An Open-Label Multicenter Phase 1b Study of E7046 in Combination With Radiotherapy/Chemoradiotherapy (RT/CRT) in Preoperative Treatment of Subjects With Rectum Cancer
This is a multicenter, open-label, Phase 1b study in participants with locally advanced rectum cancer where primary resection without chemoradiotherapy is unlikely to achieve clear margins as defined by magnetic resonance imaging (MRI). It is conducted to assess the safety, to assess the tolerability, and to determine the recommended Phase 2 dose (RP2D) of E7046 in combination with pre-operative chemoradiotherapy. The study will also assess the efficacy of the combination in the expansion part at RP2D.
• Diagnosis of histologically confirmed invasive primary rectal carcinoma
• Age ≥18 years at the time of informed consent
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
• Participants must have locally advanced rectum cancer where primary resection without chemoradiotherapy (CRT) is unlikely to achieve clear margins as defined by magnetic resonance imaging (MRI), with no metastatic disease, as assessed by independent review.
• Disease that can be encompassed within a radical radiotherapy treatment volume
• Participant must consent to repeated biopsy to allow the acquisition of fresh and/or formalin-fixed paraffin-embedded (FFPE) material. Available archived tumor material may be submitted as the pretreatment biopsy provided that minimum requirements are met by local pathology review as defined in the laboratory manual. If archived tumor material is not available or does not meet minimum requirements, then a fresh tumor biopsy must be obtained in accordance with local institutional practice.
• Adequate renal function defined as serum creatinine \<1.5 × upper limit of normal (ULN) (or use System of Units \[SI\] units or calculated creatinine clearance ≥50 milliliter per minute \[mL/min\] per the Cockcroft and Gault formula)
• Adequate bone marrow function:
‣ Absolute neutrophil count (ANC) ≥1500/millimeters cubed (mm\^3) (≥1.5 × 10\^3/microliters \[µL\])
⁃ Platelets ≥100,000/mm\^3 (≥100 × 10\^9/Liters \[L\])
⁃ Hemoglobin ≥9.0 grams per deciliter (g/dL)
• Adequate liver function:
‣ Adequate blood coagulation function as evidenced by an International Normalized Ratio (INR) ≤1.5
⁃ Total bilirubin ≤1.5 × ULN except for unconjugated hyperbilirubinemia or Gilbert's syndrome
⁃ Alkaline phosphatase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤2.5 × ULN
• No prior pelvic radiotherapy, chemotherapy, immunotherapy, or other anti-cancer treatment for rectal cancer
• No prior exposure to colony stimulating factor 1 receptor (CSF1R) antagonists such as but not limited to emactuzumab (RG7155) (Roche), PLX3397 (Plexicon), JNJ40346627 (Johnson \& Johnson), including both anti-CSF1R and small molecule inhibitors and prostaglandin E2 receptor 4 (EP4) antagonists
• No preexisting condition that would deter radiotherapy, eg, fistulas, severe ulcerative colitis (particularly participants currently taking sulphasalazine), Crohn's disease, prior adhesions
• Willing and able to give informed consent and comply with all aspects of the protocol