Avelumab in Metastatic or Locally Advanced Solid Tumors (JAVELIN Solid Tumor JPN)

Study Overview
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Brief Summary
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This was a Phase 1, open-label, dose-escalation trial of avelumab (antibody targeting programmed death ligand 1 [anti PD-L1]) in Japanese participants with metastatic or locally advanced solid tumors, followed by a consecutive expansion part in Asian participants with gastric cancer.

Official Title
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A Phase I Trial to Investigate the Tolerability, Safety, Pharmacokinetics, Biological and Clinical Activity of Avelumab (MSB0010718C) in Japanese Subjects With Metastatic or Locally Advanced Solid Tumors, With Expansion Part in Asian Subjects With Gastric Cancer

Conditions
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Solid Tumors

Intervention / Treatment
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* Drug: Avelumab 3 mg/kg
* Drug: Avelumab 10 mg/kg
* Drug: Avelumab 20 mg/kg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written informed consent Male or female participants aged greater than or equal to (>=) 20 years For dose escalation part: Histologically or cytologically proven metastatic or locally advanced solid tumors, for which no standard therapy exists or standard therapy has failed For expansion part: Availability of fresh and archive tumor in formalin fixed paraffin embedded tissue With histologically or cytologically confirmed recurrent or refractory unresectable Stage IV gastric or gastro-esophageal junctional adenocarcinoma (according to American Joint Committee on Cancer/Union Internationale Contre le Cancer [UICC] 7th edition) and whose disease progressed after one or two prior chemotherapy regimen(s) involving both fluoropyrimidines and platinum Presence of at least 1 measurable lesion according to RECIST version 1.1 Participants should not have severe peritoneal metastases. The following criteria were applied: No clinical ileus or subileus No moderate-to-severe ascites (participants with ascites restricted to the perihepatic space or pelvic cavity) Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 at the trial entry and an estimated life expectancy of at least 3 months Adequate hematological, hepatic and renal function as defined in the protocol All participants must agree to use effective means of contraception with their partner from entry into the trial through 6 months after the last dose of avelumab Exclusion Criteria: Concurrent treatment with a non-permitted drug Prior therapy with any antibody/drug targeting T cell co-regulatory proteins (immune checkpoints) Concurrent anticancer treatment or concurrent systemic therapy with steroids or other immunosuppressive agents, or use of any investigational drug within 30 days before the start of trial treatment. Short-term administration of steroids (that is, for allergic reactions or the management of immune-related adverse events [irAE]) is allowed Previous malignant disease within the last 5 years with the exception of adequately treated non-melanoma skin cancer, in situ cancer, or other cancer Non-oncology vaccine therapies for prevention of infection disease (e.g. seasonal flu vaccine, human papilloma virus vaccine) within 4 weeks of study drug administration. Vaccination while on study is also prohibited except for administration of the inactivated influenza vaccine. Pregnancy or lactation period Known alcohol or drug abuse Clinically significant (that is, active) cardiovascular disease All other significant diseases (for example, inflammatory bowel disease), which, in the opinion of the investigator, might impair the participant's tolerance of trial treatment Any psychiatric condition that would prohibit the understanding or rendering of informed consent Legal incapacity or limited legal capacity Other protocol defined exclusion criteria could apply

Ages Eligible for Study
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Minimum Age: 20 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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose-escalation Cohort: Avelumab 3 mg/kg<br> | Drug: Avelumab 3 mg/kg<br>* Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose- escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.<br>* Other names: MSB0010718C;|
| Experimental: Dose-escalation Cohort: Avelumab 10 mg/kg<br> | Drug: Avelumab 10 mg/kg<br>* Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose- escalation cohort and expansion cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.<br>|
| Experimental: Dose-escalation Cohort: Avelumab 20 mg/kg<br> | Drug: Avelumab 20 mg/kg<br>* Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose- escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.<br>|
| Experimental: Expansion Cohort: Avelumab 10 mg/kg<br> | Drug: Avelumab 10 mg/kg<br>* Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose- escalation cohort and expansion cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-escalation Cohorts: Number of Participants With Dose Limiting Toxicities (DLTs) | DLT: any Grade greater than or equal to (>=) 3 or Adverse Events (AE) according to National Cancer Institute Common Toxicity Criteria for AE Version 4.03 (NCI-CTCAE v4.03); observed during first 3 weeks of dose-escalation part and as being related to Avelumab by Investigator/Sponsor. Following events were not considered as DLT: Grade 3 infusion-related reaction resolving to (<=) Grade 1 within 6 hours and controlled with medical management; Transient (<=6 hours) Grade 3 flulike symptoms/fever controlled with medical management and resolved to <= Grade 1;Transient (<=24 hours) Grade 3 fatigue, local reactions, headache, nausea, emesis that resolved to <=Grade1 with/without medical management, Grade 3 diarrhea, Grade 3 skin toxicity, Grade3 out-of-range laboratory values without any clinical correlate that resolves to <= Grade 1 or Baseline in < 7 days after medical management; Tumor flare phenomenon defined as local pain, irritation, rash localized at sites of known or suspected tumor. | Baseline up to 3 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-escalation Cohorts: Area Under the Serum Concentration-Time Curve From the Time of Dosing to the Time of the Last Observation (AUC0-t) of Avelumab | Area under the serum concentration vs time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was calculated by linear trapezoidal summation. | Within 6 hours before the infusion, at end of 1-hour infusion (Day 1), 0.5, 1, 2, 4, 6,12, 24, 36, 48, 168 hours after end of infusion | 
| Dose-escalation Cohorts: Area Under the Serum Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Avelumab | Area under the curve from the time of dosing extrapolated to infinity was calculated by the linear trapezoidal summation and extrapolated to infinity using Clast/Lambda z after the first intravenous infusion. Clast was the last quantifiable concentration and Lambda z was terminal elimination rate constant determined by log-linear regression analysis of the measured serum concentrations of the terminal log-linear phase. | Within 6 hours before the infusion, at end of 1-hour infusion (Day 1), 0.5, 1, 2, 4, 6,12, 24, 36, 48, 168 hours after end of infusion | 
| Dose-escalation Cohorts: Maximum Observed Serum Concentration (Cmax) of Avelumab | Cmax was obtained directly from the concentration versus time curve. | Within 6 hours before the infusion, at end of 1-hour infusion (Day 1), 0.5, 1, 2, 4, 6,12, 24, 36, 48, 168 hours after end of infusion | 
| Dose-escalation Cohorts: Time to Reach Maximum Observed Serum Concentration (Tmax) of Avelumab | Tmax was time to reach maximum observed serum concentration obtained directly from the concentration versus time curve. | Within 6 hours before the infusion, at end of 1-hour infusion (Day 1), 0.5, 1, 2, 4, 6,12, 24, 36, 48, 168 hours after end of infusion | 
| Dose-escalation Cohorts: Terminal Half-Life (t1/2) of Avelumab | t1/2 was the time measured for the concentration to decrease by one half, determined as 0.693/Lambda z, here Lambda z was the terminal elimination rate constant determined by log-linear regression analysis of the measured serum concentrations of the terminal log-linear phase. | Within 6 hours before the infusion, at end of 1-hour infusion (Day 1), 0.5, 1, 2, 4, 6,12, 24, 36, 48, 168 hours after end of infusion | 
| Dose-escalation Cohorts: Terminal Elimination Rate Constant (Lambda z) of Avelumab | Terminal elimination rate constant was determined by log-linear regression analysis of the measured serum concentrations of the terminal log-linear phase. Participant wise data was reported for this outcome measure. | Within 6 hours before the infusion, at end of 1-hour infusion (Day 1), 0.5, 1, 2, 4, 6,12, 24, 36, 48, 168 hours after end of infusion | 
| Dose-escalation Cohorts: Programmed Death Ligand 1 (PD-L1) Receptor Occupancy | Percentage of PD-L1 receptors occupied by avelumab on human lymphocytes (CD3+ cells) was assessed by flow cytometry on peripheral blood mononuclear cell (PBMC) samples. Greater than or equal to [>=] 85 percent [%] of cell viability was required for reliable receptor occupancy assessment. | Pre-infusion on Day 1; 4 and 48 hours after infusion on Day 3; Pre-infusion on Days 15, 29, 43, and 85 | 
| Dose-escalation Cohorts: Absolute Value of Cytokine Levels | Cytokine analysis was performed to evaluate levels of Rantes, Monocyte chemoattractant protein-1 (MCP-1) and various interleukins (including IL-1 beta, IL-2, IL-4, IL-6, IL-10, IL-12p70, IL-13, IL-8), Tumor necrosis factors-alpha (TNF-alpha) and Interferon-gamma (IFN-gamma) in serum samples. | Day 1 (Pre-infusion), Day 3 (48 hours after infusion), Day 8 (168 hours after infusion), Day 15 (Pre-infusion), Day 43 (Pre-infusion), Day 45 (48 hours after infusion), Day 50 (168 hours after infusion) | 
| Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels | Cytokine analysis was performed to evaluate levels of Rantes, Monocyte chemoattractant protein-1 (MCP-1) and various interleukins (including IL-1beta, IL-2, IL-4, IL-6, IL-10, IL-12p70, IL-13, IL-8), Tumor necrosis factors-alpha (TNF-alpha) and Interferon-gamma (IFN-gamma) in serum samples. Log fold change from baseline (logFC) was defined as logFC (cytokine at time t) = log (cytokine signal at time t) - log (cytokine signal at baseline). | Baseline (Day 1 [Pre-infusion]), Day 3 (48 hours after infusion), Day 8 (168 hours after infusion), Day 15 (Pre-infusion), Day 43 (Pre-infusion), Day 45 (48 hours after infusion), Day 50 (168 hours after infusion) | 
| Dose-escalation Cohorts: Number of Participants With Treatment-Emergent Positive Human Anti-Human Antibody (HAHA) | Participants not having positive HAHA prior to treatment with Avelumab and with at least one positive post-baseline result in the HAHA assay were termed as treatment-emergent. Treatment-emergent participants were further classified as Transient Positive or Persistent positive. Participants were considered as transient positive if time between first and last positive result was less than 16 weeks apart and a negative result at the most recent visit. Participants were considered as persistent positive if time between first and last positive result greater than or equal to [>=] 16 weeks apart or a positive evaluation at the most recent visit. Number of participants with treatment-emergent positive HAHA were reported. | Day 15 up to Day 2205 | 
| Dose-escalation Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation | An Adverse Event (AE) was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs were those events with onset dates occurring during the on-treatment period for the first time, or if the worsening of an event was during the on-treatment period. TEAEs included both serious TEAEs and non-serious TEAEs. | Time from first dose of study treatment up to 2205 days | 
| Expansion Cohort: Area Under the Serum Concentration-Time Curve From the Time of Dosing to the End of Dose Interval (AUC0-336hour [hr]) of Avelumab | AUC0-336hour was defined as area under the serum concentration-time curve from the time of dosing to the end of dose interval (336 hr). It was calculated by linear trapezoidal summation. | Within 6 hours before and the end of the 1-hour infusion (Day 1) and 336 hours after end of infusion | 
| Expansion Cohort: Serum Trough Concentration Levels (Ctrough) of Avelumab | Ctrough was defined as the trough or minimum serum concentration. | Within 6 hours before the 1-hour infusion on Day 15, Day 29, Day 43, Day 85, Day 127 and Day 169. | 
| Expansion Cohort: Number of Participants With Programmed Death Ligand 1 (PD-L1) Tumor Expression | The PD-L1 expression was evaluated using an established antiPD-L1 immunohistochemistry (IHC) assay. | Time from first dose of study treatment up to 1906 days | 
| Expansion Cohort: Absolute Values of Cytokine Levels | Cytokine analysis was performed to evaluate levels of Monocyte chemoattractant protein-1 (MCP-1) and various interleukins (including IL-5, IL-6, IL-8), Tumor necrosis factors-alpha (TNF-alpha) and Interferon-gamma (IFN-gamma) in serum samples. | Day 1 (Pre-infusion), Day 8 (168 hour after infusion) and Day 43 (Pre-infusion) | 
| Expansion Cohort: Log Fold Change From Baseline in Cytokine Levels | Cytokine analysis was performed to evaluate levels of Monocyte chemoattractant protein-1 (MCP-1) and various interleukins (including IL-5, IL-6, IL-8), Tumor necrosis factors-alpha (TNF-alpha) and Interferon-gamma (IFN-gamma) in serum samples. Log fold change from baseline (logFC) was defined as logFC (cytokine at time t) = log (cytokine signal at time t) - log (cytokine signal at baseline). | Baseline (Day 1 [Pre-infusion]), Day 8 (168 hour after infusion) and Day 43 (Pre-infusion) | 
| Expansion Cohort: Number of Participants With Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | Confirmed BOR was defined as the best response of any of the complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from the date of randomization until disease progression or recurrence (taking the smallest measurement recorded since the start of treatment as reference). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. SD: Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions and unequivocal progression of non-target lesions. Number of participants with best overall response in each category (CR, PR, SD, PD) was reported. | Time from first dose of study treatment up to 1906 days | 
| Expansion Cohort: Number of Participants With Immune-related Best Overall Response (irBOR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | BOR: best response of any of immune related complete response (irCR), immune related partial response (irPR), immune related stable disease (irSD) and immune related progressive disease (irPD) recorded from the date of randomization until disease progression or recurrence (taking the smallest measurement recorded since the start of treatment as reference). irCR: Complete disappearance of all tumor lesions (both index and non-index lesions with no new measurable/unmeasurable lesions). irPR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions). irSD: SLD of target and new measurable lesions neither irCR, irPR, or irPD. irPD: SLD of target and new measurable lesions increases greater than or equal to [>=] 20%, confirmed by a repeat, consecutive observations at least 4 weeks from the date first documented. Number of participants with immune-related best overall response in each category (irCR, irPR, irSD, irPD) was reported. | Time from first dose of study treatment up to 1906 days | 
| Expansion Cohort: Progression-Free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | PFS was defined as the time from date of randomization until date of the first documentation of progressive disease (PD) or death due to any cause in the absence of documented PD, whichever occurs first. PD was defined as at least a 20 percent (%) increase in the sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions and unequivocal progression of non-target lesions. PFS was measured using Kaplan-Meier (KM) estimates. | Time from first dose of study treatment up to 1906 days | 
| Expansion Cohort: Immune-related Progression-Free Survival (irPFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | irPFS was defined as the time from the first dose of study treatment to the date of first documentation of immune-related progressive disease [irPD] (which was subsequently confirmed) or death due to any cause, whichever occurred first. irPD was defined as the sum of the longest diameters of target and new measurable lesions increases greater than or equal to [>=] 20 percent (%), confirmed by a repeat, consecutive observations at least 4 weeks from the date first documented. | Time from first dose of study treatment up to 1906 days | 
| Expansion Cohort: Overall Survival (OS) Time | The OS time was defined as the time from randomization to the date of death. The participants who were still alive at the time of data analysis or who were lost to follow-up OS time was censored at the last recorded date that the participant was known to be alive before the data cutoff date. OS was measured using Kaplan-Meier (KM) estimates. | Time from first dose of study treatment up to 1906 days | 
| Expansion Cohort: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation | An Adverse Event (AE) was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs were those events with onset dates occurring during the on-treatment period for the first time, or if the worsening of an event was during the on-treatment period. TEAEs included both serious TEAEs and non-serious TEAEs. | Time from first dose of study treatment up to 1906 days | 
| Expansion Cohort: Number of Participants With Treatment-Emergent Positive Human Anti-Human Antibody (HAHA) | Number of participants with positive HAHA were reported. Participants not having positive HAHA prior to treatment with avelumab and with at least one positive post-baseline result in the HAHA assay were characterized as treatment-emergent. Treatment-emergent participants were further classified as Transient Positive or Persistent positive participants were considered as transient positive if time between first and last positive result was less than 16 weeks apart and a negative result at the most recent visit. Participants were considered as persistent positive if time between first and last positive result >=16 weeks apart or a positive evaluation at the most recent visit. | Day 15 up to Day 1906 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Solid Tumors, MSB0010718C, anti PD-L1, avelumab, Phase 1