Palbociclib and Cetuximab in Treating Participants with Metastatic Colorectal Cancer and Non-Mutated KRAS, NRAS, and BRAF Genes

Status: Active

Description

This phase II trial studies how well palbociclib and cetuximab work in treating participants with colorectal cancer that has spread to other places in the body (metastatic) and have the proteins KRAS, NRAS, and BRAF that are not genetically mutated (wild type). Palbociclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as cetuximab, may interfere with the ability of tumor cells to grow and spread. Giving palbociclib and cetuximab together may work better in treating participants with wild-type metastatic colorectal cancer.

Eligibility Criteria

Inclusion Criteria

  • Written informed consent obtained to participate in the study and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information
  • Eastern Cooperative Oncology Group performance status of 0-2
  • Histologically-confirmed metastatic CRC
  • Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 for solid tumors
  • Documented wild-type in KRAS and NRAS (codons 12, 13, 59, 61, 117, and 146) and in BRAF codon 600, based on tumor tissue taken from primary or metastatic site and tested for biomarkers
  • Previously treated with at least two prior regimens of systemic chemotherapy for metastatic or locally advanced, unresectable disease, including fluoropyrimidines (5-fluorouracil and/or capecitabine), oxaliplatin, and irinotecan * A maintenance regimen of 5-fluorouracil or capecitabine, with or without bevacizumab, should not be counted as a separate line of treatment * For patients who experienced disease recurrence during or within 6 months of completion of adjuvant chemotherapy with fluoropyrimidine and oxaliplatin, only one regimen of systemic chemotherapy for metastatic disease is required
  • Hemoglobin (Hgb) >= 9 g/dL
  • Absolute neutrophil count (ANC) >= 1500/mm^3
  • Platelets >= 100,000/mm^3
  • Creatinine =< 1.5 x upper limits of normal (ULN) OR calculated creatinine clearance >= 60 mL/min by Cockcroft-Gault formula
  • Bilirubin =< 1.0 x upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) =< 3 x ULN OR =< 5 x ULN (if liver metastases present)
  • Alanine aminotransferase (ALT) =< 3 x ULN OR =< 5 x ULN (if liver metastases present)
  • Note: Hematology and other lab parameters that are =< grade 2 BUT still meet criteria for study entry are allowed; furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy
  • Females of childbearing potential must have a negative serum pregnancy test within 72 hours prior to initiating study medications; NOTE: Females are considered of childbearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months; documentation of postmenopausal status must be provided
  • Females of childbearing potential must be willing to abstain from heterosexual activity or to use 2 forms of effective methods of contraception from the time of informed consent until 6 months after treatment discontinuation; the two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method or an intrauterine device that meets < 1% failure rate for protection from pregnancy in the product label
  • Male patients with female partners must have had a prior vasectomy or agree to use an adequate method of contraception (i.e., double barrier method: condom plus spermicidal agent) starting with the first dose of study therapy through 6 months after the last dose of study therapy
  • Subjects is willing and able to comply with study procedures based on the judgement of the investigator or protocol designee
  • Able to swallow capsules, with no surgical or anatomic condition that will preclude the patient from swallowing and absorbing oral medications
  • Has not undergone any major surgical procedures for at least 4 weeks, with full healing of all surgical wounds
  • At sites in the Southeastern U.S., subject must have negative serum test for galactose-alpha-1,3-galactose IgE (Note: positive test result is predictive of immediate-onset anaphylaxis reaction during first exposure to cetuximab, which is prevalent predominantly in limited geographic region of the Southeastern U.S.
  • For study cohort A, has not had prior treatment with cetuximab, panitumumab, or other anti-EGFR therapy
  • For study cohort B, must have had previous treatment with cetuximab or panitumumab with disease control (defined as complete response, partial response, or stable disease) lasting for >= 4 months in duration and completed their last anti-EGFR therapy 8 weeks prior to initiating treatment

Exclusion Criteria

  • Active infection requiring systemic therapy
  • Pregnant or breastfeeding (Note: breast milk cannot be stored for future use while the mother is being treated on study)
  • Presence of known, active central nervous system (CNS) metastases
  • Treatment with any investigational drug within 28 days prior to initiating study medications
  • Prior treatment with drug targeting cyclin-dependent kinase (CDK) family
  • Subject is receiving prohibited medications or treatments that cannot be discontinued/replaced by an alternative therapy
  • Known hypersensitivity to the components of study drugs or analogs of study drugs
  • Has a known additional malignancy that is active and/or progressive requiring treatment; exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder cancer, or other cancer for which the subject has been disease-free for at least five years
  • Uncontrolled, severe concomitant comorbidity (e.g. uncontrolled hypertension, uncontrolled diabetes mellitus, clinically significant pulmonary disease, clinically significant neurological disorder, active or uncontrolled infection)
  • History of interstitial lung disease or pneumonitis
  • Any other clinically significant heart disease, including angina pectoris, resting bradycardia, left bundle branch block, ventricular tachyarrhythmia, unstable atrial fibrillation, acute myocardial infarction, or heart disease requiring cardiac pacemaker or implantable cardioverter/defibrillator
  • Known psychiatric or substance abuse disorder that would interfere with the ability of the patient to comply with trial requirements
  • History of long-QT syndrome
  • Baseline QT Fridericia's correction formula (QTcF) >= 470 msec
  • Concomitant use of drugs known to cause QT prolongation (Note: Ondansetron at doses =< 16 mg or less is allowed)
  • History of any of the following cardiovascular conditions within the past 6 months: * Class III or IV congestive heart failure as defined by the New York Heart Association Criteria * Cardiac angioplasty or stenting * Myocardial infarction * Unstable angina * Symptomatic peripheral vascular disease or other clinically significant cardiac disease

Locations & Contacts

North Carolina

Chapel Hill
UNC Lineberger Comprehensive Cancer Center
Status: Active
Contact: Michael Sangmin Lee
Phone: 919-843-7180
Email: Michael_s_lee@med.unc.edu
Charlotte
Carolinas Medical Center / Levine Cancer Institute
Status: Active
Contact: Mohamed E. Salem
Phone: 980-442-2200
Email: Mohamed.Salem@atriumhealth.org

Virginia

Charlottesville
University of Virginia Cancer Center
Status: Active
Contact: Paul Kunk
Phone: 434-297-5502
Email: prk5r@virginia.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To estimate the disease control rate at four months (disease control rate [DCR]: complete response [CR], partial response [PR] or stable disease [SD]) after a treatment regimen of cetuximab and palbociclib in patients with refractory KRAS/NRAS/BRAF wild-type metastatic colorectal cancer (CRC) in both a cohort of anti-EGFR naive therapy patients, and a cohort of patients who might benefit from a re-challenge of anti-EGFR therapy.

SECONDARY OBJECTIVES:

I. To estimate the overall response rate at four months (ORR: CR or PR) after a treatment regimen of cetuximab and palbociclib in patients with refractory KRAS/NRAS/BRAF wild-type metastatic CRC in both a cohort of anti-EGFR naive therapy patients, and a cohort of patients who might benefit from a re-challenge of anti-EGFR therapy.

II. To estimate overall survival (OS) after a treatment regimen of cetuximab and palbociclib in patients with refractory KRAS/NRAS/BRAF wild-type metastatic CRC in both a cohort of anti-EGFR naive therapy patients, and a cohort of patients who might benefit from a re-challenge of anti-EGFR therapy.

III. To estimate progression free survival (PFS) after a treatment regimen of cetuximab and palbociclib in patients with refractory KRAS/NRAS/BRAF wild-type metastatic CRC in both a cohort of anti-EGFR naive therapy patients, and a cohort of patients who might benefit from a re-challenge of anti-EGFR therapy.

IV. To evaluate the toxicity and safety profile of the combination of palbociclib and cetuximab in patients with refractory KRAS/NRAS/BRAF wild-type metastatic CRC.

EXPLORATORY OBJECTIVES:

I. To determine the tumor mutational profiles that characterize groups of patients that predict for response or resistance to combination of palbociclib and cetuximab.

II. To determine the pharmacodynamic biomarkers of downstream cell signaling activation that predict for response or resistance to combination palbociclib and cetuximab.

OUTLINE:

Participants receive palbociclib orally (PO) once daily (QD) on days 1-21 and cetuximab intravenously (IV) over 1-2 hours once weekly on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up at day 56 then every 90 days for up to 3 years.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
UNC Lineberger Comprehensive Cancer Center

Principal Investigator
Michael Sangmin Lee

Trial IDs

Primary ID LCCC1717
Secondary IDs NCI-2018-00380
Clinicaltrials.gov ID NCT03446157