A Phase 1, Dose-escalation Study of MEDI-551 in Japanese Adult Patients With Relapsed or Refractory Advanced B-cell Malignancies

A Phase 1, Dose-escalation Study of MEDI-551, a Humanized Monoclonal Antibody Directed Against CD19, in Japanese Adult Patients With Relapsed or Refractory Advanced B-cell Malignancies

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01957579

Enrollment

Registered

2013-10-08

Start date

2011-05-25

Completion date

2015-09-15

Last updated

2017-06-12

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Advanced B Cell Malignancies, Blood Cancer

Keywords

Phase I, advanced, B cell malignancies, dose escalation, CD19, Japanese

Brief summary

The primary objective of this study is to evaluate the safety and tolerability of MEDI-551 in Japanese patients with relapsed or refractory advanced B-cell malignancies.

Interventions

DRUGMEDI-551

MEDI-551 will be administered by intravenous infusion at dose of 2, 4 or 8 mg/kg once per week on Days 1 and 8 in the first cycle and then once every 28 days at the start of each subsequent cycle

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

20 Years to 130 Years

Healthy volunteers

Inclusion criteria

* Japanese men or women at least 20 years of age * Histologically confirmed CLL (excluding small lymphocytic lymphoma (SLL)), DLBCL, FL, or MM. * Karnofsky Performance Status ≥70; * Life expectancy of ≥12 weeks

Exclusion criteria

* Any available standard line of therapy known to be life-prolonging or life-saving * Any concurrent chemotherapy, radiotherapy, immunotherapy, biologic or hormonal therapy for treatment of cancer * Previous therapy directed against CD19, such as monoclonal antibodies or MAb conjugates

Design outcomes

Primary

Measure	Time frame
Number of Participants With Adverse Events	From baseline to 30 days after the last dose of study drug

Secondary

Measure	Time frame	Description
Maximum Tolerated Dose	From baseline to 28 days after the first dose of study drug	A dose was considered non-tolerated and dose escalation stopped if ≥2 of up to 6 evaluable patients experienced a DLT at any dose level. MTD is the last dose level before the non-tolerated dose.
MEDI-551 Trough Concentration Levels at Day 0 (Pre-dose)	Day 0 (pre-dose)	Lower limit of quantification for MEDI-551 was 0.1 μg/mL.
MEDI-551 Trough Concentration Levels at Day 7	Day 7	Lower limit of quantification for MEDI-551 was 0.1 μg/mL.
MEDI-551 Trough Concentration Levels at Day 28	Day 28	Lower limit of quantification for MEDI-551 was 0.1 μg/mL.
MEDI-551 Trough Concentration Levels at Day 56	Day 56	Lower limit of quantification for MEDI-551 was 0.1 μg/mL.
MEDI-551 Trough Concentration Levels at Day84	Day 84	Lower limit of quantification for MEDI-551 was 0.1 μg/mL.
MEDI-551 Trough Concentration Levels at Day 112	Day 112	Lower limit of quantification for MEDI-551 was 0.1 μg/mL.
Number of Participants With Dose Limiting Toxicities	From baseline to 28 days after the first dose of study drug	A MEDI-551 treatment-related AE of any toxicity grade that lead to an inability to receive a full cycle (2 doses) of MEDI-551, or, any Grade 3 or higher toxicity that could not be reasonably ascribed to another cause, such as disease progression or accident.
MEDI-551 Trough Concentration Levels at Day 168	Day 168	Lower limit of quantification for MEDI-551 was 0.1 μg/mL.
Anti-MEDI-551 Antibodies	From baseline to 30 days after the last dose of study drug	Only 1 patient was tested positive for ADA at pre-dose of Cycle 1 Day 1. However, it was considered as false-positive because the titer value was close to the cut point, and this patient was tested negative for ADA at all subsequent cycles post-baseline.
Number of Participants With Tumour Response in FL Patients	From the baseline to 30 days after the last dose of study drug	Tumour response is defined as complete remission (CR) or partial remission (PR) (Cheson BD et al 2007). CR: Nodal Masses: (a) FDG-avid or PET positive prior to therapy; mass of any size permitted if PET negative; (b) Variably FDG-avid or PET negative; regression to normal size on CT; Spleen, Liver: Not palpable, nodules disappeared. Bone Marrow: Infiltrate cleared on repeat biopsy; if indeterminate by morphology, immunohistochemistry should be negative. PR: Nodal Masses: ≥50% decrease in sum of the product of the diameters (SPD) of up to 6 largest dominant masses; no increase in size of other nodes; (a) FDG-avid or PET positive prior to therapy; ≥1 PET positive at previously involved site; (b) Variably FDG-avid or PET negative; regression on CT. Spleen, Liver: ≥50% decrease in SPD of nodules (for single nodule in greatest transverse diameter); no increase in size of liver or spleen. Bone Marrow: Irrelevant if positive prior to therapy; cell type should be specified.
Number of Participants With Tumour Response in DLBCL Patients	From the baseline to 30 days after the last dose of study drug	Tumour response is defined as complete remission (CR) or partial remission (PR) (Cheson BD et al 2007). CR: Nodal Masses: (a) FDG-avid or PET positive prior to therapy; mass of any size permitted if PET negative; (b) Variably FDG-avid or PET negative; regression to normal size on CT; Spleen, Liver: Not palpable, nodules disappeared. Bone Marrow: Infiltrate cleared on repeat biopsy; if indeterminate by morphology, immunohistochemistry should be negative. PR: Nodal Masses: ≥50% decrease in sum of the product of the diameters (SPD) of up to 6 largest dominant masses; no increase in size of other nodes; (a) FDG-avid or PET positive prior to therapy; ≥1 PET positive at previously involved site; (b) Variably FDG-avid or PET negative; regression on CT. Spleen, Liver: ≥50% decrease in SPD of nodules (for single nodule in greatest transverse diameter); no increase in size of liver or spleen. Bone Marrow: Irrelevant if positive prior to therapy; cell type should be specified.
Number of Participants With Tumour Response in CLL Patients	From the baseline to 30 days after the last dose of study drug	Tumour response is defined as complete remission (CR) or partial remission (PR) (Hallek M et al 2008). CR: all of the following criteria have to be met, and patients have to lack disease-related constitutional symptoms; Lymphadenopathy: None; Hepatomegaly: None; Splenomegaly: None; Blood lymphocytes: \<4000/μL; Marrow: Normocellular, \<30%lymphocytes, no B-lymphoid nodules, hypocellular marrow defines CR with incomplete marrow recovery; Platelet count: \>100000/μL; Hemoglobin: \>11.0 g/dL; Neutrophils: \>1500/μL PR: at least 2 of the criteria of group A plus 1 of the criteria of group B have to be met. Group A: Lymphadenopathy: Decrease ≥50%; Hepatomegaly: Decrease ≥50%; Splenomegaly: Decrease ≥50%; Blood lymphocytes: Decrease ≥50% from baseline; Marrow: 50% reduction in marrow infiltrate, or B-lymphoid nodules. Group B: Platelet count: 100000/μL or increase ≥50% over baseline; Hemoglobin: \>11.0 g/dL or increase ≥50% over baseline; Neutrophils: \>1500/μL or \>50% improvement over baseline.
Number of Participants With Tumour Response in MM Patients	From the baseline to30 days after the last dose of study drug	Tumour response is defined as complete response (CR) or partial response (PR) (Durie M et al 2006). CR: Negative immunofixation on the serum and urine, and Disappearance of any soft tissue plasmacytomas and 5% or less plasma cells in bone marrow PR: ≥50% reduction of serum M-protein and reduction in 24-h urinary M-protein by ≥90% or to \<200mg per 24 h. If the serum and urine M-protein are unmeasurable, a ≥50% decrease in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria. If serum and urine M-protein are unmeasurable, and serum free light assay is also unmeasurable, ≥50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was ≥30%. In addition to the above listed criteria, if present at baseline, a ≥50% reduction in the size of soft tissue plasmacytomas is also required.
MEDI-551 Trough Concentration Levels at Day 140	Day 140	Lower limit of quantification for MEDI-551 was 0.1 μg/mL.

Countries

Japan

Participant flow

Recruitment details

First patient enrolled on 25 May 2011. Last patient last visit on 15 September 2015.

Pre-assignment details

A total of 32 patients were enrolled into the study. Twelve patients were screen failures, thus 20 patients received MEDI-551.

Participants by arm

Arm	Count
2 mg/kg MEDI-551 2mg/kg	3
4 mg/kg MEDI-551 4 mg/kg	7
8 mg/kg MEDI-551 8 mg/kg	4
12 mg/kg MEDI-551 12 mg/kg	6
Total	20

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Overall Study	Death	0	0	2	0
Overall Study	Withdrawal of concent	0	1	0	0

Baseline characteristics

Characteristic	2 mg/kg	4 mg/kg	8 mg/kg	12 mg/kg	Total
Age, Continuous	50.3 Years STANDARD_DEVIATION 8.1	57.4 Years STANDARD_DEVIATION 10.5	67.0 Years STANDARD_DEVIATION 8.7	67.3 Years STANDARD_DEVIATION 11.4	61.3 Years STANDARD_DEVIATION 11.4
Disease Type CLL	1 Participants	0 Participants	0 Participants	1 Participants	2 Participants
Disease Type DLBCL	0 Participants	2 Participants	2 Participants	2 Participants	6 Participants
Disease Type FL	2 Participants	4 Participants	2 Participants	3 Participants	11 Participants
Disease Type MM	0 Participants	1 Participants	0 Participants	0 Participants	1 Participants
Sex: Female, Male Female	2 Participants	5 Participants	0 Participants	3 Participants	10 Participants
Sex: Female, Male Male	1 Participants	2 Participants	4 Participants	3 Participants	10 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —
other Total, other adverse events	3 / 3	6 / 7	4 / 4	6 / 6
serious Total, serious adverse events	1 / 3	0 / 7	0 / 4	0 / 6

Outcome results

Primary

Number of Participants With Adverse Events

Time frame: From baseline to 30 days after the last dose of study drug

Population: All patients who received at least 1 dose of MEDI-551.

Arm	Measure	Group	Value (NUMBER)
2 mg/kg	Number of Participants With Adverse Events	At least 1 Adverse Events (AE)	3 Participants
2 mg/kg	Number of Participants With Adverse Events	At least 1 Serious Adverse Events (SAE)	1 Participants
2 mg/kg	Number of Participants With Adverse Events	At least 1 AE of CTCAE Grade 3 or higher	2 Participants
4 mg/kg	Number of Participants With Adverse Events	At least 1 Adverse Events (AE)	6 Participants
4 mg/kg	Number of Participants With Adverse Events	At least 1 Serious Adverse Events (SAE)	0 Participants
4 mg/kg	Number of Participants With Adverse Events	At least 1 AE of CTCAE Grade 3 or higher	2 Participants
8 mg/kg	Number of Participants With Adverse Events	At least 1 AE of CTCAE Grade 3 or higher	1 Participants
8 mg/kg	Number of Participants With Adverse Events	At least 1 Adverse Events (AE)	4 Participants
8 mg/kg	Number of Participants With Adverse Events	At least 1 Serious Adverse Events (SAE)	0 Participants
12 mg/kg	Number of Participants With Adverse Events	At least 1 Adverse Events (AE)	6 Participants
12 mg/kg	Number of Participants With Adverse Events	At least 1 Serious Adverse Events (SAE)	0 Participants
12 mg/kg	Number of Participants With Adverse Events	At least 1 AE of CTCAE Grade 3 or higher	3 Participants

Secondary

Anti-MEDI-551 Antibodies

Only 1 patient was tested positive for ADA at pre-dose of Cycle 1 Day 1. However, it was considered as false-positive because the titer value was close to the cut point, and this patient was tested negative for ADA at all subsequent cycles post-baseline.

Time frame: From baseline to 30 days after the last dose of study drug

Population: Patients who have at least one post-baseline sample for Anti-MEDI-551 antibodies.

Arm	Measure	Group	Value (NUMBER)
2 mg/kg	Anti-MEDI-551 Antibodies	negative at all time points	3 Participants
2 mg/kg	Anti-MEDI-551 Antibodies	positive at least 1 time point	0 Participants
4 mg/kg	Anti-MEDI-551 Antibodies	negative at all time points	7 Participants
4 mg/kg	Anti-MEDI-551 Antibodies	positive at least 1 time point	0 Participants
8 mg/kg	Anti-MEDI-551 Antibodies	positive at least 1 time point	1 Participants
8 mg/kg	Anti-MEDI-551 Antibodies	negative at all time points	3 Participants
12 mg/kg	Anti-MEDI-551 Antibodies	negative at all time points	6 Participants
12 mg/kg	Anti-MEDI-551 Antibodies	positive at least 1 time point	0 Participants

Secondary

Maximum Tolerated Dose

A dose was considered non-tolerated and dose escalation stopped if ≥2 of up to 6 evaluable patients experienced a DLT at any dose level. MTD is the last dose level before the non-tolerated dose.

Time frame: From baseline to 28 days after the first dose of study drug

Population: All subjects in the dose escalation phase who have received MEDI-551 at Day 1 and Day 8 and completed the safety follow-up through the dose-limiting toxicity (DLT) evaluation period (28 days), or who experienced a DLT.

Arm	Measure	Value (NUMBER)
2 mg/kg	Maximum Tolerated Dose	8 mg/kg

Secondary