Trametinib, Fluorouracil, and Radiation Therapy Before Surgery in Treating Patients With Stage II-III Rectal Cancer

NCT01740648 | Completed Phase 1 DMC FDA Drug

• 2 other identifiers: OSU-12054NCI-2012-02158
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 4

Brief Summary

This phase I trial studies the side effects and best dose of trametinib when given together with fluorouracil and radiation therapy before surgery in treating patients with stage II-III rectal cancer. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving trametinib together with fluorouracil and radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed

Conditions

Recurrent Rectal Cancer; Stage IIA Rectal Cancer; Stage IIB Rectal Cancer; Stage IIC Rectal Cancer; Stage IIIA Rectal Cancer; Stage IIIB Rectal Cancer; Stage IIIC Rectal Cancer

Keywords

MEK Inhibitor; Trametinib; Rectal Cancers; KRAS; BRAF; NRAS Mutant; Fluorouracil

Outcome Measures

Primary Outcomes (1)

• Identify the maximally tolerated dose of Trametinib to be used in combination with 5FU and radiation in patients with rectal cancers.

  up to 9 weeks

Secondary Outcomes (6)

• Frequency of dose-limiting toxicities, assessed according to the NCI CTCAE version 4

  up to 9 weeks

• Local failure rate

  From the time of study enrollment until the first documented date of local failure, assessed up to 5 years

• Progression free survival

  From the time of study enrollment until the first documented date of disease progression, assessed up to 5 years

• Overall survival

  From the time of study enrollment until the time of death, assessed up to 5 years

• Pathological response rate, defined as extent of tumor in the resected specimen that is classified by tumor, lymph node, metastasis (TNM) staging of the AJCC/International Union Against Cancer (UICC)

  Up to 5 years

Study Arms (1)

Treatment (trametinib, fluorouracil, radiation, surgery)

EXPERIMENTAL

Patients receive trametinib PO (by mouth) QD (daily) on days -14 through -10 and 1-38 and fluorouracil IV continuously 5 days a week from days 1-38. Patients also undergo radiation therapy 5 days a week on days 1-33. Patients then undergo surgery 6-10 weeks later. Patients achieving negative surgical margins after complete resection of tumor receive postoperative chemotherapy comprising leucovorin calcium IV over 2 hours and fluorouracil IV continuously over 46 hours on days 1 and 15 OR oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours and fluorouracil IV continuously over 46 hours on days 1 and 15. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

Drug: trametinib; Drug: fluorouracil; Radiation: radiation therapy

Interventions

trametinib DRUG

Trametinib will be given for 5-day lead-in period by mouth daily Monday-Friday starting at day -14 through -10 and concurrently for the duration of radiation therapy (approximately days 1-38).The dose of Trametinib will be escalated: 0.5 mg, 1.0 mg, 2mg. If the 2 mg dose level causes DLT (dose-limiting toxicity)in 2 out of 6 patients and the 1mg dose level was acceptable, then a 1.5 mg dose cohort will be used.

Also known as: GSK1120212

Treatment (trametinib, fluorouracil, radiation, surgery)

fluorouracil DRUG

Will be administered as a continuous infusion over 120 hours at a dose of 225 mg/m2/day on Monday to Friday of every week starting day 1-38.

Also known as: 5-fluorouracil, 5-Fluracil, 5-FU

Treatment (trametinib, fluorouracil, radiation, surgery)

radiation therapy RADIATION

Radiation therapy will be delivered to the pelvis during (approximately) days 1-33 (five days a week, Mondays through Fridays for 25 fractions) using a 3-field or 4-field 3-D conformal plan to the primary tumor, surrounding soft tissues, and at risk lymph node stations (peri-rectal, presacral, internal iliac, with or without external iliac) to a total dose of 45 Gy in 1.8 Gy daily fractions. A boost radiation field will be delivered during (approximately) days 36-38. The boost will encompass the primary rectal tumor and involved lymph nodes with a 2-2.5 cm margin, which should include the presacral space. The boost dose will be 5.4 Gy in 1.8 Gy fractions for a total dose of 50.4 Gy.

Also known as: irradiation, radiotherapy, therapy, radiation

Treatment (trametinib, fluorouracil, radiation, surgery)

Eligibility Criteria

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

You may qualify if:

• All prior treatment-related toxicities must be Common Terminology Criteria for Adverse Events (CTCAE) (version 4.0) =\< grade 1 (except alopecia) at the time of enrollment
• Absolute neutrophil count \>= 1.5 x 10\^9/L
• Hemoglobin \>= 9 g/dL
• Platelets \>= 100 x 10\^9/L
• Prothrombin time (PT)/international normalized ratio (INR) =\< 1.5 x upper limit of normal (ULN)
• Partial thromboplastin time (PTT) =\< 1.5 x ULN
• Albumin \>= 2.5 g/dL
• Total bilirubin =\< 1.5 x ULN
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 2.5 x ULN
• Creatinine =\< 1.5 ULN or calculated creatinine clearance \>= 50 mL/min or 24-hour urine creatinine clearance \>= 50 mL/min
• Left ventricular ejection fraction (LVEF) \>= lower limit of normal (LLN) by echocardiogram (ECHO) or multi gated acquisition scan (MUGA)
• Life expectancy of at least 3 months in the opinion of investigator
• Able to swallow and retain orally administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels
• Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed

You may not qualify if:

• History of another malignancy; exception: subjects who have been disease-free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible
• Any serious and/or unstable pre-existing medical disorder (aside from malignancy exception above), psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures, in the opinion of the Investigator
• Prior chemotherapy treatment unless \> 5 years ago
• Prior treatment with a selective inhibitor of v-raf-1 murine leukemia viral oncogene homolog 1 (RAF) or mitogen-activated protein kinase kinase 1 (MEK)
• Prior radiation therapy to the abdomen or pelvis
• Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to study drug, or excipients or to dimethyl sulfoxide (DMSO)
• Current use of a prohibited medication
• History or current evidence / risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR):
• History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes)
• Visible retinal pathology as assessed by ophthalmic exam that is considered a risk factor for RVO or CSR such as:
• Evidence of optic disc cupping
• Evidence of visual field defects
• Intraocular pressure \> 21 mm Hg
• Known human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (with the exception of chronic or cleared HBV and HCV infection which will be allowed)
• History or evidence of cardiovascular risk including any of the following:

Sponsors & Collaborators

• Ohio State University Comprehensive Cancer Center: lead
• National Comprehensive Cancer Network: collaborator
• Novartis Pharmaceuticals: collaborator

Study Sites (4)

Siteman Cancer Center at Washington University

St Louis, Missouri, 63110, United States

Location

Roswell Park Cancer Institute

Buffalo, New York, 14263, United States

Location

Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center

Columbus, Ohio, 43210, United States

Location

Vanderbilt University

Nashville, Tennessee, 37235, United States

Location

Related Links

• The Jamesline

MeSH Terms

Conditions

Rectal Neoplasms

Interventions

trametinib; Fluorouracil; Radiotherapy; Radiation

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Therapeutics; Physical Phenomena

Study Officials

• Sameek Roychowdhury, MD

  Ohio State University Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: November 30, 2012
• First Posted: December 4, 2012
• Study Start: November 26, 2012
• Primary Completion: September 29, 2021
• Study Completion: September 29, 2021
• Last Updated: September 18, 2023

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (4)