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.
- 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.
