Phase II Open-Label Study to Assess the Safety and Efficacy of AlloStim® + Anti-PDL1 as Fourth Line Therapy for MSS Metastatic Colorectal Cancer
试验速览
- 阶段
- 2 期
- 状态
- 撤回
- 入组人数
- 50
- 试验地点
- 6
- 主要终点
- Objective Tumor Response
研究概览
简要总结
Experimental immunotherapy in chemotherapy-refractory and immunotherapy-refractory metastatic colorectal cancer patients that have progressed, or are intolerant to, Longsurf (TAS-102) +/- Avastin (bevacizumab) or Stivarga (regorafenib) combining experimental AlloStim with an anti-programmed death ligand 1 (PD-L1) checkpoint inhibitor drug.
详细描述
The protocol provides fourth-line experimental treatment for subjects with microsatellite stable (MSS)/ proficient mismatch repair (pMMR) metastatic colorectal cancer. These patients do not respond to checkpoint inhibitors. This study will investigate whether AlloStim® administered weekly in three-21 day cycles with each cycle consisting of 3 weekly intradermal (ID) doses followed the last week with an intravenous (IV) dose (3 cycles =Days 0 through 77) can prime patients to become responsive to checkpoint inhibition immunotherapy. A restaging computed tomography (CT) scan is conducted on day 84 after the priming and will be compared to the baseline CT scan by Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Scans at day 84 are expected to be read as radiological progression upon restaging after AlloStim® priming possibly due to immunological swelling, known as "pseudoprogression", consistent with the presumed inflammatory mechanism of action of AlloStim®. This mechanism may convert "cold" tumors to "hot" tumors. The immune cell infiltrates of tumors after AlloStim® include T-helper cell type 1 (Th1) memory cells which produce interferon-gamma. Interferon-gamma is known to increase expression of anti-programmed death ligand 1 (PD-L1) checkpoint molecules in the tumor microenvironment. Higher PD-L1 expression may convert checkpoint inhibitor unresponsive tumors to become checkpoint inhibitor responsive. After three 21-day cycles of AlloStim® priming, a combination of AlloStim® IV boosters and anti-PD-L1 checkpoint therapy (with avelumab 800 mg q/2 weeks) is scheduled between days 91 to day161, A restaging CT scan at day 175 is then compared to day 84 and baseline to determine if the tumor target lesions' size has changed.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adult male and female subjects aged 18-80 years at screening visit
- •Pathologically confirmed diagnosis of MSS/pMMR colorectal adenocarcinoma
- •Presenting with metastatic disease:
- •Primary tumor can be intact or previously resected
- •Previous treatment failure of at least two lines of active systemic chemotherapy:
- •Previous chemotherapy must have included a fluoropyrimidine, oxaliplatin (e.g. FOLFOX, CAPOX), and irinotecan-containing (e.g. FOLFIRI) regimens (single regimen of FOLFIRINOX satisfies)
- •Administered in adjuvant setting or for treatment of metastatic disease
- •If KRAS wild type, must have at least one prior anti-EGFR therapy if left sided primary tumor
- •Treatment failure or refusal/not qualified for at least one third-line treatment
- •TAS-102 +/- bevacizumab or regorafenib
- •Treatment failure can be due to disease progression or toxicity
- •Time from last treatment failure to Informed Consent must be no more than 30 days
- •ECOG performance score: 0-1
- •Adequate hematological function:
- •Absolute granulocyte count ≥ 1,200/mm3
- •Platelet count ≥ 100,000/mm3
- •Hemoglobin ≥ 9.0 g/dL (may be corrected by transfusion)
- •Adequate Organ Function:
- •Creatinine ≤ 1.5 mg/dL
- •Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
- •Alkaline phosphatase ≤ 2.5 times ULN *
- •Aspartate aminotransferase (AST) or (SGOT) ≤ 2.5 times ULN *
- •Alanine aminotransferase (ALT) or (SGPT) ≤ 2.5 times ULN*
- •EKG without clinically relevant abnormalities
- •Female subjects: Not pregnant or lactating
- •Patients with childbearing potential must have a negative ß-HCG test and agree to use a highly effective contraceptive method during the course of the study
- •Study specific Informed Consent in the native language of the subject
- •≤ 5 times ULN if liver involvement
排除标准
- •High frequency microsatellite instability (MSI-H) or deficient mismatched repair dMMR
- •Bowel obstruction or high risk for obstruction if tumors become inflamed
- •Moderate or severe ascites requiring medical intervention
- •Clinical evidence of brain metastasis or leptomeningeal involvement
- •Widespread peritoneal carcinomatous (e.g. CT scan shows innumerable lesions visible and/or abnormal thickening of greater omentum) that increases risk of a major morbidity (e.g. bowel obstruction) in the opinion of the Investigator
- •Pulmonary lymphangitis or symptomatic pleural effusion (grade ≥ 2) that results in pulmonary dysfunction requiring active treatment; or, oxygen saturation <92% on room air
- •Any of the following mood disorders: active major depressive episode, recent history of suicidal attempt or ideation
- •Prior allogeneic bone marrow/stem cell or solid organ transplant
- •Chronic use (> 2 weeks) of greater than physiologic doses of a corticosteroid agent (dose equivalent to > 5 mg/day of prednisone) planned or anticipated during the study before the end of the Safety Evaluation Period (28 days after the last dose of IP)
- •Topical corticosteroids are permitted
- •Prior diagnosis of an active autoimmune disease (e.g., rheumatoid arthritis, multiple sclerosis, autoimmune thyroid disease, uveitis)
- •Well controlled Type I diabetes allowed (HbA1c < 8.5%)
- •Prior experimental immunotherapy
- •History of blood transfusion reactions
- •Progressive viral or bacterial infection
- •o All infections must be resolved and the subject must remain afebrile for seven days without antibiotics prior to being placed on study
- •Cardiac disease of symptomatic nature
- •History of HIV positivity or AIDS
- •History of severe hypersensitivity to monoclonal antibody drugs
- •Psychiatric or addictive disorders or other condition that, in the opinion of the Investigator, would preclude study participation.
- •Subjects that lack ability to provide consent for themselves
- •Any prior cancer diagnosis (other than cured basal cell carcinoma, head and neck carcinoma in-situ, superficial Ta, Tis, T1 bladder cancer, or papillary carcinoma of thyroid) or concurrent cancer histologically different than colorectal adenocarcinoma
结局指标
主要结局
Objective Tumor Response
时间窗: day 168
CT scan RESIST 1.1
Overall Survival
时间窗: 2 years
survival from signing consent until death by any cause
次要结局
未报告次要终点