Study in Pediatrics With Relapsed or Refractory Pediatric Acute Lymphoblastic Leukemia (pALL) or Lymphoblastic Lymphoma

Phase 2

Terminated

Conditions: B-Cell Pediatric ALL

Interventions: Drug: Moxetumomab Pasudotox

Registration Number: NCT02227108

Lead Sponsor: MedImmune LLC

Brief Summary: The primary objective of this study is to evaluate the efficacy of moxetumomab pasudotox in pediatric participants with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) or B-cell lymphoblastic lymphoma.

Detailed Description: This is a global, multicenter, open-label, single-arm Phase 2 study to evaluate the efficacy and safety of moxetumomab pasudotox monotherapy in pediatric participants with relapsed or refractory B-cell ALL or B-cell lymphoblastic lymphoma. Participants will be enrolled at sites in North America, Europe, and Australia. This is an approximate 35 month study.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 37

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Moxetumomab Pasudotox 40 mcg/kg	Moxetumomab Pasudotox	Participants received 6 doses of moxetumomab pasudotox 40 microgram per kilogram (mcg/kg) intravenous infusion over 30 minutes every other day (Days 1, 3, 5, 7, 9, and 11) in 21-day treatment cycles until completion of a maximum of 6 cycles of therapy.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Composite Complete Response (CRc)	Prior to Cycle 1, and prior to every cycle, at the end of treatment, at post-treatment follow-up visits, and at the end of the study, up to 1 year	The CRc is defined as achieving complete response (CR), or CR with incomplete count recovery \[CRi\]) in participants with relapsed or refractory B-cell ALL or B-cell lymphoblastic lymphoma. Complete response (CR) as per International Working Group (IWG) is complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. Morphologic CR with incomplete blood count recovery (CRi) is defined as the above CR criteria without specified blood counts. The efficacy assessments were evaluated as per investigator assessment.

Secondary Outcome Measures

Name	Time	Method
Best Overall Response (BOR)	Prior to Cycle 1, and prior to every cycle, at the end of treatment, at post-treatment follow-up visits, and at the end of the study, up to 1 year	The best overall response was calculated, based upon the disease assessments recorded during the study visits, and summarized with the number and percentage of participants for the following categories: CRc, PR, HA, SD, PD, and not evaluable. Overall best response is the best response observed for a participant during the study based on International Working Group (IWG) Response Criteria for malignant lymphoma. Complete response (CR) as per IWG is complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. PR is a minimum of 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses and no increase in the size of other nodes and in size of liver or spleen. Stable disease (SD) is when a participant fails to attain the criteria needed for a CR or PR, but does not fulfill those for PD.
Bone Marrow Blast Percentage Change	Prior to Cycle 1, and prior to every cycle, at the end of treatment, at post-treatment follow-up visits, and at the end of the study, up to 1 year	Change in bone marrow blast percentage from baseline was evaluated. If the percentage (%) blasts (at least 200 cells counted) is less than (\<) 5%, it is considered as M1, 5 to 25% considered as M2, greater than (\>) 25% considered as M3. Stages with the higher blasts relate to worse outcomes.
Percentage of Participants With Minimal Residual Disease (MRD)-Negative CRc Rate	Prior to Cycle 1, and prior to every cycle, at the end of treatment, at post-treatment follow-up visits, and at the end of the study, up to 1 year	The MRD-negative CRc rate was defined as the percentage of participants who achieved CRc and became MRD-negative as determined by flow cytometry performed by a central analysis laboratory. The CRc is defined as complete response (CR), or complete response with incomplete count recovery (CRi). Complete response (CR) as per International Working Group (IWG) is complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. Morphologic CR with incomplete blood count recovery (CRi) is defined as the above CR criteria without specified blood counts.
Overall Response Rate (ORR)	Prior to Cycle 1, and prior to every cycle, at the end of treatment, at post-treatment follow-up visits, and at the end of the study, up to 1 year	The ORR, defined as the percentage of participants with CRc or partial response (PR), was estimated; the Clopper Pearson (Exact) 95% CI was calculated. The CRc is defined as complete response (CR), or complete response with incomplete count recovery (CRi). Complete response (CR) as per International Working Group (IWG) is complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. Morphologic CR with incomplete blood count recovery (CRi) is defined as the above CR criteria without specified blood counts.
Time to Overall Response	Prior to Cycle 1, and prior to every cycle, at the end of treatment, at post-treatment follow-up visits, and at the end of the study, up to 1 year	Time to overall response was evaluated using the Kaplan-Meier method.
Percentage of Participants Who Became Eligible to Receive an Stem Cell Transplant (SCT) After Treatment With Moxetumomab Pasudotox	Prior to Cycle 1, and prior to every cycle, at the end of treatment, at post-treatment follow-up visits, and at the end of the study, up to 1 year	The percentage of participants who became eligible for SCT after treatment with moxetumomab pasudotox were provided. The Clopper Pearson (Exact) 95% CI was calculated.
Time to Transplant to Receive an Stem Cell Transplant (SCT) After Treatment With Moxetumomab Pasudotox	Prior to Cycle 1, and prior to every cycle, at the end of treatment, at post-treatment follow-up visits, and at the end of the study, up to 1 year	The time to SCT was defined as the duration from the start of treatment with moxetumomab pasudotox until the date when the subject became eligible for SCT. The time to SCT was to be summarized using the Kaplan-Meier method, and was only to be evaluated for the subgroup of subjects who became eligible for SCT after treatment with moxetumomab pasudotox.
Percentage of Participants Who Were Neutropenic at Study Entry and Who Experienced Hematologic Activity (HA)	Prior to Cycle 1, and prior to every cycle, at the end of treatment, at post-treatment follow-up visits, and at the end of the study, up to 1 year	The percentage of participants who were neutropenic at study entry and experienced HA after treatment with moxetumomab pasudotox was evaluated. The Clopper Pearson (Exact) 95% CI was calculated.
Duration of Complete Response (DOCR)	Prior to Cycle 1, and prior to every cycle, at the end of treatment, at post-treatment follow-up visits, and at the end of the study, up to 1 year	DOCR was defined as the duration from the first documentation of CRc to the first documented disease progression.The CRc is defined as achieving complete response (CR), or CR with incomplete count recovery \[CRi\]) in participants with relapsed or refractory B-cell ALL or B-cell lymphoblastic lymphoma. Kaplan-Meier method was used for evaluation.
Duration of Overall Response (DOR)	Prior to Cycle 1, and prior to every cycle, at the end of treatment, at post-treatment follow-up visits, and at the end of the study, up to 1 year	DOR was to be defined as the duration from the first documentation of overall response to the first documented disease progression. Kaplan-Meier method was used for evaluation.
Progression-Free Survival (PFS)	Prior to Cycle 1, and prior to every cycle, at the end of treatment, at post-treatment follow-up visits, and at the end of the study, up to 1 year	PFS was measured from the start of treatment with moxetumomab pasudotox until the first documentation of disease progression or death due to any cause, whichever occurred first. Kaplan-Meier method was used for evaluation.
Overall Survival (OS)	Baseline to end of study or last contact date, up to 1 year	OS was determined as the time from the start of treatment with moxetumomab pasudotox until death due to any cause. For participants who were alive at the end of the study or lost to follow-up, OS was censored on the last date when the participant was known be alive. Kaplan-Meier method was used for evaluation.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)	Baseline up to 30 days after the last dose of study drug, up to 1 year	Treatment-emergent adverse events (TEAEs), were defined as events present at baseline that worsened in intensity after administration of investigational product or events absent at baseline that emerged after administration of study drug.
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as Treatment-Emergent Adverse Events (TEAE)	Baseline up to 30 days after the last dose of study drug, up to 1 year	Laboratory tests were grouped according to hematology, serum chemistry, and urinalysis. Laboratory abnormalities with toxicity grades according to NCI CTCAE Version 4.03 were derived according to laboratory values and reported as treatment-emergent adverse events.
Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities	Baseline up to 30 days after the last dose of study drug, up to 1 year	Participants were evaluated for ECG abnormalities.
Number of Participants With Abnormal Vital Signs Reported as Treatment-Emergent Adverse Events (TEAEs)	Baseline up to 30 days after the last dose of study drug, up to 1 year	Participants who experienced vital signs abnormalities recorded as TEAEs were reported.
Number of Participants With Positive Anti-drug Antibody (ADA) and Neutralizing Antibodies (NAb)	Prior to the Start of Each Cycle for Cycles 1, 2, 3, and Subsequent Odd-Numbered Cycles, End of Treatment, and 30 Day Follow-up Visit, up to 1 year	Immunogenicity assessment included determination of antidrug (moxetumomab pasudotox) antibodies and neutralizing antidrug antibodies in serum samples. Titers and specificity were determined for NAb-positive participants. Specificity were observed in participants who had ADAs directed to the PE38 domain of moxetumomab pasudotox and increase in titers were observed in participants who tested ADA-positive at baseline. Moxetumomab pasudotox ADA-titer is a validated immunoassay, which determines titers or levels of ADAs present in ADA-positive samples.
Area Under the Plasma Concentration Time Curve From Time 0 to Infinity (AUC0-inf) After the First Dose of Cycle 1	Pre-infusion, end of infusion (EOI); 1, 3, and 6 hours post-infusion of Day 1 of Cycle 1	AUC (0-infinity) = Area under the serum concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0-infinity). It is obtained from AUC (0-t) plus AUC (tinfinity). It was calculated by extrapolating the concentrationtime curve from time zero to infinity using the linear/log trapezoidal rule.
Area Under the Concentration Versus Time Curve From Time Zero to Last Quantifiable Concentration [AUC0-last] After the First Dose of Cycle 1	Pre-infusion, end of infusion (EOI); 1, 3, and 6 hours post-infusion at Day 1 of Cycle 1	AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. AUC0-t is defined as AUC from time zero to the last data point above the lower limit of quantification.
Maximum Observed Drug Concentration in Plasma (Cmax) After the First Dose of Cycle 1	Pre-infusion, end of infusion (EOI); 1, 3, and 6 hours post-infusion at Day 1 of Cycle 1	Cmax refers to the highest measured drug concentration which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample.
Time to Reach Maximum Drug Concentration in Plasma (Tmax) After the First Dose of Cycle 1	Pre-infusion, end of infusion (EOI); 1, 3, and 6 hours post-infusion at Day 1 of Cycle 1	Tmax refers to the time after dosing when a drug attains its highest measurable concentration (Cmax). It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content.
Terminal Phase Elimination Half Life (t1/2) After the First Dose of Cycle 1	Pre-infusion, end of infusion (EOI); 1, 3, and 6 hours post-infusion at Day 1 of Cycle 1	Terminal phase elimination half-life is the time measured for the serum/plasma concentration to decrease by one half, calculated as natural logarithmic (log)-transformed (ln) value of 2 divided by elimination rate constant (lambda); that is \[ln(2)/lambda\]. Elimination rate constant (lambda) was estimated via linear regression of the time versus log concentration.
Systemic Clearance (CL) After the First Dose of Cycle 1	Pre-infusion, end of infusion (EOI); 1, 3, and 6 hours post-infusion at Day 1 of Cycle 1	CL is a quantitative measure of the rate at which a drug substance is removed from the body. The total systemic clearance after intravenous dose was estimated by dividing the total administered dose by the plasma Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC\[0-infinity\]).