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T2020-006

TACL T2020-006: Tagraxofusp

Protocol Title:

A Phase I Study of Tagraxofusp With or Without Chemotherapy in Pediatric Patients with Relapsed or Refractory CD123 Expressing Hematologic Malignancies

Study Chair:

Adam Lamble, MD, Seattle Children’s Hospital

Study Vice-Chair:

Todd Cooper, DO, Seattle Children’s Hospital

What is this study about:

Tagraxofusp is a protein-drug conjugate consisting of a diphtheria toxin redirected to target CD123. Tagraxofusp has demonstrated tolerability and promising activity in adults with BPDCN. This trial aims to efficient examine the safety of this novel agent in pediatric patients with relapsed/refractory hematologic malignancies.

The mechanism by which tagraxofusp kills cells is distinct from that of conventional chemotherapy. Tagraxofusp directly targets CD123 that is present on both tumor bulk and LSC, but not on normal hematopoietic stem cells. Tagraxofusp also utilizes a payload that is not cell cycle dependent, making it effective against both highly proliferative tumor cells but also the relatively quiescent LSCs.

The rationale for clinical development of tagraxofusp for pediatric patients with hematologic malignancies is based on the ubiquitous and high expression of CD123 on many of these diseases, as well as the highly potent preclinical activity and robust clinical responsiveness in adults observed to date.

This trial includes two parts: a monotherapy phase and a combination chemotherapy phase. This design will provide further monotherapy safety data and confirm the FDA approved pediatric dose, as well as provide safety data when combined with chemotherapy.

The goal of this study is to improve survival rates in children and young adults with relapsed hematological malignancies, determine the RP2D of tagraxofusp given alone and in combination with chemotherapy, as well as to describe the toxicities, pharmacokinetics, and pharmacodynamic properties of tagraxofusp in pediatric patients.

About 54 children and young adults will participate in this study.

Patients with Down syndrome will be included in phase 1 of the study

The goals of this study are:

  • To assess safety and tolerability of tagraxofusp monotherapy and determine the recommended dose for combination with chemotherapy in pediatric and young adult patients with relapsed/refractory CD123+ hematologic malignancies.
  • To assess safety and tolerability of tagraxofusp when given in combination with chemotherapy in pediatric and young adult patients with relapsed/refractory CD123+ hematologic malignancies.
  • To estimate the response rate (CR + CRi) after tagraxofusp monotherapy.
  • To estimate the response rate (CR + CRi) when tagraxofusp is given in combination with chemotherapy.
  • To describe the pharmacokinetics of tagraxofusp monotherapy in pediatrics and young adult patients with relapsed/refractory CD123+ hematologic malignancies
  • To describe the pharmacokinetics of tagraxofusp combined with chemotherapy in pediatrics and young adult patients with relapsed/refractory CD123+ hematologic malignancies
  • To describe minimal residual disease (MRD) levels present at the end of cycle 1 therapy in patients with bone marrow involvement

 

Criteria that need to be met to participate in this study: (Abbreviated List)

  • Patients must be ≥ 1 and ≤21 years of age at the time of enrollment.
  • Patients must have a diagnosis of Relapsed and/or refractory CD123+ 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).

Phase 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

Phase 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
  • Adequate Bone Marrow, cardiac, pulmonary, reproductive, renal, and liver function
  • Karnofsky > 50% for patients > 16 years of age and Lansky > 50% for patients ≤ 16 years of age
  • 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. (Please see study protocol section 3.3 Inclusion Critieria for Prior Therapy Specifics)
  • Patients with Down syndrome are eligible.

Patients cannot participate in this study if: (Abbreviated List)

  • Isolated CNS for Part 1 and 2. CNS disease in general for Part 1.
  • Systemic uncontrolled fungal, bacterial, viral or other infection with ongoing symptoms
  • Patients with DNA fragility syndromes (such as Fanconi anemia, Bloom syndrome)
  • Patients who are currently receiving another investigational drug or plan to receive non-protocol chemotherapy, radiation therapy, or immunotherapy during the protocol period
  • Patients who are at less than 90 days since HSCT and patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post hematopoetic stem cell transplant. At least 4 weeks must have elapsed after the last dose of GVHD.
  • 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.
  • Patients with a known allergy to to any study drugs.
  • 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.

Treatment

Tagraxofusp will be administered intravenously once daily over 5 days. Patients in Part 1 will receive tagraxofusp monotherapy over the first 5 days of a 21-day cycle. During Part 2, tagraxofusp will be given in combination with chemotherapy during a 28-day cycle. Patients in all parts and cohorts will be eligible to receive subsequent cycles of tagraxofusp for up to a total of 6 cycles (inclusive of first cycle). Subsequent cycles will consist of tagraxofusp monotherapy given on 21-day cycles. The first cycle of tagraxofusp must be given inpatient. Subsequent cycles of tagraxofusp may be given outpatient if the initial cycle was well tolerated. The DLT evaluation period will be based on cycle 1 and the toxicity of tagraxofusp combined with chemotherapy will be assessed separately.

 

Tagraxofusp Dose Levels

Level

Dose

-2

7 mcg/kg/dose

-1

9 mcg/kg/dose

1

12 mcg/kg/dose

2

14 mcg/kg/dose

 

 

Part 1:

 

 

1

2

3

4

5

6

7

8

9

10

11

15

22

Tagraxofusp

X

 

X

X

 

 

 

 

 

 

 

 

 

Intrathecal Therapy

X

 

 

 

 

 

 

 

 

 

 

 

X

 

Part 2, Cohort A:

             

 

1

2

3

4

5

6

7

8

9

10

11

15

22

29

Fludarabine

X

X

X

X

X

 

 

 

 

 

 

 

 

 

Cytarabine

X

X

X

X

X

 

 

 

 

 

 

 

 

 

Tagraxofusp

 

 

 

X

X

X

X

X

 

 

 

 

 

 

CNS1 IT Therapy

X

 

 

 

 

 

 

 

 

 

 

 

 

X

CNS2/3 IT Therapy

X

 

 

 

 

 

 

X

 

 

 

X

X

X

 

Part 2, Cohort B:

 

1

2

3

4

5

8

9

10

11

12

15

16

17

18

19

22

29

Dexamethasone

X

X

X

X

X

 

 

 

 

 

X

X

X

X

X

 

 

Vincristine

X

 

 

 

 

X

 

 

 

 

X

 

 

 

 

X

 

Tagraxofusp

 

 

 

 

 

X

X

X

X

X

 

 

 

 

 

 

 

CNS1 IT Therapy

X

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

X

CNS2/3 IT Therapy

X

 

 

 

 

X

 

 

 

 

X

 

 

 

 

X

X

 

Part 2, Cohort C:

 

 

1

2

3

4

5

6

7

8

9

10

11

15

22

29

Tagraxofusp

X

X

X

X

X

 

 

 

 

 

 

 

 

 

Azacytidine

X

X

X

X

X

 

 

 

 

 

 

 

 

 

CNS1 IT Therapy

X

 

 

 

 

 

 

 

 

 

 

 

 

X

CNS2/3 IT Therapy

X

 

 

 

 

 

 

X

 

 

 

X

X

X

 

Subsequent Cycles, All Parts and all Cohorts:

 

 

1

2

3

4

5

6

7

8

9

10

11

15

22

Tagraxofusp

X

X

X

X

X

 

 

 

 

 

 

 

 

Intrathecal Therapy

X

 

 

 

 

 

 

 

 

 

 

 

X

 

To access mor information about this study, click here to be taken to clinicaltrials.gov - NCT05476770