Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of VAY736 in Relapsed or Refractory CLL Patients (VAY736Y)

A Phase 1, Muticenter, Open-label, Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of VAY736 When Administered Intravenously in Relapsed or Refractory Chronic Lymphocytic Leukemia Patients

This study will assess the safety and preliminary efficacy of escalating doses of VAY736 in relapsed or refractory CLL patients.

Study Overview

• Status: Terminated
• Conditions: Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)
• Intervention / Treatment: Drug: VAY736

Detailed Description

This Phase 1, multicenter, open-label, study will investigate the safety, pharmacokinetics, pharmacodynamics, and preliminary antil-CLL activity of VAY736 in patients with relapsed/refractory CLL who have received at least two prior regimens. The study will include one arm in the dose escalation phase and two arms in the dose expansion phase.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 1

Contacts and Locations

Study Locations

• Spain
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
• United States
  • Florida
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center & Research Institute Moffitt Cancer SC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Dose escalation: Relapsed/refractory CLL following at least -two prior treatment regimen

• Dose expansion:

  • Arm 1: Relapsed/refractory CLL following two to three prior treatment regimens
  • Arm 2: Relapsed/refractory CLL following four or more prior treatment regimens
• Discontinued any previous anti-cancer and investigational therapy including radiation, radioimmunotherapy, and monoclonal antibody therapy for at least 28 days or 5 half-lives of the investigational product, whichever is longer, before study treatment administration, and must have recovered fully from the adverse effects of such treatment before beginning study treatment
• Discontinued prior alemtuzumab therapy for at least 6 months
• Age 18 years
• Eastern cooperative oncology group (ECOG) performance status grade ≤ 1
• Life expectancy > 3 months

• Meet the following laboratory criteria (must be obtained within 14 days of enrollment):

  • Adequate end-organ function as assessed by laboratory tests, as specified in the protocol.

• Written informed consent obtained prior to any screening procedures

Exclusion Criteria:

• Major surgery within 28 days before study treatment or have not recovered fully from the adverse effects of any major or minor surgical procedures before study treatment
• History of another primary malignancy that is currently clinically significant or currently requires active intervention (except adequately treated in situ carcinoma of the cervix or non-melanoma carcinoma of the skin or any other curatively treated malignancy that has not been treated in the prior 3 months or expected to require treatment for recurrence during the course of the study).
• Prior anaphylactic or other severe infusion reaction such that the patient is unable to tolerate human immunoglobulin or monoclonal antibody administration
• Clinically significant central nervous system disease
• Myocardial infarction within 6 months prior to enrollment or New York Hospital Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or significant conduction system abnormalities in the opinion of the investigator
• History of an active infection requiring systemic therapy within 14 days before study treatment. Prophylactic antibiotics and antiviral therapies are permitted.
• Active autoimmune disease requiring immunosuppressive therapy
• Known history of human immunodeficiency virus (HIV) or active infection with hepatitis C virus or hepatitis B virus or any active bacterial, viral, or fungal infection requiring systemic therapy
• Ongoing corticosteroid use (>10 mg/day prednisone or equivalent)
• Pregnant or nursing (lactating) women.
• Sexually active males must use a condom during intercourse while taking the drug and for 3 months after stopping treatment and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1- relapsed/refractory CLL patients; Patients with relapsed/refractory CLL with two or three prior treatment regimens	Drug: VAY736; VAY736 is a human immunoglobulin of the G class (IgG1/k) monoclonal antibody (mAb) designed to specifically bind the BAFF receptor. VAY736 binds primarily to B-cells through its fragment antigen binding (Fab) region, in human whole blood and spleen samples; it does not bind to natural killer (NK) cells, monocytes, dendritic cells, granulocytes, or platelets.
Experimental: Arm 2 - rituximab or ofatumumab refractory CLL patients; Patients with relapsed/refractory CLL with four or more prior treatment regimens	Drug: VAY736; VAY736 is a human immunoglobulin of the G class (IgG1/k) monoclonal antibody (mAb) designed to specifically bind the BAFF receptor. VAY736 binds primarily to B-cells through its fragment antigen binding (Fab) region, in human whole blood and spleen samples; it does not bind to natural killer (NK) cells, monocytes, dendritic cells, granulocytes, or platelets.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose limiting toxicities (DLTs)	Frequency and characteristics of DLTs. Determination of the maximum tolerated dose (MTD) and/or the recommended dose for expansion (RDE) of VAY736 when administered weekly in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) (dose escalation only).	8 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate (ORR)	Determine the preliminary anti-CLL (chronic lymphocytic leukemia) activity of VAY736 at the MTD/RDE in patients with relapsed or refractory CLL.	1 year
VAY736 plasma concentrations	Plasma concentrations to characterize the pharmaconinetics of VAY736	1 year
Blood Serum concentrations of antibodies to VAY736	To assess the immunogenicity of VAY736.	1 year
Hematology parameters of VAY736	To assess the pharmacodynamics of VAY736.	1 year
Number of patients with Advers Events (AEs) as a measure of safety and tolerability.	To assess the safety and tolerability of VAY736 by type, frequency, and severity of AEs, changes in hematology and blood chemistry values, assessments of physical examinations, vital signs, and electrocardiograms.	1 year
PharmacoKinetics (PK) parameters of VAY736	PK parameters include AUC0-tlast, Cmax, T1/2	1 year
Receptor occupancy for VAY736	To assess the pharmacodynamic effect of VAY736.	1 year

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start: July 1, 2012
• Primary Completion (Actual): November 1, 2012
• Study Completion (Actual): November 1, 2012

Study Registration Dates

• First Submitted: April 29, 2014
• First Submitted That Met QC Criteria: May 12, 2014
• First Posted (Estimate): May 14, 2014

Study Record Updates

• Last Update Posted (Actual): February 28, 2018
• Last Update Submitted That Met QC Criteria: February 27, 2018
• Last Verified: February 1, 2018

More Information

Terms related to this study

• Keywords: CLL
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia, B-Cell; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid
• Other Study ID Numbers: CVAY736Y2101; 2011-005485-38 (EudraCT Number)