J14126, A Phase 1, First-in-Human, Open Label, Dose Escalation Study of MGD007, A Humanized gpA33 x CD3 Dual-Affinity Re-Targeting (DART®) Protein in Patients with Relapsed/Refractory Metastatic Colorectal Carcinoma
Johns Hopkins Kimmel Cancer Center in Baltimore
To characterize the safety, tolerability, dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of MGD007 when administered intravenously (IV) on weekly and every three week schedules in patients with relapsed/refractory metastatic colorectal carcinoma.
Inclusion1. Ability to provide informed consent and able to comply with study procedures, including the acquisition of specified research specimens.2. Age equal to 18 years old.3. Histologically-proven metastatic relapsed/refractory colorectal carcinoma.4. ECOG performance status of 0 or 1 5. Life expectancy equal to 12 weeks.6. Measurable disease as per RECIST 1.1 criteria 7. During the dose escalation portion of the study, patients must have had recurrence, progression or intolerance to standard therapy consisting of at least 2 prior standard regimens. Patients should have received no more than 5 prior therapies.8. Documentation of tumor K-ras status via the provision of a copy of prior results of Ras mutation testing (cohort expansion only). 9. In addition, patients to be enrolled in the study must have an identified formalin-fixed, paraffin embedded tumor specimen to enable determination of the expression of gpA33 within tumor.10. Acceptable laboratory parameters.11. Female patients of childbearing potential (not surgically sterilized and between menarche and 1 year postmenopause) must have a negative serum or urine pregnancy test performed within 72 hours prior to the initiation of study drug administration. Further, female patients of childbearing potential mustagree to use acceptable contraceptive measures from the time of consent through 90 days after discontinuation of study drug administration. For female patients, two forms of contraception must be utilized and may include oral, transdermal, injectable or implantable contraceptives, intrauterine device(IUD), female condom, diaphragm with spermacide, cervical cap, use of a condom by the sexual partner or a sterile sexual partner. Periodic abstinence (e.g., calendar, ovulation, symptothermal, and post-ovulation methods) and withdrawal are not considered acceptable forms of contraception in thisstudy.12. Male patients with partners of childbearing potential must use barrier contraception. In addition, it is strongly recommended that male patients ask their partners to use another method of contraception from the time of consent through 90 days after discontinuation of study drug administration.13. Female patients must not be breast-feeding.Exclusion1.Patients with known brain metastasis. 2. Patients with any history of known or suspected autoimmune disease with the specific exceptions of vitiligo, resolved childhood atopic dermatitis, and patients with a history of Grave’s disease that are now euthyroid clinically and by laboratory testing.3. History of prior allogeneic bone marrow, stem-cell or solid organ transplantation.4. History of prior treatment with checkpoint inhibitors including anti-LAG-3, anti-PD-1, anti-PD-L1 or anti-CTLA-4 antibodies, if less than 5 half-lives have passed since the last dose of checkpoint inhibitor and the initiation of study drug administration.5. Prior history of Grade 3 or greater drug-related diarrhea/colitis during treatment with checkpoint inhibitors including anti-LAG-3, anti-PD-1, anti-PD-L1 or anti-CTLA-4 antibodies.6. Treatment with any local or systemic anti-neoplastic therapy or any investigational therapy within the 4 weeks prior to the initiation of study drug administration.7. Treatment of growth factors including but not limited to G-CSF, GM-CSF, erythropoietin, etc. within the 4 weeks prior to the initiation of study drug administration. 8. Transfusion with red blood cells (RBC) or platelets (PLT) within the 4 weeks prior to the initiation of study drug administration.9. Treatment with corticosteroids ( equal to prednisone 10 mg per day or equivalent) or other immune suppressive drugs within the 2 weeks prior to the initiation of study drug administration.10. History of clinically significant cardiovascular disease.11. Clinically-significant gastrointestinal disorders. 12. Clinically-significant pulmonary compromise, particularly a requirement for supplemental oxygen use to maintain adequate oxygenation.13. Evidence of active viral, bacterial, or systemic fungal infection requiring parenteral treatment within 7 days prior to the initiation of study drug. 14. Known positive testing for human immunodeficiency virus or acquired immune deficiency syndrome.15. History of hepatitis B or hepatitis C infection or positive test for hepatitis B surface antigen, hepatitis B core antigen, or hepatitis C PCR.16. Second primary malignancy that has not been in remission for greater than 3 years. Exceptions that do not require a 3 year remission include: related non-melanoma skin cancer; cervical carcinoma in situ on biopsy; or squamous intraepithelial lesion on PAP smear; localized prostate cancer (Gleason score less than 6); or resected melanoma in situ.17. History of trauma or major surgery within 4 weeks prior to the initiation of study drug administration.18. Requirement for concurrent steroids greater than 10 mg/day of oral prednisone or the equivalent, except of topical use, steroid inhaler, nasal spray or ophthalmic solution.19. Any serious underlying medical or psychiatric condition that would impair the ability of the patient to receive or tolerate the planned treatment at the investigational site.20. Known allergic hypersensitivity to recombinant proteins, polysorbate 80, or any excipient contained in the drug or vehicle formulation for MGD007.21. Vaccination with any live virus vaccine within 4 weeks prior to the initiation of study drug administration. Inactivated annual influenza vaccination is allowed.22. Dementia or altered mental status that would preclude understanding and rendering of informed consent.23. Active or history of alcohol or other substance abuse within 1 year prior to the initiation of study drug administration.24. Any investigative site personnel directly affiliated with this study.25. Employees of MacroGenics, Inc.26. Prisoners or other individuals who are involuntarily detained.27. Any issue that in the opinion of the investigator, would contraindicate the patient’s participation in the study or confound the results of the study.
This study will be an open-label, two-arm, dose escalation, Phase 1 study designed to characterize the safety,tolerability, PK, pharmacodynamics, immunogenicity and preliminary anti-tumor activity of MGD007administered IV on weekly and every three week schedules in patients with relapsed/refractory metastatic colorectal carcinoma that has progressed after prior standard chemotherapy. The study will proceed in two distinct phases: Dose Escalation and Cohort Expansion.
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