Phase I Clinical Trial Evaluating the Safety and Response With PF-05082566, Cetuximab, and Irinotecan in Patients With Advanced Colorectal Cancer
Overview
- Phase
- Phase 1
- Intervention
- Cetuximab
- Conditions
- Not specified
- Sponsor
- M.D. Anderson Cancer Center
- Enrollment
- 34
- Locations
- 1
- Primary Endpoint
- Recommended phase 2 dose of irinotecan hydrochloride (Dose escalation)
- Status
- Completed
- Last Updated
- 3 months ago
Overview
Brief Summary
This phase I trial studies the best dose and side effects of irinotecan hydrochloride when given with utomilumab and cetuximab in treating patients with colorectal cancer that has spread to other places in the body (metastatic). Monoclonal antibodies, such as utomilumab and cetuximab, may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving utomilumab, cetuximab, and irinotecan hydrochloride may work better in treating patients with colorectal cancer.
Detailed Description
PRIMARY OBJECTIVES: I. To evaluate maximal tolerated dose (MTD), and recommended phase 2 dose (RP2D) of the combination of utomilumab (PF-05082566), cetuximab and irinotecan hydrochloride (irinotecan) (PCI) in patients with metastatic colorectal cancer refractory to standard therapy. (Dose escalation) II. To determine the antitumor activity overall response rate (ORR) by immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) of the study regimen specifically in patients with advanced colorectal cancer who are RAS-RAF wild type (WT) (Arm A) or RAS mutant (Arm B). (Dose expansion) SECONDARY OBJECTIVES: I. To evaluate overall safety profile. II. To evaluate the anti-tumor activity. III. To evaluate pharmacodynamics (PD) biomarkers expressed by peripheral blood mononuclear cells (PBMC) and tissue samples. IV. To characterize serum biomarkers linked to immunomodulation and cytokine release. V. To assess markers of T and natural killer (NK) cell phenotype (such as CD3, CD4, CD8, FoxP3, CD14, CD33, CCR7, CD45RO, CD16, CD56, CD69, CD25, or VCAM1), TNF alpha, IFN gamma, IL10, IL-8, IL-6, IL-4, IL-2, IL-1b, or IL-12p70, CD127, Ki67, eomesodermin, KLRG1, CD14, CD33, human leukocyte antigen- D related (HLA-DR), CD16, CD56, granzyme B, CD68, PD-1, CD11c, sCD137, and 4-1BB. OUTLINE: This is a dose escalation study of irinotecan hydrochloride. Patients receive irinotecan hydrochloride intravenously (IV) over 90 minutes and cetuximab IV over 1-2 hours on days 1 and 15, and utomilumab IV over 1 hour on day 2. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must have histologically and or cytologically confirmed metastatic colorectal cancer
- •Patients must have a wild type or mutated RAS tumor status known prior to enrollment
- •Metastatic colorectal cancer patients have progressed following at least one line of fluorouracil (5-FU)-based chemotherapy
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
- •Patients must have measurable disease per irRECIST criteria for part 2 (dose expansion)
- •Absolute neutrophil count (ANC) \>= 1.0 x 10\^9/L (1,000/uL)
- •Platelet count \>= 75 x 10\^9/L (75000/L)
- •Hemoglobin \>= 8.0 g/dL (\>= 5.0 mmol/L)
- •Patients must be transfusion independent (i.e., no blood product transfusions for a period of at least 14 days prior to screening)
- •Serum creatinine \< 2 x upper limit of normal (ULN) or estimated creatinine clearance \> 30 ml/min as calculated using the method standard for the institution
Exclusion Criteria
- •Patients with known symptomatic brain metastases requiring steroids. Patients with previously diagnosed brain metastases are eligible if they are asymptomatic or have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to the start of study medication, have discontinued corticosteroid treatment for these metastases for at least 4 weeks and are neurologically stable
- •Patient has had any treatment specific for tumor control within 3 weeks of dosing, or for investigational drugs and cytotoxic agents, within 5 half-lives or 3 weeks, whichever is shorter
- •Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A4 complex. Lists including medications and substances known or with the potential to interact with the CYP3A4 isoenzymes
- •Prior therapy with a compound of the same mechanism as PF-05082566 (immunomodulation of 4-1BB)
- •Major surgery within 28 days of starting study treatment
- •Radiation therapy within 14 days of starting study treatment
- •Autoimmune disorders (e.g., Crohn's disease, rheumatoid arthritis, scleroderma, systemic lupus erythematosus) and other diseases that compromise or impair the immune system except patients who have grade 1 psoriasis (in remission or controlled with topical steroids) or mild degree of autoimmune thyroiditis that are controlled with medications
- •Active and clinically significant bacterial, fungal or viral infection including hepatitis B (HBV), hepatitis C (HCV), known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness (HIV testing is not required)
- •Unstable or serious concurrent medical conditions in the previous 6 months, e.g., pancreatitis, severe/unstable angina, prolonged QT interval corrected by Fridericia's formula (QTcF) \> 470 msec (calculated as average of triplicate readings, taken no greater than 2 minutes apart, and no history of torsades de pointes or symptomatic corrected QT \[QTc\] abnormality), symptomatic congestive heart failure, myocardial infarction and/or pulmonary hypertension, ongoing maintenance therapy for life-threatening ventricular arrhythmia, stroke, and uncontrolled major seizure disorder
- •Concurrent active malignancy other than non-melanoma skin cancer or carcinoma in situ of the cervix
Arms & Interventions
Treatment (irinotecan hydrochloride, cetuximab, utomilumab)
Patients receive irinotecan hydrochloride IV over 90 minutes and cetuximab IV over 1-2 hours on days 1 and 15, and utomilumab IV over 1 hour on day 2. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Cetuximab
Treatment (irinotecan hydrochloride, cetuximab, utomilumab)
Patients receive irinotecan hydrochloride IV over 90 minutes and cetuximab IV over 1-2 hours on days 1 and 15, and utomilumab IV over 1 hour on day 2. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Utomilumab
Treatment (irinotecan hydrochloride, cetuximab, utomilumab)
Patients receive irinotecan hydrochloride IV over 90 minutes and cetuximab IV over 1-2 hours on days 1 and 15, and utomilumab IV over 1 hour on day 2. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Irinotecan Hydrochloride
Treatment (irinotecan hydrochloride, cetuximab, utomilumab)
Patients receive irinotecan hydrochloride IV over 90 minutes and cetuximab IV over 1-2 hours on days 1 and 15, and utomilumab IV over 1 hour on day 2. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Pharmacodynamic Study
Outcomes
Primary Outcomes
Recommended phase 2 dose of irinotecan hydrochloride (Dose escalation)
Time Frame: Up to 4 years
A modified 3+3 design will be used to determine the maximum tolerated dose.
Objective response rate (Dose expansion)
Time Frame: Up to 4 years
Assessed by using the immune-related Response Evaluation Criteria in Solid Tumors (irRECIST).
Secondary Outcomes
- Overall response rate(Up to 4 years)
- Progression free survival(Up to 4 years)
- Duration of response(Up to 4 year)
- Incidence of adverse events(Up to 4 years)
- Overall survival(Up to 4 years.)