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Cetuximab and Pembrolizumab in Treating Patients With Colorectal Cancer That is Metastatic or Cannot Be Removed by Surgery

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ClinicalTrials.gov Identifier: NCT02713373
Recruitment Status : Recruiting
First Posted : March 18, 2016
Last Update Posted : April 1, 2019
Sponsor:
Collaborators:
National Cancer Institute (NCI)
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Roswell Park Cancer Institute

Brief Summary:
This phase I/II trial studies the side effects and best dose of cetuximab when given together with pembrolizumab in treating patients with colorectal cancer that has spread from the primary site (place where it started) to other places in the body (metastatic) or that cannot be removed by surgery. Monoclonal antibodies, such as cetixumab and pembrolizumab, may block tumor growth in different ways by targeting certain cells.

Condition or disease Intervention/treatment Phase
Recurrent Colorectal Carcinoma Stage IVA Colorectal Cancer Stage IVB Colorectal Cancer Biological: Cetuximab Other: Laboratory Biomarker Analysis Biological: Pembrolizumab Phase 1 Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To estimate the objective response rate of patients with metastatic colorectal cancer treated with pembrolizumab and cetuximab.

II. To estimate the 6-month progression free survival (PFS) rate of patients with metastatic colorectal cancer treated with pembrolizumab and cetuximab.

III. To examine the adverse event profile of combining pembrolizumab and cetuximab.

SECONDARY OBJECTIVES:

I. To examine the PFS of patients with metastatic colorectal cancer treated with pembrolizumab and cetuximab.

II. To determine the objective response rate by immune-related response criteria (irRC) of patients with metastatic colorectal cancer.

III. To examine the overall survival of patients with metastatic colorectal cancer treated with pembrolizumab and cetuximab.

EXPLORATORY OBJECTIVES:

I. Identify tumor and peripheral blood biomarkers of response and/or resistance to the study treatment.

OUTLINE:

Patients receive cetuximab intravenously (IV) over 120 minutes on day 1, 8, and 15 (as monotherapy for cycle 1 only) and pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for 24 months in the absence of disease progression or unacceptable toxicity. Patients may continue pembrolizumab treatment for up to 1 year if they experience disease progression.

After completion of the study treatment, patients are followed up every 3 months for up to 2 years.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 42 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase Ib/II Study of Cetuximab and Pembrolizumab in Metastatic Colorectal Cancer
Actual Study Start Date : August 5, 2016
Estimated Primary Completion Date : August 15, 2019
Estimated Study Completion Date : January 13, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm I (cetuximab and pembrolizumab)
Patients receive cetuximab IV over 120 minutes on day 1 (days 1, 7, and 14 of course 1 only) and pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for 24 months in the absence of disease progression or unacceptable toxicity. Patients may continue pembrolizumab treatment for up to 1 year if they experience disease progression.
Biological: Cetuximab
Given IV
Other Names:
  • Chimeric Anti-Epidermal Growth Factor Receptor (EGFR) Monoclonal Antibody
  • Chimeric MoAb C225
  • Chimeric Monoclonal Antibody C225
  • Erbitux
  • IMC-C225

Other: Laboratory Biomarker Analysis
Correlative studies

Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475




Primary Outcome Measures :
  1. Incidence of adverse events, categorized and graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) [ Time Frame: Up to 30 days after last dose of study drug ]
    The frequency of toxicities will be tabulated by maximum grade by preferred term within a patient across all cycles.

  2. Progression free survival (PFS), evaluated according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 [ Time Frame: At 6 months ]
    Will be tabulated and will be compared to the null values using exact tests. Distributions of PFS will be estimated using the Kaplan-Meier method.

  3. Tumor response rate, evaluated according to RECIST 1.1 [ Time Frame: Up to 2 years ]
    Will be tabulated and will be compared to the null values using exact tests.


Secondary Outcome Measures :
  1. Objective tumor response using immune-related RECIST [ Time Frame: Up to 2 years ]
    Will be tabulated.

  2. Overall survival (OS) [ Time Frame: Up to death, withdrawal of consent, or the end of the study, whichever occurs first, assessed up to 2 years ]
    Distributions of OS will be estimated using the Kaplan-Meier method.

  3. Progression Free Survival (PFS) [ Time Frame: At 6 months ]
    PFS will be tested using an exact binomial test. Distributions of PFS will be estimated using the Kaplan-Meier method.


Other Outcome Measures:
  1. Change in peripheral blood biomarkers using ELISA (enzyme linked immunosorbent assay). [ Time Frame: Day 1 of course 1 to up to day 1 of course 4 (12 weeks) ]
    Pre- and post-treatment levels and changes from pre- to post-treatment in biomarkers will be summarized overall and by response and 6-month PFS categories using summary statistics (e.g., mean or median, with dispersion measures, and using transformed values as appropriate). Depending on the number of responses, logistic regression models may be used to compare response rates across pre-treatment biomarker levels. Proportional hazards models may be used to examine progression-free survival and overall survival across biomarker levels.

  2. Change in tumor biomarkers using immunohistochemistry [ Time Frame: Day 1 of course 1 to up to day 1 of course 4 (12 weeks) ]
    Pre- and post-treatment levels and changes from pre- to post-treatment in biomarkers will be summarized overall and by response and 6-month PFS categories using summary statistics (e.g., mean or median, with dispersion measures, and using transformed values as appropriate). Depending on the number of responses, logistic regression models may be used to compare response rates across pre-treatment biomarker levels. Proportional hazards models may be used to examine progression-free survival and overall survival across biomarker levels.

  3. Change in tumor immune cell populations using flow cytometry [ Time Frame: Day 1 of course 1 to up to day 1 of course 4 (12 weeks) ]
    Pre- and post-treatment levels and changes from pre- to post-treatment in biomarkers will be summarized overall and by response and 6-month PFS categories using summary statistics (e.g., mean or median, with dispersion measures, and using transformed values as appropriate). Depending on the number of responses, logistic regression models may be used to compare response rates across pre-treatment biomarker levels. Proportional hazards models may be used to examine progression-free survival and overall survival across biomarker levels.

  4. Change in peripheral blood biomarkers using flow cytometry [ Time Frame: Day 1 of course 1 to up to day 1 of course 4 (12 weeks) ]
    Pre and post treatment levels and changes form pre to post treatment in biomarkers will be summarized overall and by response and 6-month PFS categories using summary statistics (e.g., mean or median, with dispersion measures, and using transformed values as appropriate). Depending on the number of responses, logistic regression models may be used to compare response rates across pre-treatment biomarker levels. Proportional hazards models may be used to examine progression-free survival and overall survival across biomarker levels.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Have a pathologically confirmed diagnosis of colorectal cancer, which is metastatic or otherwise unresectable
  • Have received at least 1 prior systemic therapy in the metastatic or unresectable disease setting; patients who have recurred within six months of adjuvant chemotherapy are not required to have received an additional line of chemotherapy
  • Retrovirus-associated deoxyribonucleic acid (DNA) sequence (RAS) wild-type; v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) testing must be completed, with full KRAS and neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS) testing strongly advised; the presence of known mutations in KRAS or NRAS is exclusionary; primary tumor or metastatic tumor may be tested; (note: in the case of multiple genomic evaluations with conflicting results - e.g. KRAS mutant in one sample, but wild-type in another - the patient may be included as RAS wild-type, if clinically justified, after review with the principal investigator [PI])
  • Naive to anti-EGFR therapy (cetuximab or panitumumab)
  • Have an Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • Have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria present
  • Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion; newly-obtained is defined as a specimen obtained up to 30 days prior to initiation of treatment on day 1; subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the principal investigator
  • Hemoglobin >= 8 g/dL (performed within 14 days of treatment initiation)
  • Absolute neutrophil count >= 1000/mm3 (performed within 14 days of treatment initiation)
  • Platelet count >= 100,000/mm3 (performed within 14 days of treatment initiation)
  • Serum creatinine =< 2 upper limit of normal (ULN) or, >= 15 mL/min for participants with creatinine levels > 2 ULN (performed within 14 days of treatment initiation)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 ULN or, =< 5 ULN for participants with liver metastases (performed within 14 days of treatment initiation)
  • Female participants of childbearing potential are to have a negative serum pregnancy test
  • Female participants of child-bearing potential must agree to use an acceptable method of birth control, be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; participants of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
  • Male participants must agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy
  • Participant or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure

Exclusion Criteria:

  • Participants who have had chemotherapy, targeted therapies, radiotherapy, or used an investigational device within 2 weeks prior to the first dose of treatment or those who have not recovered from adverse events (i.e., =< grade 1 or at baseline) due to agents administered more than 2 weeks earlier; note: participants with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study
  • Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
  • Has a known history of active TB (Bacillus Tuberculosis)
  • Hypersensitivity to pembrolizumab or any of its excipients
  • Has a known additional malignancy that requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
  • Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; participants with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability
  • Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment
  • Has known history of, or any evidence of active, non-infectious pneumonitis
  • Uncontrolled clinically significant intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, unstable cardiac arrhythmia, or psychiatric illness, substance abuse disorders or social situations that would limit compliance with study requirements
  • Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
  • Has a known history of human immunodeficiency virus (HIV or HIV 1/2 antibodies); testing not required
  • Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected); testing not required
  • Has received a live vaccine within 30 days of planned start of study therapy (note: seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and shingles are not allowed)
  • Received an investigational agent within 30 days prior to starting study treatment
  • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
  • Unwilling or unable to follow protocol requirements

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02713373


Locations
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United States, New York
Roswell Park Cancer Institute Recruiting
Buffalo, New York, United States, 14263
Contact: Roswell Park    877-275-7724    askrpci@roswellpark.org   
Principal Investigator: Patrick M. Boland         
United States, Ohio
University Hospitals Seidman Cancer Center Recruiting
Cleveland, Ohio, United States, 44106
Contact: Janette Gortz, RN    216-844-1545    Janette.Grotz@uhhospitals.org   
Principal Investigator: Jennifer Eads         
Sponsors and Collaborators
Roswell Park Cancer Institute
National Cancer Institute (NCI)
Merck Sharp & Dohme Corp.
Investigators
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Principal Investigator: Patrick Boland Roswell Park Cancer Institute

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Responsible Party: Roswell Park Cancer Institute
ClinicalTrials.gov Identifier: NCT02713373     History of Changes
Other Study ID Numbers: I 274515
NCI-2016-00228 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
I 274515 ( Other Identifier: Roswell Park Cancer Institute )
P30CA016056 ( U.S. NIH Grant/Contract )
First Posted: March 18, 2016    Key Record Dates
Last Update Posted: April 1, 2019
Last Verified: March 2019

Additional relevant MeSH terms:
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Colorectal Neoplasms
Colonic Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Pembrolizumab
Antineoplastic Agents, Immunological
Cetuximab
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents