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A Study to Assess the Antitumor Activity and Safety of 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

NCT03816163

Description:

The purpose of this study is to confirm the recommended phase 2 dose (RP2D) of zolbetuximab in combination with Nab-P + GEM, determine overall survival and assess the safety and tolerability of the combination treatment. This study will also evaluate other anti-tumor effects, tumor markers and pharmacokinetics (PK) of zolbetuximab, Nab-P and GEM.

Related Conditions:
  • Pancreatic Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study to Assess the Antitumor Activity and Safety of 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
  • Official Title: A Phase 2, Open-Label, Randomized Study to Assess the Antitumor Activity 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

Clinical Trial IDs

  • ORG STUDY ID: 8951-CL-5201
  • SECONDARY ID: 2018-002551-15
  • NCT ID: NCT03816163

Conditions

  • Pancreatic Cancer
  • Metastatic Pancreatic Cancer
  • Metastatic Pancreatic Adenocarcinoma

Interventions

DrugSynonymsArms
zolbetuximabIMAB362zolbetuximab +nab-paclitaxel + gemcitabine
nab-paclitaxelnab-paclitaxel + gemcitabine
gemcitabinenab-paclitaxel + gemcitabine

Purpose

The purpose of this study is to confirm the recommended phase 2 dose (RP2D) of zolbetuximab in combination with Nab-P + GEM, determine overall survival and assess the safety and tolerability of the combination treatment. This study will also evaluate other anti-tumor effects, tumor markers and pharmacokinetics (PK) of zolbetuximab, Nab-P and GEM.

Detailed Description

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

Trial Arms

NameTypeDescriptionInterventions
zolbetuximab +nab-paclitaxel + gemcitabineExperimentalParticipants will be treated with zolbetuximab in combination with nab-paclitaxel and gemcitabine for the phase 1 portion of the study to establish the recommended dose of zolbetuximab for the phase 2 portion. In the phase 2 portion, the participants will be treated with zolbetuximab at dose determined by the phase 1 portion of the study in combination with nab-paclitaxel and gemcitabine. Participants will be treated on continuous cycles until they no longer derive clinical benefit in the judgment of the treating physician, have unacceptable toxicity, undergo hematopoietic stem cell transplantation (HSCT), or meet one of the discontinuation criteria; whichever occurs first.
  • zolbetuximab
  • nab-paclitaxel
  • gemcitabine
nab-paclitaxel + gemcitabineActive ComparatorParticipants will be treated with nab-paclitaxel and gemcitabine. Participants will be treated on continuous cycles until they no longer derive clinical benefit in the judgment of the treating physician, have unacceptable toxicity, undergo hematopoietic stem cell transplantation (HSCT), or meet one of the discontinuation criteria; whichever occurs first.
  • nab-paclitaxel
  • gemcitabine

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 cancer 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 therapy in the adjuvant setting, tumor recurrence or
                  disease progression must have occurred at least 6 months after completing the
                  last dose of adjuvant therapy.

          -  Subject has a measurable lesion(s) on at least 1 metastatic site based on RECIST 1.1
             within 28 days prior to the first dose of study treatment. For subjects with only 1
             measureable 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 on the laboratory tests that will be
             analyzed centrally within 14 days prior to the first dose of study drug. 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
             screening.

          -  Subject has received radiotherapy for metastatic pancreatic adenocarcinoma within 28
             days prior to the first dose of study treatment. Subject who received palliative
             radiotherapy to peripheral bone metastases ≥ 14 days prior to first dose of study
             treatment and has recovered from all acute toxicities is eligible.

          -  Subject has received systemic immunosuppressive therapy, including systemic
             corticosteroids within 14 days prior to first dose of study treatment. 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) or a single dose of
             systemic corticosteriods is eligible.

          -  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. 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. Subjects with positive serology but negative Hepatitis C virus RNA
             test 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 2 years

          -  Subject has active infection requiring systemic therapy that has not completely
             resolved within 14 days prior to first dose of study treatment.

          -  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 administration of first dose of study treatment;

               -  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 first dose of study
                  treatment are eligible.)

          -  Subject has known active or treated central nervous system metastases and/or
             carcinomatous meningitis.

          -  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 the first dose of study
             drug.

          -  Subject without complete recovery from a major surgical procedure ≤ 14 days prior to
             the first dose of study treatment.

          -  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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose Limiting Toxicities (DLT) - (safety lead in)
Time Frame:Up to 28 days
Safety Issue:
Description:Incidence of dose limiting toxicities.

Secondary Outcome Measures

Measure:Progression Free Survival (PFS)
Time Frame:Up to 35 months
Safety Issue:
Description:PFS is defined as the time from the date of randomization until the date of radiological progressive disease (PD) per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 by investigator evaluation or death from any cause, whichever is earliest.
Measure:Objective Response Rate (ORR)
Time Frame:Up to 35 months
Safety Issue:
Description:ORR is defined as the proportion of participants who have a best overall response of Complete Response (CR) or Partial Response (PR) as assessed by investigator evaluation per RECIST 1.1.
Measure:Number of anti-drug antibody (ADA) Positive Participants
Time Frame:Up to 29 months
Safety Issue:
Description:Immunogenicity will be measured by the number of participants that are ADA positive.
Measure:Disease Control Rate (DCR)
Time Frame:Up to 35 months
Safety Issue:
Description:DCR is defined as the proportion of participants who have best overall response of stable disease, complete response (CR) or partial response (PR) as assessed by investigator evaluation per RECIST 1.1
Measure:Duration Of Response (DOR)
Time Frame:Up to 35 months
Safety Issue:
Description:DOR is defined as the time from the date of the first response (CR/PR) until the date of progressive disease as assessed by investigator evaluation per RECIST 1.1 or date of death from any cause, whichever is earliest.
Measure:Change in CA (Cancer Antigen) 19-9
Time Frame:Baseline up to 27 months
Safety Issue:
Description:Change from baseline in serum CA19-9 will be assessed.
Measure:PK of zolbetuximab: Concentration Immediately Prior to Dosing (Ctrough)
Time Frame:Up to 29 months
Safety Issue:
Description:Ctrough will be derived from the PK serum samples collected.
Measure:PK of paclitaxel: Area Under the Concentration-time Curve from the Time of Dosing Extrapolated to Time Infinity (AUCinf)
Time Frame:Up to 30 days
Safety Issue:
Description:AUCinf will be derived from the PK plasma samples collected.
Measure:PK of paclitaxel: Area Under the Concentration-time Curve from the Time of Dosing Until the Last Measurable Concentration (AUClast)
Time Frame:Up to 30 days
Safety Issue:
Description:AUClast will be derived from the PK plasma samples collected.
Measure:PK of paclitaxel: Maximum Concentration (Cmax)
Time Frame:Up to 30 days
Safety Issue:
Description:Cmax will be derived from the PK plasma samples collected.
Measure:PK of paclitaxel: Time of Maximum Concentration (Tmax)
Time Frame:Up to 30 days
Safety Issue:
Description:Tmax will be derived from the PK plasma samples collected.
Measure:PK of paclitaxel: Terminal Elimination Half-life (T1/2)
Time Frame:Up to 30 days
Safety Issue:
Description:T1/2 will be derived from the PK plasma samples collected.
Measure:PK of paclitaxel: Clearance (CL)
Time Frame:Up to 30 days
Safety Issue:
Description:CL will be derived from the PK plasma samples collected.
Measure:PK of paclitaxel: Volume of Distribution During the Terminal Phase (Vz)
Time Frame:Up to 30 days
Safety Issue:
Description:Vz will be derived from the PK plasma samples collected.
Measure:PK of gemcitabine: Area Under the Concentration-time Curve from the Time of Dosing Extrapolated to Time Infinity (AUCinf)
Time Frame:Up to 30 days
Safety Issue:
Description:AUCinf will be derived from the PK plasma samples collected.
Measure:PK of gemcitabine: Area Under the Concentration-time Curve from the Time of Dosing Until the Last Measurable Concentration (AUClast)
Time Frame:Up to 30 days
Safety Issue:
Description:AUClast will be derived from the PK plasma samples collected.
Measure:PK of gemcitabine: Maximum Concentration (Cmax)
Time Frame:Up to 30 days
Safety Issue:
Description:Cmax will be derived from the PK plasma samples collected.
Measure:PK of gemcitabine: Time of Maximum Concentration (Tmax)
Time Frame:Up to 30 days
Safety Issue:
Description:Tmax will be derived from the PK plasma samples collected.
Measure:PK of gemcitabine: Terminal Elimination Half-life (T1/2)
Time Frame:Up to 30 days
Safety Issue:
Description:T1/2 will be derived from the PK plasma samples collected.
Measure:PK of gemcitabine: Clearance (CL)
Time Frame:Up to 30 days
Safety Issue:
Description:CL will be derived from the PK plasma samples collected.
Measure:PK of gemcitabine: Volume of Distribution During the Terminal Phase (Vz)
Time Frame:Up to 30 days
Safety Issue:
Description:Vz will be derived from the PK plasma samples collected.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Astellas Pharma Global Development, Inc.

Trial Keywords

  • metastatic pancreatic cancer
  • IMAB362
  • nab-paclitaxel
  • gemcitabine
  • zolbetuximab
  • metastatic pancreatic adenocarcinoma
  • pancreatic cancer
  • CLDN 18.2

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