A Phase I, Multicenter Dose Escalation Study in Patients With Hairy Cell Leukemia

Hairy Cell Leukemia Clinical Trial

Official title:

A Phase I, Multicenter, Dose Escalation Study of CAT-8015 in Patients With Relapsed or Refractory Hairy Cell Leukemia (HCL)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00586924
• Other study ID #: CAT-8015-1001
• Status: Completed
• Phase: Phase 1
• Start date: May 10, 2007
• Est. completion date: May 6, 2015

Study information

• Verified date: December 2018
• Source: MedImmune LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

A dose-escalation study to identify the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD), defined as the highest dose that can safely be given to a participant and establish the safest dose based on the highest tolerated dose for clinical testing.

Description:

A Phase 1, multicenter, dose escalation study of moxetumomab pasudotox (CAT-8015) in participants with relapsed or refractory hairy cell leukemia (HCL) to estimate the MTD, defined as the highest dose that can be safely administered to a patient, and to establish a safe dose, based on the MTD, for subsequent clinical testing (Phase 2 recommended dose).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 49
• Est. completion date: May 6, 2015
• Est. primary completion date: May 6, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

Inclusion Criteria: Confirmed diagnosis of HCL, Measurable disease, Participant's must have had at least 2 prior systemic therapies. There must have been at least 2 prior courses of purine analog, or 1 if the response to this course lasted less than (<) 2 years, or if the participant had unacceptable toxicity to purine analog, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, Participant's with other cancers who meet eligibility criteria and have less than 5 years of disease free survival will be considered on a case-by-case basis, Life expectancy of greater than 6 months, as assessed by principal investigator, Must be able to understand and sign informed consent, Must be at least 18 years old, Female and male participants must agree to use an approved method of contraception during the study.

Exclusion Criteria: - History of allogeneic bone marrow transplant, Documented and ongoing central nervous system involvement with their malignant disease (history of central nervous system (CNS) involvement is not an exclusion criteria), Pregnant or breast-feeding females, HIV positive serology (due to increased risk of severe infection and unknown interaction of CAT-8015 with antiretroviral drugs, Hepatitis B surface antigen positive. - Hepatic function: Serum transaminases (either alanine transaminase (ALT) or aspartate transaminase (AST)) or bilirubin: greater than or equal to (>=) Grade 2, unless bilirubin is due to Gilbert's disease. -Renal function: Serum creatinine clearance less than or equal to (<=) 60 millilitre per minute (mL/min) as estimated by Cockroft-Gault formula. -Hematologic function: The absolute neutrophil count (ANC) < 1000/ cubic millimetres (cmm), or platelet count <50,000/cmm, if these cytopenias are not judged by the investigator to be due to underlying disease (i.e. potentially reversible with anti-neoplastic therapy). -Pulmonary function: Participant's with < 50% of predicted forced expiratory volume (FEV1) or <50% of predicted diffusing capacity for carbon monoxide (DLCO), corrected for hemoglobin concentration and alveolar volume. Uncontrolled pulmonary infection, presence of pulmonary edema, Oxygen saturation at rest < 88% measured by pulse oximetry or partial pressure of oxygen (PaO2) < 55 millimetre(s) of mercury (mm Hg), Serum albumin < 2 g/dL, Radioimmunotherapy within 2 years prior to enrollment in study.

Related Conditions & MeSH terms

• Hairy Cell Leukemia
• Leukemia
• Leukemia, Hairy Cell

Intervention

Drug:
• Moxetumomab Pasudotox (CAT 8015)
Participants received intravenous infusion of 5 microgram per kilogram (mcg/kg) moxetumomab pasudotox (CAT-8015) on Days 1, 3, and 5 of every 28-day cycle and continued cycles of therapy until complete response (CR), progressive disease (PD), initiation of alternative anticancer therapy, unacceptable toxicity, development of neutralizing antibodies, or another reason to discontinue therapy.
• Moxetumomab Pasudotox (CAT 8015)
Participants received intravenous infusion of 10 mcg/kg moxetumomab pasudotox on Days 1, 3, and 5 of every 28-day cycle and continued cycles of therapy until CR, PD, initiation of alternative anticancer therapy, unacceptable toxicity, development of neutralizing antibodies, or another reason to discontinue therapy.
• Moxetumomab Pasudotox (CAT 8015)
Participants received intravenous infusion of 20 mcg/kg moxetumomab pasudotox on Days 1, 3, and 5 of every 28-day cycle and continued cycles of therapy until CR, PD, initiation of alternative anticancer therapy, unacceptable toxicity, development of neutralizing antibodies, or another reason to discontinue therapy.
• Moxetumomab Pasudotox (CAT 8015)
Participants received intravenous infusion of 30 mcg/kg moxetumomab pasudotox on Days 1, 3, and 5 of every 28-day cycle and continued cycles of therapy until CR, PD, initiation of alternative anticancer therapy, unacceptable toxicity, development of neutralizing antibodies, or another reason to discontinue therapy.
• CAT 8015 (Moxetumomab Pasudotox)
Participants received intravenous infusion of 40 mcg/kg moxetumomab pasudotox on Days 1, 3, and 5 of every 28-day cycle and continued cycles of therapy until CR, PD, initiation of alternative anticancer therapy, unacceptable toxicity, development of neutralizing antibodies, or another reason to discontinue therapy.
• Moxetumomab Pasudotox (CAT 8015)
Participants received intravenous infusion of 50 mcg/kg moxetumomab pasudotox on Days 1, 3, and 5 of every 28-day cycle and continued cycles of therapy until CR, PD, initiation of alternative anticancer therapy, unacceptable toxicity, development of neutralizing antibodies, or another reason to discontinue therapy.

Locations

Country	Name	City	State
Poland	Research Site	Lodz
United States	Research Site	Bethesda	Maryland
United States	Research Site	Chicago	Illinois
United States	Research Site	Stanford	California

Sponsors (2)

Lead Sponsor	Collaborator
MedImmune LLC	Cambridge Antibody Technology

Countries where clinical trial is conducted

United States,  Poland, 

References & Publications (1)

Kreitman RJ, Tallman MS, Robak T, Coutre S, Wilson WH, Stetler-Stevenson M, Fitzgerald DJ, Lechleider R, Pastan I. Phase I trial of anti-CD22 recombinant immunotoxin moxetumomab pasudotox (CAT-8015 or HA22) in patients with hairy cell leukemia. J Clin Onc — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Dose Limiting Toxicities (DLTs)	Adverse events are suspected of causal relationship to drug and are >=Grade (G) 3 in severity considered DLTs: G 3 or 4 hematologic abnormalities at baseline due to disease were not evaluable for hematologic DLT, G 2 allergic reactions of bronchospasm or urticaria, or any >= G3 allergic reaction, in presence of pre-medication were considered DLTs. Following >= G 3 non-hematological treatment-related toxicities not considered DLTs: Tumor lysis syndrome, G 3 low electrolyte levels with pre-existing low levels of same electrolytes, anticoagulant therapy, G 3 or 4 infection or neutropenic fever unless relationship to IP is suspected, G 3 transaminase, alkaline phosphatase, bilirubin or other liver function test elevation provided resolution to values required for study entry prior to start of next cycle, G 3 fever, G 3 hypertriglyceridemia and hypercholesterolemia, and G 4 hypertriglyceridemia lasting <2 months, G 3 hypoalbuminemia lasting <7 days occurred in absence of CLS.	Cycle 1 Day 1 to Cycle 2 Day 10 (each cycle duration was 28 days)
Primary	Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)	The TEAEs are defined as adverse events (AEs) present at baseline that worsened in intensity after administration of investigational product or events absent at baseline that emerged after administration of study drug, for the period extending to 30 days after the last dose of study drug. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening situation (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly/birth defect in the offspring of a participant who received moxetumomab pasudotox.	From start of study drug administration until 30 days after the last dose of study drug (approximately 8 years)
Primary	Number of Participants With Vital Signs Abnormalities Recorded as Treatment-Emergent Adverse Events (TEAEs)	Vital signs abnormalities reported as TEAEs included pyrexia, weight increased, dyspnoea, hypoxia, hypertension, hypotension.	From start of study drug administration until 30 days after the last dose of study drug (approximately 8 years)
Primary	Number of Participants With Clinically Relevant Electrocardiogram (ECG) Abnormalities Recorded as Adverse Events (AEs)	Cardiac AEs observed in participants with clinically significant ECG abnormalities included; ECG QT prolonged, Sinus tachycardia and Atrioventricular block first degree.	From start of study drug administration until 30 days after the last dose of study drug (approximately 8 years)
Primary	Number of Participants With Clinically Significant Laboratory Abnormalities Recorded as Treatment-Emergent Adverse Events (TEAEs)	An abnormal laboratory finding which required an action or intervention by the investigator, or a finding judged by the investigator to represent a change beyond the range of normal physiologic fluctuation were reported as an adverse event.	From start of study drug administration until 30 days after the last dose of study drug (approximately 8 years)
Primary	Number of Participants With Objective Response Rate (ORR): Complete Response (CR) or Partial Response (PR)	Objective response rate defined as proportion of participants with confirmed CR or confirmed PR according to Response Evaluation Criteria for hairy cell leukemia (HCL). A CR is defined as: No evidence of leukemic cells by routine H/E stains of peripheral blood and bone marrow. No hepatomegaly, splenomegaly, or lymphadenopathy by physical examination and/or appropriate radiographic techniques. Normal complete blood count as: Neutrophils >= 1,500/mcL, Platelets >= 100,000/mcL, and Hemoglobin >= 11.0 gm/dL without transfusions or growth factors for at least 4 weeks. Partial response requires all of following: >=50% reduction in peripheral blood lymphocyte from pretreatment baseline value, lymphadenopathy, and abnormal hepatosplenomegaly by CT scan or physical exam, and complete blood count as Neutrophils >= 1,500/mcL, Platelets >=100,000/mcL, and Hemoglobin >= 11.0 g/dL or 50% improvement of all parameters over baseline without transfusions or growth factors for at least 4 weeks.	From Baseline (predose of Cycle 1 Day 1) through end of study (until CR, PD, initiation of alternative therapy, unacceptable toxicity, development of neutralizing antibodies, or other study discontinuation reasons) (approximately 8 years)
Primary	Number of Participants With Complete Response (CR)	The CR is defined by: No evidence of leukemic cells by routine H/E stains of the peripheral blood and bone marrow. No hepatomegaly, splenomegaly, or lymphadenopathy by physical examination and/or appropriate radiographic techniques. Normal complete blood count as exhibited by: Neutrophils >= 1,500/microliter (mcL), Platelets >= 100,000/mcL, and Hemoglobin >= 11.0 gram per deciliter (gm/dL) without transfusions or growth factors for at least 4 weeks.	From Baseline (predose of Cycle 1 Day 1) through end of study (until CR, PD, initiation of alternative therapy, unacceptable toxicity, development of neutralizing antibodies, or other study discontinuation reasons) (approximately 8 years)
Primary	Number of Participants With Partial Response (PR)	Partial response requires all of the following: >=50% decrease in peripheral blood lymphocyte count from the pretreatment baseline value, >=50% reduction in lymphadenopathy, >=50% reduction in abnormal hepatosplenomegaly by computed tomography or physical exam, Neutrophils >= 1,500/mcL or 50% improvement over baseline without growth factors for at least 4 weeks, Platelets >=100,000/mcL or 50% improvement over baseline, and Hemoglobin >= 11.0 g/dL or 50% improvement over baseline without transfusions or growth factors for at least 4 weeks. For participants who are transfusion-dependent at baseline, a hemoglobin of >= 9.0 g/dL without transfusions or growth factors for at least 4 weeks.	From Baseline (predose of Cycle 1 Day 1) through end of study (until CR, PD, initiation of alternative therapy, unacceptable toxicity, development of neutralizing antibodies, or other study discontinuation reasons) (approximately 8 years)
Primary	Number of Participants With Stable Disease (SD)	Stable disease was characterized by not meeting the criteria for CR, PR or PD.	From Baseline (predose of Cycle 1 Day 1) through end of study (until CR, PD, initiation of alternative therapy, unacceptable toxicity, development of neutralizing antibodies, or other study discontinuation reasons) (approximately 8 years)
Primary	Number of Participants With Progressive Disease (PD)	Progressive disease is defined by at least one of the following compared to pretreatment:>= 25% increase in the sum of the products of the greatest perpendicular dimensions of at least two lymph nodes on two consecutive examinations at least 2 weeks apart (at least 1 node must be >= 2 cm) or appearance of new palpable lymph nodes, >=25% increase in the size of the liver and/or spleen as determined by measurement below the respective costal margin, or appearance of new palpable hepatomegaly or splenomegaly that was not previously present, >=50% increase in the absolute number of circulating lymphocytes, >=25% decrease in hemoglobin (must be < 11g/dL), platelets (must be < 100,000/mcL), or absolute neutrophil count (must be < 1500/mcL) unless these are judged to be effects of treatment.	From Baseline (predose of Cycle 1 Day 1) through end of study (until CR, PD, initiation of alternative therapy, unacceptable toxicity, development of neutralizing antibodies, or other study discontinuation reasons) (approximately 8 years)
Primary	Time to Complete Response	Time to complete response (CR) was measured from the start of moxetumomab pasudotox treatment to the first documentation of CR and was evaluated only in participants who received any treatment of moxetumomab pasudotox and had achieved a CR. Time to complete response was summarized using Kaplan-Meier estimates (median time, 95% confidence interval [CI] for median time).	From Baseline (predose of Cycle 1 Day 1) through end of study (until CR, PD, initiation of alternative therapy, unacceptable toxicity, development of neutralizing antibodies, or other study discontinuation reasons) (approximately 8 years)
Primary	Time to Objective Response	Time to OR was measured from the start of moxetumomab pasudotox treatment to the first documentation of OR and was evaluated only in participants who received any treatment of moxetumomab pasudotox and had achieved an OR (CR or PR). Objective response (OR) was defined as the participants with confirmed CR or confirmed PR according to Response Evaluation Criteria.	From Baseline (predose of Cycle 1 Day 1) through end of study (until CR, PD, initiation of alternative therapy, unacceptable toxicity, development of neutralizing antibodies, or other study discontinuation reasons) (approximately 8 years)
Primary	Duration of Complete Response	Duration of CR was measured from the first documentation of CR to the first documented non-CR and was evaluated in participants who had achieved an CR. Duration of CR were summarized using Kaplan-Meier estimates (median time, 95% CI for median time).	From Baseline (predose of Cycle 1 Day 1) through end of study (until CR, PD, initiation of alternative therapy, unacceptable toxicity, development of neutralizing antibodies, or other study discontinuation reasons) (approximately 8 years)
Primary	Duration of Objective Response	Duration of response was measured from the first documentation of objective response (OR) to the first documented non-response of SD, PD, or relapse and was only evaluated in participants who had achieved an OR (CR or PR). Duration of OR was summarized using Kaplan-Meier estimates (median time, 95% CI for median time).	From Baseline (predose of Cycle 1 Day 1) through end of study (until CR, PD, initiation of alternative therapy, unacceptable toxicity, development of neutralizing antibodies, or other study discontinuation reasons) (approximately 8 years)
Primary	Time to Progression	Time to disease progression/relapse is measured from the start of moxetumomab pasudotox treatment until the first documentation of disease progression or relapse and was summarized using Kaplan-Meier estimates (median time, 95% CI for median time).	From Baseline (predose of Cycle 1 Day 1) through end of study (until CR, PD, initiation of alternative therapy, unacceptable toxicity, development of neutralizing antibodies, or other study discontinuation reasons) (approximately 8 years)
Primary	Progression-free Survival (PFS)	PFS was measured from the start of moxetumomab pasudotox treatment until the first documentation of disease progression/relapse or death, whichever occurred first. PFS was summarized using Kaplan-Meier estimates (median time, 95% CI for median time).	From Baseline (predose of Cycle 1 Day 1) through end of study (until CR, PD, initiation of alternative therapy, unacceptable toxicity, development of neutralizing antibodies, or other study discontinuation reasons) (approximately 8 years)
Primary	Time to Reach Maximum Observed Plasma Concentration (Tmax) of Moxetumomab Pasudotox for Cycle 1 on Day 1	The Tmax is the time to reach maximum observed plasma concentration of Moxetumomab Pasudotox.	Cycle 1 Day 1: pre-infusion; at 15 minutes (min) during the infusion; at the end of infusion (approximately 5-7 minutes before the end of infusion); and at 1, 1.5, 2, 4, 8, and 12 hours (h) post infusion
Primary	Time to Reach Maximum Observed Plasma Concentration (Tmax) of Moxetumomab Pasudotox for Cycle 1 on Day 5	The Tmax is the time to reach maximum observed plasma concentration of Moxetumomab Pasudotox.	Cycle 1 Day 5: pre infusion; at 15 min during the infusion, at the end of infusion (approximately 5-7 minutes before the end of infusion); and at 1, 1.5, 2, 4, 8, and 12 h post infusion
Primary	Maximum Observed Serum Concentration (Cmax) for Moxetumomab Pasudotox for Cycle 1 on Day 1	The Cmax is the maximum observed plasma concentration of Moxetumomab Pasudotox.	Cycle 1 Day 1: pre-infusion; at 15 min during the infusion; at the end of infusion (approximately 5-7 minutes before the end of infusion); and at 1, 1.5, 2, 4, 8, and 12 h post infusion
Primary	Maximum Observed Serum Concentration (Cmax) for Moxetumomab Pasudotox for Cycle 1 on Day 5	The Cmax is the maximum observed plasma concentration of Moxetumomab Pasudotox.	Cycle 1 Day 5: pre infusion; at 15 min during the infusion, at the end of infusion (approximately 5-7 minutes before the end of infusion); and at 1, 1.5, 2, 4, 8, and 12 h post infusion
Primary	Area Under the Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC[0-last]) of Moxetumomab Pasudotox for Cycle 1 on Day 1	The AUC (0-last) is the area under the plasma concentration-time curve from time zero to last quantifiable time.	Cycle 1 Day 1: pre-infusion; at 15 min during the infusion; at the end of infusion (approximately 5-7 minutes before the end of infusion); and at 1, 1.5, 2, 4, 8, and 12 h post infusion
Primary	Area Under the Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC[0-last]) of Moxetumomab Pasudotox for Cycle 1 on Day 5	The AUC (0-last) is the area under the plasma concentration-time curve from time zero to last quantifiable time.	Cycle 1 Day 5: pre infusion; at 15 min during the infusion, at the end of infusion (approximately 5-7 minutes before the end of infusion); and at 1, 1.5, 2, 4, 8, and 12 h post infusion
Primary	Systemic Clearance (CL) of Moxetumomab Pasudotox for Cycle 1 on Day 1	Systemic Clearance (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 area under plasma concentration-time curve from time zero to infinite time (AUC[0-infinity]).	Cycle 1 Day 1: pre-infusion; at 15 min during the infusion; at the end of infusion (approximately 5-7 minutes before the end of infusion); and at 1, 1.5, 2, 4, 8, and 12 h post infusion
Primary	Systemic Clearance (CL) of Moxetumomab Pasudotox for Cycle 1 on Day 5	Systemic Clearance (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 AUC(0-infinity).	Cycle 1 Day 5: pre infusion; at 15 min during the infusion, at the end of infusion (approximately 5-7 minutes before the end of infusion); and at 1, 1.5, 2, 4, 8, and 12 h post infusion
Primary	Terminal Phase Elimination Half Life (t1/2) of Moxetumomab Pasudotox for Cycle 1 on Day 1	The elimination half-life (t1/2) is the time measured for the plasma concentration to decrease by 1 half to its original concentration. It is associated with the terminal slope of the semi logarithmic drug concentration-time curve, and is calculated as 0.693/lambda(z).	Cycle 1 Day 1: pre-infusion; at 15 min during the infusion; at the end of infusion (approximately 5-7 minutes before the end of infusion); and at 1, 1.5, 2, 4, 8, and 12 h post infusion
Primary	Terminal Phase Elimination Half Life (t1/2) of Moxetumomab Pasudotox for Cycle 1 on Day 5	The elimination half-life (t1/2) is the time measured for the plasma concentration to decrease by 1 half to its original concentration. It is associated with the terminal slope of the semi logarithmic drug concentration-time curve, and is calculated as 0.693/lambda(z).	Cycle 1 Day 5: pre infusion; at 15 min during the infusion, at the end of infusion (approximately 5-7 minutes before the end of infusion); and at 1, 1.5, 2, 4, 8, and 12 h post infusion
Primary	AUC Accumulation Ratio of Moxetumomab Pasudotox for Cycle 1	The AUC accumulation ratio of moxetumomab pasudotox was calculated as the geometric mean ratio of AUC(0-last) on the last day and the first day of a multiple dose regimen: Day 5/Day 1.	Cycle 1 Day 1 and Day 5: pre-infusion, at 15 min during the infusion, at the end of infusion, and at 1, 1.5, 2, 4, 8, and 12 h post infusion
Primary	Cmax Accumulation Ratio of Moxetumomab Pasudotox for Cycle 1	The Cmax accumulation ratio of moxetumomab pasudotox was calculated as the geometric mean ratio of Cmax on the last day and the first day of a multiple dose regimen: Day 5/Day 1.	Cycle 1 Day 1 and Day 5: pre-infusion, at 15 min during the infusion, at the end of infusion, and at 1, 1.5, 2, 4, 8, and 12 h post infusion
Secondary	Number of Participants With Positive Neutralizing Antibodies and Correlation to Antitumor Activity	Participants tested for immunogenicity to moxetumomab pasudotox prior to enrollment, before each cycle and at end of study. The neutralization assay measures the capacity of participant's plasma (antibodies) to inhibit the binding of moxetumomab pasudotox to its target, cluster of differentiation 22 (CD22), coated onto enzyme linked immunosorbent assay (ELISA) plates. Significant level of neutralizing antibody activity defined as the capacity of test plasma to inhibit >50% of the binding of CAT-8015 to CD22 using an ELISA-based method.	Up to end of treatment (approximately 8 years)
Secondary	CD22 Expression Levels From Peripheral Blood by Best Response	Participants malignant cells (peripheral blood) were tested for cluster of differentiation 22 (CD22) expression by fluorescence-activated cell sorter (FACS) analysis.	Prior to enrollment during screening, and for participants still having malignant cells, the test was to be repeated prior to each cycle of therapy, at the end of treatment, and end of the study (approximately 8 years)
Secondary	CD22 Expression Levels From Bone Marrow by Best Response	Participants malignant cells (paraffin block biopsy specimen) were tested for CD22 expression by FACS analysis.	Prior to enrollment during screening, and for participants still having malignant cells, the test was to be repeated prior to each cycle of therapy, at the end of treatment, and end of the study (approximately 8 years)
Secondary	Soluble CD22 Levels by Best Response	Soluble CD22 was collected from the participant's plasma and was performed at the NCI using an ELISA method.	Prior to enrollment during screening, and for participants still having malignant cells, the test was to be repeated prior to each cycle of therapy, at the end of treatment, and end of the study (approximately 8 years)

External Links

•   Click here and search for drug information provided by the FDA.
•   Click here and search for information on any recalls, market or product safety alerts by the FDA which might have occurred with this product.