Clinical trial NCT03816163: A Study of Zolbetuximab (IMAB362) in Adults With Pancreatic Cancer
Official title: A Phase 2, Open-Label, Randomized Study to Assess the Efficacy and Safety of Zolbetuximab (IMAB362) in Combination With Nab-Paclitaxel and Gemcitabine (Nab-P + GEM) as First Line Treatment in Subjects With Claudin 18.2 (CLDN18.2) Positive, Metastatic Pancreatic Adenocarcinoma
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Pancreatic Cancer
Metastatic Pancreatic Cancer
Metastatic Pancreatic Adenocarcinoma
Keywords: metastatic pancreatic cancer
IMAB362
nab-paclitaxel
gemcitabine
zolbetuximab
metastatic pancreatic adenocarcinoma
pancreatic cancer
CLDN 18.2
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
First posted: 2019-01-25
Enrollment: 393
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Zolbetuximab is being studied as a treatment for people with pancreatic cancer. Most people with pancreatic cancer have a protein called Claudin 18.2 (CLDN18.2) in their tumor. Zolbetuximab is thought to work by attaching to CLDN 18.2 in their tumor. This switches on the body's immune system to attack the tumor. Zolbetuximab is a potential treatment for people with pancreatic cancer.

There is an unmet medical need to treat people with pancreatic cancer. This study will help find the dose of zolbetuximab to be used with chemotherapy and provide more information on this treatment in adults with metastatic pancreatic cancer. The study is currently ongoing globally. People in this study will be treated with either zolbetuximab and chemotherapy or chemotherapy by itself.

The study's main aims are to find a suitable dose of zolbetuximab to be used with chemotherapy in the second part of this study, to check if zolbetuximab and chemotherapy compared to chemotherapy by itself can improve the survival of people with pancreatic cancer, and to check the safety of zolbetuximab when given with chemotherapy and how well people cope with medical problems during the study.

Adults with metastatic pancreatic cancer can take part. Their cancer is metastatic, has the CLDN18.2 marker in a tumor sample and has not previously been treated with chemotherapy. Metastatic means the cancer has spread to other parts of the body. People cannot take part are if they have recently had radiotherapy and have not recovered, need to take medicines to suppress their immune system, have history of nervous system metastases from their pancreatic cancer, or they have other active cancers that need treatment. People who have a specific heart condition or infections also cannot take part.

This study will be in 2 parts. Part 1 is called the Safety Lead-in Phase. Groups of people will receive 1 of 2 different doses of zolbetuximab: a lower dose or a higher dose, both together with chemotherapy. A medical expert panel will check the results and decide the dose to use in Part 2.

Part 2 is called the Randomization Phase. People will be put in 1 of 2 groups by chance and will be given different treatments either zolbetuximab and chemotherapy or chemotherapy by itself. The chance of receiving zolbetuximab and chemotherapy is twice as high as receiving chemotherapy by itself. In both parts of the study, zolbetuximab and chemotherapy or chemotherapy by itself will be given through a vein. This is called an infusion. Each treatment cycle is 4 weeks (28 days) long and people will have either 2 infusions of zolbetuximab and 3 infusions of chemotherapy or 3 infusions of chemotherapy by itself during each treatment cycle. People will visit the clinic on certain days during their treatment. The study doctors will check for any medical problems from zolbetuximab. Also, people in the study will have a health check including blood tests. On some visits they will also have scans to check for any changes in their cancer. Tumor samples will be taken before treatment if a previous sample is not available. People will have the option of giving a tumor sample after treatment has finished. People will visit the clinic after they stop treatment. They will be asked about any medical problems and will have a health check including blood tests. The number of visits and checks done at each visit will depend on the health of each person and whether they completed their treatment or not.

Detailed description: This study will have a safety lead in phase and a randomization phase.

Eligibility criteria: Inclusion Criteria:

* A female subject is eligible to participate if she is not pregnant or lactating and at least 1 of the following conditions applies:

  * Not a woman of childbearing potential (WOCBP) OR
  * WOCBP who agrees to follow the contraceptive guidance throughout the treatment period and for at least 6 months after the final study drug administration.
* Female subject must agree not to breastfeed starting at screening and throughout the study period, and for 6 months after the final study drug administration.
* Female subject must not donate ova starting at screening and throughout the study period, and for 6 months after the final study drug administration.
* A male subject with female partner(s) of child-bearing potential must agree to use contraception during the treatment period and for at least 6 months after the final study drug administration.
* A male subject must not donate sperm during the treatment period and for at least 6 months after the final study drug administration.
* Male subject with a pregnant or breastfeeding partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy or time partner is breastfeeding throughout the study period and for 6 months after the final study drug administration.
* Subject agrees not to participate in other interventional studies while receiving study drug in present study.
* Subject has histologically or cytologically confirmed adenocarcinoma of pancreas.
* Subjects must have metastatic pancreatic adenocarcinoma that has not been previously treated with chemotherapy.

  * Prior treatment with fluorouracil (5-FU) or GEM administered as a radiation sensitizer during and up to 4 weeks after radiation therapy is allowed
  * If a subject received adjuvant therapy, tumor recurrence or disease progression must have occurred at least 6 months after completing the last dose of the adjuvant therapy.
  * Subjects whose disease progressed on prior treatment with Nab-P and GEM are not eligible.
* Subject has a measurable lesion(s) on at least 1 metastatic site based on RECIST 1.1 within 28 days prior to randomization. For subjects with only 1 measurable lesion and prior radiotherapy, the lesion must be outside the field of prior radiotherapy or must have documented progression following radiation therapy.
* Subject's tumor sample has CLDN18.2 expression in ≥ 75% of tumor cells demonstrating moderate to strong membranous staining as determined by central immunohistochemistry (IHC) testing
* Subject has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* Subject has predicted life expectancy ≥ 12 weeks.
* Subject must meet all of the following criteria based on the laboratory tests that will be collected within 14 days prior to randomization. In case of multiple laboratory data within this period, the most recent data should be used.

  * Hemoglobin ≥ 9 g/dl (no transfusion within 14 days of start of study treatment)
  * Absolute neutrophil count ≥ 1.5 x 10\^9/L
  * Platelets ≥ 100 x 10\^9/L
  * Albumin ≥ 2.5 g/dL
  * Total bilirubin ≤ 1.5 x upper limit of normal (ULN)
  * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN without liver metastases (≤ 5 x ULN if liver metastases are present)
  * Estimated creatinine clearance ≥ 30 mL/min
  * Prothrombin time/international normalized ratio (INR) and partial thromboplastin time ≤ 1.5 x ULN (except for subjects receiving anticoagulation therapy)

Exclusion Criteria:

* Subject has received other investigational treatment within 28 days prior to randomization.
* Subject has received radiotherapy for metastatic pancreatic adenocarcinoma ≤ 14 days prior to randomization and has not recovered from any related toxicity.
* Subject has received systemic immunosuppressive therapy, including systemic corticosteroids within 14 days prior to randomization. Subject using a physiologic replacement dose of hydrocortisone or its equivalent (defined as up to 30 mg per day of hydrocortisone or up to 10 mg per day of prednisone), receiving a single dose of systemic corticosteroids or receiving systemic corticosteroids as premedication for radiologic imaging contrast use are allowed.
* Subject has prior severe allergic reaction or intolerance to known ingredients of zolbetuximab or other monoclonal antibody, including humanized or chimeric antibodies.
* Subject has known immediate or delayed hypersensitivity, intolerance or contraindication to any component of study treatment.
* Subject has a known history of a positive test for human immunodeficiency virus infection or known active hepatitis B (positive HBs antigen \[Ag\]) or hepatitis C infection. NOTE: Screening for these infections should be conducted per local requirements.

  1. For subjects who are negative for HBs Ag, but hepatitis B core antibody positive, a hepatitis B virus DNA test will be performed and if positive, the subject will be excluded.
  2. Subjects with positive hepatitis C serology but negative hepatitis C virus RNA test results are eligible.
  3. Subjects treated for hepatitis C with undetectable viral load results are eligible.
* Subject has a history of interstitial pneumonia or pulmonary fibrosis.
* Subject has pleural effusion or ascites ≥ Grade 3.
* Subject has an active autoimmune disease that has required systemic treatment in the past 3 months prior to randomization.
* Subject has active infection requiring systemic therapy that has not completely resolved per investigator judgment within 7 days prior to randomization.
* Subject has significant cardiovascular disease, including:

  * Congestive heart failure (defined as New York Heart Association Class III or IV), myocardial infarction, unstable angina, coronary angioplasty, coronary stenting, coronary artery bypass graft, cerebrovascular accident or hypertensive crisis within 6 months prior to randomization;
  * History of clinically significant ventricular arrhythmias (i.e., sustained ventricular tachycardia, ventricular fibrillation or Torsades de Pointes);
  * QTc interval \> 450 msec for male subjects; QTc interval \> 470 msec for female subjects;
  * Cardiac arrhythmias requiring anti-arrhythmic medications (Subjects with rate controlled atrial fibrillation for \> 1 month prior to randomization.)
* Subject has a history of central nervous system metastases and/or carcinomatous meningitis from pancreatic adenocarcinoma.
* Subject has known peripheral sensory neuropathy ≥ Grade 2 unless the absence of deep tendon reflexes is the sole neurological abnormality.
* Subject has had a major surgical procedure ≤ 28 days prior to randomization.
* Subject without complete recovery from a major surgical procedure ≤ 14 days prior to randomization.
* Psychiatric illness or social situations that would preclude study compliance.
* Subject has another malignancy for which treatment is required.
* Subject has any concurrent disease, infection or co-morbid condition that interferes with the ability of the subject to participate in the study, which places the subject at undue risk or complicates the interpretation of data.

Primary outcomes:
measure: Dose Limiting Toxicities (DLT) - (safety lead in)
timeFrame: Up to 28 days
measure: Overall Survival (OS)
timeFrame: Up to 65 months
measure: Safety assessed by Adverse Events (AEs)
timeFrame: Up to 65 months
measure: Safety assessed by incidence of serious adverse events (SAE)
timeFrame: Up to 65 months
measure: Safety assessed by incidence of treatment emergent adverse events (TEAE)
timeFrame: Up to 65 months
measure: Number of participants with laboratory value abnormalities and/or adverse events (AEs)
timeFrame: Up to 65 months
measure: Number of participants with vital sign abnormalities and /or adverse events (AEs)
timeFrame: Up to 65 months
measure: Number of participants with electrocardiograms (ECG) abnormalities and or adverse events
timeFrame: Up to 65 months
measure: Number of participants with Eastern Cooperative Oncology Group (ECOG) performance status abnormalities and or adverse events
timeFrame: Up to 65 months
Secondary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: Up to 65 months
measure: Objective Response Rate (ORR)
timeFrame: Up to 65 months
measure: Number of anti-drug antibody (ADA) Positive Participants
timeFrame: Up to 65 months
measure: Disease Control Rate (DCR)
timeFrame: Up to 65 months
measure: Duration Of Response (DOR)
timeFrame: Up to 65 months
measure: Change in CA (Cancer Antigen) 19-9
timeFrame: Baseline up to 65 months
measure: PK of zolbetuximab: Concentration Immediately Prior to Dosing (Ctrough)
timeFrame: Up to 65 months
measure: PK of Nab-P: Area Under the Concentration-time Curve from the Time of Dosing Extrapolated to Time Infinity (AUCinf)
timeFrame: Up to 30 days
measure: PK of Nab-P: Area Under the Concentration-time Curve from the Time of Dosing Until the Last Measurable Concentration (AUClast)
timeFrame: Up to 30 days
measure: PK of Nab-P: Maximum Concentration (Cmax)
timeFrame: Up to 30 days
measure: PK of Nab-P: Time of Maximum Concentration (Tmax)
timeFrame: Up to 30 days
measure: PK of Nab-P: Terminal Elimination Half-life (T1/2)
timeFrame: Up to 30 days
measure: PK of Nab-P: Clearance (CL)
timeFrame: Up to 30 days
measure: PK of Nab-P: Volume of Distribution During the Terminal Phase (Vz)
timeFrame: Up to 30 days
measure: PK of gemcitabine: Area Under the Concentration-time Curve from the Time of Dosing Extrapolated to Time Infinity (AUCinf)
timeFrame: Up to 30 days
measure: PK of gemcitabine: Area Under the Concentration-time Curve from the Time of Dosing Until the Last Measurable Concentration (AUClast)
timeFrame: Up to 30 days
measure: PK of gemcitabine: Maximum Concentration (Cmax)
timeFrame: Up to 30 days
measure: PK of gemcitabine: Time of Maximum Concentration (Tmax)
timeFrame: Up to 30 days
measure: PK of gemcitabine: Terminal Elimination Half-life (T1/2)
timeFrame: Up to 30 days
measure: PK of gemcitabine: Clearance (CL)
timeFrame: Up to 30 days
measure: PK of gemcitabine: Volume of Distribution During the Terminal Phase (Vz)
timeFrame: Up to 30 days
measure: Health Related Quality of Life (HRQoL) measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core Questionnaire (EORTC-QLQ-C30)
timeFrame: Up to 65 months
measure: Health Related Quality of Life (HRQoL) measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Pancreatic Cancer Module (EORTC-QLQ-PAN-26)
timeFrame: Up to 65 months
measure: Health Related Quality of Life (HRQoL) measured by the EuroQOL Five Dimensions Questionnaire 5L (EQ-5D-5L)
timeFrame: Up to 65 months
measure: Health Related Quality of Life (HRQoL) measured by the Patient Global Impression of Change (PGIC) scale
timeFrame: Up to 65 months
measure: Health Related Quality of Life (HRQoL) measured by the Patient Global Impression of Severity (PGIS) Scale
timeFrame: Up to 65 months
measure: Time to Improvement of pancreatic pain as measured by Quality-of-Life Questionnaire - Core Questionnaire (QLQ-C30)
timeFrame: Up to 65 months
measure: Time to worsening of global health status (GHS)/quality of life (QoL) as measured by QLQ-C30
timeFrame: Up to 65 months
measure: Time to Improvement of pancreatic pain as measured by Quality of Life Questionnaire - Pancreatic Cancer Module 26 (QLQ-PAN26)
timeFrame: Up to 65 months
measure: Time to worsening of GHS/QoL as measured by QLQ-PAN26
timeFrame: Up to 65 months
measure: Time to Improvement of pancreatic pain as measured by PGIS
timeFrame: Up to 65 months
measure: Time to worsening of GHS/QoL as measured by PGIS
timeFrame: Up to 65 months
Other outcomes:
Locations:
city: Fullerton
country: United States
facility: St. Joseph Heritage Medical Group
state: California
city: Whittier
country: United States
facility: TOI Clinical research
state: California
city: Meriden
country: United States
facility: Midstate Medical Center
state: Connecticut
city: Boca Raton
country: United States
facility: Lynn Cancer Institute
state: Florida
city: Miami
country: United States
facility: Baptist Health
state: Florida
city: Newnan
country: United States
facility: Cancer Treatment Centers of Atlanta
state: Georgia
city: Chicago
country: United States
facility: University of Illinois at Chicago
state: Illinois
city: Louisville
country: United States
facility: Norton Cancer Institute (NCI)
state: Kentucky
city: New Orleans
country: United States
facility: Ochsner Health System
state: Louisiana
city: Creve Coeur
country: United States
facility: David C Pratt Cancer Center
state: Missouri
city: Basking Ridge
country: United States
facility: Memorial Sloan Kettering Basking Ridge
state: New Jersey
city: Montvale
country: United States
facility: Memorial Sloan Kettering Bergen
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Commack
country: United States
facility: Memorial Sloan Kettering Commack
state: New York
city: Harrison
country: United States
facility: Memorial Sloan Kettering Westchester
state: New York
city: Lake Success
country: United States
facility: Northwell Health Cancer Institute
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Uniondale
country: United States
facility: Memorial Sloan Kettering Nassau
state: New York
city: Charlotte
country: United States
facility: Novant Health Presbyterian Medical Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Novant Health
state: North Carolina
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
city: Salt Lake City
country: United States
facility: Utah Cancer Specialists
state: Utah
city: Gig Harbor
country: United States
facility: MultiCare Regional Cancer Center - Gig Harbor
state: Washington
city: Olympia
country: United States
facility: Vista Oncology
state: Washington
city: Seattle
country: United States
facility: Virginia Mason
state: Washington
city: Gosford
country: Australia
facility: Site AU61008
state: New South Wales
city: Wollongong
country: Australia
facility: Site AU61007
state: New South Wales
city: Fitzroy
country: Australia
facility: Site AU61005
state: Victoria
city: Warrnambool
country: Australia
facility: Site AU61006
state: Victoria
city: Porto Alegre
country: Brazil
facility: Site BR55012
state: Rio Grande Do Sul
city: Centro Passo Fundo
country: Brazil
facility: Site BR55009
city: Rio Grande Do Sul
country: Brazil
facility: Site BR55008
city: Santa Catarina
country: Brazil
facility: Site BR55004
city: Sao Paulo
country: Brazil
facility: Site BR55010
city: Sao Paulo
country: Brazil
facility: Site BR55011
city: Beijing
country: China
facility: Site CN86001
city: Beijing
country: China
facility: Site CN86008
city: Beijing
country: China
facility: Site CN86014
city: Changchun
country: China
facility: Site CN86026
city: Chongqing
country: China
facility: Site CN86009
city: Guangdong
country: China
facility: Site CN86004
city: Guangdong
country: China
facility: Site CN86020
city: Guangzhou
country: China
facility: Site CN86016
city: Harbin
country: China
facility: Site CN86012
city: Hubei
country: China
facility: Site CN86002
city: Jiangsu
country: China
facility: Site CN86005
city: Jiangsu
country: China
facility: Site CN86011
city: Jiangsu
country: China
facility: Site CN86025
city: Shan XI
country: China
facility: Site CN86024
city: Shandong
country: China
facility: Site CN86023
city: Shanghai
country: China
facility: Site CN86006
city: Shanghai
country: China
facility: Site CN86013
city: Shanghai
country: China
facility: Site CN86019
city: Tianjin
country: China
facility: Site CN86007
city: Xinjiang
country: China
facility: Site CN86022
city: Zhejiang
country: China
facility: Site CN86003
city: Zhejiang
country: China
facility: Site CN86018
city: Zhengzhou
country: China
facility: Site CN86010
city: Besancon
country: France
facility: Site FR33008
state: Besancon Cedex
city: Brest
country: France
facility: Site FR33010
state: Brest Cedex
city: Caen
country: France
facility: Site FR33015
state: Cedex 5
city: Chambray
country: France
facility: Site FR33006
state: Cedex 9
city: Herblain
country: France
facility: Site FR33012
state: Herblain Cedex
city: La Chaussee Saint Victor
country: France
facility: Site FR33016
state: Loir-et-Cher
city: Nancy
country: France
facility: Site FR33009
state: Nancy Cedex
city: Rouen
country: France
facility: Site FR33017
state: Normandy
city: Aquitaine
country: France
facility: Site FR33003
state: Pessac
city: Villejuif
country: France
facility: Site FR33013
state: Villejuif Cedex
city: Bayonne Cedex
country: France
facility: Site FR33001
city: Bordeaux
country: France
facility: Site FR33018
city: Grenoble
country: France
facility: Site FR33002
city: Nice Cedex 2
country: France
facility: Site FR33021
city: Pierre Benite
country: France
facility: Site FR33023
city: Plerin
country: France
facility: Site FR33014
city: Pringy Cedex
country: France
facility: Site FR33005
city: Roche-Sur-Yon
country: France
facility: Site FR33019
city: Strasbourg
country: France
facility: Site FR33007
city: Elm Park
country: Ireland
facility: Site IR35301
state: Dublin
city: Rozzano
country: Italy
facility: Site IT39006
state: Milan
city: Candiolo
country: Italy
facility: Site IT39004
state: Torino
city: Cremona
country: Italy
facility: Site IT39002
city: Lombardia
country: Italy
facility: Site IT39010
city: Milan
country: Italy
facility: Site IT39003
city: Toscana
country: Italy
facility: Site IT39014
city: Veneto
country: Italy
facility: Site IT39008
city: Nagoya
country: Japan
facility: Site JP81007
state: Aichi
city: Kashiwa
country: Japan
facility: Site JP81001
state: Chiba
city: Sapporo
country: Japan
facility: Site JP81005
state: Hokkaido
city: Yokohama
country: Japan
facility: Site JP81006
state: Kanagawa
city: Kashihara
country: Japan
facility: Site JP81003
state: Nara
city: Bunkyo-ku
country: Japan
facility: Site JP81011
state: Tokyo
city: Chuo-ku
country: Japan
facility: Site JP81012
state: Tokyo
city: Koto-ku
country: Japan
facility: Site JP81014
state: Tokyo
city: Mitaka
country: Japan
facility: Site JP81013
state: Tokyo
city: Shinjuku-ku
country: Japan
facility: Site JP81002
state: Tokyo
city: Ube
country: Japan
facility: Site JP81015
state: Yamaguchi
city: Fukuoka
country: Japan
facility: Site JP81004
city: Osaka
country: Japan
facility: Site JP81010
city: Wakayama
country: Japan
facility: Site JP81009
city: Seongnam-Si
country: Korea, Republic of
facility: Site KR82005
state: Gyeonggi-do
city: Suwon-si
country: Korea, Republic of
facility: Site KR82008
state: Gyeonggi-do
city: Daegu
country: Korea, Republic of
facility: Site KR82010
city: Gyeonggi-do
country: Korea, Republic of
facility: Site KR82009
city: Seoul
country: Korea, Republic of
facility: Site KR82001
city: Seoul
country: Korea, Republic of
facility: Site KR82003
city: Seoul
country: Korea, Republic of
facility: Site KR82004
city: Seoul
country: Korea, Republic of
facility: Site KR82007
city: Seoul
country: Korea, Republic of
facility: Site KR82002
city: Seoul
country: Korea, Republic of
facility: Site KR82006
city: Distrito Federal
country: Mexico
facility: Site MX52004
city: San Luis Potosi
country: Mexico
facility: Site MX52003
city: Veracruz
country: Mexico
facility: Site MX52005
city: Llobregat
country: Spain
facility: Site ES34004
state: Barcelona
city: Pamplona
country: Spain
facility: Site ES34003
state: Navarra
city: Barcelona
country: Spain
facility: Site ES34010
city: Barcelona
country: Spain
facility: Site ES34013
city: Barcelona
country: Spain
facility: Site ES34007
city: Barcelona
country: Spain
facility: Site ES34018
city: Barcelona
country: Spain
facility: Site ES34021
city: Caceres
country: Spain
facility: Site ES34014
city: Cordoba
country: Spain
facility: Site ES34022
city: Lleida
country: Spain
facility: Site ES34005
city: Madrid
country: Spain
facility: Site ES34015
city: Madrid
country: Spain
facility: Site ES34006
city: Madrid
country: Spain
facility: Site ES34009
city: Malaga
country: Spain
facility: Site ES34026
city: Santiago de Compostela
country: Spain
facility: Site ES34017
city: New Taipei City
country: Taiwan
facility: Site TW88608
city: Taichung City
country: Taiwan
facility: Site TW88602
city: Taipei City
country: Taiwan
facility: Site TW88601
city: Taipei City
country: Taiwan
facility: Site TW88609
city: Ankara
country: Turkey
facility: Site TR90004
city: Ankara
country: Turkey
facility: Site TR90006
city: Diyarbakir
country: Turkey
facility: Site TR90003
city: Istanbul
country: Turkey
facility: Site TR90002
city: Konya
country: Turkey
facility: Site TR90001
Study officials:
affiliation: Astellas Pharma Global Development
name: Medical Director
role: STUDY_DIRECTOR
References: