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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

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ClinicalTrials.gov Identifier: NCT03816163
Recruitment Status : Recruiting
First Posted : January 25, 2019
Last Update Posted : March 15, 2019
Sponsor:
Information provided by (Responsible Party):
Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Pancreatic Cancer Metastatic Pancreatic Cancer Metastatic Pancreatic Adenocarcinoma Drug: zolbetuximab Drug: nab-paclitaxel Drug: gemcitabine Phase 2

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 141 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : February 14, 2019
Estimated Primary Completion Date : February 2022
Estimated Study Completion Date : February 2022


Arm Intervention/treatment
Experimental: zolbetuximab +nab-paclitaxel + gemcitabine
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.
Drug: zolbetuximab
Administered as an intravenous infusion.
Other Name: IMAB362

Drug: nab-paclitaxel
Administered as an intravenous infusion

Drug: gemcitabine
Administered as an intravenous infusion

Active Comparator: nab-paclitaxel + gemcitabine
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.
Drug: nab-paclitaxel
Administered as an intravenous infusion

Drug: gemcitabine
Administered as an intravenous infusion




Primary Outcome Measures :
  1. Dose Limiting Toxicities (DLT) - (safety lead in) [ Time Frame: Up to 28 days ]
    Incidence of dose limiting toxicities.

  2. Overall Survival (OS) [ Time Frame: Up to 35 months ]
    OS is defined as the time from the date of randomization until the date of death from any cause.

  3. Safety assessed by Adverse Events (AEs) [ Time Frame: Up to 29 months ]
    An AE is any untoward medical occurrence in a subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product.

  4. Safety assessed by incidence of serious adverse events (SAE) [ Time Frame: Up to 29 months ]
    Adverse Event (AE) is considered "serious" if the investigator or sponsor view any of the following outcomes: Death, life-threatening, persistent or significant disability/incapacity, congenital anomaly or birth defect, hospitalization, or medically important event.

  5. Safety assessed by incidence of treatment emergent adverse events (TEAE) [ Time Frame: Up to 27 months ]
    Treatment Emergent Adverse Event (TEAE) is defined as any AE which starts, or worsens, after the first dose of study drug through 30 days after the last dose of study drug.

  6. Number of participants with laboratory value abnormalities and/or adverse events (AEs) [ Time Frame: Up to 27 months ]
    Number of participants with potentially clinically significant laboratory values.

  7. Number of participants with vital sign abnormalities and /or adverse events (AEs) [ Time Frame: Up to 29 months ]
    Number of participants with potentially clinically significant vital sign values.

  8. Number of participants with electrocardiograms (ECG) abnormalities and or adverse events [ Time Frame: Up to 27 months ]
    12-lead ECGs will be recorded. Prior to the ECG, participants should rest in supine position for 10 minutes. ECGs will be read and assessed locally.

  9. Number of participants with Eastern Cooperative Oncology Group (ECOG) performance status abnormalities and or adverse events [ Time Frame: Up to 29 months ]
    Number of participants with potentially clinically significant ECOG performance status values. ECOG grades 0-5, where 0 = Fully active, able to carry on all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work; 2 = Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours; 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours; 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair and 5 = Dead.


Secondary Outcome Measures :
  1. Progression Free Survival (PFS) [ Time Frame: Up to 35 months ]
    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.

  2. Objective Response Rate (ORR) [ Time Frame: Up to 35 months ]
    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.

  3. Number of anti-drug antibody (ADA) Positive Participants [ Time Frame: Up to 29 months ]
    Immunogenicity will be measured by the number of participants that are ADA positive.

  4. Disease Control Rate (DCR) [ Time Frame: Up to 35 months ]
    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

  5. Duration Of Response (DOR) [ Time Frame: Up to 35 months ]
    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.

  6. Change in CA (Cancer Antigen) 19-9 [ Time Frame: Baseline up to 27 months ]
    Change from baseline in serum CA19-9 will be assessed.

  7. PK of zolbetuximab: Concentration Immediately Prior to Dosing (Ctrough) [ Time Frame: Up to 29 months ]
    Ctrough will be derived from the PK serum samples collected.

  8. 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 ]
    AUCinf will be derived from the PK plasma samples collected.

  9. 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 ]
    AUClast will be derived from the PK plasma samples collected.

  10. PK of paclitaxel: Maximum Concentration (Cmax) [ Time Frame: Up to 30 days ]
    Cmax will be derived from the PK plasma samples collected.

  11. PK of paclitaxel: Time of Maximum Concentration (Tmax) [ Time Frame: Up to 30 days ]
    Tmax will be derived from the PK plasma samples collected.

  12. PK of paclitaxel: Terminal Elimination Half-life (T1/2) [ Time Frame: Up to 30 days ]
    T1/2 will be derived from the PK plasma samples collected.

  13. PK of paclitaxel: Clearance (CL) [ Time Frame: Up to 30 days ]
    CL will be derived from the PK plasma samples collected.

  14. PK of paclitaxel: Volume of Distribution During the Terminal Phase (Vz) [ Time Frame: Up to 30 days ]
    Vz will be derived from the PK plasma samples collected.

  15. 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 ]
    AUCinf will be derived from the PK plasma samples collected.

  16. 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 ]
    AUClast will be derived from the PK plasma samples collected.

  17. PK of gemcitabine: Maximum Concentration (Cmax) [ Time Frame: Up to 30 days ]
    Cmax will be derived from the PK plasma samples collected.

  18. PK of gemcitabine: Time of Maximum Concentration (Tmax) [ Time Frame: Up to 30 days ]
    Tmax will be derived from the PK plasma samples collected.

  19. PK of gemcitabine: Terminal Elimination Half-life (T1/2) [ Time Frame: Up to 30 days ]
    T1/2 will be derived from the PK plasma samples collected.

  20. PK of gemcitabine: Clearance (CL) [ Time Frame: Up to 30 days ]
    CL will be derived from the PK plasma samples collected.

  21. PK of gemcitabine: Volume of Distribution During the Terminal Phase (Vz) [ Time Frame: Up to 30 days ]
    Vz will be derived from the PK plasma samples collected.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03816163


Contacts
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Contact: Astellas Pharma Global Development 800-888-7704 astellas.registration@astellas.com

Locations
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United States, Arizona
Cancer Treatment Centers of Phoenix Recruiting
Goodyear, Arizona, United States, 85338
United States, Georgia
Cancer Treatment Centers of Atlanta Recruiting
Newnan, Georgia, United States, 30265
United States, Illinois
Cancer Treatment Centers of America, Chicago Recruiting
Zion, Illinois, United States, 60099
United States, Washington
MultiCare Regional Cancer Center - Gig Harbor Recruiting
Gig Harbor, Washington, United States, 98335
Sponsors and Collaborators
Astellas Pharma Global Development, Inc.
Investigators
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Study Director: Medical Director Astellas Pharma Global Development

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Responsible Party: Astellas Pharma Global Development, Inc.
ClinicalTrials.gov Identifier: NCT03816163     History of Changes
Other Study ID Numbers: 8951-CL-5201
2018-002551-15 ( EudraCT Number )
First Posted: January 25, 2019    Key Record Dates
Last Update Posted: March 15, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: Studies conducted with product indications or formulations that remain in development are assessed after study completion to determine if Individual Participant Data can be shared. The plan to share Individual Participant Data is based on the status of product approval or termination of the compound, in addition to other study-specific criteria described on www.clinicalstudydatarequest.com under "Sponsor Specific Details for Astellas."

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. ):
metastatic pancreatic cancer
IMAB362
nab-paclitaxel
gemcitabine
zolbetuximab
metastatic pancreatic adenocarcinoma
pancreatic cancer
CLDN 18.2

Additional relevant MeSH terms:
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Pancreatic Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Pancreatic Diseases
Adenocarcinoma
Carcinoma
Digestive System Diseases
Endocrine System Diseases
Paclitaxel
Albumin-Bound Paclitaxel
Gemcitabine
Antibodies, Monoclonal
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs