M7824 (MSB0011359C) in Combination With Gemcitabine in Adults With Previously Treated Advanced Adenocarcinoma of the Pancreas

Study Overview
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Brief Summary
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Background: Pancreas cancer ranks 4th in all cancer-related deaths in the United States (U.S.) Gemcitabine is a standard treatment for it. M7824 (MSB0011359C) blocks a pathway that prevents the immune system from effectively fighting cancer. The two drugs together might help people with pancreas cancer. Objective: To test if giving M7824 together with gemcitabine is safe and causes tumors to shrink. Eligibility: People ages 18 and older with pancreatic cancer already treated with standard therapies Design: Participants will be screened with: Medical history Physical exam Scans in a machine that takes pictures of the body Blood, urine, and heart tests Some participants may have a tumor sample removed. Participants will get M7824 by intravenous (IV) once every 2 weeks. They will continue until their disease gets worse or they have unacceptable side effects. After the first dose, participants will also get gemcitabine by IV once weekly for 7 weeks. Then they will get it as follows for up to 6 months: Skip 1 week, get the drug once a week for 3 weeks, skip 1 week. Before treatment on the first day of each cycle, participants will repeat screening tests. They will also have: Optional tumor biopsies before and after 3 cycles of therapy Questions about their well-being and function Genetic testing of tissue and blood samples Participants will have a follow-up visit 4-5 weeks after they stop therapy. This includes a physical exam, blood and urine tests, and maybe a scan. If their disease does not get worse, they will be invited for scans every 12 weeks.

Detailed Description
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Background: M7824 (MSB0011359C) is an investigational agent in phase IB/II clinical development with dual activity against transforming growth factor beta (TGF)-beta signaling (TGF-beta ligand trap; extracellular domain of human TGF-beta receptor II) and immune checkpoint ligand inhibition (PD-L1 inhibition; avelumab, fully human immunoglobulin G1 (IgG1) monoclonal antibody (mAb) directed against human PD-L1) with an acceptable toxicity profile and early signals of anti-cancer activity including in pancreas cancer. Gemcitabine (2 <=,2 <=-Difluorodeoxycytidine) is a standard-of-care nucleoside analogue in pancreas cancer with immunomodulatory mechanisms of actions in pancreas cancer patients. Preclinical studies in autochthonous and syngeneic murine models have shown that TGF-beta inhibition and PD-L1 inhibition cooperate with gemcitabine to achieve reduction of tumor growth and extension of survival induce anti-tumor immunity and reprogram the immune landscape. Objectives: To determine the safety and tolerability of M7824 in combination with gemcitabine in subjects with metastatic or locally advanced pancreas cancer. To determine best overall response (BOR) rate according to Response Evaluation Criteria (Response Evaluation Criteria in Solid Tumors (RECIST) 1.1) in advanced pancreas cancer subjects. Eligibility: Histologically confirmed diagnosis of adenocarcinoma of the pancreas. Patients must have progressed on prior chemotherapeutic regimen. Concurrent treatment with non-permitted drugs and other interventions, prior therapy with gemcitabine or any antibody / drug targeting T cell co-regulatory proteins (immune checkpoints) such as anti-PD 1, anti PD-L1, or anti-cytotoxic T lymphocyte antigen-4 (CTLA 4 antibody) is not allowed. Design: - The proposed study is a phase IB/II study of M7824 in combination with gemcitabine in a safety run-in of 6-18 patients and, if safe and tolerated, will proceed to an expansion phase II cohort with a standard Simon Minimax design.

Official Title
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A Phase IB/II Single-arm Study of M7824 (MSB0011359C) in Combination With Gemcitabine in Adults With Previously Treated Advanced Adenocarcinoma of the Pancreas

Conditions
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Cancer of Pancreas, Pancreas Cancer, Pancreatic Adenocarcinoma, Pancreatic Cancer, Pancreatic Neoplasms

Intervention / Treatment
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* Drug: M7824
* Drug: Gemcitabine


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Patient must be able to understand and willing to sign a written informed consent document Age greater than of equal to 18 years. Because no dosing or adverse event data are currently available on the use of M7824 (MSB0011359C) in combination with gemcitabine in patients <18 years of age, children are excluded from this study, but will be eligible for future pediatric trials Histologically or cytologically proven pancreatic adenocarcinoma (subjects with endocrine or acinar pancreatic carcinoma are not eligible). Patients must have disease that is not amenable to potentially curative resection. Subjects must have progressed on or after standard first-line systemic chemotherapy. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 Must have evaluable or measurable disease per Response Evaluation in Solid Tumors (RECIST) 1.1. Adequate hematological function defined by: white blood cell (WBC) count greater than or equal to 3x10(9)/L with absolute neutrophil count (ANC) greater than or equal to 1.5x10(9)/L lymphocyte count greater than or equal to 0.5x10(9)/L, platelet count greater than or equal to 120x10(9)/L, and Hemoglobin (Hgb) greater than or equal to 9 g/dL (in absence of blood transfusion) Adequate hepatic function defined by: a total bilirubin level less than or equal to 1.5xUpper limit of normal (ULN), an aspartate aminotransferase (AST) level less than or equal to 2.5xULN, alanine aminotransferase (ALT) level less than or equal to 2.5Xuln. Adequate renal function defined by: Creatinine up to 1.5 upper institutional limits OR creatinine clearance (CrCl) >50 mL/min/1.73 m^2 OR within normal as predicted by the Cockcroft-Gault formula: Creatinine Clearance (CrCl)=(140-age) x (weight in kg) x (0.85, if female)/72 x Serum Creatinine (mg/dL) - The effects of the study treatment on the developing human fetus are unknown; thus, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) within 28 days prior to study entry, for the duration of study participation and up to 120 days after the last dose of the drug. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. EXCLUSION CRITERIA: Patients who are receiving any other investigational agents Prior therapy with any antibody / drug targeting T cell coregulatory proteins (immune checkpoints) such as anti-Programmed cell death protein 1 (PD-1), anti-Programmed death-ligand 1 (PD-L1), or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody. Anticancer treatment within designated period before enrollment including: minor surgical procedure (such as biliary stenting) within 14 days major surgical procedure or radiation treatment within 28 days chemotherapy or experimental drug treatment with published half-life known to be 72 hours within 14 days experimental drug treatment with unpublished or half-life greater than 72 hours within 28 days radiotherapy for measurable lesions delivered in a normal organ-sparing technique within 21 days (except for palliative radiotherapy) Concurrent treatment with non-permitted drugs including herbal remedies with immunostimulating properties (for example, mistletoe extract) or known to potentially interfere with major organ function (for example, hypericin). Previous malignant disease (other than the target malignancy to be investigated in this trial) within the last 3 years. Subjects with a history of cervical carcinoma in situ, superficial or no-invasive bladder cancer, or basal cell or squamous cell carcinoma in situ previously treated with curative intent are NOT excluded. Rapidly progressive disease which, in the opinion of the Investigator, may predispose to inability to tolerate treatment or trial procedures. Subjects with active central nervous system (CNS) metastases causing clinical symptoms or metastases that require therapeutic intervention are excluded. Subjects with a history of treated CNS metastases (by surgery or radiation therapy) are not eligible unless they have fully recovered from treatment, demonstrated no progression for at least 2 months, and do not require continued steroid therapy. Subjects with CNS metastases incidentally detected during Screening which do not cause clinical symptoms and for which standard of care suggests no therapeutic intervention is needed are eligible. Receipt of any organ transplantation, including allogeneic stem-cell transplantation, except of transplants that do not require immunosuppression (e.g., corneal transplant, hair transplant) Significant acute or chronic infections including tuberculosis (history of exposure or history of positive tuberculosis test; plus, presence of clinical symptoms, physical or radiographic findings) Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent with the exceptions: diabetes type I, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible; subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses less than or equal to 10 mg of prednisone or equivalent per day; administration of steroids for other conditions through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) is acceptable. Known severe hypersensitivity reactions to monoclonal antibodies (Grade greater than or equal to 3 National Cancer Institute Common Terminology Criteria in Adverse Events (NCI-CTCAE) v4.03, any history of anaphylaxis or history of uncontrolled asthma. Known severe hypersensitivity to gemcitabine. Female patients who are pregnant or breastfeeding. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with M7824 in combination with gemcitabine, breastfeeding should be discontinued. Known alcohol or drug abuse. Clinically significant cardiovascular / cerebrovascular disease as follows: cerebral vascular accident / stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association Classification Class greater than or equal to II), or serious cardiac arrhythmia. Clinically relevant diseases (for example, inflammatory bowel disease) and/or uncontrolled medical conditions, which, in the opinion of the Investigator, might impair the subject's tolerance or ability to participate in the trial. Vaccine administration of live vaccines within 28 days of enrollment. Patients with known contrast allergies requiring pre-medication with steroids. Human immunodeficiency virus (HIV), hepatitis C virus (HCV), hepatitis B virus (HBV) positive patients on antiviral drugs are excluded due to the absence of previous experience with concurrent use of antiviral medications and the investigational drug product to be evaluated in the current study and possible for adverse pharmacokinetic and/or pharmacodynamic interactions. Known inherited bleeding disorder and/or history of bleeding diathesis such as von Willebrand factor (vWF) deficiency.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1/ Arm 1-Gemcitabine + de-escalating dose of M7824 (MSB0011359C)<br>Gemcitabine (dose based on genetic testing results) + de-escalating dose of M7824 | Drug: M7824<br>* 1,200 or 500mg every 2 weeks by intravenous (IV) infusion<br>* Other names: MSB0011359C;Drug: Gemcitabine<br>* Standard (1,000 mg/m^2) or reduced (600 mg/m^2 for 4 doses) intravenous (IV) once a week for first 4 weeks. Then, once weekly for 3 weeks with one week rest. Gemcitabine will be discontinued after 6 months of therapy<br>* Other names: Gemzar;|
| Experimental: 2/ Arm 2-Gemcitabine + Recommended Phase 2 Dose (RP2D) of M7824 (MSB0011359C)<br>Gemcitabine (dose based on genetic testing results) + RP2D of M7824 | Drug: M7824<br>* 1,200 or 500mg every 2 weeks by intravenous (IV) infusion<br>* Other names: MSB0011359C;Drug: Gemcitabine<br>* Standard (1,000 mg/m^2) or reduced (600 mg/m^2 for 4 doses) intravenous (IV) once a week for first 4 weeks. Then, once weekly for 3 weeks with one week rest. Gemcitabine will be discontinued after 6 months of therapy<br>* Other names: Gemzar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase IB: Number and Severity of Grade 1-2 Adverse Events Possibly, Probably, or Definitely Related to Treatment | Safety and tolerability of M7824 in combination with gemcitabine was assessed by the Common Terminology Criteria for Adverse Events (CTCAE)v5.0. Grade 1 is mild; asymptomatic or mild symptoms. Grade 2 is moderate; minimal non-invasive intervention indicated. | 30 days after treatment | 
| Phase IB: Number and Severity of Grade 3-5 Adverse Events Possibly, Probably, or Definitely Related to Treatment | Safety and tolerability of M7824 in combination with gemcitabine was assessed by the Common Terminology Criteria for Adverse Events (CTCAE)v5.0. Grade 3 is severe or medically significant but not immediately life-threatening, Grade 4 is life-threatening consequences, and Grade 5 is death related to adverse event. | 30 days after treatment | 
| Phase II: Number of Participants With a Best Overall Response (BOR) | Changes in tumor size and occurrence of metastases was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 to determine the best overall response: Complete Response (CR), Partial Response (PR), and Stable Disease (SD), whichever is recorded first. Complete Response is disappearance of all lesions, Partial Response is at least a 30% decrease in the sum of diameters of target lesions, and Stable Disease is when the sum of all target lesions does not qualify for CR, PR, or Progressive Disease (PD), defined as the appearance of new lesions. | Every 8 weeks, up to 2 years | 
| Duration of Treatment-related Adverse Events (AEs) | Duration of treatment-related AE's is defined as the time from the date treatment consent signed to end of treatment. Grade 1-4 adverse events observed in participants with pancreatic cancer assessed by the Common Terminology Criteria in Adverse Events (CTCAE) v5.0. Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe or medically significant. And Grade 4 is life-threatening. | Time to resolution of adverse events, which is the time recorded until it took for the adverse event to resolve to grade 1 or less (if there is a death, it is that time), approximately 12 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With an Immune-related Best Overall Response (irBOR) | irBOR is defined as the duration of immune-related best overall response measured from the time measurement criteria are met for Immune-related Complete Response (irCR) or Immune-related Partial Response (irPR) (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented. Immune related changes in tumor size and occurrence of metastases was assessed by the Modified Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST). Immune-related Complete Response (irCR) is complete disappearance of all lesions and no new lesions. Immune-related Partial Response (irPR) is sum of the longest diameters of target and new measurable lesions neither irCR, irPR (compared to baseline) or irPD (compared to nadir). Immune-related Progressive Disease (irPD) is appearance of new lesions. | Every 6-12 weeks, up to 1 year | 
| Percentage of Evaluable Participants Alive at 6 Months and 9 Months | Participants who are alive at 6 months and 9 months after therapy. | At 6 and 9 months | 
| Percentage of Participants Who Have Not Progressed at 3 Months | Percentage of participants who have not progressed at 3 months. Progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) and is defined as the appearance of new lesions. | 3 months | 
| Overall Median Survival | OS is the median amount of time subject survives after therapy. | up to 1 year | 
| Overall Progression Free Survival | PFS is the median amount of time subject survives without disease progression after treatment. Progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) and is defined as the appearance of new lesions. | up to 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TGF Ligand Trap, Extracellular Domain of Human TGF Receptor II, Avelumab, Human IgG1 mAb Directed Against Human PD-L1, Health-Related Quality of Life