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:
Criteria that need to be met to participate in this study: (Abbreviated List)
Phase 1:
Phase 2:
Patients cannot participate in this study if: (Abbreviated List)
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 |
|
1 |
2 |
3 |
4 |
5 |
6 |
7 |
8 |
9 |
10 |
11 |
15 |
22 |
Tagraxofusp |
X |
|
X |
X |
|
|
|
|
|
|
|
|
|
Intrathecal Therapy |
X |
|
|
|
|
|
|
|
|
|
|
|
X |
|
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 |
|
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 |
|
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 |
|
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