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
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 tumour cells to grow and spread. Chemotherapy drugs, such as
gemcitabine hydrochloride, work in different ways to stop the growth of tumour 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.
Trial Description
Primary Outcome:
- Maximum tolerated dose (MTD)
Secondary Outcome:
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-tumour 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 Tumours (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 tumour microenvironment and immune changes in tumour 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 tumour 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
tumour 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.
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.
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.
After completion of study treatment, patients are followed up every 8 weeks for up to 100
days, then every 12 weeks thereafter.
View this trial on ClinicalTrials.gov
