Ignite Creation Date:
2025-12-25 @ 12:18 AM
Ignite Modification Date:
2026-01-06 @ 8:36 PM
Study NCT ID:
NCT03816358
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2025-09-15
First Post:
2019-01-24
Is NOT Gene Therapy:
True
Has Adverse Events:
False
Brief Title:
Testing the Combination of Anetumab Ravtansine With Either Nivolumab, Nivolumab and Ipilimumab, or Gemcitabine and Nivolumab in Advanced Pancreatic Cancer
Sponsor:
National Cancer Institute (NCI)
Organization:
Study Overview
Official Title:
A Phase I Study of Anetumab Ravtansine in Combination With Either Anti-PD-1 Antibody, or Anti-CTLA4 and Anti-PD-1 Antibodies or Anti-PD-1 Antibody and Gemcitabine in Mesothelin-Positive Advanced Pancreatic Adenocarcinoma
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2025-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This phase I trial studies the side effects and best dose of anetumab ravtansine when given together with nivolumab, ipilimumab and gemcitabine hydrochloride in treating patients with mesothelin positive pancreatic cancer that has spread to other places in the body (advanced). Anetumab ravtansine is a monoclonal antibody, called anetumab ravtansine, linked to a chemotherapy drug called DM4. Anetumab attaches to mesothelin positive cancer cells in a targeted way and delivers DM4 to kill them. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving anetumab ravtansine together with nivolumab, ipilimumab, and gemcitabine hydrochloride may work better in treating patients with pancreatic cancer.
Detailed Description:
PRIMARY OBJECTIVE:
I. To evaluate the safety and tolerability of anetumab ravtansine with the following combinations in patients with mesothelin positive pancreatic adenocarcinoma.
SECONDARY OBJECTIVES:
I. To assess the preliminary anti-tumor activity of anetumab ravtansine (anetumab) in combination with nivolumab, nivolumab and ipilimumab, nivolumab and gemcitabine hydrochloride (gemcitabine) as measured by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 overall response rate (ORR).
II. To characterize the pharmacokinetics (PK) profile of anetumab (apparent diffusion coefficient \[ADC\]), total antibody (ADC and cleaved free antibody), DM4 and DM4-Me (S-Methyl metabolite of DM4).
III. To evaluate the tumor microenvironment and immune changes in tumor and peripheral blood over the course of treatment to identify predictors of response or resistance to treatment.
IV. To measure the progressive disease (PD) effects of this combination including molecular and immune biomarkers in tumor biopsies and peripheral blood.
EXPLORATORY OBJECTIVES:
I. To characterize mesothelin, PD-L1, CD3, CD4, CD8 expressions at baseline and after treatment in mesothelin positive pancreatic cancer patients.
II. To evaluate level of soluble mesothelin and megakaryocyte potentiation factor (MPF) over the course of treatment and to correlate these biomarkers with clinical outcome.
III. To perform whole exome sequencing (WES) +/- ribonucleic acid sequencing (RNAseq) in the tumor biopsy specimens and correlation genomic (e.g. mutational burden) and transcriptomic biomarkers with clinical outcome.
IV. To evaluate mononuclear phagocyte system (MPS) function, Fc-gamma receptors (FcgammaRs) and hormone and chemokine mediators as methods to evaluate factors affecting the PK and PD of these agents.
V. To evaluate anti-drug antibody (ADA) titres changes pre and post treatment and correlate them with PK, toxicity and responses.
OUTLINE: This is a dose-escalation study of anetumab ravtansine. Patients are assigned to 1 of 3 arms.
ARM I: Patients receive anetumab ravtansine intravenously (IV) over 1 hour on day 1 and nivolumab IV over 30 minutes on day 8 of cycle 1 and on day 1 of subsequent cycles. Treatment repeats every 21 or 28 days (cycle 1) for up to 17 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo a biopsy and collection of blood on study.
ARM II: Patients receive anetumab ravtansine IV over 1 hour on day 1 and nivolumab IV over 30 minutes on day 8 of cycle 1 and on day 1 of subsequent cycles. Patients also receive ipilimumab IV over 30 minutes on day 8 of cycle 1 and on day 1 of cycles 2-4. Treatment repeats every 21 or 28 days (cycle 1) for up to 17 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo a biopsy and collection of blood on study.
ARM III: Patients receive anetumab ravtansine IV over 1 hour on day 1 and nivolumab IV over 30 minutes on day 8 of cycle 1 and on day 1 of subsequent cycles. Patients also receive gemcitabine hydrochloride over 30-40 minutes on days 1 and 8. Treatment repeats every 21 or 28 days (cycle 1) for up to 17 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo a biopsy and collection of blood on study.
After completion of study treatment, patients are followed up every 8 weeks for up to 100 days, then every 12 weeks thereafter.
I. To evaluate the safety and tolerability of anetumab ravtansine with the following combinations in patients with mesothelin positive pancreatic adenocarcinoma.
SECONDARY OBJECTIVES:
I. To assess the preliminary anti-tumor activity of anetumab ravtansine (anetumab) in combination with nivolumab, nivolumab and ipilimumab, nivolumab and gemcitabine hydrochloride (gemcitabine) as measured by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 overall response rate (ORR).
II. To characterize the pharmacokinetics (PK) profile of anetumab (apparent diffusion coefficient \[ADC\]), total antibody (ADC and cleaved free antibody), DM4 and DM4-Me (S-Methyl metabolite of DM4).
III. To evaluate the tumor microenvironment and immune changes in tumor and peripheral blood over the course of treatment to identify predictors of response or resistance to treatment.
IV. To measure the progressive disease (PD) effects of this combination including molecular and immune biomarkers in tumor biopsies and peripheral blood.
EXPLORATORY OBJECTIVES:
I. To characterize mesothelin, PD-L1, CD3, CD4, CD8 expressions at baseline and after treatment in mesothelin positive pancreatic cancer patients.
II. To evaluate level of soluble mesothelin and megakaryocyte potentiation factor (MPF) over the course of treatment and to correlate these biomarkers with clinical outcome.
III. To perform whole exome sequencing (WES) +/- ribonucleic acid sequencing (RNAseq) in the tumor biopsy specimens and correlation genomic (e.g. mutational burden) and transcriptomic biomarkers with clinical outcome.
IV. To evaluate mononuclear phagocyte system (MPS) function, Fc-gamma receptors (FcgammaRs) and hormone and chemokine mediators as methods to evaluate factors affecting the PK and PD of these agents.
V. To evaluate anti-drug antibody (ADA) titres changes pre and post treatment and correlate them with PK, toxicity and responses.
OUTLINE: This is a dose-escalation study of anetumab ravtansine. Patients are assigned to 1 of 3 arms.
ARM I: Patients receive anetumab ravtansine intravenously (IV) over 1 hour on day 1 and nivolumab IV over 30 minutes on day 8 of cycle 1 and on day 1 of subsequent cycles. Treatment repeats every 21 or 28 days (cycle 1) for up to 17 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo a biopsy and collection of blood on study.
ARM II: Patients receive anetumab ravtansine IV over 1 hour on day 1 and nivolumab IV over 30 minutes on day 8 of cycle 1 and on day 1 of subsequent cycles. Patients also receive ipilimumab IV over 30 minutes on day 8 of cycle 1 and on day 1 of cycles 2-4. Treatment repeats every 21 or 28 days (cycle 1) for up to 17 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo a biopsy and collection of blood on study.
ARM III: Patients receive anetumab ravtansine IV over 1 hour on day 1 and nivolumab IV over 30 minutes on day 8 of cycle 1 and on day 1 of subsequent cycles. Patients also receive gemcitabine hydrochloride over 30-40 minutes on days 1 and 8. Treatment repeats every 21 or 28 days (cycle 1) for up to 17 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo a biopsy and collection of blood on study.
After completion of study treatment, patients are followed up every 8 weeks for up to 100 days, then every 12 weeks thereafter.
Study Oversight
Has Oversight DMC:
False
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?: