TPO-Mimetic Use in Children for Hemotopoietic Failure

Sponsor

Anjali Sharathkumar (Other)

Overall Status

Recruiting

CT.gov ID

NCT04478227

Collaborator

Amgen (Industry)

Enrollment

Location

Arms

27.5

Anticipated Duration (Months)

0.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is an open label, prospective Pilot interventional study will investigate the safety and efficacy of Romiplostim, thrombopoietin (TPO) mimetic, in children (ages: 0 to 21 years) with broad scope of bone marrow failure disorders including acquired and inherited conditions as a first line of therapy along with standard of care.

Condition or Disease	Intervention/Treatment	Phase
Bone Marrow Failure Disorders Aplastic Anemia Thrombocytopenia Refractory Cytopenia of Childhood Myelodysplastic Syndrome(MDS)	Drug: Romiplostim	Early Phase 1

Detailed Description

This investigator-initiated study will investigate the safety and efficacy of Romiplostim, thrombopoietin (TPO) mimetic, in children (ages: 0 to 21 years) with broad scope of bone marrow failure disorders (BMF) including acquired and inherited conditions as a first line of therapy along with standard of care.

Objectives: Primary objectives are to evaluate safety and preliminary efficacy of Romiplostim in children with BMF. Methods: This open label, prospective Pilot interventional study has two arms.

Arm A will include acquired bone marrow failure (BMF) disorders including aplastic anemia, refractory cytopenia of childhood without monosomy 7 and 5q deletion abnormalities, toxin induced myelosuppression due to infection and inherited cytopenia with or without involvement of other cell lines who are transfusion dependent and or showing progression to bone marrow failure. Arm B will include children with chemo and or radiotherapy induced thrombocytopenia/cytopenia and children undergoing stem cell transplantation (SCT). Children with cancer predisposition and other morbidities which are considered significant by the investigator will be excluded from the study.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

25 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Single Arm Prospective Open Label Pilot Study Evaluating Short-Term Safety and Efficacy of Romiplostim in Children With Inherited and Acquired Disorders of Hematopoietic Failure

Actual Study Start Date :

Aug 18, 2020

Anticipated Primary Completion Date :

Jun 1, 2022

Anticipated Study Completion Date :

Dec 3, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A Arm A will include acquired bone marrow failure (BMF) disorders including aplastic anemia, refractory cytopenia of childhood/Myelodysplastic Syndrome(MDS) without monosomy 7 and 5q deletion abnormalities, toxin induced myelosuppression due to infection and inherited cytopenia with or without involvement of other cell lines who are transfusion dependent and or showing progression to bone marrow failure. Arm A: Start at 5 microgram/kg/dose per week along with standard of care and escalate with 2.5 microgram/kg/dose increments (per week at physician's discretion depending on the clinical and laboratory response) (Maximum: 20 microgram/kg/dose) based on response for at least 24 weeks or until hematopoietic response is seen, whichever comes first. If patient shows response, therapy will be continued for a total of 52 weeks.	Drug: Romiplostim Nplate is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Other Names: Nplate
Experimental: Arm B Arm B will include children with chemo and or radiotherapy induced thrombocytopenia/cytopenia and children undergoing stem cell transplantation (SCT). Arm B: Starting dose 2 microgram/kg/dose per week with increments at 1 microgram/kg/dose (Maximum: 10 micrograms/kg/dose) depending on the laboratory response.	Drug: Romiplostim Nplate is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Other Names: Nplate

Arm

Intervention/Treatment

Experimental: Arm A

Arm A will include acquired bone marrow failure (BMF) disorders including aplastic anemia, refractory cytopenia of childhood/Myelodysplastic Syndrome(MDS) without monosomy 7 and 5q deletion abnormalities, toxin induced myelosuppression due to infection and inherited cytopenia with or without involvement of other cell lines who are transfusion dependent and or showing progression to bone marrow failure. Arm A: Start at 5 microgram/kg/dose per week along with standard of care and escalate with 2.5 microgram/kg/dose increments (per week at physician's discretion depending on the clinical and laboratory response) (Maximum: 20 microgram/kg/dose) based on response for at least 24 weeks or until hematopoietic response is seen, whichever comes first. If patient shows response, therapy will be continued for a total of 52 weeks.

Drug: Romiplostim

Nplate is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Other Names:

Nplate

Experimental: Arm B

Arm B will include children with chemo and or radiotherapy induced thrombocytopenia/cytopenia and children undergoing stem cell transplantation (SCT). Arm B: Starting dose 2 microgram/kg/dose per week with increments at 1 microgram/kg/dose (Maximum: 10 micrograms/kg/dose) depending on the laboratory response.

Drug: Romiplostim

Other Names:

Nplate

Outcome Measures

Primary Outcome Measures

Occurrence of treatment-related adverse events (AEs) according to NCI CTCAE v5.0 [During treatment and through 90 days following discontinuation of treatment]
Categorize and quantify AEs per CTCAE version 5.0
To estimate preliminary efficacy of Romiplostim as measured by improvement in hematopoiesis [By 24 weeks of therapy]
Improvement in at least one of the cell blood lineages by 24 weeks of therapy: Platelet response (increase to 10 X 103/mL above baseline or stable platelet counts with transfusion independence for a minimum of 2 weeks in those who were transfusion dependent on entry into the protocol) Erythroid response (when pretreatment hemoglobin was, below 7 g/dL, defined as an increase in hemoglobin by 1.5 g/dL or, in transfused patients, a reduction in the units of packed red blood cell transfusions by an absolute number of at least 4 transfusions for 8 consecutive weeks, compared with the pretreatment transfusion number in the previous 8 weeks) Neutrophil response (when pretreatment absolute neutrophil count [ANC] of 0.5 x103 /mL as at least a 100% increase in ANC, or an ANC increase by 0.5 x103 /mL)

Secondary Outcome Measures

To assess time to hematological response [Time from Romiplostim initiation to response, by 24 weeks of therapy]
Time from Romiplostim initiation to response, as defined in Outcome 2, for each cell lineage
To assess longitudinal changes in blood counts [From treatment beginning to end, up to 52 weeks]
Change in blood counts from Romiplostim initiation until the end of treatment
To assess the incidence of bleeding (including muco-cutaneous bleeding) [From treatment beginning to end, up to 52 weeks]
Occurrences of bleeding as defined by the International Society of Haemostasis and Thrombosis Bleeding Assessment Tool (https://bleedingscore.certe.nl/)
To assess the incidence of neutropenic fever [From treatment beginning to end, up to 52 weeks]
Number of occurrences of neutropenic fever
To assess the requirement of blood product support [Prior to initiation of treatment through end of treatment, up to 52 weeks]
Change in number of platelet and red call transfusions without active bleeding diathesis
To assess development of bone marrow myelofibrosis [at 3 to 6 months after treatment initiation; within 4 to 6 weeks after discontinuation of treatment or any other time-point if deemed clinically indicated]
Increase in bone marrow myelofibrosis as measured by reticulin staining of bone marrow biopsy at diagnosis and follow up bone marrow testing upon initiation of Romiplostim
To assess transfusion dependence or decreased platelet transfusion requirement among subjects who receive pretreatment platelet transfusion [Up to 24 weeks after treatment initiation]
Number of patients who are transfusion dependent or who require decreased platelet transfusion

Eligibility Criteria

Criteria

Ages Eligible for Study:

0 Years to 21 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age 0 to 21 years
Child should be receiving ongoing care with pediatric hematology/oncology providers
Confirmed diagnosis of any of the following

aplastic anemia

Diagnosis of severe Aplastic anemia is established if Bone marrow cellularity <25% or and at least two of the following criteria are met:- (i) absolute neutrophil count less than 0.5 × 109/L, (ii) platelet count less than 20 × 109/L, and (iii) reticulocyte count less than 20 × 109/L
Moderate aplastic anemia is defined as bone marrow cellularity <50 percent and depression of at least two out of three blood counts below the normal values: criteria are met:- (i) absolute neutrophil count less than 1200/mm3, (ii) platelet count less than 70,000/mm3, and (iii) anemia with hemoglobin less than or equal to 8.5 g/dL and absolute reticulocyte count less than or equal to 60,000/mm3 in transfusion-dependent patients but not fulfilling the criteria of sever aplastic anemia

refractory cytopenia of childhood without monosomy 7 or 5q- and without an evidence of cytogenetic abnormality with predisposition to leukemia
myelo-suppression specifically thrombocytopenia as defined by primary oncologist in children with solid tumors secondary to chemotherapy or radiation therapy contributing to delay in chemotherapy
myelo-suppression contributing to severe pancytopenia (absolute neutrophil count <0.5 x 0.5 × 109/L; platelet count less than 20 × 109/L, and reticulocyte count less than 20 × 109/L secondary to any other drug or infection
patient undergoing stem cell transplantation and experiencing persistent thrombocytopenia (platelet count <10 x 109/L) requiring platelet transfusions
diagnosis of inherited bone marrow failure without chromosomal fragility disorder

Adequate organ function within 7 days of enrollment defined as:

Creatinine: ≤ 2.0 mg/dL
Hepatic function:

For arm A, elevation of liver enzymes is acceptable for patients with hepatitis induced SAA as long as patient does not have history of chronic liver problem. If necessary, liver biopsy will be performed.
For Arm B, elevation of liver enzymes will be accepted as long as no chronic liver problem. Liver biopsy will be performed if necessary.
Females of childbearing potential agree to use effective contraception during the study period and for 4 months after completion of therapy
Must be able to provide written and voluntary informed consent.

Exclusion Criteria:

Gestational age < 32 weeks or Age ≥ 21 years at the time of study enrolment
Preexisting condition with predisposition for thrombosis
Diagnosis of bone marrow failure syndrome with cancer predisposition including chromosomal fragility disorders (Fanconi anemia, Bloom syndrome, Ataxia Telangiectasia) and other conditions with known association towards cancer predisposition
Presence of complex karyotype or monosomy 7 or 5q- or other cytogenetic abnormality with known predisposition to cancer.
Diagnosis of MDS
Female subjects who are nursing or pregnant (positive serum or urine β-human chorionic gonadotropin [β-hCG] pregnancy test) at screening or pre-dose on Day 1.
Current alcohol or drug abuse.
Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) preceding the first dose of study medication.
Active and uncontrolled infections (e.g. sepsis, hepatitis B, hepatitis C).
Chronic liver disease ie. Fibrosis or cirrhosis
Subjects infected with Human Immunodeficiency Virus (HIV).
Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to Romiplostim that contraindicates the subjects' participation
Known history of sensitivity or allergy to the active substance, to any of the excipients, or to any E. coli-derived product.
Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary, infectious, or metabolic disease of such severity that it would preclude the patient's ability to tolerate protocol therapy, or that death within 7-10 days is likely.
Subjects who have participated in any study using an investigational drug during the previous 30 days.
Non-English-speaking families who cannot speak or read English