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

Phase 1

Completed

Conditions: Solid Tumors

Interventions: Drug: Avelumab 10 mg/kg
Drug: Avelumab 20 mg/kg
Drug: Avelumab 3 mg/kg

Registration Number: NCT01943461

Lead Sponsor: Merck KGaA, Darmstadt, Germany

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 57

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Dose-escalation Cohort: Avelumab 10 mg/kg	Avelumab 10 mg/kg	-
Dose-escalation Cohort: Avelumab 20 mg/kg	Avelumab 20 mg/kg	-
Dose-escalation Cohort: Avelumab 3 mg/kg	Avelumab 3 mg/kg	-
Expansion Cohort: Avelumab 10 mg/kg	Avelumab 10 mg/kg	-

Primary Outcome Measures

Name	Time	Method
Dose-escalation Cohorts: Number of Participants With Dose Limiting Toxicities (DLTs)	Baseline up to 3 weeks	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.

Secondary Outcome Measures

Name	Time	Method
Dose-escalation Cohorts: Time to Reach Maximum Observed Serum Concentration (Tmax) of Avelumab	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	Tmax was time to reach maximum observed serum concentration obtained directly from the concentration versus time curve.
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	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	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.
Dose-escalation Cohorts: Area Under the Serum Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Avelumab	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	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.
Dose-escalation Cohorts: Terminal Half-Life (t1/2) of Avelumab	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	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.
Dose-escalation Cohorts: Terminal Elimination Rate Constant (Lambda z) of Avelumab	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	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.
Dose-escalation Cohorts: Programmed Death Ligand 1 (PD-L1) Receptor Occupancy	Pre-infusion on Day 1; 4 and 48 hours after infusion on Day 3; Pre-infusion on Days 15, 29, 43, and 85	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.
Expansion Cohort: Number of Participants With Programmed Death Ligand 1 (PD-L1) Tumor Expression	Time from first dose of study treatment up to 1906 days	The PD-L1 expression was evaluated using an established antiPD-L1 immunohistochemistry (IHC) assay.
Dose-escalation Cohorts: Maximum Observed Serum Concentration (Cmax) of Avelumab	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	Cmax was obtained directly from the concentration versus time curve.
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels	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)	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).
Dose-escalation Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation	Time from first dose of study treatment up to 2205 days	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.
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	Within 6 hours before and the end of the 1-hour infusion (Day 1) and 336 hours after end of infusion	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.
Expansion Cohort: Serum Trough Concentration Levels (Ctrough) of Avelumab	Within 6 hours before the 1-hour infusion on Day 15, Day 29, Day 43, Day 85, Day 127 and Day 169.	Ctrough was defined as the trough or minimum serum concentration.
Expansion Cohort: Number of Participants With Treatment-Emergent Positive Human Anti-Human Antibody (HAHA)	Day 15 up to Day 1906	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.
Dose-escalation Cohorts: Absolute Value of Cytokine Levels	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)	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.
Expansion Cohort: Absolute Values of Cytokine Levels	Day 1 (Pre-infusion), Day 8 (168 hour after infusion) and Day 43 (Pre-infusion)	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.
Expansion Cohort: Log Fold Change From Baseline in Cytokine Levels	Baseline (Day 1 [Pre-infusion]), Day 8 (168 hour after infusion) and Day 43 (Pre-infusion)	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).
Expansion Cohort: Number of Participants With Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1	Time from first dose of study treatment up to 1906 days	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.
Expansion Cohort: Progression-Free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1	Time from first dose of study treatment up to 1906 days	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.
Dose-escalation Cohorts: Number of Participants With Treatment-Emergent Positive Human Anti-Human Antibody (HAHA)	Day 15 up to Day 2205	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.
Expansion Cohort: Number of Participants With Immune-related Best Overall Response (irBOR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1	Time from first dose of study treatment up to 1906 days	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.
Expansion Cohort: Immune-related Progression-Free Survival (irPFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1	Time from first dose of study treatment up to 1906 days	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.
Expansion Cohort: Overall Survival (OS) Time	Time from first dose of study treatment up to 1906 days	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.
Expansion Cohort: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation	Time from first dose of study treatment up to 1906 days	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.