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Clinical Trial 19581

Cancer Type: Gastrointestinal Tumor
Study Type: Treatment
NCT#: NCT03712943

Phase: Phase I
Prinicipal Investigator:

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Study Title

Phase I study of Regorafenib and Nivolumab in Mismatch Repair (MMR) Proficient Advanced Refractory Colorectal Cancer


This is a phase I trial using the combination of nivolumab and regorafenib in refractory metastatic colorectal cancer. This will be a 3+3 design with 2 dose cohort.


Primary Objective To assess safety and tolerability, describe the dose-limiting toxicities (DLTs), and determine the maximum tolerated dose (MTD) or the highest protocol-defined dose level in the absence of establishing an MTD of regorafenib in combination with nivolumab in subjects with advanced, refractory colorectal cancers Secondary Objectives 1. To access response rate using RECIST criteria 2. To access overall survival 3. To further evaluate the frequency and severity of adverse events and tolerability of the combination regimen. Exploratory Objectives 1. To evaluate potential correlations between blood or tumor biomarkers and clinical outcome.




BAY 73-4506 (Regorafenib); BMS-936558 (Nivolumab); Nivolumab (); Regorafenib (Stivarga)

Inclusion Criteria

  • Histologically confirmed diagnosis of colorectal adenocarcinoma
  • Proficient DNA mismatch repair (MMR) or stable microsatellite disease confirmed by immunohistochemical staining or PCR
  • Patients with the presence of at least one lesion with measurable disease as defined by 10mm in longest diameter for a soft tissue lesions or 15mm in short axis for a lymph node by RECIST 1.1 for response assessment
  • Patients must have received and progressed through or become intolerant to fluoropyrimidine, irinotecan, oxaliplatin, and bevacizumab, and if K-ras wild type, cetuximab or panitumumab containing therapies. Prior TAS 102 is allowed
  • ECOG Performance Score 0 or 1
  • Estimated life expectancy over 3 months
  • Adequate bone marrow, liver and renal function.
  • Patients must not have had chemotherapy, major surgery, monoclonal antibody therapy or experimental therapy within the 21 days prior to the start of regorafenib and nivolumab administration
  • Women of childbearing potential must have a negative serum or urine pregnancy test performed within 24 hours prior to the start of study drug and then every 4 weeks. Post-menopausal women and surgically sterilized women are not required to undergo a pregnancy test.
  • Patients (men and women) of childbearing potential must agree to use adequate contraception beginning at the signing of the ICF until at least 5 months for females and 7 months for males after the last dose of study drug
  • Patients must be able to understand and be willing to sign the written informed consent formand be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other study requirements.

  • Exclusion Criteria

  • Patients with active Central Nervous System (CNS) metastases.
  • Uncontrolled hypertension despite optimal medical management.
  • Active or clinically significant cardiac disease
  • Women who are pregnant or breast-feeding
  • Prior therapy with regorafenib, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways).
  • Previous or concurrent cancer within 3 years prior to treatment. Some exclusions apply.
  • Active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy is not considered a form of systemic treatment.
  • Ascites, pleural effusion, or pericardial fluid requiring drainage in the last 4 weeks.
  • Patients with phaeochromocytoma
  • Ongoing infection > Grade 2 NCI-CTCAE v5.0.
  • Presence of a non-healing wound, or bone fracture.
  • Renal failure requiring hemo-or peritoneal dialysis.
  • Seizure disorder requiring medication.
  • Interstitial lung disease with ongoing signs and symptoms at the time of informed consent.
  • Pleural effusion or ascites that causes respiratory compromise (≥ NCI-CTCAE version 5.0 Grade 2 dyspnea).
  • Any condition which, in the investigator¿s opinion, makes the subject unsuitable for trial participation.
  • Known or suspected allergy or hypersensitivity to any of the study drugs, study drug classes, or excipients of the formulations given during the course of this trial.
  • Persistent proteinuria ≥ Grade 3 NCI-CTCAE v5.0 (> 3.5 g/24 hrs, measured by urine protein:creatinine ratio on a random urine sample).
  • History of organ allograft
  • Requiring warfarin or equivalent vitamin K antagonists (e.g. phenprocoumon)
  • Patients with a condition requiring a strong CYP3A4 inhibitors or strong CYP3A4 inducers
  • Unresolved toxicity higher than CTCAE grade 1 attributed to any prior therapy or procedure, excluding alopecia.
  • Any hemorrhage or bleeding event ≥ NCI CTCAE Grade 3 within 4 weeks prior to start of study medication.
  • Substance abuse, medical, psychological or social conditions that may interfere with the patient¿s participation in the study or evaluation of the study results.
  • Arterial thrombotic or thromboembolic event within 6 months of informed consent.
  • Known history of human immunodeficiency virus (HIV) infection or current chronic or active hepatitis B or C infection.
  • Child-Pugh B cirrhosis (or worse) or a history of hepatic encephalopathy
  • History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
  • Major surgery or a wound that has not fully healed within 4 weeks of enrollment.
  • Patients requiring concurrent anti-cancer therapy other than study treatment
  • Patients requiring hormonal therapy during the study or within 2 weeks of first study enrollment.

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