.g. karyotype, FISH, PCR, or NGS) shows = 1% leukemic blasts and/or flow cytometry demonstrates a stable or rising level of disease on two serial bone marrows.

For relapsed/refractory non-Hodgkin or Hodgkin lymphoma, patients must have:

* Histologic verification of relapse
* Measurable disease documented by radiographic criteria or bone marrow
* Patients in Part 1 may have sites of non-CNS extramedullary disease, but no CNS disease. Patients in Part 2 may have CNS disease and/or other non-CNS extramedullary disease. No cranial irradiation is allowed during the protocol therapy.
* Patients with Down syndrome are eligible to participate in Part 1 only.

Performance Level

* Karnofsky > 50% for patients > 16 years of age and Lansky > 50% for patients = 16 years of age (See Appendix I for Performance Scales). Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.

Prior Therapy

* Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy, defined as resolution of all such toxicities to = Grade 2 or lower per the inclusion/exclusion criteria.

Myelosuppressive chemotherapy: Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study. At least 14 day must have elapsed since the completion of myelosuppressive therapy. However, individuals 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 a maximum of one-time weekly), oral 6-mercaptopurine, oral methotrexate (dosed a maximum of one-time weekly), intrathecal therapy (dosed a maximum of one-time weekly) and/or dexamethasone (dosed at =3 mg/m2/dose twice daily) or prednisone (dosed at =20 mg/m2/dose twice daily) can be continued for up to 24 hours prior to entering the study.
* 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) and are at least 100 days post-transplant at the time of enrollment.
* Hematopoietic growth factors: It must have been at least 7 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 agent): At least 7 days after 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.
* Monoclonal antibodies: Maximum of 3 half-lives of the antibody or 21 days (whichever is shorter) must have elapsed after the last dose of monoclonal antibody.
* Immunotherapy: At least 30 days from last infusion of chimeric antigen receptor T cell (CART) therapy or tumor vaccine.
* Radiation Therapy (XRT):

1. = 84 days must have passed, from the end of therapy, if patient received prior total body irradiation (TBI).
2. = 42 days must have passed, from the end of therapy, if patient received craniospinal irradiation (CSI).
3. = 14 days must have passed after whole brain radiotherapy or stereotactic radiation therapy.
4. No washout period is required for:

i. Extramedullary site other than CNS that is a maximum 10 x 10 cm total radiation non-CNS field. If the field is > 10 x 10 cm, a 14-day washout period is required. ii. Local ocular radiotherapy as long as subject has measurable/evaluable disease outside the radiation port.
* Patients that have received other non-tagraxofusp CD123 targeting agents are eligible. Patients that have previously received tagraxofusp are not eligible.

Organ Function Requirements

Adequate Bone Marrow Function Defined as:

* Patients should not be known to be refractory to red blood cell or platelet transfusions.
* Blood counts are not required to be normal prior to enrollment on trial. However, platelet count must be =20,000/mm3 to initiate therapy (may receive platelet transfusions).

Adequate Renal Function Defined as:

* Patient must have a calculated creatinine clearance or radioisotope GFR = 70ml/min/1.73m2 OR a normal serum creatinine based on age/gender in the chart below:

Maximum Serum Creatinine (mg/dL):

* 1 to < 2 years old - Male: 0.6, Female: 0.6
* 2 to < 6 years old - Male:0.8, Female: 0.8
* 6 to < 10 years old - Male: 1, Female: 1
* 10 to < 13 years old - Male: 1.2, Female: 1.2
* 13 to < 16 years old - Male: 1.5, Female: 1.4
* = 16 years old - Male: 1.7, Female: 1.4

The threshold creatinine values in this Table were derived from the Schwartz formula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature data published by the CDC.

Adequate Liver Function Defined as:

* Total bilirubin (sum of conjugated + unconjugated) = 1.5 x institutional upper limit of normal for age
* SGPT (ALT) and SGOT (AST) must be less than 3x institutional upper limit of normal.
* Serum albumin =3.2 g/dL (albumin infusion independent).

Adequate Cardiac Function Defined as:

* Shortening fraction of =27% by echocardiogram, or
* Ejection fraction of = 50% by gated radionuclide study/echocardiogram.

Adequate Pulmonary Function Defined as:

* Pulse oximetry > 94% on room air (> 90% if at high altitude)
* No evidence of dyspnea at rest and no exercise intolerance.

Reproductive Function

* Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed within 2 weeks prior to enrollment.
* Female patients with infants must agree not to breastfeed their infants while on this study.
* 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 12 weeks after the last dose of tagraxofusp.
Minimum age
1 Year
Maximum age
21 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion Criteria

Disease Status:

* Patients with CNS disease are not eligible for Part 1.
* Patients with isolated CNS disease are not eligible for Part 1 or Part 2.
* Patients with isolated non-CNS disease are eligible for Part 1 and Part 2.

Concomitant Medications

* Corticosteroids - Patients receiving corticosteroids for disease control who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible.
* Investigational Drugs - Patients who are currently receiving another investigational drug are not eligible. The definition of "investigational" for use in this protocol means any drug that is not licensed by the FDA, Health Canada or the Therapeutic Goods Administration to be sold in the countries they govern. (United States, Canada and Australia)
* Anti-cancer Agents - Patients who are currently receiving or may receive while on therapy, other anti-cancer agents, radiation therapy or immunotherapy are not eligible [with the exceptions being laid out in the inclusion criteria under 'Prior Therapy']. Intrathecal chemotherapy (at the discretion of the primary oncologist) may be given up to one week prior to the initiation of study treatment (day 1 therapy).
* Anti-GVHD or agents to prevent organ rejection post-transplant - Patients who are receiving cyclosporine, tacrolimus or other agents to prevent either graft-versus-host disease post bone marrow transplant or organ rejection post-transplant are not eligible for this trial. At least 4 weeks must have elapsed after the last dose of GVHD meds.

Infection Criteria - Patients are excluded if they have:

* Positive blood culture within 48 hours of study enrollment;
* Fever above 38.2 within 48 hours of study enrollment with clinical signs of infection. Fever that is determined to be due to tumor burden is allowed if patients have documented negative blood cultures for at least 48 hours prior to enrollment and no concurrent signs or symptoms of active infection or hemodynamic instability.
* A positive fungal culture within 30 days of study enrollment.
* Active fungal, viral, bacterial, or protozoal infection requiring IV treatment. Chronic prophylaxis therapy to prevent infections is allowed.
* Patients will be excluded if they have a known allergy to any of the drugs used in the study.
* 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.

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
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
11/11/2022
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
11/11/2027
Actual
Sample size
Target
54
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 0 0
Children's Hospital at Westmead - Westmead
Recruitment hospital [2] 0 0
Sydney Children's Hospital - Sydney
Recruitment postcode(s) [1] 0 0
- Westmead
Recruitment postcode(s) [2] 0 0
- Sydney
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
Colorado
Country [3] 0 0
United States of America
State/province [3] 0 0
District of Columbia
Country [4] 0 0
United States of America
State/province [4] 0 0
Florida
Country [5] 0 0
United States of America
State/province [5] 0 0
Georgia
Country [6] 0 0
United States of America
State/province [6] 0 0
Illinois
Country [7] 0 0
United States of America
State/province [7] 0 0
Indiana
Country [8] 0 0
United States of America
State/province [8] 0 0
Maryland
Country [9] 0 0
United States of America
State/province [9] 0 0
Massachusetts
Country [10] 0 0
United States of America
State/province [10] 0 0
Michigan
Country [11] 0 0
United States of America
State/province [11] 0 0
Minnesota
Country [12] 0 0
United States of America
State/province [12] 0 0
New York
Country [13] 0 0
United States of America
State/province [13] 0 0
North Carolina
Country [14] 0 0
United States of America
State/province [14] 0 0
Ohio
Country [15] 0 0
United States of America
State/province [15] 0 0
Oregon
Country [16] 0 0
United States of America
State/province [16] 0 0
Pennsylvania
Country [17] 0 0
United States of America
State/province [17] 0 0
Tennessee
Country [18] 0 0
United States of America
State/province [18] 0 0
Texas
Country [19] 0 0
United States of America
State/province [19] 0 0
Utah
Country [20] 0 0
United States of America
State/province [20] 0 0
Washington
Country [21] 0 0
United States of America
State/province [21] 0 0
Wisconsin

Funding & Sponsors
Primary sponsor type
Other
Name
Therapeutic Advances in Childhood Leukemia Consortium
Address
Country

Ethics approval
Ethics application status

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

Contacts
Principal investigator
Name 0 0
Adam Lamble, MD
Address 0 0
Seattle Children's
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Benjamin N Brookhart
Address 0 0
Country 0 0
Phone 0 0
323-361-5429
Fax 0 0
Email 0 0
[email protected]
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/NCT05476770