VAY736 in Combination With Ibrutinib in Patients With CLL on Ibrutinib

Study Overview
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Brief Summary
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Patients enrolled to the study had chronic lymphocytic leukemia (CLL) and received ibrutinib. Patients have either received ibrutinib for one year without having had a complete response or patients developed a resistance mutation to ibrutinib. This study had two parts, a dose escalation part and a dose expansion part. Patients in the expansion part were enrolled into two arms depending on whether they had ibrutinib resistance mutations present at baseline.

Official Title
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Phase Ib Open-label Study of VAY736 and Ibrutinib in Patients With Chronic Lymphocytic Leukemia (CLL) on Ibrutinib Therapy

Conditions
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Chronic Lymphocytic Leukemia (CLL)

Intervention / Treatment
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* Drug: VAY736
* Drug: ibrutinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of CLL per the WHO classification At least 18 years of age Lack of a complete response after receiving ibrutinib for > 1 year OR presence of known ibrutinib resistance mutation Actively receiving ibrutinib at either 420 mg (patients enrolled to the escalation arm) or at a stable dose for at least 2 months prior to starting study treatment (patients enrolled to the expansion arm) Exclusion Criteria: Known history of HIV Active hepatitis B or C infection Receipt of attenuated vaccine within 2 weeks prior to starting study treatment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation<br>Increasing doses of VAY736 in combination with a fixed dose of ibrutinib. | Drug: VAY736<br>* Experimental<br>Drug: ibrutinib<br>* Approved medication<br>* Other names: Imbruvica;|
| Experimental: Dose expansion<br>Evaluation of the MTD/RD of the combination of VAY736 and ibrutinib that was identified in dose escalation. | Drug: VAY736<br>* Experimental<br>Drug: ibrutinib<br>* Approved medication<br>* Other names: Imbruvica;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 (Dose escalation only) | A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 assessed as unrelated to disease, disease progression, inter-current illness or concomitant medications that occurs within the first cycle of treatment during the dose escalation part of the study. Other clinically significant toxicities may be considered to be DLTs, even if not CTCAE grade 3 or higher. The duration of one treatment cycle is 28 days. | 28 days | 
| Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Number of participants with AEs and SAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs. | 2 years | 
| Incidence of dose reductions and dose interruptions of the combination of VAY736 and ibrutinib | Dose reductions and interruptions to assess the tolerability of the combination of VAY736 and ibrutinib. | 2 years | 
| Dose intensity of the combination of VAY736 and ibrutinib | Dose intensity is calculated as actual cumulative dose divided by duration of exposure. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of patients with complete response (CR) as assessed by investigators per IWCLL | Assessment of anti-tumor activity based on investigator assessment per International Working Group - Chronic Lymphocytic Leukemia (IWCLL) | Cycle 9 Day 1. The duration of one cycle is 28 days. | 
| Overall response rate (ORR) assessed by investigators per IWCLL criteria | ORR is defined as best overall response (BOR) of complete response (CR) or partial response (PR), assessed by investigators per IWCLL criteria. | 2 years | 
| Time to progression (TTP) | TTP is the time from start of treatment to the date of event which is defined as the first documented progression or death due to underlying cancer. | 2 years | 
| Clearance of ibrutinib resistance mutations (BTKC481 and/or PLCγ2 hotspot) | Clearance of ibrutinib resistance mutation is defined as less than 1% mutation bearing alleles (BTKC481 and/or PLCγ2) during treatment. This endpoint is only applicable to the expansion arm involving chronic lymphocytic leukemia (CLL) patients on ibrutinib with acquired resistance mutations but without clinical relapse. | 2 years | 
| Peak plasma concentration (Cmax) of VAY736 and ibrutinib | Plasma pharmacokinetic (PK) parameters calculated using non-compartmental methods. | 2 years | 
| Area under the plasma concentration- time curve (AUC) of VAY736 and ibrutinib | Plasma pharmacokinetic (PK) parameters calculated using non-compartmental methods. | 2 years | 
| Presence of anti-VAY736 antibodies | Number of participants with anti-VAY736 antibodies at baseline and on treatment. | Baseline, up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ibrutinib, CLL, VAY736, Chronic lymphocytic leukemia, Bruton's Tyrosine Kinase, BTK mutation