Safety and Dose Ranging Study of Samalizumab to Treat Relapsing or Refractory CLL or MM

Phase 1

Terminated

• Conditions: B-cell Chronic Lymphocytic Leukemia; Multiple Myeloma
• Interventions: Drug: Samalizumab

• Registration Number: NCT00648739
• Lead Sponsor: Alexion Pharmaceuticals, Inc.

Brief Summary

The purpose of this study was to determine the safety and maximum tolerated dose (MTD) of ALXN6000 (samalizumab) in treating relapsing or refractory B-cell chronic lymphocytic leukemia (B-CLL) or multiple myeloma (MM) and to study how samalizumab may help the immune system fight tumors that express CD200.

Detailed Description

This was an open-label multicenter study for participants with relapsing or refractory B-CLL or MM. The study was planned to be conducted in 2 parts: Part A and Part B. Both parts were to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy (to the extent possible) of samalizumab in the target participant population. Part A was designed as the open-label, intravenous (IV) single dose-escalation portion of the study to determine the MTD and to assess the overall safety of different dose levels of up to 4 IV doses of samalizumab in participants with either refractory or relapsing B-CLL or MM. Initially, at least 3 participants would be enrolled into a cohort until a dose-limiting toxicity (DLT) was reached. If any 1 of the initial 3 participants in the cohort experienced a DLT, the cohort would be expanded to at least 6 participants.

After determination of the MTD in Part A, the Sponsor was to review the safety, PK, and relevant PD data to determine the dosing administration schedule for Part B. However, no participants were enrolled for Part B, as the study was terminated by the Sponsor for administrative reasons.

Participant enrollment in Cohort 7 (600 milligrams per square meter \[mg/m\^2\] dose level), Part A, was halted after enrollment of the first participant. The study was terminated by the Sponsor for administrative reasons and not due to any safety concerns. Participants who were on study at the time of study termination were allowed to continue until the expiry date of the drug lot being used and then were followed for 30 (±1) days per protocol. The study was terminated by the Sponsor at that time. Part B of the study was not conducted.

Study Timeline

• Study First Submitted: 2008-03-28
• Study First Submitted QC: 2008-03-31
• Study First Posted: 2008-04-01
• Study Start: 2008-06-19
• Primary Completion: 2010-12-14
• Study Completion: 2010-12-14
• Disposition First Submitted: 2017-01-27
• Disposition First Submitted QC: 2017-01-27
• Disposition First Posted: 2017-01-30
• Results First Submitted: 2018-09-28
• Status Verified: 2019-02
• Results First Submitted QC: 2019-02-12
• Last Update Submitted: 2019-02-12
• Results First Posted: 2019-03-05
• Last Update Posted: 2019-03-05

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 26

Inclusion Criteria

• Relapsing or Refractory B-CLL or MM
• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2
• Anticipated survival of greater than 6 months
• Female participants of childbearing potential must agree to use 2 forms of contraception
• Participants must have a standard indication for treatment of their malignancy
• Is willing and able to give written informed consent prior to any procedure not considered standard of care

Exclusion Criteria

• Absolute neutrophil count (ANC) < 1000 x 10^9/liter (L)
• Platelet count < 50,000 x 10^9/L
• Pregnant or lactating women
• Prior history of autoimmune hemolysis requiring therapy
• Prior history of immune thrombocytopenia
• Active autoimmune disease requiring immunosuppressive therapy
• Positive Coombs' Test (neither direct or indirect)
• Ongoing corticosteroid treatment equivalent to the mineralocorticoid potency of 10 milligrams (mg) /day of prednisone, or greater, for any condition
• Prior stem cell transplantation within 4 weeks prior to enrollment
• Prior chemotherapy for the applicable malignancy within 30 days of enrollment
• Neurosurgery or cranial radiation therapy within 1 year of enrollment
• Clinically significant renal, hepatic, or cardiopulmonary disease

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Samalizumab	Samalizumab	All doses of samalizumab were individualized based on the participant's body surface area in mg/m\^2 based on screening height and weight. Participants were assigned to a dose cohort, ranging from 50 to 600 mg/m\^2, and received a single IV dose of samalizumab. Participants who tolerated the drug and demonstrated at least stable disease received up to 3 additional cycles of samalizumab at the same dose originally received at a minimum of 28-day intervals and beginning no sooner than 6 weeks after the initial dose. If no participants enrolled into a cohort experienced a DLT, escalation to the next dose level occurred with a new cohort. If any 1 of the initial 3 participants in the cohort experienced a DLT, the cohort was expanded to at least 6 participants. Then, if less than one third of participants within the cohort experienced a DLT, escalation to the next dose level occurred with a new cohort. Dose cohorts were enrolled sequentially.

Primary Outcome Measures

Name	Time	Method
Number Of Participants With Treatment-Emergent Adverse Events (TEAEs)	From first dose through 10 weeks after the last dose	A TEAE was defined as any event not present prior to exposure to samalizumab or any event already present that worsened in either intensity or frequency following exposure to samalizumab. A treatment-emergent serious adverse event was defined as any event that resulted in death, was immediately life threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, or was a congenital anomaly/birth defect. A summary of serious and all other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.
Maximum Tolerated Dose (MTD) Of Samalizumab	From first dose through 10 weeks after the last dose	The MTD was to be defined as the dose level at which less than one-third of participants experienced a dose-limiting toxicity (DLT) during the first 28 days of treatment and immediately below the dose at which at least one-third of participants experienced a DLT.; A DLT was defined as any Grade 3 or greater toxicity according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 not related to the disease under study or its sequelae that occurred in the first 28 days after dosing in Cycle 1. The NCI CTCAE grading system for the organ of involvement was used to classify severity of adverse autoimmune reactions.

Secondary Outcome Measures

Name	Time	Method
Density Of B-CLL Cells Bound At Baseline (Predose) And Day 1 (Postdose)	Baseline (Predose) and Day 1 (Postdose)	Bound samalizumab was detected using a mAb specific for samalizumab. The binding of samalizumab to CD200 on peripheral B-CLL tumor cells was evaluated in participants with B-CLL by flow cytometry and expressed as mean channel fluorescence intensity (MFI) of bound samalizumab to provide an indication of the density of bound samalizumab on target B-CLL cells. For participants with insufficient numbers of peripheral B-CLL for analysis, the samples were documented as "unevaluable" and an analysis was not performed.
Percent Of Bound Samalizumab On B-Cell Chronic Lymphocytic Leukemia (B-CLL) Cells In Participants With B-CLL At Baseline (Predose) And Day 1 (Postdose)	Baseline (Predose) and Day 1 (Postdose)	Bound samalizumab was detected using a monoclonal antibody (mAb) specific for samalizumab. The binding of samalizumab to CD200 on peripheral B-CLL tumor cells was evaluated in participants with B-CLL by flow cytometry and expressed as the percent of B-CLL cells bound by samalizumab. For participants with insufficient numbers of peripheral B-CLL for analysis, the samples were documented as "unevaluable" and an analysis was not performed.
Clinical Response Of Participants With B-CLL Following Samalizumab Dosing Using Modified NCI Working Group Response Criteria For ORR Rate	From first dose through 10 weeks after the last dose	Clinical responses assessed using the Modified NCI Working Group Response Criteria. Overall Response Rate (ORR)=percentage of participants who maintained best response for ≥1 month after achieving that best response and having complete response (CR), partial response (PR), nodular partial response (nPR), or stable disease (SD). CR=absence of lymphadenopathy, hepatomegaly, or splenomegaly and normal complete blood count (CBC). PR=≥50% decrease in peripheral lymphocyte count or ≥50% reduction in lymphadenopathy, hepatomegaly, or splenomegaly and normal or 50% improvement over baseline CBC. nPR=CR participants with lymphoid aggregates. Progressive disease (PD)=\>50% increase for \>2 lymph nodes, spleen and/or liver size, or absolute number of circulating lymphocytes; or new lymph nodes. SD=have not achieved CR, PR, or nPR or have not shown PD. Features must be exhibited for ≥1month for CR/PR. Number of participants with individual best response and ORR for each cohort is presented.
Clinical Response Of Participants With Multiple Myeloma (MM) Following Dosing With Samalizumab	From first dose through 10 weeks after the last dose	Clinical responses of samalizumab were assessed using the International Myeloma Working Group Uniform Response Criteria. ORR was defined as the percentage of participants who had either stringent complete response, complete response, very good partial response, or partial response on 2 consecutive assessments made at any time before the administration of any new therapy.; The number of participants with the individual best response and ORR for each cohort is presented.