Clinical Trials /

Utomilumab, Cetuximab, and Irinotecan Hydrochloride in Treating Patients With Metastatic Colorectal Cancer

NCT03290937

Description:

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.

Related Conditions:
  • Colorectal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Clinical Trial Evaluating the Safety and Response With PF-05082566, Cetuximab and Irinotecan in Patients With Advanced Colorectal Cancer
  • Official Title: Phase I Clinical Trial Evaluating the Safety and Response With PF-05082566, Cetuximab and Irinotecan in Patients With Advanced Colorectal Cancer

Clinical Trial IDs

  • ORG STUDY ID: 2017-0180
  • SECONDARY ID: NCI-2018-01036
  • SECONDARY ID: 2017-0180
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03290937

Conditions

  • Stage IV Colorectal Cancer AJCC v8
  • Stage IVA Colorectal Cancer AJCC v8
  • Stage IVB Colorectal Cancer AJCC v8
  • Stage IVC Colorectal Cancer AJCC v8

Interventions

DrugSynonymsArms
CetuximabCetuximab Biosimilar CMAB009, Chimeric Anti-EGFR Monoclonal Antibody, Chimeric MoAb C225, Chimeric Monoclonal Antibody C225, Erbitux, IMC-C225Treatment (irinotecan hydrochloride, cetuximab, utomilumab)
IrinotecanTreatment (irinotecan hydrochloride, cetuximab, utomilumab)
Irinotecan HydrochlorideCampto, Camptosar, Camptothecin 11, Camptothecin-11, CPT 11, CPT-11, Irinomedac, U-101440ETreatment (irinotecan hydrochloride, cetuximab, utomilumab)
UtomilumabPF 05082566, PF 5082566, PF-05082566, PF-2566Treatment (irinotecan hydrochloride, cetuximab, utomilumab)

Purpose

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. 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 PCI combination
      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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (irinotecan hydrochloride, cetuximab, utomilumab)ExperimentalPatients 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.
  • Cetuximab
  • Irinotecan
  • Irinotecan Hydrochloride
  • Utomilumab

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

          -  Total serum bilirubin < 1.5 x ULN, unless the patient has documented Gilbert syndrome

          -  Aspartate and Alanine Aminotransferase (AST and ALT) < 3 x ULN

          -  Left ventricular ejection fraction (LVEF) that is greater than 40%, or the absence of
             New York Heart Association (NYHA) classification of greater than stage II congestive
             heart failure

          -  Resolved acute effects of any prior therapy to baseline severity or grade =< 2 Common
             Terminology Criteria for Adverse Events (CTCAE) version (v.) 4.03 except for adverse
             events (AEs) not constituting a safety risk by investigator judgment

          -  Serum or urine pregnancy test (for females of childbearing potential) negative at
             screening and at the baseline visit (before the patient may receive the
             investigational product)

          -  Male and female patients of childbearing potential and at risk for pregnancy must
             agree to use two highly effective methods of contraception throughout the study and
             for at least 90 days after the last dose of assigned treatment. Female patients who
             are not of childbearing potential (permanently sterilized or postmenopausal; i.e.,
             meet at least one of the following criteria):

               -  Have undergone a documented hysterectomy and/or bilateral oophorectomy; or

               -  Have medically confirmed ovarian failure; or

               -  Achieved postmenopausal status, defined as follows: cessation of regular menses
                  for at least 12 consecutive months with no alternative pathological or
                  physiological cause; status may be confirmed by having a serum follicle
                  stimulating hormone (FSH) level within the laboratory's reference range for
                  postmenopausal women

          -  High microsatellite instability (MSI-H) colorectal cancer patients must have received
             an approved PD-1 targeted agent prior to enrolling in this trial

          -  Evidence of a personally signed and dated informed consent document indicating that
             the patient has been informed of all pertinent aspects of the study

          -  Willingness and ability to comply with the study scheduled visits, treatment plans,
             laboratory tests and other procedures

        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

          -  Patients who are pregnant or breastfeeding

          -  Patients with intolerance to or who have had a severe allergic or anaphylactic
             reaction to antibodies or infused therapeutic proteins, or patients who have had a
             severe allergic or anaphylactic reaction to any of the substances included in the
             study drug (including excipients)

          -  Other severe acute or chronic medical or psychiatric condition, including recent
             (within the past year) or active suicidal ideation or behavior, or laboratory
             abnormality that may increase the risk associated with study participation or
             investigational product administration or may interfere with the interpretation of
             study results and, in the judgment of the investigator, would make the patient
             inappropriate for entry into this study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:16 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended phase 2 dose of irinotecan hydrochloride
Time Frame:Up to 4 years
Safety Issue:
Description:A modified 3+3 design will be used to determine the maximum tolerated dose.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated