Clinical trial NCT01943461: Avelumab in Metastatic or Locally Advanced Solid Tumors (JAVELIN Solid Tumor JPN)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Solid Tumors
Keywords: Solid Tumors
MSB0010718C
anti PD-L1
avelumab
Phase 1
Lead sponsor: Merck KGaA, Darmstadt, Germany
Sponsor class: INDUSTRY
First posted: 2013-09-17
Enrollment: 57
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Dose-escalation Cohorts: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: Baseline up to 3 weeks
Secondary outcomes:
measure: 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
timeFrame: 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
measure: Dose-escalation Cohorts: Area Under the Serum Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Avelumab
timeFrame: 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
measure: Dose-escalation Cohorts: Maximum Observed Serum Concentration (Cmax) of Avelumab
timeFrame: 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
measure: Dose-escalation Cohorts: Time to Reach Maximum Observed Serum Concentration (Tmax) of Avelumab
timeFrame: 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
measure: Dose-escalation Cohorts: Terminal Half-Life (t1/2) of Avelumab
timeFrame: 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
measure: Dose-escalation Cohorts: Terminal Elimination Rate Constant (Lambda z) of Avelumab
timeFrame: 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
measure: Dose-escalation Cohorts: Programmed Death Ligand 1 (PD-L1) Receptor Occupancy
timeFrame: Pre-infusion on Day 1; 4 and 48 hours after infusion on Day 3; Pre-infusion on Days 15, 29, 43, and 85
measure: Dose-escalation Cohorts: Absolute Value of Cytokine Levels
timeFrame: 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)
measure: Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels
timeFrame: 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)
measure: Dose-escalation Cohorts: Number of Participants With Treatment-Emergent Positive Human Anti-Human Antibody (HAHA)
timeFrame: Day 15 up to Day 2205
measure: Dose-escalation Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation
timeFrame: Time from first dose of study treatment up to 2205 days
measure: 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
timeFrame: Within 6 hours before and the end of the 1-hour infusion (Day 1) and 336 hours after end of infusion
measure: Expansion Cohort: Serum Trough Concentration Levels (Ctrough) of Avelumab
timeFrame: Within 6 hours before the 1-hour infusion on Day 15, Day 29, Day 43, Day 85, Day 127 and Day 169.
measure: Expansion Cohort: Number of Participants With Programmed Death Ligand 1 (PD-L1) Tumor Expression
timeFrame: Time from first dose of study treatment up to 1906 days
measure: Expansion Cohort: Absolute Values of Cytokine Levels
timeFrame: Day 1 (Pre-infusion), Day 8 (168 hour after infusion) and Day 43 (Pre-infusion)
measure: Expansion Cohort: Log Fold Change From Baseline in Cytokine Levels
timeFrame: Baseline (Day 1 [Pre-infusion]), Day 8 (168 hour after infusion) and Day 43 (Pre-infusion)
measure: Expansion Cohort: Number of Participants With Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
timeFrame: Time from first dose of study treatment up to 1906 days
measure: Expansion Cohort: Number of Participants With Immune-related Best Overall Response (irBOR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
timeFrame: Time from first dose of study treatment up to 1906 days
measure: Expansion Cohort: Progression-Free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
timeFrame: Time from first dose of study treatment up to 1906 days
measure: Expansion Cohort: Immune-related Progression-Free Survival (irPFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
timeFrame: Time from first dose of study treatment up to 1906 days
measure: Expansion Cohort: Overall Survival (OS) Time
timeFrame: Time from first dose of study treatment up to 1906 days
measure: Expansion Cohort: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation
timeFrame: Time from first dose of study treatment up to 1906 days
measure: Expansion Cohort: Number of Participants With Treatment-Emergent Positive Human Anti-Human Antibody (HAHA)
timeFrame: Day 15 up to Day 1906
Other outcomes:
Locations:
city: Darmstadt
country: Germany
facility: Research site
Study officials:
affiliation: Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References:
citation: Doi T, Iwasa S, Muro K, Satoh T, Hironaka S, Esaki T, Nishina T, Hara H, Machida N, Komatsu Y, Shimada Y, Otsu S, Shimizu S, Watanabe M. Phase 1 trial of avelumab (anti-PD-L1) in Japanese patients with advanced solid tumors, including dose expansion in patients with gastric or gastroesophageal junction cancer: the JAVELIN Solid Tumor JPN trial. Gastric Cancer. 2019 Jul;22(4):817-827. doi: 10.1007/s10120-018-0903-1. Epub 2018 Dec 4.
citation: Novakovic AM, Wilkins JJ, Dai H, Wade JR, Neuteboom B, Brar S, Bello CL, Girard P, Khandelwal A. Changing Body Weight-Based Dosing to a Flat Dose for Avelumab in Metastatic Merkel Cell and Advanced Urothelial Carcinoma. Clin Pharmacol Ther. 2020 Mar;107(3):588-596. doi: 10.1002/cpt.1645. Epub 2019 Nov 18.