A Proof-of-Concept Study of Combination Therapy With INCMGA00012 (Anti-PD-1), INCAGN02385 (Anti-LAG-3), and INCAGN02390 (Anti-TIM-3) in Participants With Advanced or Metastatic PD-(L)1 Refractory Merkel Cell Carcinoma
概览
- 阶段
- 2 期
- 干预措施
- Biopsy
- 疾病 / 适应症
- Unresectable Clinical Stage III Merkel Cell Carcinoma AJCC v8
- 发起方
- University of Washington
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- Objective response rate
- 状态
- 进行中（未招募）
- 最后更新
- 3个月前
概览
简要总结
This phase II trial tests how well a combination of three immunotherapy drugs work for patients with Merkel cell carcinoma that has spread to lymph nodes and/or distant parts of the body and cannot be treated with surgery (advanced or metastatic MCC) and grew despite prior PD-(L)1 therapy. The three drugs INCMGA00012 (retifanlimab, anti-PD-1), INCAGN02385 (tuparstobart, anti-LAG-3), and INCAGN02390 (verzistobart, anti-TIM-3) are monoclonal antibodies given periodically via IV to reactivate the body's immune system to attack the cancer. This combination may stop tumor growth if tumors have grown despite anti-PD-(L)1 therapy alone.
详细描述
OUTLINE: All patients receive the same investigational drug combination. SCREENING: Patients undergo history and physical examination, adverse event assessment, safety and eligibility labs, radiologic evaluation with computed tomography (CT)/magnetic resonance imaging (MRI), and complete informed consent. INDUCTION PHASE: Patients receive anti-LAG-3 and anti-TIM-3 intravenously (IV) every 2 weeks along with retifanlimab (anti-PD-1) IV every 4 weeks, along with clinical visit, physical examination, and labs for safety. Treatment continues for up to day 169 in the absence of disease progression or unacceptable toxicity. Patients undergo CT/MRI every 8 weeks. Research tumor biopsies will be obtained on day 1 and day 15 unless unsafe and unfeasible. Research blood draws will occur at day 1, day 15, and periodically throughout Induction Phase. MAINTENANCE PHASE: Patients receive all three drugs IV every 6 weeks along with clinical visit, physical examination, and labs for safety. Treatment continues for up to day 715 in the absence of disease progression or unacceptable toxicity. Patients undergo CT/MRI every 12 weeks. Research blood sample collection will continue periodically. Patients with progressive disease per investigator evaluation will stop receiving therapy. Research blood and tumor biopsies will be obtained at time of progression if safe and feasible. Upon completion of study treatment (day 715 or sooner for disease progression), safety visits occur at 30 and 90 days. Follow up for long term outcomes continues every 6 months for up to 5 years.
研究者
入排标准
入选标准
- •Presence of histologically confirmed, advanced or metastatic Merkel cell carcinoma (MCC), which is considered incurable with standardly available therapies
- •Presence of at least one MCC tumor, considered measurable per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1
- •Age 18 or older. (NOTE: Both men and women, and members of all races and ethnic groups are eligible for this trial.)
- •Eastern Cooperative Oncology Group (ECOG) performance score of 0-2
- •Must have previously received at least one prior systemic treatment regimen with an anti-PD-(L)1 agent (administered as monotherapy or in combination with another treatment)
- •Must meet the following criteria defining anti-PD-(L)1 refractory MCC: Best response of progressive disease (PD) or development of PD after best response of complete response (CR), partial response (PR), or stable disease (SD) after receiving at least 6 weeks of therapy with an anti-PD-(L)1 agent; PD must develop within 6 months of the last administration of anti-PD-(L)1 agent
- •Absolute neutrophil count (ANC) \>= 1 x 10\^9/L
- •Platelet count \>= 100 × 10\^9/L
- •Hemoglobin \>= 9 g/dL (may have been transfused)
- •Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin level =\< 2 x the upper limit of normal (ULN) (or total bilirubin =\< 2.5 x ULN in patients with Gilbert's syndrome, and AST, ALT =\< 2.5 x ULN in patients with hepatic metastases)
排除标准
- •Residual adverse event(s) from prior therapy grade \> 1 (National Cancer Institute \[NCI\]-Common Terminology Criteria for Adverse Events \[CTCAE\] v 5.0) that could interfere with study endpoints or put patient safety at risk
- •Known active central nervous system (CNS) metastases and/or prior history of carcinomatous meningitis. (NOTE: Participants with previously treated brain metastases may participate provided that they are stable, without evidence of progression by brain imaging performed within the screening period and at least 4 weeks after the treatment of brain metastases, and any neurologic symptoms must have stabilized. Patients must not have any evidence of new or enlarging brain metastases or increasing CNS edema and must not have required steroids for this purpose for at least 7 days before the first dose of study treatment.)
- •History of serious immune-related adverse events (IRAEs) from prior immunotherapy that resulted in permanent discontinuation of anti-PD-(L)1 and could jeopardize patient safety with the investigational regimen. (NOTE: Any prior grade 2 or higher IRAE must be discussed with the Principal Investigator or designee for risk/benefit assessment.)
- •Known allergy or hypersensitivity to any component of the study drugs formulation (including excipients and additives) that could interfere with study endpoints or put patient safety at risk
- •Previous malignant disease (other than MCC) diagnosed within 3 years from day 1 of study treatment that could interfere with study endpoints or put patient safety at risk. (NOTE: Exception will be made for adequately treated basal or squamous cell carcinoma of the skin or carcinoma in situ (skin, bladder, cervical, colorectal, breast) or low grade prostatic intraepithelial neoplasia or grade 1 prostate cancer. Any other neoplasm, which has been treated adequately and is adjudged by the treating investigator to have a low risk of recurrence during the study, could be enrolled only after written approval from the principal investigator or designee.)
- •Known active hepatitis B virus (HBV) or hepatitis C virus (HCV), defined as follows:
- •Active HBV is defined as a known positive hepatitis B virus surface antigen (HBsAg) result or positive total hepatitis B virus core antibody (anti-HBc) results in the absence of hepatitis B virus surface antibody (anti-HBsAb). NOTE: When HBsAg is negative and hepatitis B virus core antibody (HBcAb) is positive, HBV-deoxyribonucleic acid (DNA) should be measured. When HBV-DNA is negative, this participant could be enrolled with close monitoring of HBV activities.)
- •Active HCV is defined as a known positive HCV antibody result and quantitative HCV-ribonucleic acid (RNA) results greater than the lower limits of detection of the assay. (NOTE: Participants who have had definitive treatment for HCV are permitted if HCV-RNA is undetectable.)
- •Known uncontrolled human immunodeficiency (HIV) infection. (NOTE: HIV-positive patients may be allowed if all of the following criteria are met: CD4 count \>= 300/uL, undetectable viral load, receiving antiretroviral therapy, and risk/benefit ratio is deemed favorable when considering enrollment.)
- •Known active autoimmune disease, allograft requiring systemic immunosuppression, or other condition requiring chronic systemic corticosteroids (\> 10 mg/day of prednisone or equivalent). (NOTE: Exceptions will be made for patients with autoimmune conditions such as diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment; patients receiving physiologic corticosteroid replacement therapy at doses =\< 10 mg/day of prednisone or equivalent for adrenal or pituitary insufficiency; patients with a condition such as asthma or chronic obstructive pulmonary disease that requires intermittent use of bronchodilators, inhaled steroids, or local steroid injections; or those who required brief courses of corticosteroids for prophylaxis (e.g., contrast dye allergy) or study treatment-related standard premedication. Any other situation must be discussed with the principal investigator or designee for risk/benefit assessment.)
研究组 & 干预措施
Treatment (retifanlimab, tuparstobart, and verzistobart)
INDUCTION PHASE: Patients receive retifanlimab IV over 30 minutes every 4 weeks and tuparstobart and verzistobart IV over 30 minutes every 2 weeks. Treatment continues for up to day 169 in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography CT/MRI during screening and on study and blood sample collection on study and may undergo during screening. Patients may also undergo a tumor biopsy during screening and on study. MAINTENANCE PHASE: Patients receive retifanlimab, tuparstobart and verzistobart IV over 30 minutes every 6 weeks. Treatment continues for up to day 715 in the absence of disease progression or unacceptable toxicity. Patients undergo CT/MRI on study and blood sample collection on study and may undergo during follow-up. Patients may also undergo tumor biopsy on study and during follow-up.
干预措施: Biopsy
Treatment (retifanlimab, tuparstobart, and verzistobart)
INDUCTION PHASE: Patients receive retifanlimab IV over 30 minutes every 4 weeks and tuparstobart and verzistobart IV over 30 minutes every 2 weeks. Treatment continues for up to day 169 in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography CT/MRI during screening and on study and blood sample collection on study and may undergo during screening. Patients may also undergo a tumor biopsy during screening and on study. MAINTENANCE PHASE: Patients receive retifanlimab, tuparstobart and verzistobart IV over 30 minutes every 6 weeks. Treatment continues for up to day 715 in the absence of disease progression or unacceptable toxicity. Patients undergo CT/MRI on study and blood sample collection on study and may undergo during follow-up. Patients may also undergo tumor biopsy on study and during follow-up.
干预措施: Biospecimen Collection
Treatment (retifanlimab, tuparstobart, and verzistobart)
INDUCTION PHASE: Patients receive retifanlimab IV over 30 minutes every 4 weeks and tuparstobart and verzistobart IV over 30 minutes every 2 weeks. Treatment continues for up to day 169 in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography CT/MRI during screening and on study and blood sample collection on study and may undergo during screening. Patients may also undergo a tumor biopsy during screening and on study. MAINTENANCE PHASE: Patients receive retifanlimab, tuparstobart and verzistobart IV over 30 minutes every 6 weeks. Treatment continues for up to day 715 in the absence of disease progression or unacceptable toxicity. Patients undergo CT/MRI on study and blood sample collection on study and may undergo during follow-up. Patients may also undergo tumor biopsy on study and during follow-up.
干预措施: Computed Tomography
Treatment (retifanlimab, tuparstobart, and verzistobart)
INDUCTION PHASE: Patients receive retifanlimab IV over 30 minutes every 4 weeks and tuparstobart and verzistobart IV over 30 minutes every 2 weeks. Treatment continues for up to day 169 in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography CT/MRI during screening and on study and blood sample collection on study and may undergo during screening. Patients may also undergo a tumor biopsy during screening and on study. MAINTENANCE PHASE: Patients receive retifanlimab, tuparstobart and verzistobart IV over 30 minutes every 6 weeks. Treatment continues for up to day 715 in the absence of disease progression or unacceptable toxicity. Patients undergo CT/MRI on study and blood sample collection on study and may undergo during follow-up. Patients may also undergo tumor biopsy on study and during follow-up.
干预措施: Magnetic Resonance Imaging
Treatment (retifanlimab, tuparstobart, and verzistobart)
INDUCTION PHASE: Patients receive retifanlimab IV over 30 minutes every 4 weeks and tuparstobart and verzistobart IV over 30 minutes every 2 weeks. Treatment continues for up to day 169 in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography CT/MRI during screening and on study and blood sample collection on study and may undergo during screening. Patients may also undergo a tumor biopsy during screening and on study. MAINTENANCE PHASE: Patients receive retifanlimab, tuparstobart and verzistobart IV over 30 minutes every 6 weeks. Treatment continues for up to day 715 in the absence of disease progression or unacceptable toxicity. Patients undergo CT/MRI on study and blood sample collection on study and may undergo during follow-up. Patients may also undergo tumor biopsy on study and during follow-up.
干预措施: Retifanlimab
Treatment (retifanlimab, tuparstobart, and verzistobart)
INDUCTION PHASE: Patients receive retifanlimab IV over 30 minutes every 4 weeks and tuparstobart and verzistobart IV over 30 minutes every 2 weeks. Treatment continues for up to day 169 in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography CT/MRI during screening and on study and blood sample collection on study and may undergo during screening. Patients may also undergo a tumor biopsy during screening and on study. MAINTENANCE PHASE: Patients receive retifanlimab, tuparstobart and verzistobart IV over 30 minutes every 6 weeks. Treatment continues for up to day 715 in the absence of disease progression or unacceptable toxicity. Patients undergo CT/MRI on study and blood sample collection on study and may undergo during follow-up. Patients may also undergo tumor biopsy on study and during follow-up.
干预措施: Tuparstobart
Treatment (retifanlimab, tuparstobart, and verzistobart)
INDUCTION PHASE: Patients receive retifanlimab IV over 30 minutes every 4 weeks and tuparstobart and verzistobart IV over 30 minutes every 2 weeks. Treatment continues for up to day 169 in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography CT/MRI during screening and on study and blood sample collection on study and may undergo during screening. Patients may also undergo a tumor biopsy during screening and on study. MAINTENANCE PHASE: Patients receive retifanlimab, tuparstobart and verzistobart IV over 30 minutes every 6 weeks. Treatment continues for up to day 715 in the absence of disease progression or unacceptable toxicity. Patients undergo CT/MRI on study and blood sample collection on study and may undergo during follow-up. Patients may also undergo tumor biopsy on study and during follow-up.
干预措施: Verzistobart
结局指标
主要结局
Objective response rate
时间窗: Up to 5 years following completion of study treatment
Defined as the proportion of participants having a best objective response of complete response (CR) or partial response (PR), as determined by investigator assessment per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1.
次要结局
- Overall survival(From date of first dose of study treatment until the date of death from any cause, assessed up to 5 years following the completion of treatment)
- Disease specific survival(From date of first dose of study treatment until the date of death from Merkle cell carcinoma, assessed up to 5 years following completion of treatment)
- Progression free survival(From date of first dose of study treatment until the earliest date of disease progression, per RECIST v1.1, or the date of death from any cause, if occurring sooner than progression, assessed up to 5 years following completion of treatment)
- Duration of response(From the earliest date of disease response (CR or PR) until the earliest date of disease progression, per RECIST v1.1, or the date of death from any cause, if occurring sooner than progression, assessed up to 5 years following completion of treatment)
- Disease control rate(Up to 5 years following completion of treatment)
- Incidence and severity of adverse events(Up to 90 days following completion of study treatment)