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

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ClinicalTrials.gov Identifier: NCT03451773
Recruitment Status : Recruiting
First Posted : March 2, 2018
Last Update Posted : May 15, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

Background:

Pancreas cancer ranks 4th in all cancer-related deaths in the U.S. Gemcitabine is a standard treatment for it. M7824 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 IV once every 2 weeks. They will continue until their disease gets worse or they have unacceptable side effects. In addition they will get

Participants will 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.


Condition or disease Intervention/treatment Phase
Cancer of Pancreas Pancreas Cancer Pancreatic Adenocarcinoma Pancreatic Cancer Pancreatic Neoplasms Drug: M7824 Drug: Gemcitabine Phase 1 Phase 2

Detailed Description:

Background:

  • M7824 is an investigational agent in phase IB/II clinical development with dual activity against 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 IgG1 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 <=-Difluordesoxycytidine) is a standard-of-care nucleoside analogue in pancreas cancer with immunomodulatory mechanisms of actions in pancreas cancer patients.
  • Preclinical studies in authochtenous 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 (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 .


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 41 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase IB/II Single-arm Study of M7824 (MSB0011359C) in Combination With Gemcitabine in Adults With Previously Treated Advanced Adenocarcinoma of the Pancreas
Actual Study Start Date : May 17, 2018
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 1/ Arm 1
Gemcitabine (dose based on genetic testing results) + de-escalating dose of M7824
Drug: M7824
1,200 or 500mg every 2 weeks by IV infusion

Drug: Gemcitabine
Standard (1,000 mg/m2) or reduced (600 mg/m2 for 4 doses) 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

Experimental: 2/ Arm 2
Gemcitabine (dose based on genetic testing results) + RP2D of M7824
Drug: M7824
1,200 or 500mg every 2 weeks by IV infusion

Drug: Gemcitabine
Standard (1,000 mg/m2) or reduced (600 mg/m2 for 4 doses) 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




Primary Outcome Measures :
  1. Safety and tolerability of M7824 in combination with gemcitabine [ Time Frame: 30 days after treatment ]
    Number, severity and duration of treatment-related AEs

  2. Best overall response (BOR) [ Time Frame: every 6-12 weeks ]
    Changes in tumor size and occurrence of metastases


Secondary Outcome Measures :
  1. Immune-related best overall response (irBOR) [ Time Frame: every 6-12 weeks ]
    Immune related changes in tumor size and occurrence of metastases

  2. Overall survival (OS) [ Time Frame: death ]
    Median amount of time subject survives after therapy

  3. Progression-free survival (PFS) [ Time Frame: at progression ]
    Median amount of time subject survives without disease progression after treatment



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • 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 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.
  • ECOG performance status of 0 to 1
  • Must have evaluable or measurable disease per 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
    • 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 1.5xULN,
    • an AST level less than or equal to 2.5xULN,
    • 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 m2 OR within normal as predicted by the Cockcroft-Gault formula:

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-PD-1, anti-PD-L1, or anti-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 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.
  • HIV, HCV, 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 vWF deficiency.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03451773


Contacts
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Contact: Santhana B Webb, R.N. (240) 858-3165 santhana.webb@nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Udo Rudloff, M.D. National Cancer Institute (NCI)

Additional Information:
Publications:
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03451773     History of Changes
Other Study ID Numbers: 180061
18-C-0061
First Posted: March 2, 2018    Key Record Dates
Last Update Posted: May 15, 2019
Last Verified: April 23, 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
TGF Ligand Trap
Extracellular Domain of Human TGF Receptor II
Avelumab
Human IgG1 mAb Directed Against Human PD-L1
Health-Related Quality of Life

Additional relevant MeSH terms:
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Adenocarcinoma
Pancreatic Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Gemcitabine
Pancrelipase
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Gastrointestinal Agents