Safety and Efficacy Study of Neratinib and Cetuximab to Treat Patients With Quadruple Wild-Type Metastatic Colorectal Cancer

NCT01960023 | Withdrawn Phase 1

• 1 other identifier: NSABP FC-7
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 12

Brief Summary

The FC-7 study is designed as an open label, single arm, Phase I/II dose-escalation study evaluating the combination of neratinib and cetuximab in patients with metastatic colorectal cancer primary tumor that is "quadruple wild-type " (wild-type KRAS, NRAS, BRAF, PIK3CA). The primary aim in the Phase I portion of this study is to determine the safety and tolerability of the two-drug combination. The primary aim of the Phase II part is to determine the overall objective response rate (complete and partial responses) by Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Patients will receive concurrent therapy with cetuximab (400 mg/m2 IV loading dose followed by 250 mg/m2 IV weekly), and neratinib.

Conditions

Colorectal Cancer

Keywords

Colorectal cancer; KRAS; BRAF; NRAS; PIK3CA; NSABP

Outcome Measures

Primary Outcomes (2)

• The safety and tolerability of cetuximab and neratinib during the Phase I portion of the study.

  Number of patients experiencing dose limiting toxicities (DLT).

  From start of study therapy weekly through disease progression or end of therapy, approximately 2 years

• Number of patients with Overall response rate (ORR)(complete response/partial response) and progression free survival (PFS) during the Phase II portion of the study

  Response as measured by RECIST 1.1 criteria.

  From start of study through 16 weeks.

Secondary Outcomes (4)

• Progression-free survival (PFS). The time to progression and the time to progression based on tumor HER2 status.

  From start of study through disease progression or end of therapy, approximately 2 years

• Tumor measurement to determine objective tumor decrease and stable disease

  From start of study through desease progression or end of therapy, approximately 2 years

• Measure molecular and genetic correlatives for neratinib and cetuximab

  Baseline (prior to treatment assignment), prior to therapy, after completion of cycle 1, and at disease progression approximately 2 years.

• The frequency and severity of adverse events to evaluate the overall toxicity in the Phase II portion of the study.

  From start of study therapy through 30 days after end of therapy, approximately 2 years

Study Arms (1)

Arm 1: Cetuximab and Neratinib

EXPERIMENTAL

Cetuximab 400 mg/m2 IV loading dose followed by weekly cetuximab 250 mg/m2 IV plus neratinib per oral daily until disease progression

Drug: Cetuximab; Drug: Neratinib

Interventions

Cetuximab DRUG

400 mg/m2 IV loading dose followed by weekly cetuximab 250 mg/m2 IV until disease progression

Arm 1: Cetuximab and Neratinib

Neratinib DRUG

Phase I portion of the study: Dose level 1: 120 mg/day; Dose level 2: 160 mg/day; Dose level 3: 200 mg/day; Dose level 4: 240 mg/day Phase II portion of the study: The recommended dose determined in the Phase I portion of the study.

Arm 1: Cetuximab and Neratinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with resected primary must be active participants of the NSABP Patient Registry and Biospecimen Profiling Repository (MPR-1) study. Patients with intact primary and metastatic KRAS wild-type disease at presentation (treatment naive), must have signed consent for quadruple wild-type central testing for treatment-naive tumor sample submission
• The Eastern Cooperative Oncology Group (ECOG) performance status must be 0, 1, or 2.
• Patients must have the ability to swallow oral medication.
• The tumor tissue must have been determined to be KRAS, NRAS, BRAF, PIK3CA wild-type by central CLIA testing.
• There must be documentation by PET/CT scan, CT scan, or MRI, that the patient has evidence of measurable metastatic disease per RECIST criteria.
• Patients must have an accessible metastatic lesion for pretreatment core biopsy procurement.
• Unless either drug is medically contraindicated, patients must have received oxaliplatin and irinotecan as part of standard chemotherapy regimens. (This includes adjuvant therapy.)
• Patients must have had at least one prior treatment for metastatic disease with standard chemotherapy and cetuximab in combination or as monotherapy. \[Note: patients who received panitumumab instead of cetuximab are eligible.\]
• At the time of study entry, blood counts performed within 4 weeks prior to study entry must meet the following criteria: absolute neutrophil count (ANC) must be greater than or equal to 1000/mm3; Platelet count must be greater than or equal to 100,000/mm3; Hemoglobin must be greater than or equal to 9 g/dL
• The following criteria for evidence of adequate hepatic function performed within 4 weeks prior to study entry must be met: Total bilirubin must be less than or equal to 1.5 x upper limit of normal (ULN); aspartate aminotransferase (AST) and ALT must be less than or equal to 2.5 x ULN for the lab or less than or equal to 5 x ULN if liver metastasis;
• Serum creatinine performed within 4 weeks prior to study entry must be less than or equal to 1.5 x ULN for the lab.
• Female patients and male patients with female partners of reproductive potential must agree to use an effective method of contraception during therapy and for at least 6 months after the last dose of study therapy.
• Patients with acquired immunodeficiency syndrome (AIDS-related illnesses) or known human immunodeficiency virus (HIV) disease must: Have a CD4 count greater than or equal to 200 cells/uL within 30 days prior to beginning study therapy; Be off all antiretroviral therapy (prophylaxis/treatment) greater than 60 days prior to beginning study therapy; Have no evidence of opportunistic infections.

You may not qualify if:

• Diagnosis of anal or small bowel carcinoma.
• Colorectal cancer other than adenocarcinoma, e.g., sarcoma, lymphoma, carcinoid.
• Previous therapy with any HER2 TKI (such as trastuzumab, lapatinib, neratinib, etc.) for any malignancy.
• Symptomatic brain metastases or brain metastases requiring chronic steroids to control symptoms.
• Active hepatitis B or hepatitis C with abnormal liver function tests.
• Malabsorption syndrome, ulcerative colitis, inflammatory bowel disease, resection of the stomach or small bowel, or other disease or condition significantly affecting gastrointestinal function.
• Persistent Common Toxicity Criteria for Adverse Effects (CTCAE v4.0) greater than or equal to grade 2 diarrhea regardless of etiology.
• Chronic daily treatment with corticosteroids with a dose of greater than or equal to 10 mg/day methylprednisolone equivalent (excluding inhaled steroids).
• CTCAE v4.0 grade 3 or 4 anorexia or nausea related to metastatic disease.
• CTCAE v4.0 greater than or equal to grade 2 vomiting related to metastatic disease.
• Any of the following cardiac conditions: Documented congestive heart failure; Myocardial infarction within 6 months prior to study entry; Unstable angina within 6 months prior to study entry; Symptomatic arrhythmia
• Serious or non-healing wound, skin ulcer, or bone fracture.
• History of bleeding diathesis or coagulopathy. (Patients on stable anticoagulant therapy are eligible.)
• Symptomatic interstitial lung disease or definitive evidence of interstitial lung disease described on CT scan, MRI, or chest x-ray in asymptomatic patients; dyspnea at rest requiring current continuous oxygen therapy.
• Other malignancies unless the patient is considered to be disease-free and has completed therapy for the malignancy greater than or equal to 12 months prior to study entry. Patients with the following cancers are eligible if diagnosed and treated within the past 12 months: carcinoma in situ of the cervix, colorectal carcinoma in situ, melanoma in situ, and basal cell and squamous cell carcinoma of the skin.

Sponsors & Collaborators

• NSABP Foundation Inc: lead

Study Sites (12)

University of Florida

Gainesville, Florida, 32610, United States

Location

MD Anderson Cancer Center Orlando

Orlando, Florida, 32806, United States

Location

Saint Luke's Mountain States Tumor Institute

Boise, Idaho, 83712, United States

Location

Decatur Memorial Hospital

Decatur, Illinois, 62526, United States

Location

Saint Joseph Mercy Hospital

Ann Arbor, Michigan, 48106, United States

Location

Henry Ford Health System

Detroit, Michigan, 48202, United States

Location

Levine Cancer Institute

Charlotte, North Carolina, 28204, United States

Location

Novant Health Presbyterian Medical Center

Charlotte, North Carolina, 28204, United States

Location

Thomas Jefferson University Hospital

Philadelphia, Pennsylvania, 19107, United States

Location

Allegheny General Hospital

Pittsburgh, Pennsylvania, 15215, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, 15232, United States

Location

Reading Hospital and Medical Center

West Reading, Pennsylvania, 19611, United States

Location

Related Publications (1)

• Jacobs SA, Lee JJ, George TJ, Wade JL 3rd, Stella PJ, Wang D, Sama AR, Piette F, Pogue-Geile KL, Kim RS, Gavin PG, Lipchik C, Feng H, Wang Y, Finnigan M, Kiesel BF, Beumer JH, Wolmark N, Lucas PC, Allegra CJ, Srinivasan A. Neratinib-Plus-Cetuximab in Quadruple-WT (KRAS, NRAS, BRAF, PIK3CA) Metastatic Colorectal Cancer Resistant to Cetuximab or Panitumumab: NSABP FC-7, A Phase Ib Study. Clin Cancer Res. 2021 Mar 15;27(6):1612-1622. doi: 10.1158/1078-0432.CCR-20-1831. Epub 2020 Nov 17.

  PMID: 33203645 DERIVED

MeSH Terms

Conditions

Colorectal Neoplasms; Hereditary Sensory and Autonomic Neuropathies

Interventions

Cetuximab; neratinib

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Nervous System Malformations; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Polyneuropathies; Peripheral Nervous System Diseases; Neuromuscular Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Norman Wolmark, MD

  NSABP Foundation Inc

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 17, 2013
• First Posted: October 10, 2013
• Study Start: October 1, 2013
• Primary Completion: July 13, 2016
• Study Completion: July 13, 2016
• Last Updated: October 27, 2021

Record last verified: 2021-10

Locations

US (12)