Testing the Combination of Anetumab Ravtansine With Either Nivolumab, Nivolumab and Ipilimumab, or Gemcitabine and Nivolumab in Advanced Pancreatic Cancer

Titre officiel

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

Sommaire:

Cet essai de phase I étudie les effets secondaires et la meilleure dose d’anétumab ravtansine lorsqu’il est associé au nivolumab, à l’ipilimumab et au chlorhydrate de gemcitabine dans le traitement de patients atteints d’un cancer du pancréas positif pour la mésothéline qui s’est propagé à d’autres zones de l’organisme (stade avancé). L’anétumab ravtansine est un anticorps monoclonal, appelé anétumab ravtansine, lié à un médicament de chimiothérapie appelé DM4. L’anétumab se fixe de manière ciblée aux cellules cancéreuses positives pour la mésothéline et délivre le DM4 pour détruire ces cellules. L’immunothérapie au moyen d’anticorps monoclonaux, comme le nivolumab et l’ipilimumab, peut aider le système immunitaire de l’organisme à attaquer le cancer et entraver la capacité des cellules tumorales à croître et à se propager. Les médicaments utilisés en chimiothérapie, comme le chlorhydrate de gemcitabine, agissent de différentes manières pour arrêter la croissance des cellules tumorales, soit en tuant les cellules, soit en les empêchant de se diviser ou de se propager. L’administration d’anétumab ravtansine en association avec le nivolumab, l’ipilimumab et le chlorhydrate de gemcitabine présenterait une efficacité supérieure dans le traitement des patients atteints d’un cancer du pancréas.

Description de l'essai

Primary Outcome:

• Maximum tolerated dose (MTD)

Secondary Outcome:

• Biomarker analysis

PRIMARY OBJECTIVE:

• To evaluate the safety and tolerability of anetumab ravtansine with the following combinations in patients with mesothelin positive pancreatic adenocarcinoma.

SECONDARY OBJECTIVES:

• 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).
• 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).
• 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.
• To measure the progressive disease (PD) effects of this combination including molecular and immune biomarkers in tumour biopsies and peripheral blood.

EXPLORATORY OBJECTIVES:

• To characterize mesothelin, PD-L1, CD3, CD4, CD8 expressions at baseline and after treatment in mesothelin positive pancreatic cancer patients.
• To evaluate level of soluble mesothelin and megakaryocyte potentiation factor (MPF) over the course of treatment and to correlate these biomarkers with clinical outcome.
• 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.
• 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.
• 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.

Voir cet essai sur ClinicalTrials.gov