A Phase IIa, Non-Randomized, Open-Label Dose Expansion Trial of Isunakinra in Combination With Pembrolizumab in Patients With Metastatic or Unresectable, Locally Advanced Colorectal Cancer
This study will enroll patients with colorectal cancer that is locally advanced or metastatic. The tumor must be microsatellite stable (MSS), have a tumor mutational burden that is high (TMB-H) and be kras mutated. Patients must have been treated with available approved treatments already. In this study the investigators are testing a new type of immunotherapy, the potent IL-1 inhibitor isunakinra to be added to already approved immunotherapy (PD-1/PD-L1 inhibitor) in an attempt to get this treatment to work in this treatment resistant type of tumor.
• 1\. Subjects must have:
⁃ Histologically or cytologically confirmed adenocarcinoma of the colon or the rectum
∙ Tumor is determined to be RAS-mutated (KRAS, NRAS or HRAS) and microsatellite stable/proficient in mismatch repair, as assessed by immunohistochemistry (IHC) and/or polymerase chain reaction (PCR)/next generation sequencing (NGS) in a Clinical Laboratory Improvement Act (CLIA) environment and with a tumor mutational burden (TMB) of 10 MB or more.
∙ 2\. The study patients are required to have measurable disease by radiographic criteria (RECIST 1.1 and iRECIST).
∙ 3\. Prior therapy: Patients must have completed or had disease progression on at least one prior line of disease-appropriate therapy for metastatic disease (with or without PD-1 inhibitors), with no available therapy likely to convey clinical benefit, or not be candidates for therapy of proven efficacy for their disease.
∙ 4\. There should be a minimum of 4 weeks from any prior chemotherapy (except for the nitrosoureas and mitomycin C, requiring a minimum of 6 weeks), immunotherapy and/or radiation. Patients with prostate cancer on hormone deprivation therapy may continue that therapy while on study.
∙ 5\. Patients must have recovered (grade 1 or baseline) from any clinically significant toxicity associated with prior therapy (for example, alopecia is not clinically significant).
∙ 6\. ECOG performance status ≤ 1 7. Patients must have normal organ and hematologic function as defined below:
‣ Serum creatinine ≤ 1.5 x upper limit of normal OR creatinine clearance and a 24-h urine collection of ≥ 60 mL/min.
‣ ALT and AST ≤ 3x the upper limits of normal.
‣ Total bilirubin ≤ 1.5 x upper limit of normal OR in patients with Gilbert's syndrome, a total bilirubin ≤ 3.0.
‣ Hematological eligibility parameters (within 16 days of starting therapy):
⁃ Granulocyte count ≥ 1,500/mm3
• Platelet count ≥ 75.000/mm3 8. Patients must have baseline pulse oximetry \> 90% on room air at rest.