Chronic Lymphocytic Leukemia (CLL)
Conditions
Keywords
Ibrutinib, VAY736, Chronic lymphocytic leukemia, CLL, Bruton's Tyrosine Kinase, BTK mutation
Brief summary
Patients enrolled to the study had chronic lymphocytic leukemia (CLL) and received ibrutinib. Patients had 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.
Interventions
DRUGVAY736
Experimental
DRUGibrutinib
Approved medication
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose-Limiting Toxicities (DLTs) in Cycle 1 (Escalation Only) | 28 days | 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 28 days of treatment with the combination of VAY736 and ibrutinib and meets the criteria defined in the study protocol. Other clinically significant toxicities may be considered to be DLTs, even if not CTCAE grade 3 or higher. |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | From first dose of study treatment up to 30 days after the last dose of VAY736, up to approximately 8.8 months | Number of participants with AEs (any AE regardless of seriousness) and SAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs. AE grades to characterize the severity of the AEs were based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. For CTCAE v4.03, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE. All patients were followed for a 30-day safety follow-up period subsequent to completion of VAY736 therapy. No new AEs or SAEs were collected beyond the 30-day safety follow-up or during the efficacy follow up period. |
| Number of Participants With Dose Reductions and Dose Interruptions of VAY736 | Up to 7.8 months | For patients who did not tolerate the protocol-specified dosing schedule of the study drugs, dose adjustments could be permitted in order to allow the patient to continue study treatment. |
| Number of Participants With Dose Reductions and Dose Interruptions of Ibrutinib | Up to 8.5 months | For patients who did not tolerate the protocol-specified dosing schedule of the study drugs, dose adjustments could be permitted in order to allow the patient to continue study treatment. |
| Dose Intensity of VAY736 | Up to 7.8 months | Dose intensity of VAY736 was calculated as: Actual Cumulative dose (mg/kg) / (Duration of exposure in weeks/2) |
| Dose Intensity of Ibrutinib | Up to 8.5 months | Dose intensity of ibrutinib was calculated as: Actual Cumulative dose (mg) / (Duration of exposure in days) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression (TTP) in the Dose Expansion Part | Up to approximately 2.7 years | Efficacy was based on local investigator assessment per International Working Group - Chronic Lymphocytic Leukemia (IWCLL) response criteria. TTP is defined as the time from start of treatment to date of event which is defined as the first documented progression or death due to underlying cancer. If a patient had not had an event, TTP was censored at the date of the last adequate disease assessment. TTP was analyzed using Kaplan-Meier estimates. |
| Percentage of Participants With Clearance of Ibrutinib Resistance Mutation During Treatment (up to C9) for Expansion Arm B | Up to Cycle 9 Day 1. The duration of each cycle was 28 days. | Clearance was defined as less than 1% mutation bearing alleles (BTKC481 and/or PLCγ2) during treatment. Negative mutation is defined as having clearance of the baseline ibrutinib resistance mutation during treatment (up to Cycle 9 (C9)). |
| Maximum Observed Serum Concentration (Cmax) of VAY736 | Pre-infusion and 2, 6, 24, 72, 168 and 336 hours after end of infusion on Cycle 1 Day 1 and Cycle 3 Day 1. The duration of the infusion was approximately 2 hours. 1 cycle=28 days | Pharmacokinetic (PK) parameters were calculated based on VAY736 serum concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed concentration following a dose. |
| Time to Reach Maximum Serum Concentration (Tmax) of VAY736 | Pre-infusion and 2, 6, 24, 72, 168 and 336 hours after end of infusion on Cycle 1 Day 1 and Cycle 3 Day 1. The duration of the infusion was approximately 2 hours. 1 cycle=28 days | PK parameters were calculated based on VAY736 serum concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) concentration following a dose. Actual recorded sampling times were considered for the calculations. |
| CR or CRi Rate at C9 for Expansion Arm A and Arm B by Investigator Per IWCLL | Cycle 9 Day 1 (C9). The duration of each cycle was 28 days. | Percentage of participants with Complete Response (CR) or Complete Response with Incomplete Marrow Recovery (CRi) by investigator assessment per International Working Group - Chronic Lymphocytic Leukemia (IWCLL) response criteria. |
| Maximum Observed Plasma Concentration (Cmax) of Ibrutinib | Pre-dose and 0.5, 2, 6 and 24 hours post-dose on Cycle 1 Day 1 and Cycle 1 Day 8. 1 cycle=28 days | PK parameters were calculated based on ibrutinib plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed concentration following a dose. |
| Time to Reach Maximum Plasma Concentration (Tmax) of Ibrutinib | Pre-dose and 0.5, 2, 6 and 24 hours post-dose on Cycle 1 Day 1 and Cycle 1 Day 8. 1 cycle=28 days | PK parameters were calculated based on ibrutinib plasma concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) concentration following a dose. Actual recorded sampling times were considered for the calculations. |
| Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Ibrutinib | Pre-dose and 0.5, 2, 6 and 24 hours post-dose on Cycle 1 Day 1 and Cycle 1 Day 8. 1 cycle=28 days | PK parameters were calculated based on ibrutinib plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation. |
| Number of Participants With Anti-VAY736 Antibodies | Baseline (before first dose) and post-baseline (assessed throughout the VAY736 treatment, up to 7.8 months). | VAY736 immunogenicity was evaluated in serum samples. Anti-drug antibodies (ADA) status was defined as follows: * ADA-negative at baseline: baseline sample where assay is ADA negative * ADA-positive at baseline: baseline sample where assay is ADA positive * ADA-negative post-baseline: ADA-negative sample at baseline and at least 1 post-baseline sample, all of which are ADA-negative samples * Treatment-induced ADA-positive: ADA-negative sample at baseline and at least 1 treatment-induced ADA-positive sample * Treatment-boosted ADA-positive: ADA-positive sample at baseline and at least 1 treatment-boosted ADA-positive sample * ADA-inconclusive post-baseline: patient who does not qualify for any of the above definitions |
| Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of VAY736 | Pre-infusion and 2, 6, 24, 72, 168 and 336 hours after end of infusion on Cycle 1 Day 1 and Cycle 3 Day 1. The duration of the infusion was approximately 2 hours. 1 cycle=28 days | PK parameters were calculated based on VAY7736 serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation. |
| Posterior Mean of CR or CRi Response Rate at C9 for Expansion Arm A and Arm B (Bayesian Analysis) | Cycle 9 Day 1 (C9). The duration of each cycle was 28 days. | The rate of CR/CRi at C9 was analyzed for each expansion arm using a Bayesian modeling approach. A minimally informative beta distribution was used as prior distribution with parameters a=0.25 and b=1. This assumed, a priori, that the response rate was 20%. Values estimated from the model at Cycle 9 are presented in the table. Posterior geometric mean for CR/CRi rate and 90% credible intervals in each group are presented. |
| Posterior Probability That the True CR or CRi Response Rate at C9 for Expansion Arm A and Arm B Falls in Pre-defined Activity Intervals (Bayesian Analysis) | Cycle 9 Day 1 (C9). The duration of each cycle was 28 days. | The rate of CR/CRi at C9 was analyzed for each expansion arm using a Bayesian modeling approach. A minimally informative beta distribution was used as prior distribution with parameters a=0.25 and b=1. This assumed, a priori, that the response rate was 20%. Values estimated from the model at Cycle 9 are presented in the table. The posterior probability that the true CR/CRi rate falls in the activity intervals defined below is presented: * \[0, 20%) - clinically not meaningful * \[20%, 40%) - moderate clinical benefit * \[40%, 100%\] - superior clinical benefit |
| Overall Response Rate (ORR) Assessed by Investigator Per IWCLL in the Dose Escalation Part | Up to approximately 2.5 years | Efficacy was based on local investigator assessment per International Working Group - Chronic Lymphocytic Leukemia (IWCLL) response criteria. ORR per IWCLL is defined as the percentage of participants with a best overall response of Complete Response (CR), Complete Response with Incomplete Marrow Recovery (CRi) or Partial Response (PR). |
| Overall Response Rate (ORR) Assessed by Investigator Per IWCLL in the Dose Expansion Part | Up to approximately 2.7 years | Efficacy was based on local investigator assessment per International Working Group - Chronic Lymphocytic Leukemia (IWCLL) response criteria. ORR per IWCLL is defined as the percentage of participants with a best overall response of Complete Response (CR), Complete Response with Incomplete Marrow Recovery (CRi) or Partial Response (PR). |
| Time to Progression (TTP) in the Dose Escalation Part | Up to approximately 2.5 years | Efficacy was based on local investigator assessment per International Working Group - Chronic Lymphocytic Leukemia (IWCLL) response criteria. TTP is defined as the time from start of treatment to date of event which is defined as the first documented progression or death due to underlying cancer. If a patient had not had an event, TTP was censored at the date of the last adequate disease assessment. TTP was analyzed using Kaplan-Meier estimates. |
Countries
United States
Participant flow
Recruitment details
A total of 39 patients were enrolled in the study. Fifteen patients participated in the dose escalation part across four treatment arms: VAY736 0.3 mg/kg Q2W + ibrutinib 420 mg, VAY736 1 mg/kg Q2W + ibrutinib 420 mg, VAY736 3 mg/kg Q2W + ibrutinib 420 mg, and VAY735 9 mg/kg + ibrutinib 420 mg. The remaining 24 subjects were enrolled in the expansion part and were treated with VAY736 3 mg/kg Q2W in combination with ibrutinib 420 mg or 280 mg.
Pre-assignment details
The screening period began once patients had signed the study informed consent. Screening evaluations had to be completed within 21 days prior to the first dose of study treatment with the exception of baseline tumor assessments that could be conducted within 28 days prior to the first dose of study treatment. After screening, the treatment period started on Cycle 1 Day 1.
Participants by arm
| Arm | Count |
|---|---|
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg VAY736 0.3 mg/kg i.v. once every 2 weeks in combination with ibrutinib 420 mg oral once daily | 4 |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg VAY736 1 mg/kg i.v. once every 2 weeks in combination with ibrutinib 420 mg oral once daily | 3 |
| VAY736 3mg/kg Q2W + Ibrutinib 280mg VAY736 3 mg/kg i.v. once every 2 weeks in combination with ibrutinib 280 mg oral once daily | 1 |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg VAY736 3 mg/kg i.v. once every 2 weeks in combination with ibrutinib 420 mg oral once daily | 27 |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg VAY736 9 mg/kg i.v. once every 2 weeks in combination with ibrutinib 420 mg oral once daily | 4 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Dose Escalation | Patient decision | 0 | 0 | 0 | 0 | 1 |
| Dose Escalation | Progressive disease | 1 | 1 | 0 | 0 | 1 |
| Dose Expansion | Adverse Event | 0 | 0 | 0 | 1 | 0 |
| Dose Expansion | Patient decision | 0 | 0 | 0 | 1 | 0 |
| Dose Expansion | Physician Decision | 0 | 0 | 0 | 1 | 0 |
| Dose Expansion | Progressive disease | 0 | 0 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | VAY736 1mg/kg Q2W + Ibrutinib 420mg | VAY736 3mg/kg Q2W + Ibrutinib 280mg | VAY736 3mg/kg Q2W + Ibrutinib 420mg | VAY736 9mg/kg Q2W + Ibrutinib 420mg | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 69.3 years STANDARD_DEVIATION 6.02 | 61.0 years STANDARD_DEVIATION 1.73 | 57.0 years | 63.5 years STANDARD_DEVIATION 10.36 | 65.0 years STANDARD_DEVIATION 10.42 | 63.9 years STANDARD_DEVIATION 9.5 |
| Age, Customized 18 - < 65 years | 1 Participants | 3 Participants | 1 Participants | 12 Participants | 2 Participants | 19 Participants |
| Age, Customized 65 - < 85 years | 3 Participants | 0 Participants | 0 Participants | 15 Participants | 2 Participants | 20 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Missing | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 4 Participants | 2 Participants | 1 Participants | 26 Participants | 3 Participants | 36 Participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 0 Participants | 7 Participants | 3 Participants | 11 Participants |
| Sex: Female, Male Male | 4 Participants | 2 Participants | 1 Participants | 20 Participants | 1 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 3 | 0 / 1 | 0 / 27 | 0 / 4 | 0 / 39 | 0 / 4 | 0 / 3 | 0 / 1 | 1 / 27 | 0 / 4 |
| other Total, other adverse events | 4 / 4 | 3 / 3 | 1 / 1 | 27 / 27 | 4 / 4 | 39 / 39 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 4 | 2 / 3 | 0 / 1 | 2 / 27 | 0 / 4 | 4 / 39 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 |
Outcome results
Primary
Dose Intensity of Ibrutinib
Dose intensity of ibrutinib was calculated as: Actual Cumulative dose (mg) / (Duration of exposure in days)
Time frame: Up to 8.5 months
Population: All patients who received at least one dose of study treatment in the dose escalation or dose expansion part of the study. Patients were analyzed according to the study treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Dose Intensity of Ibrutinib | 420.00 mg/day |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Dose Intensity of Ibrutinib | 420.00 mg/day |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | Dose Intensity of Ibrutinib | 280.00 mg/day |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Dose Intensity of Ibrutinib | 420.00 mg/day |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Dose Intensity of Ibrutinib | 420.00 mg/day |
Primary
Dose Intensity of VAY736
Dose intensity of VAY736 was calculated as: Actual Cumulative dose (mg/kg) / (Duration of exposure in weeks/2)
Time frame: Up to 7.8 months
Population: All patients who received at least one dose of study treatment in the dose escalation or dose expansion part of the study. Patients were analyzed according to the study treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Dose Intensity of VAY736 | 0.30 mg/kg/2 weeks |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Dose Intensity of VAY736 | 0.98 mg/kg/2 weeks |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | Dose Intensity of VAY736 | 3.00 mg/kg/2 weeks |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Dose Intensity of VAY736 | 3.00 mg/kg/2 weeks |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Dose Intensity of VAY736 | 8.97 mg/kg/2 weeks |
Primary
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Number of participants with AEs (any AE regardless of seriousness) and SAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs. AE grades to characterize the severity of the AEs were based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. For CTCAE v4.03, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE. All patients were followed for a 30-day safety follow-up period subsequent to completion of VAY736 therapy. No new AEs or SAEs were collected beyond the 30-day safety follow-up or during the efficacy follow up period.
Time frame: From first dose of study treatment up to 30 days after the last dose of VAY736, up to approximately 8.8 months
Population: All patients who received at least one dose of study treatment in the dose escalation or dose expansion part of the study. Patients were analyzed according to the study treatment received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 4 Participants |
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Fatal SAEs | 0 Participants |
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related SAEs | 0 Participants |
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs with grade >=3 | 1 Participants |
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related AEs | 2 Participants |
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related AEs with grade >=3 | 0 Participants |
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 1 Participants |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related AEs with grade >=3 | 1 Participants |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related AEs | 2 Participants |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 3 Participants |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related SAEs | 1 Participants |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs with grade >=3 | 2 Participants |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Fatal SAEs | 0 Participants |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related AEs with grade >=3 | 1 Participants |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 1 Participants |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related AEs | 1 Participants |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs with grade >=3 | 1 Participants |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related SAEs | 0 Participants |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Fatal SAEs | 0 Participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs with grade >=3 | 12 Participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 1 Participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related AEs | 15 Participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Fatal SAEs | 0 Participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related SAEs | 1 Participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 27 Participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related AEs with grade >=3 | 7 Participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs with grade >=3 | 0 Participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Fatal SAEs | 0 Participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related SAEs | 0 Participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related AEs | 1 Participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 4 Participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related AEs with grade >=3 | 0 Participants |
Primary
Number of Participants With Dose-Limiting Toxicities (DLTs) in Cycle 1 (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 28 days of treatment with the combination of VAY736 and ibrutinib and meets the criteria defined in the study protocol. Other clinically significant toxicities may be considered to be DLTs, even if not CTCAE grade 3 or higher.
Time frame: 28 days
Population: All patients in the dose escalation part who received at least one dose of study treatment and who either met the minimum exposure criterion defined in the protocol and had sufficient safety evaluations, or experienced a DLT during the first 28 days of treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Dose-Limiting Toxicities (DLTs) in Cycle 1 (Escalation Only) | 0 Participants |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Dose-Limiting Toxicities (DLTs) in Cycle 1 (Escalation Only) | 0 Participants |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Dose-Limiting Toxicities (DLTs) in Cycle 1 (Escalation Only) | 0 Participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Dose-Limiting Toxicities (DLTs) in Cycle 1 (Escalation Only) | 0 Participants |
Primary
Number of Participants With Dose Reductions and Dose Interruptions of Ibrutinib
For patients who did not tolerate the protocol-specified dosing schedule of the study drugs, dose adjustments could be permitted in order to allow the patient to continue study treatment.
Time frame: Up to 8.5 months
Population: All patients who received at least one dose of study treatment in the dose escalation or dose expansion part of the study. Patients were analyzed according to the study treatment received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Dose Reductions and Dose Interruptions of Ibrutinib | At least one dose reduction or interruption | 0 Participants |
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Dose Reductions and Dose Interruptions of Ibrutinib | At least one dose interruption | 0 Participants |
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Dose Reductions and Dose Interruptions of Ibrutinib | At least one dose reduction | 0 Participants |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Dose Reductions and Dose Interruptions of Ibrutinib | At least one dose reduction | 0 Participants |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Dose Reductions and Dose Interruptions of Ibrutinib | At least one dose reduction or interruption | 1 Participants |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Dose Reductions and Dose Interruptions of Ibrutinib | At least one dose interruption | 1 Participants |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Dose Reductions and Dose Interruptions of Ibrutinib | At least one dose reduction | 0 Participants |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Dose Reductions and Dose Interruptions of Ibrutinib | At least one dose reduction or interruption | 0 Participants |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Dose Reductions and Dose Interruptions of Ibrutinib | At least one dose interruption | 0 Participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Dose Reductions and Dose Interruptions of Ibrutinib | At least one dose reduction or interruption | 10 Participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Dose Reductions and Dose Interruptions of Ibrutinib | At least one dose interruption | 10 Participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Dose Reductions and Dose Interruptions of Ibrutinib | At least one dose reduction | 0 Participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Dose Reductions and Dose Interruptions of Ibrutinib | At least one dose reduction | 0 Participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Dose Reductions and Dose Interruptions of Ibrutinib | At least one dose reduction or interruption | 0 Participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Dose Reductions and Dose Interruptions of Ibrutinib | At least one dose interruption | 0 Participants |
Primary
Number of Participants With Dose Reductions and Dose Interruptions of VAY736
For patients who did not tolerate the protocol-specified dosing schedule of the study drugs, dose adjustments could be permitted in order to allow the patient to continue study treatment.
Time frame: Up to 7.8 months
Population: All patients who received at least one dose of study treatment in the dose escalation or dose expansion part of the study. Patients were analyzed according to the study treatment received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Dose Reductions and Dose Interruptions of VAY736 | At least one dose reduction | 0 Participants |
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Dose Reductions and Dose Interruptions of VAY736 | At least one dose reduction or interruption | 0 Participants |
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Dose Reductions and Dose Interruptions of VAY736 | At least one dose interruption | 0 Participants |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Dose Reductions and Dose Interruptions of VAY736 | At least one dose reduction | 0 Participants |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Dose Reductions and Dose Interruptions of VAY736 | At least one dose reduction or interruption | 1 Participants |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Dose Reductions and Dose Interruptions of VAY736 | At least one dose interruption | 1 Participants |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Dose Reductions and Dose Interruptions of VAY736 | At least one dose reduction | 0 Participants |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Dose Reductions and Dose Interruptions of VAY736 | At least one dose reduction or interruption | 0 Participants |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Dose Reductions and Dose Interruptions of VAY736 | At least one dose interruption | 0 Participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Dose Reductions and Dose Interruptions of VAY736 | At least one dose reduction or interruption | 5 Participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Dose Reductions and Dose Interruptions of VAY736 | At least one dose interruption | 5 Participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Dose Reductions and Dose Interruptions of VAY736 | At least one dose reduction | 1 Participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Dose Reductions and Dose Interruptions of VAY736 | At least one dose reduction | 0 Participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Dose Reductions and Dose Interruptions of VAY736 | At least one dose reduction or interruption | 0 Participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Dose Reductions and Dose Interruptions of VAY736 | At least one dose interruption | 0 Participants |
Secondary
Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Ibrutinib
PK parameters were calculated based on ibrutinib plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation.
Time frame: Pre-dose and 0.5, 2, 6 and 24 hours post-dose on Cycle 1 Day 1 and Cycle 1 Day 8. 1 cycle=28 days
Population: Patients in the pharmacokinetic analysis set (PAS) who had an available value for the outcome measure at each timepoint. PAS consists of all patients who received one of the planned treatments, provided at least one primary PK parameter and did not vomit within 8 hours after the dosing of ibrutinib. Patients were analyzed according to the study treatment received.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Ibrutinib | Cycle 1 Day 8 | 338 hr*ng/mL | Geometric Coefficient of Variation 69.6 |
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Ibrutinib | Cycle 1 Day 1 | 541 hr*ng/mL | Geometric Coefficient of Variation 145.3 |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Ibrutinib | Cycle 1 Day 8 | 552 hr*ng/mL | Geometric Coefficient of Variation 41.8 |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Ibrutinib | Cycle 1 Day 1 | 938 hr*ng/mL | Geometric Coefficient of Variation 63.4 |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Ibrutinib | Cycle 1 Day 1 | 890 hr*ng/mL | — |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Ibrutinib | Cycle 1 Day 1 | 696 hr*ng/mL | Geometric Coefficient of Variation 98.5 |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Ibrutinib | Cycle 1 Day 8 | 226 hr*ng/mL | Geometric Coefficient of Variation 134 |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Ibrutinib | Cycle 1 Day 8 | 323 hr*ng/mL | Geometric Coefficient of Variation 54.7 |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Ibrutinib | Cycle 1 Day 1 | 634 hr*ng/mL | Geometric Coefficient of Variation 34.6 |
Secondary
Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of VAY736
PK parameters were calculated based on VAY7736 serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation.
Time frame: Pre-infusion and 2, 6, 24, 72, 168 and 336 hours after end of infusion on Cycle 1 Day 1 and Cycle 3 Day 1. The duration of the infusion was approximately 2 hours. 1 cycle=28 days
Population: Patients in the pharmacokinetic analysis set (PAS) who had an available value for the outcome measure at each timepoint. PAS consists of all patients who received one of the planned treatments, provided at least one primary PK parameter and did not vomit within 8 hours after the dosing of ibrutinib. Patients were analyzed according to the study treatment received.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of VAY736 | Cycle 3 | 75.6 hr*µg/mL | Geometric Coefficient of Variation 31.7 |
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of VAY736 | Cycle 1 | 46.0 hr*µg/mL | Geometric Coefficient of Variation 29.1 |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of VAY736 | Cycle 3 | 166 hr*µg/mL | Geometric Coefficient of Variation 48.2 |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of VAY736 | Cycle 1 | 55.5 hr*µg/mL | Geometric Coefficient of Variation 46 |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of VAY736 | Cycle 1 | 217 hr*µg/mL | — |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of VAY736 | Cycle 1 | 256 hr*µg/mL | Geometric Coefficient of Variation 19.1 |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of VAY736 | Cycle 3 | 368 hr*µg/mL | Geometric Coefficient of Variation 55.2 |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of VAY736 | Cycle 3 | 1780 hr*µg/mL | Geometric Coefficient of Variation 18.1 |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of VAY736 | Cycle 1 | 930 hr*µg/mL | Geometric Coefficient of Variation 25 |
Secondary
CR or CRi Rate at C9 for Expansion Arm A and Arm B by Investigator Per IWCLL
Percentage of participants with Complete Response (CR) or Complete Response with Incomplete Marrow Recovery (CRi) by investigator assessment per International Working Group - Chronic Lymphocytic Leukemia (IWCLL) response criteria.
Time frame: Cycle 9 Day 1 (C9). The duration of each cycle was 28 days.
Population: All patients who received at least one dose of study treatment in the dose expansion part of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | CR or CRi Rate at C9 for Expansion Arm A and Arm B by Investigator Per IWCLL | 47.4 percentage of participants |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | CR or CRi Rate at C9 for Expansion Arm A and Arm B by Investigator Per IWCLL | 0 percentage of participants |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | CR or CRi Rate at C9 for Expansion Arm A and Arm B by Investigator Per IWCLL | 0 percentage of participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | CR or CRi Rate at C9 for Expansion Arm A and Arm B by Investigator Per IWCLL | 37.5 percentage of participants |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Ibrutinib
PK parameters were calculated based on ibrutinib plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed concentration following a dose.
Time frame: Pre-dose and 0.5, 2, 6 and 24 hours post-dose on Cycle 1 Day 1 and Cycle 1 Day 8. 1 cycle=28 days
Population: Patients in the pharmacokinetic analysis set (PAS) who had an available value for the outcome measure at each timepoint. PAS consists of all patients who received one of the planned treatments, provided at least one primary PK parameter and did not vomit within 8 hours after the dosing of ibrutinib. Patients were analyzed according to the study treatment received.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Maximum Observed Plasma Concentration (Cmax) of Ibrutinib | Cycle 1 Day 8 | 94.9 ng/mL | Geometric Coefficient of Variation 84.4 |
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Maximum Observed Plasma Concentration (Cmax) of Ibrutinib | Cycle 1 Day 1 | 93.5 ng/mL | Geometric Coefficient of Variation 120.6 |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Maximum Observed Plasma Concentration (Cmax) of Ibrutinib | Cycle 1 Day 8 | 158 ng/mL | Geometric Coefficient of Variation 53 |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Maximum Observed Plasma Concentration (Cmax) of Ibrutinib | Cycle 1 Day 1 | 123 ng/mL | Geometric Coefficient of Variation 28.8 |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | Maximum Observed Plasma Concentration (Cmax) of Ibrutinib | Cycle 1 Day 1 | 212 ng/mL | — |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Maximum Observed Plasma Concentration (Cmax) of Ibrutinib | Cycle 1 Day 1 | 83.3 ng/mL | Geometric Coefficient of Variation 146.9 |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Maximum Observed Plasma Concentration (Cmax) of Ibrutinib | Cycle 1 Day 8 | 62.2 ng/mL | Geometric Coefficient of Variation 149.4 |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Maximum Observed Plasma Concentration (Cmax) of Ibrutinib | Cycle 1 Day 8 | 97.0 ng/mL | Geometric Coefficient of Variation 54.1 |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Maximum Observed Plasma Concentration (Cmax) of Ibrutinib | Cycle 1 Day 1 | 104 ng/mL | Geometric Coefficient of Variation 62.7 |
Secondary
Maximum Observed Serum Concentration (Cmax) of VAY736
Pharmacokinetic (PK) parameters were calculated based on VAY736 serum concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed concentration following a dose.
Time frame: Pre-infusion and 2, 6, 24, 72, 168 and 336 hours after end of infusion on Cycle 1 Day 1 and Cycle 3 Day 1. The duration of the infusion was approximately 2 hours. 1 cycle=28 days
Population: Patients in the pharmacokinetic analysis set (PAS) who had an available value for the outcome measure at each timepoint. PAS consists of all patients who received one of the planned treatments, provided at least one primary PK parameter and did not vomit within 8 hours after the dosing of ibrutinib. Patients were analyzed according to the study treatment received.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Maximum Observed Serum Concentration (Cmax) of VAY736 | Cycle 3 | 11.2 µg/mL | Geometric Coefficient of Variation 21.2 |
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Maximum Observed Serum Concentration (Cmax) of VAY736 | Cycle 1 | 9.61 µg/mL | Geometric Coefficient of Variation 23 |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Maximum Observed Serum Concentration (Cmax) of VAY736 | Cycle 3 | 21.6 µg/mL | Geometric Coefficient of Variation 38.8 |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Maximum Observed Serum Concentration (Cmax) of VAY736 | Cycle 1 | 15.8 µg/mL | Geometric Coefficient of Variation 59.8 |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | Maximum Observed Serum Concentration (Cmax) of VAY736 | Cycle 1 | 65.9 µg/mL | — |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Maximum Observed Serum Concentration (Cmax) of VAY736 | Cycle 1 | 59.4 µg/mL | Geometric Coefficient of Variation 15.8 |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Maximum Observed Serum Concentration (Cmax) of VAY736 | Cycle 3 | 72.5 µg/mL | Geometric Coefficient of Variation 33.9 |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Maximum Observed Serum Concentration (Cmax) of VAY736 | Cycle 3 | 260 µg/mL | Geometric Coefficient of Variation 13.3 |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Maximum Observed Serum Concentration (Cmax) of VAY736 | Cycle 1 | 178 µg/mL | Geometric Coefficient of Variation 26.7 |
Secondary
Number of Participants With Anti-VAY736 Antibodies
VAY736 immunogenicity was evaluated in serum samples. Anti-drug antibodies (ADA) status was defined as follows: * ADA-negative at baseline: baseline sample where assay is ADA negative * ADA-positive at baseline: baseline sample where assay is ADA positive * ADA-negative post-baseline: ADA-negative sample at baseline and at least 1 post-baseline sample, all of which are ADA-negative samples * Treatment-induced ADA-positive: ADA-negative sample at baseline and at least 1 treatment-induced ADA-positive sample * Treatment-boosted ADA-positive: ADA-positive sample at baseline and at least 1 treatment-boosted ADA-positive sample * ADA-inconclusive post-baseline: patient who does not qualify for any of the above definitions
Time frame: Baseline (before first dose) and post-baseline (assessed throughout the VAY736 treatment, up to 7.8 months).
Population: Patients who received at least 1 dose of VAY736 and had a determinant baseline immunogenicity (IG) sample and at least 1 determinant post-baseline IG sample for assessing anti-VAY736 antibodies. Patients were analyzed according to the study treatment received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Anti-VAY736 Antibodies | ADA-negative at baseline | 4 participants |
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Anti-VAY736 Antibodies | ADA-positive at baseline | 0 participants |
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Anti-VAY736 Antibodies | ADA-negative post-baseline | 4 participants |
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Anti-VAY736 Antibodies | ADA-inconclusive post-baseline | 0 participants |
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Anti-VAY736 Antibodies | Treatment-induced ADA-positive | 0 participants |
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Anti-VAY736 Antibodies | Treatment-boosted ADA-positive | 0 participants |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Anti-VAY736 Antibodies | Treatment-induced ADA-positive | 0 participants |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Anti-VAY736 Antibodies | Treatment-boosted ADA-positive | 0 participants |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Anti-VAY736 Antibodies | ADA-negative at baseline | 3 participants |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Anti-VAY736 Antibodies | ADA-negative post-baseline | 3 participants |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Anti-VAY736 Antibodies | ADA-inconclusive post-baseline | 0 participants |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Anti-VAY736 Antibodies | ADA-positive at baseline | 0 participants |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Anti-VAY736 Antibodies | ADA-inconclusive post-baseline | 0 participants |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Anti-VAY736 Antibodies | Treatment-induced ADA-positive | 0 participants |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Anti-VAY736 Antibodies | ADA-negative at baseline | 1 participants |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Anti-VAY736 Antibodies | ADA-negative post-baseline | 1 participants |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Anti-VAY736 Antibodies | ADA-positive at baseline | 0 participants |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Anti-VAY736 Antibodies | Treatment-boosted ADA-positive | 0 participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Anti-VAY736 Antibodies | ADA-inconclusive post-baseline | 0 participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Anti-VAY736 Antibodies | ADA-positive at baseline | 3 participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Anti-VAY736 Antibodies | ADA-negative post-baseline | 24 participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Anti-VAY736 Antibodies | Treatment-boosted ADA-positive | 0 participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Anti-VAY736 Antibodies | Treatment-induced ADA-positive | 0 participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Anti-VAY736 Antibodies | ADA-negative at baseline | 24 participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Anti-VAY736 Antibodies | Treatment-induced ADA-positive | 0 participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Anti-VAY736 Antibodies | ADA-negative post-baseline | 4 participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Anti-VAY736 Antibodies | ADA-positive at baseline | 0 participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Anti-VAY736 Antibodies | Treatment-boosted ADA-positive | 0 participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Anti-VAY736 Antibodies | ADA-inconclusive post-baseline | 0 participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Number of Participants With Anti-VAY736 Antibodies | ADA-negative at baseline | 4 participants |
Secondary
Overall Response Rate (ORR) Assessed by Investigator Per IWCLL in the Dose Escalation Part
Efficacy was based on local investigator assessment per International Working Group - Chronic Lymphocytic Leukemia (IWCLL) response criteria. ORR per IWCLL is defined as the percentage of participants with a best overall response of Complete Response (CR), Complete Response with Incomplete Marrow Recovery (CRi) or Partial Response (PR).
Time frame: Up to approximately 2.5 years
Population: All patients who received at least one dose of study treatment in the dose escalation part of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Overall Response Rate (ORR) Assessed by Investigator Per IWCLL in the Dose Escalation Part | 50.0 percentage of participants |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Overall Response Rate (ORR) Assessed by Investigator Per IWCLL in the Dose Escalation Part | 0 percentage of participants |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | Overall Response Rate (ORR) Assessed by Investigator Per IWCLL in the Dose Escalation Part | 50.0 percentage of participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Overall Response Rate (ORR) Assessed by Investigator Per IWCLL in the Dose Escalation Part | 50.0 percentage of participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Overall Response Rate (ORR) Assessed by Investigator Per IWCLL in the Dose Escalation Part | 40.0 percentage of participants |
Secondary
Overall Response Rate (ORR) Assessed by Investigator Per IWCLL in the Dose Expansion Part
Efficacy was based on local investigator assessment per International Working Group - Chronic Lymphocytic Leukemia (IWCLL) response criteria. ORR per IWCLL is defined as the percentage of participants with a best overall response of Complete Response (CR), Complete Response with Incomplete Marrow Recovery (CRi) or Partial Response (PR).
Time frame: Up to approximately 2.7 years
Population: All patients who received at least one dose of study treatment in the dose expansion part of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Overall Response Rate (ORR) Assessed by Investigator Per IWCLL in the Dose Expansion Part | 84.2 percentage of participants |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Overall Response Rate (ORR) Assessed by Investigator Per IWCLL in the Dose Expansion Part | 0 percentage of participants |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | Overall Response Rate (ORR) Assessed by Investigator Per IWCLL in the Dose Expansion Part | 25.0 percentage of participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Overall Response Rate (ORR) Assessed by Investigator Per IWCLL in the Dose Expansion Part | 70.8 percentage of participants |
Secondary
Percentage of Participants With Clearance of Ibrutinib Resistance Mutation During Treatment (up to C9) for Expansion Arm B
Clearance was defined as less than 1% mutation bearing alleles (BTKC481 and/or PLCγ2) during treatment. Negative mutation is defined as having clearance of the baseline ibrutinib resistance mutation during treatment (up to Cycle 9 (C9)).
Time frame: Up to Cycle 9 Day 1. The duration of each cycle was 28 days.
Population: All patients in the dose expansion arm B who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Percentage of Participants With Clearance of Ibrutinib Resistance Mutation During Treatment (up to C9) for Expansion Arm B | 0 percentage of participants |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Percentage of Participants With Clearance of Ibrutinib Resistance Mutation During Treatment (up to C9) for Expansion Arm B | 0 percentage of participants |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | Percentage of Participants With Clearance of Ibrutinib Resistance Mutation During Treatment (up to C9) for Expansion Arm B | 0 percentage of participants |
Secondary
Posterior Mean of CR or CRi Response Rate at C9 for Expansion Arm A and Arm B (Bayesian Analysis)
The rate of CR/CRi at C9 was analyzed for each expansion arm using a Bayesian modeling approach. A minimally informative beta distribution was used as prior distribution with parameters a=0.25 and b=1. This assumed, a priori, that the response rate was 20%. Values estimated from the model at Cycle 9 are presented in the table. Posterior geometric mean for CR/CRi rate and 90% credible intervals in each group are presented.
Time frame: Cycle 9 Day 1 (C9). The duration of each cycle was 28 days.
Population: All patients who received at least one dose of study treatment in the dose expansion part of the study.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Posterior Mean of CR or CRi Response Rate at C9 for Expansion Arm A and Arm B (Bayesian Analysis) | 45.68 percentage of participants |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Posterior Mean of CR or CRi Response Rate at C9 for Expansion Arm A and Arm B (Bayesian Analysis) | 11.11 percentage of participants |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | Posterior Mean of CR or CRi Response Rate at C9 for Expansion Arm A and Arm B (Bayesian Analysis) | 4.76 percentage of participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Posterior Mean of CR or CRi Response Rate at C9 for Expansion Arm A and Arm B (Bayesian Analysis) | 36.63 percentage of participants |
Secondary
Posterior Probability That the True CR or CRi Response Rate at C9 for Expansion Arm A and Arm B Falls in Pre-defined Activity Intervals (Bayesian Analysis)
The rate of CR/CRi at C9 was analyzed for each expansion arm using a Bayesian modeling approach. A minimally informative beta distribution was used as prior distribution with parameters a=0.25 and b=1. This assumed, a priori, that the response rate was 20%. Values estimated from the model at Cycle 9 are presented in the table. The posterior probability that the true CR/CRi rate falls in the activity intervals defined below is presented: * \[0, 20%) - clinically not meaningful * \[20%, 40%) - moderate clinical benefit * \[40%, 100%\] - superior clinical benefit
Time frame: Cycle 9 Day 1 (C9). The duration of each cycle was 28 days.
Population: All patients who received at least one dose of study treatment in the dose expansion part of the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Posterior Probability That the True CR or CRi Response Rate at C9 for Expansion Arm A and Arm B Falls in Pre-defined Activity Intervals (Bayesian Analysis) | [0, 20%) - clinically not meaningful | 0.5 percentage of participants |
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Posterior Probability That the True CR or CRi Response Rate at C9 for Expansion Arm A and Arm B Falls in Pre-defined Activity Intervals (Bayesian Analysis) | 40%, 100%] - superior clinical benefit | 69.1 percentage of participants |
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Posterior Probability That the True CR or CRi Response Rate at C9 for Expansion Arm A and Arm B Falls in Pre-defined Activity Intervals (Bayesian Analysis) | [20%, 40%) - moderate clinical benefit | 30.4 percentage of participants |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Posterior Probability That the True CR or CRi Response Rate at C9 for Expansion Arm A and Arm B Falls in Pre-defined Activity Intervals (Bayesian Analysis) | [0, 20%) - clinically not meaningful | 80.2 percentage of participants |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Posterior Probability That the True CR or CRi Response Rate at C9 for Expansion Arm A and Arm B Falls in Pre-defined Activity Intervals (Bayesian Analysis) | 40%, 100%] - superior clinical benefit | 8.5 percentage of participants |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Posterior Probability That the True CR or CRi Response Rate at C9 for Expansion Arm A and Arm B Falls in Pre-defined Activity Intervals (Bayesian Analysis) | [20%, 40%) - moderate clinical benefit | 11.3 percentage of participants |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | Posterior Probability That the True CR or CRi Response Rate at C9 for Expansion Arm A and Arm B Falls in Pre-defined Activity Intervals (Bayesian Analysis) | [20%, 40%) - moderate clinical benefit | 5.3 percentage of participants |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | Posterior Probability That the True CR or CRi Response Rate at C9 for Expansion Arm A and Arm B Falls in Pre-defined Activity Intervals (Bayesian Analysis) | [0, 20%) - clinically not meaningful | 93.6 percentage of participants |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | Posterior Probability That the True CR or CRi Response Rate at C9 for Expansion Arm A and Arm B Falls in Pre-defined Activity Intervals (Bayesian Analysis) | 40%, 100%] - superior clinical benefit | 1.1 percentage of participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Posterior Probability That the True CR or CRi Response Rate at C9 for Expansion Arm A and Arm B Falls in Pre-defined Activity Intervals (Bayesian Analysis) | [0, 20%) - clinically not meaningful | 3 percentage of participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Posterior Probability That the True CR or CRi Response Rate at C9 for Expansion Arm A and Arm B Falls in Pre-defined Activity Intervals (Bayesian Analysis) | 40%, 100%] - superior clinical benefit | 35.2 percentage of participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Posterior Probability That the True CR or CRi Response Rate at C9 for Expansion Arm A and Arm B Falls in Pre-defined Activity Intervals (Bayesian Analysis) | [20%, 40%) - moderate clinical benefit | 61.8 percentage of participants |
Secondary
Time to Progression (TTP) in the Dose Escalation Part
Efficacy was based on local investigator assessment per International Working Group - Chronic Lymphocytic Leukemia (IWCLL) response criteria. TTP is defined as the time from start of treatment to date of event which is defined as the first documented progression or death due to underlying cancer. If a patient had not had an event, TTP was censored at the date of the last adequate disease assessment. TTP was analyzed using Kaplan-Meier estimates.
Time frame: Up to approximately 2.5 years
Population: All patients who received at least one dose of study treatment in the dose escalation part of the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Time to Progression (TTP) in the Dose Escalation Part | 23.3 months |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Time to Progression (TTP) in the Dose Escalation Part | 8.3 months |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | Time to Progression (TTP) in the Dose Escalation Part | 24.2 months |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Time to Progression (TTP) in the Dose Escalation Part | 19.4 months |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Time to Progression (TTP) in the Dose Escalation Part | 19.4 months |
Secondary
Time to Progression (TTP) in the Dose Expansion Part
Efficacy was based on local investigator assessment per International Working Group - Chronic Lymphocytic Leukemia (IWCLL) response criteria. TTP is defined as the time from start of treatment to date of event which is defined as the first documented progression or death due to underlying cancer. If a patient had not had an event, TTP was censored at the date of the last adequate disease assessment. TTP was analyzed using Kaplan-Meier estimates.
Time frame: Up to approximately 2.7 years
Population: All patients who received at least one dose of study treatment in the dose expansion part of the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Time to Progression (TTP) in the Dose Expansion Part | NA months |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Time to Progression (TTP) in the Dose Expansion Part | 2.3 months |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | Time to Progression (TTP) in the Dose Expansion Part | NA months |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Time to Progression (TTP) in the Dose Expansion Part | NA months |
Secondary
Time to Reach Maximum Plasma Concentration (Tmax) of Ibrutinib
PK parameters were calculated based on ibrutinib plasma concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) concentration following a dose. Actual recorded sampling times were considered for the calculations.
Time frame: Pre-dose and 0.5, 2, 6 and 24 hours post-dose on Cycle 1 Day 1 and Cycle 1 Day 8. 1 cycle=28 days
Population: Patients in the pharmacokinetic analysis set (PAS) who had an available value for the outcome measure at each timepoint. PAS consists of all patients who received one of the planned treatments, provided at least one primary PK parameter and did not vomit within 8 hours after the dosing of ibrutinib. Patients were analyzed according to the study treatment received.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Time to Reach Maximum Plasma Concentration (Tmax) of Ibrutinib | Cycle 1 Day 8 | 2.00 hours |
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Time to Reach Maximum Plasma Concentration (Tmax) of Ibrutinib | Cycle 1 Day 1 | 2.10 hours |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Time to Reach Maximum Plasma Concentration (Tmax) of Ibrutinib | Cycle 1 Day 8 | 2.00 hours |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Time to Reach Maximum Plasma Concentration (Tmax) of Ibrutinib | Cycle 1 Day 1 | 2.00 hours |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | Time to Reach Maximum Plasma Concentration (Tmax) of Ibrutinib | Cycle 1 Day 1 | 2.30 hours |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Time to Reach Maximum Plasma Concentration (Tmax) of Ibrutinib | Cycle 1 Day 1 | 2.10 hours |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Time to Reach Maximum Plasma Concentration (Tmax) of Ibrutinib | Cycle 1 Day 8 | 2.00 hours |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Time to Reach Maximum Plasma Concentration (Tmax) of Ibrutinib | Cycle 1 Day 8 | 2.00 hours |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Time to Reach Maximum Plasma Concentration (Tmax) of Ibrutinib | Cycle 1 Day 1 | 2.00 hours |
Secondary
Time to Reach Maximum Serum Concentration (Tmax) of VAY736
PK parameters were calculated based on VAY736 serum concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) concentration following a dose. Actual recorded sampling times were considered for the calculations.
Time frame: Pre-infusion and 2, 6, 24, 72, 168 and 336 hours after end of infusion on Cycle 1 Day 1 and Cycle 3 Day 1. The duration of the infusion was approximately 2 hours. 1 cycle=28 days
Population: Patients in the pharmacokinetic analysis set (PAS) who had an available value for the outcome measure at each timepoint. PAS consists of all patients who received one of the planned treatments, provided at least one primary PK parameter and did not vomit within 8 hours after the dosing of ibrutinib. Patients were analyzed according to the study treatment received.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Time to Reach Maximum Serum Concentration (Tmax) of VAY736 | Cycle 3 | 2.00 hours |
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | Time to Reach Maximum Serum Concentration (Tmax) of VAY736 | Cycle 1 | 4.30 hours |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Time to Reach Maximum Serum Concentration (Tmax) of VAY736 | Cycle 3 | 2.20 hours |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | Time to Reach Maximum Serum Concentration (Tmax) of VAY736 | Cycle 1 | 3.90 hours |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | Time to Reach Maximum Serum Concentration (Tmax) of VAY736 | Cycle 1 | 2.20 hours |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Time to Reach Maximum Serum Concentration (Tmax) of VAY736 | Cycle 1 | 4.70 hours |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Time to Reach Maximum Serum Concentration (Tmax) of VAY736 | Cycle 3 | 2.10 hours |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Time to Reach Maximum Serum Concentration (Tmax) of VAY736 | Cycle 3 | 2.15 hours |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | Time to Reach Maximum Serum Concentration (Tmax) of VAY736 | Cycle 1 | 5.80 hours |
Post Hoc
All-Collected Deaths
On-treatment deaths were collected from first dose of study treatment to 30 days after the last dose of VAY736. Post-treatment deaths were collected from 31 days after last dose of VAY736 until end of study. All deaths refer to the sum of on-treatment and post-treatment deaths.
Time frame: On-treatment deaths: up to approximately 8.8 months. Post-treatment deaths: up to approximately 2.7 years
Population: All patients who received at least one dose of study treatment in the dose escalation or dose expansion part of the study. Patients were analyzed according to the study treatment received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | All-Collected Deaths | On-treatment deaths | 0 participants |
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | All-Collected Deaths | All deaths | 0 participants |
| VAY736 0.3mg/kg Q2W + Ibrutinib 420mg | All-Collected Deaths | Post-treatment deaths | 0 participants |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | All-Collected Deaths | Post-treatment deaths | 0 participants |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | All-Collected Deaths | On-treatment deaths | 0 participants |
| VAY736 1mg/kg Q2W + Ibrutinib 420mg | All-Collected Deaths | All deaths | 0 participants |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | All-Collected Deaths | Post-treatment deaths | 0 participants |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | All-Collected Deaths | On-treatment deaths | 0 participants |
| VAY736 3mg/kg Q2W + Ibrutinib 420mg | All-Collected Deaths | All deaths | 0 participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | All-Collected Deaths | On-treatment deaths | 0 participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | All-Collected Deaths | All deaths | 1 participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | All-Collected Deaths | Post-treatment deaths | 1 participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | All-Collected Deaths | Post-treatment deaths | 0 participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | All-Collected Deaths | On-treatment deaths | 0 participants |
| VAY736 9mg/kg Q2W + Ibrutinib 420mg | All-Collected Deaths | All deaths | 0 participants |