MC# 16-31 - Study Title: A Phase 1 Multicenter, Open-label, Dose-escalation and Dose-expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Immunogenicity, and Antitumor Activity of MEDI9447 Alone and in Combination with MEDI4736 in Adult Subjects with Select Advanced Solid Tumors
Agent(s): MEDI9447, MEDI4736 (Durvalumab)
Disease Type(s): Lung-NSCLC
Drug Classification(s): Immunotherapy, Monoclonal Antibody, Targeted Therapy
Molecular Target(s): PD-L1 (CD274), CD73
Mechanism of Action
- Durvalumab (MEDI4736) is a humanized monoclonal antibody targeting PD-L1, which is a transmembrane protein on dendritic cells that when engaged with the PD-1 receptor on T-cells delivers an inhibitory signal that promotes T-cell anergy/apoptosis.
- MEDI9447 is a human immunoglobulin G1 lambda (IgG1λ) monoclonal antibody that selectively binds to CD73 (expressed on the surface of various immune and tumor cells) and inhibits the catalysis of AMP to adenosine and organic phosphate. Extracellular adenosine is believed to mediate cellular immunosuppressive effects. Blocking CD73 may improve antitumor immunity.
In this study, the sponsor and investigators want to learn:
- how much MEDI9447, when given with Durvalumab, can be given with an acceptable level of side effects
- the effects of the combination of MEDI9447 and Durvalumab
- how much of MEDI9447 and Durvalumab are absorbed into the blood and how fast they are cleared from the body
- if research tests can predict who will benefit from MEDI9447 when given with Durvalumab
- if MEDI9447, when given with Durvalumab, prevents or delays tumor growth or shrinks an existing tumor
- how proteins that indicate the status of your disease are affected with use of MEDI9447 when given with Durvalumab
- if your body develops proteins that work against MEDI9447 and/or Durvalumab
- Adult subjects; age ≥ 18
- Written and signed informed consent must be obtained
- Have histologic or cytologic documentation of solid tumor ◦ Must have received and have progressed, are refractory, or are intolerant to standard therapy appropriate for the specific tumor type. Depending on tumor type, subjects should not have received more than 5 prior lines of therapy for recurrent or metastatic disease including both standards of care and investigational therapies
- Subjects must have at least 1 lesion that is measureable using RECIST guidelines
- Subjects must consent to provide archived tumor specimens or tumor biopsies for correlative biomarker studies (core biopsies or larger resections, no fine-needle aspiration samples).
- All subjects are encouraged to consent to and provide paired pretreatment and on-treatment tumor biopsies.
- In the dose-expansion phase, all subjects are encouraged to consent and provide paired pretreatment and on-treatment tumor biopsies
- Eastern Cooperative Oncology Group performance score of 0 or 1
- In the opinion of the investigator, likely to complete ≥ 56 days of treatment
- Adequate organ function as determined by: I.Absolute neutrophil count ≥ 1.5 × 109/L (1,500/mm3) II.Platelet count ≥ 75 × 109/L (75,000/mm3) III.Hemoglobin ≥ 9.0 g/dL IV.Prothrombin time-international normalized ratio and partial thromboplastin time ≤ 1.5 × ULN V.Calculated creatinine clearance* (CrCl) or 24 hour urine CrCl > 50 mL/minute VI.Total bilirubin ≤ 1.5 × ULN; for subjects with documented/suspected Gilbert's disease, bilirubin ≤ 3 × UL VII.AST and ALT ≤ 2.5 × ULN VIII.Serum electrolytes within normal limits
- Female subjects of childbearing potential who are sexually active with a non-sterilized male partner must use at least one highly effective method of contraception from the time of screening, and must agree to continue using such precautions for 90 days (or 180 days) after the final dose of investigational product.
- Nonsterilized males who are sexually active with a female partner of childbearing potential must use condom plus spermicide from Day 1 through 90 days (or 180 days) after receipt of the last dose of investigational product
- Prior treatment with tumor necrosis factor receptor superfamily agonists including OX40, CD27, CD137 (4-1BB), CD357 (GITR).
- Subjects who have received prior therapy with regimens containing CTLA-4, PD-L1, or PD-1 antagonists are NOT permitted to enroll unless all of the following apply:
- Dose of immunotherapy must have been administered at least 28 days or 5 half lives, whichever is shorter, prior to planned first dose of MEDI9447/MEDI4736
- Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy
- All AEs while receiving prior immunotherapy must have resolved to ≤ Grade 1 or baseline prior to screening for this study
- Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not currently require maintenance doses of > 10 mg prednisone or equivalent per day
- Known allergy or hypersensitivity to investigational product formulations
- History of more than one event of IRR requiring permanent discontinuation of IV drug treatment
- History of severe drug allergies or anaphylaxis to 2 or more food products or medicine (including known sensitivity to acetaminophen/paracetamol, diphenhydramine or equivalent antihistamine, and methylprednisolone or equivalent glucocorticoid)
- Cardiac or peripheral vascular disease meeting any of the following criteria:
- Past history of myocardial infarction in the prior 12 months
- Past history of stroke or transient ischemic attack requiring medical therapy
- Congestive heart failure ≥ Class 3 based on New York Heart Association Functional Classification
- Grade 3 or greater edema (eg, peripheral, pulmonary)
- History of Grade 3 or greater thromboembolic events in the prior 12 months or unresolved thromboembolic event of any grade
- Subjects with active tuberculosis are ineligible. In settings where there is clinical or radiographic evidence of tuberculosis, active disease must be ruled out
- Active or prior documented autoimmune disorders (including inflammatory bowel disease [eg, colitis, Crohn's disease], celiac disease, or other serious gastrointestinal chronic conditions associated with diarrhea, etc) within the past 3 years prior to the start of treatment. The following are exceptions to this criterion are subjects s with vitiligo or alopecia or hypothyroidism.
- Untreated CNS metastatic disease
- Concurrent enrollment in another clinical study, unless it is an observational (non interventional) clinical study or the follow-up period of an interventional study
- Receipt of any conventional or investigational anticancer therapy not otherwise specified above within 28 days prior to the first dose of Investigational product
- Any concurrent chemotherapy, immunotherapy, or biologic or hormonal therapy for cancer treatment.
- Unresolved toxicities from prior anticancer therapy
- Current or prior use of immunosuppressive medication within 14 days prior to the first dose of Investigational product
- History of primary immunodeficiency, solid organ transplantation
- Known positive for human immunodeficiency virus (HIV), chronic or active hepatitis B or active hepatitis A or C
- Receipt of live, attenuated vaccine within 28 days prior to the first dose of investigational products
- Females who are pregnant, lactating, or intend to become pregnant during their participation in the study
- Major surgery within 28 days prior to first dose of Investigational Product or still recovering from prior surgery.
- Other invasive malignancy within 2 years except for noninvasive malignancies such as cervical carcinoma in situ, in situ prostate cancer, non-melanomatous carcinoma of the skin, ductal carcinoma in situ of the breast that has been surgically cured
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, active peptic ulcer disease or gastritis, uncontrolled hypertension, uncontrolled diabetes, or psychiatric illness/social situations that would limit compliance with study requirement
- Dallas, TX - Mary Crowley Cancer Research - Medical City