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.
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
Drug | Synonyms | Arms |
---|
zolbetuximab | IMAB362 | zolbetuximab +nab-paclitaxel + gemcitabine |
nab-paclitaxel | | nab-paclitaxel + gemcitabine |
gemcitabine | | nab-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
Name | Type | Description | Interventions |
---|
zolbetuximab +nab-paclitaxel + gemcitabine | Experimental | Participants 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 + gemcitabine | Active Comparator | Participants 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 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 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 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.
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 41 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 41 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 41 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 41 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 41 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 41 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 41 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
Last Updated
August 30, 2021