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Brief Title: Testing the Combination of Anetumab Ravtansine With Either Nivolumab, Nivolumab and Ipilimumab, or Gemcitabine and Nivolumab in Advanced Pancreatic Cancer
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
Study ID: NCT03816358
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.
Minimum Age: 18 Years
Eligible Ages: ADULT, OLDER_ADULT
Sex: ALL
Healthy Volunteers: No
University of Alabama at Birmingham Cancer Center, Birmingham, Alabama, United States
City of Hope Comprehensive Cancer Center, Duarte, California, United States
City of Hope at Irvine Lennar, Irvine, California, United States
Keck Medicine of USC Koreatown, Los Angeles, California, United States
Los Angeles General Medical Center, Los Angeles, California, United States
USC / Norris Comprehensive Cancer Center, Los Angeles, California, United States
UC Irvine Health/Chao Family Comprehensive Cancer Center, Orange, California, United States
University of California Davis Comprehensive Cancer Center, Sacramento, California, United States
UCHealth University of Colorado Hospital, Aurora, Colorado, United States
UM Sylvester Comprehensive Cancer Center at Coral Gables, Coral Gables, Florida, United States
UM Sylvester Comprehensive Cancer Center at Deerfield Beach, Deerfield Beach, Florida, United States
University of Miami Miller School of Medicine-Sylvester Cancer Center, Miami, Florida, United States
UM Sylvester Comprehensive Cancer Center at Plantation, Plantation, Florida, United States
Northwestern University, Chicago, Illinois, United States
University of Kansas Clinical Research Center, Fairway, Kansas, United States
HaysMed, Hays, Kansas, United States
University of Kansas Cancer Center, Kansas City, Kansas, United States
Lawrence Memorial Hospital, Lawrence, Kansas, United States
Olathe Health Cancer Center, Olathe, Kansas, United States
University of Kansas Cancer Center-Overland Park, Overland Park, Kansas, United States
University of Kansas Hospital-Indian Creek Campus, Overland Park, Kansas, United States
Ascension Via Christi - Pittsburg, Pittsburg, Kansas, United States
Salina Regional Health Center, Salina, Kansas, United States
University of Kansas Health System Saint Francis Campus, Topeka, Kansas, United States
University of Kansas Hospital-Westwood Cancer Center, Westwood, Kansas, United States
University of Kentucky/Markey Cancer Center, Lexington, Kentucky, United States
Wayne State University/Karmanos Cancer Institute, Detroit, Michigan, United States
Weisberg Cancer Treatment Center, Farmington Hills, Michigan, United States
Siteman Cancer Center at West County Hospital, Creve Coeur, Missouri, United States
University Health Truman Medical Center, Kansas City, Missouri, United States
University of Kansas Cancer Center - North, Kansas City, Missouri, United States
University of Kansas Cancer Center - Lee's Summit, Lee's Summit, Missouri, United States
University of Kansas Cancer Center at North Kansas City Hospital, North Kansas City, Missouri, United States
Washington University School of Medicine, Saint Louis, Missouri, United States
Siteman Cancer Center-South County, Saint Louis, Missouri, United States
Siteman Cancer Center at Christian Hospital, Saint Louis, Missouri, United States
Siteman Cancer Center at Saint Peters Hospital, Saint Peters, Missouri, United States
Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center, Lebanon, New Hampshire, United States
Laura and Isaac Perlmutter Cancer Center at NYU Langone, New York, New York, United States
Wake Forest University Health Sciences, Winston-Salem, North Carolina, United States
Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States
Vanderbilt University/Ingram Cancer Center, Nashville, Tennessee, United States
M D Anderson Cancer Center, Houston, Texas, United States
Huntsman Cancer Institute/University of Utah, Salt Lake City, Utah, United States
University Health Network-Princess Margaret Hospital, Toronto, Ontario, Canada
Name: Anna Spreafico
Affiliation: University Health Network Princess Margaret Cancer Center LAO
Role: PRINCIPAL_INVESTIGATOR