M7824 and Gemcitabine Hydrochloride in Treating Participants with Previously Treated Advanced Pancreatic Cancer
This phase I / II trial studies the side effects of anti-PD-L1 / transforming growth factor (TGF)betaRII fusion protein M7824 (M7824) and gemcitabine hydrochloride and to see how well they work in treating participants with previously treated pancreatic cancer that has spread to other places in the body. M7824 may target and block a pathway that prevents the immune system from effectively fighting cancer. Drugs used in chemotherapy, 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 M7824 and gemcitabine hydrochloride may work better in treating participants with pancreatic cancer.
- Patient must be able to understand and willing to sign a written informed consent document
- 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, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as > 20 mm with conventional techniques or as > 10 mm with spiral computed tomography (CT) scan
- White blood cell (WBC) count ≥ 3 × 10^9/L
- Absolute neutrophil count (ANC) ≥ 1.5 ×10^9/L
- Lymphocyte count ≥ 0.5 × 10^9/L
- Platelet count ≥ 120 × 10^9/L
- Hemoglobin (Hgb) ≥ 9 g/dL (in absence of blood transfusion)
- Total bilirubin level ≤ 1.5 × upper limit of normal (ULN)
- Aspartate aminotransferase (AST) level ≤ 2.5 × ULN
- Alanine aminotransferase (ALT) level ≤ 2.5 × ULN
- Creatinine up to 1.5 upper institutional limits OR creatinine clearance (CrCl) > 50 mL/min/1.73 m^2 according to the Cockcroft-Gault formula
- Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) 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
- Prior systemic therapy with gemcitabine (patient with prior weekly low-dose radiosensitizing gemcitabine (75 mg/m^2) are eligible)
- 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 ≤ 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 ≥ 3 National Cancer Institute-Common Terminology Criteria for Adverse Events [NCI-CTCAE] version [v] 4.03), any history of anaphylaxis or history of uncontrolled asthma
- Known severe hypersensitivity to gemcitabine
- Female patients who are pregnant or breastfeeding
- 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 ≥ 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 21 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 on combination of antiviral and this trial drugs and possible interaction
Locations & Contacts
Contact: Udo Rudloff
Phone: 240-760-6238 Email: firstname.lastname@example.org
Trial Objectives and Outline
I. To determine the safety and tolerability of M7824 in combination with gemcitabine hydrochloride (gemcitabine) in subjects with metastatic or locally advanced pancreas cancer. (Phase IB)
II. To determine the best overall response (BOR) rate according to Response Evaluation Criteria (RECIST 1.1) in advanced pancreas cancer subjects. (Phase II)
I. To assess progression-free survival (PFS) according to RECIST 1.1.
II. To characterize overall survival (OS).
III. To assess the immune-related BOR (irBOR) using the immune-related RECIST (irRECIST).
I. Determine the impact of M7824 on tumor perfusion by dynamic contrast enhanced magnetic resonance imaging (MRI) (DCE-MRI).
II. To evaluate impact of genomic profile of advanced pancreatic cancers on clinical response to M7824.
III. To correlate circulating free tumor DNA (cftDNA) levels with clinical course of pancreatic cancer patients treated with M7824 in combination with gemcitabine.
IV. To evaluate the intratumoral immunogenicity of M7824 in combination with gemcitabine.
V. To characterize plasma concentration maximum (Cmax) and concentration minimum (Cmin) of M7824 and gemcitabine when given in combination.
VI. To measure subjective health-related quality of life (HRQoL) affecting disease-specific symptoms and treatment-related concerns.
Participants receive anti-PD-L1/TGFbetaRII fusion protein M7824 intravenously (IV) over 60 minutes on day 1 every 14 days in the absence of disease progression or unacceptable toxicity. Beginning course 2, participants also receive gemcitabine hydrochloride IV over 30 minutes once weekly for 7 weeks with 1 week rest. Starting course 6, participants receive gemcitabine hydrochloride once weekly for 3 weeks with 1 week rest for every 4 weeks for up to 13 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, participants are followed up at 28 days and then every 12 weeks for 1 year.
Trial Phase & Type
NCI - Center for Cancer Research
Secondary IDs NCI-2018-00374, P173276
Clinicaltrials.gov ID NCT03451773