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

NCT03451773 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: 18006118-C-0061
• Study Type: interventional
• Target: 7
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Cancer of Pancreas; Pancreas Cancer; Pancreatic Adenocarcinoma; Pancreatic Cancer; Pancreatic Neoplasms

Keywords

TGF Ligand Trap; Extracellular Domain of Human TGF Receptor II; Avelumab; Human IgG1 mAb Directed Against Human PD-L1; Health-Related Quality of Life

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (5)

• Number of Participants With an Immune-related Best Overall Response (irBOR)

  Every 6-12 weeks, up to 1 year

• Percentage of Evaluable Participants Alive at 6 Months and 9 Months

  At 6 and 9 months

• Percentage of Participants Who Have Not Progressed at 3 Months

  3 months

• Overall Median Survival

  up to 1 year

• Overall Progression Free Survival

  up to 6 months

Other Outcomes (1)

• Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)

  Date treatment consent signed to date off study, approximately 7 months and 20 days for Dose Level -1, and 15 months and 20 days for Dose Level 0.

Study Arms (2)

1/ Arm 1-Gemcitabine + de-escalating dose of M7824 (MSB0011359C)

EXPERIMENTAL

Gemcitabine (dose based on genetic testing results) + de-escalating dose of M7824

Drug: M7824; Drug: Gemcitabine

2/ Arm 2-Gemcitabine + Recommended Phase 2 Dose (RP2D) of M7824 (MSB0011359C)

EXPERIMENTAL

Gemcitabine (dose based on genetic testing results) + RP2D of M7824

Drug: M7824; Drug: Gemcitabine

Interventions

M7824 DRUG

1,200 or 500mg every 2 weeks by intravenous (IV) infusion

Also known as: MSB0011359C

1/ Arm 1-Gemcitabine + de-escalating dose of M7824 (MSB0011359C); 2/ Arm 2-Gemcitabine + Recommended Phase 2 Dose (RP2D) of M7824 (MSB0011359C)

Gemcitabine DRUG

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

Also known as: Gemzar

1/ Arm 1-Gemcitabine + de-escalating dose of M7824 (MSB0011359C); 2/ Arm 2-Gemcitabine + Recommended Phase 2 Dose (RP2D) of M7824 (MSB0011359C)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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),

You may not qualify if:

• 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:

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Song S, Yuan P, Wu H, Chen J, Fu J, Li P, Lu J, Wei W. Dendritic cells with an increased PD-L1 by TGF-beta induce T cell anergy for the cytotoxicity of hepatocellular carcinoma cells. Int Immunopharmacol. 2014 May;20(1):117-23. doi: 10.1016/j.intimp.2014.02.027. Epub 2014 Mar 4.

  PMID: 24606770 BACKGROUND

• Akhurst RJ, Hata A. Targeting the TGFbeta signalling pathway in disease. Nat Rev Drug Discov. 2012 Oct;11(10):790-811. doi: 10.1038/nrd3810. Epub 2012 Sep 24.

  PMID: 23000686 BACKGROUND

• Ding X, Chen W, Fan H, Zhu B. Cytidine deaminase polymorphism predicts toxicity of gemcitabine-based chemotherapy. Gene. 2015 Mar 15;559(1):31-7. doi: 10.1016/j.gene.2015.01.010. Epub 2015 Jan 10.

  PMID: 25582275 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Pancreatic Neoplasms

Interventions

Gemcitabine

Condition Hierarchy (Ancestors)

Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring

Results Point of Contact

• Title: Dr. Udo Rudloff
• Organization: National Cancer Institute

rudloffu@mail.nih.gov

240-760-6238

Study Officials

• Udo Rudloff, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: March 1, 2018
• First Posted: March 2, 2018
• Study Start: May 17, 2018
• Primary Completion: May 5, 2020
• Study Completion: May 5, 2020
• Last Updated: June 16, 2021
• Results First Posted: June 16, 2021

Record last verified: 2021-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)