TAS-102 With Concurrent Radiation for the Treatment of Untreated Resectable Stage II-III Rectal Cancer
Primary Purpose
Rectal Adenocarcinoma, Stage IIA Rectal Cancer AJCC v8, Stage IIB Rectal Cancer AJCC v8
Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
3-Dimensional Conformal Radiation Therapy
Intensity-Modulated Radiation Therapy
Trifluridine and Tipiracil Hydrochloride
Sponsored by
About this trial
This is an interventional treatment trial for Rectal Adenocarcinoma
Eligibility Criteria
Inclusion Criteria:
- All races and ethnic groups will be included
- Histologically confirmed diagnosis of adenocarcinoma of the rectum
- Clinical stage II (T3-4aN0M0) and stage III (T1-4aN1+M0) based on MRI
- Resectable primary rectal tumor at baseline
- No evidence of distant metastases
- No prior pelvic radiation therapy
- No prior chemotherapy or surgery for rectal cancer
- No active infections requiring systemic antibiotic treatment (oral antibiotics are acceptable at the discretion of the treating physician)
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1
- Leukocytes >= 3,000/uL
- Absolute neutrophil count >= 1,500/uL
- Hemoglobin >= 9.0 gm/dL
- Platelets >= 100,000/uL
- Total bilirubin within normal institutional limits
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal (ULN)
- Creatinine within normal institutional limits, OR creatinine clearance >= 60 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal
- Female participants of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. A female of childbearing potential is defined of one who is biologically capable of becoming pregnant. Reliable contraception should be used starting from trial screening and must be continued throughout the study
- Females of childbearing potential must agree to use effective contraceptive method starting with the first dose of study therapy through 6 months after the last dose of study therapy
- Male participants must agree to use an effective method of contraception starting with the first dose of study therapy through 6 months after the last dose of study therapy
- Participants must read, have the ability to understand, agree to, and sign a statement of Informed Consent prior to participation in this study
Participants must, as part of their planned treatment per institutional guidelines, be:
- Scheduled to receive preoperative FOLFOX or CAPOX chemotherapy, which requires a central venous access device for administration
- Able to undergo planned TME of the rectal tumor per institutional standards
Exclusion Criteria:
- Recurrent rectal cancer
- Primary unresectable rectal cancer. A tumor is considered unresectable when invading adjacent organs (T4b disease) and an en bloc resection will not achieve negative margins. Rectal cancer presenting with concurrent or overlapping sites in the colon is eligible if these sites could be removed with surgery
- Distant nodal disease (retroperitoneal nodes), or any metastatic disease by computed tomography (CT) or positron emission tomography (PET)
- Creatinine > 1.5 x ULN
- History of peripheral neuropathy > grade 2
- History of malabsorption syndromes or inflammatory bowel disease
- Use of immunosuppressive or myelosuppressive medications including but not limited to adalimumab, azathioprine, BCG, clozapine, cyclosporine, deferiprone, etanercept, fingolimod, hydroxyurea, interferon, leflunomide, methotrexate, mycophenolate, natalizumab, pimecrolimus, rituximab, sirolimus, and tacrolimus
- Inability to take oral medications
- Participants who received prior pelvic radiotherapy
- Use of induction chemotherapy prior to chemo-radiation of rectal cancer
- Use of other chemotherapy regimens other than FOLFOX or CAPOX
- Participants who are unable to undergo an MRI
- Participants who are unable to undergo TME
- Refusal of standard-of-care TME of the rectal tumor if there is persistent disease after neoadjuvant treatment
- Participants with a history of any arterial thrombotic event within the past 6 months, including angina (stable or unstable), myocardial infarction (MI), transient ischemic attack (TIA), or cerebrovascular accident (CVA)
- Participants with a recent history of venous thrombotic episodes such as deep venous thrombosis and pulmonary embolism within the past 3 months. If these episodes occurred more than three months prior to enrollment, they may be considered for protocol participation, provided they are on stable doses of anticoagulant therapy. Similarly, participants who are anticoagulated for atrial fibrillation or other conditions may participate, provided they are on stable doses of anticoagulant therapy
- Febrile illness within 7 days of study enrollment
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to TAS-102 or other agents used in this study
- Other anticancer or experimental therapy. No other experimental therapies including for other disease indications are allowed while the participant is receiving study treatment
- Women who are pregnant or breast-feeding
- Participants with any other concurrent medical or psychiatric condition or disease which, in the investigator's judgment, would make them inappropriate candidates for entry into this study
- Participants with a history of a prior malignancy within the past 5 years, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer
Sites / Locations
- OHSU Knight Cancer InstituteRecruiting
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Treatment (TAS-102, IMRT, 3D-CRT)
Arm Description
Patients receive TAS-102 PO BID Monday-Friday on weeks 1, 3, and 5. Patients also undergo IMRT or 3D-CRT 5 days per week on weeks 1-5. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients then undergo standard of care FOLFOX or CAPOX.
Outcomes
Primary Outcome Measures
Proportion of dose limiting toxicity (DLT)s for TAS-102 at the maximum tolerated dose (MTD)
Will be assessed through the Bayesian optimal interval design and will be determined by the proportion of grade 3 or higher adverse events during chemo-radiation therapy (CRT) with TAS-102 at the MTD by allowing no more than 30% DLT. The proportion will be descriptively noted.
Secondary Outcome Measures
Incidence of adverse events (AEs) (all grade) for TAS-102 concurrent with radiation therapy (RT)
Descriptive statistics of safety will be presented using National cancer Institute Common Terminology Criteria for Adverse Events version 5.0., with AEs tabulated by the MedDRA preferred term and system organ class. The incidence of AEs (all grades) for TAS-102 with concurrent RT will be assessed using the CRT analysis set.
Incidence of grade 3 or higher treatment emergent adverse events (TEAEs) during FOLFOX or CAPOX treatment
The incidence of grade 3 or higher TEAEs during FOLFOX or CAPOX chemotherapy will be assessed using the FOLFOX/CAPOX analysis set.
Full Information
NCT ID
NCT04104139
First Posted
September 24, 2019
Last Updated
July 21, 2023
Sponsor
OHSU Knight Cancer Institute
Collaborators
Oregon Health and Science University, Taiho Pharmaceutical Co., Ltd.
1. Study Identification
Unique Protocol Identification Number
NCT04104139
Brief Title
TAS-102 With Concurrent Radiation for the Treatment of Untreated Resectable Stage II-III Rectal Cancer
Official Title
Phase 1b Study to Assess the Safety of Neoadjuvant TAS-102 (Trifluridine/Tipiracil) With Concurrent Radiation in Previously Untreated Resectable Stage II and Stage III Rectal Cancer (FIERCE)
Study Type
Interventional
2. Study Status
Record Verification Date
July 2023
Overall Recruitment Status
Recruiting
Study Start Date
December 11, 2019 (Actual)
Primary Completion Date
June 1, 2024 (Anticipated)
Study Completion Date
December 31, 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
OHSU Knight Cancer Institute
Collaborators
Oregon Health and Science University, Taiho Pharmaceutical Co., Ltd.
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This phase 1b trial studies the side effects and best dose of TAS-102 when given together with radiation therapy in treating patients with stage II-III rectal cancer that has not been treated and can be removed by surgery (resectable). Drugs used in chemotherapy, such as TAS-102, 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. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. This study is being done to find out the safest dose of TAS-102 that can be used with radiation treatment for rectal cancer.
Detailed Description
PRIMARY OBJECTIVE:
I. To determine the recommended phase 2 dose of trifluridine and tipiracil hydrochloride (TAS-102) per the proportion of grade 3 or higher adverse events during chemo-radiation therapy (CRT) with concurrent TAS-102 at the maximum tolerated dose by allowing no more than 30% grade 3 or higher adverse events.
SECONDARY OBJECTIVES:
I. Evaluate safety of participants treated with TAS-102 during radiation therapy (RT).
II. Evaluate treatment emergent adverse events (TEAEs) attributable to TAS-102 with RT during fluorouracil/leucovorin calcium/oxaliplatin (FOLFOX) or capecitabine/oxaliplatin (CAPOX) treatment.
EXPLORATORY OBJECTIVES:
I. To preliminary assess the rates of complete clinical response (cCR) by magnetic resonance imaging (MRI) and by endoscopy after TAS-102 with concurrent CRT.
II. To preliminary assess the rates of cCR by MRI and by endoscopy after treatment with FOLFOX.
III. To preliminary assess the rates of pCR after standard total mesorectal excision (TME).
OUTLINE: This is dose-escalation study of TAS-102.
Patients receive TAS-102 orally (PO) twice daily (BID) Monday-Friday on weeks 1, 3, and 5. Patients also undergo intensity modulated radiotherapy (IMRT) or 3-dimensional conformal radiotherapy (3D-CRT) 5 days per week on weeks 1-5. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients then undergo standard of care FOLFOX or CAPOX.
After completion of study treatment, patients are followed for up to a total of 16 weeks (3 months) from end of FOLFOX or CAPOX treatment until rectal cancer surgery or death, whichever occurs first. Participants that opt for a non-surgical option at the end of chemotherapy may be followed for a longer period of time.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Rectal Adenocarcinoma, Stage IIA Rectal Cancer AJCC v8, Stage IIB Rectal Cancer AJCC v8, Stage III Rectal Cancer AJCC v8, Stage IIIA Rectal Cancer AJCC v8, Stage IIIB Rectal Cancer AJCC v8, Stage IIIC Rectal Cancer AJCC v8
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
18 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Treatment (TAS-102, IMRT, 3D-CRT)
Arm Type
Experimental
Arm Description
Patients receive TAS-102 PO BID Monday-Friday on weeks 1, 3, and 5. Patients also undergo IMRT or 3D-CRT 5 days per week on weeks 1-5. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients then undergo standard of care FOLFOX or CAPOX.
Intervention Type
Radiation
Intervention Name(s)
3-Dimensional Conformal Radiation Therapy
Other Intervention Name(s)
3-dimensional radiation therapy, 3D Conformal, 3D CONFORMAL RADIATION THERAPY, 3D CRT, 3D-CRT, Conformal Therapy, Radiation Conformal Therapy, Radiation, 3D Conformal
Intervention Description
Undergo 3D-CRT
Intervention Type
Radiation
Intervention Name(s)
Intensity-Modulated Radiation Therapy
Other Intervention Name(s)
IMRT, Intensity Modulated RT, Intensity-Modulated Radiotherapy, Radiation, Intensity-Modulated Radiotherapy
Intervention Description
Undergo IMRT
Intervention Type
Drug
Intervention Name(s)
Trifluridine and Tipiracil Hydrochloride
Other Intervention Name(s)
Lonsurf, TAS 102, TAS-102, Tipiracil Hydrochloride Mixture with Trifluridine, Trifluridine/Tipiracil, Trifluridine/Tipiracil Hydrochloride Combination Agent TAS-102
Intervention Description
Given PO
Primary Outcome Measure Information:
Title
Proportion of dose limiting toxicity (DLT)s for TAS-102 at the maximum tolerated dose (MTD)
Description
Will be assessed through the Bayesian optimal interval design and will be determined by the proportion of grade 3 or higher adverse events during chemo-radiation therapy (CRT) with TAS-102 at the MTD by allowing no more than 30% DLT. The proportion will be descriptively noted.
Time Frame
Up to end of week 8, or start of fluorouracil/leucovorin calcium/oxaliplatin (FOLFOX) or capecitabine/oxaliplatin (CAPOX) chemotherapy, whichever occurs first
Secondary Outcome Measure Information:
Title
Incidence of adverse events (AEs) (all grade) for TAS-102 concurrent with radiation therapy (RT)
Description
Descriptive statistics of safety will be presented using National cancer Institute Common Terminology Criteria for Adverse Events version 5.0., with AEs tabulated by the MedDRA preferred term and system organ class. The incidence of AEs (all grades) for TAS-102 with concurrent RT will be assessed using the CRT analysis set.
Time Frame
Up to start of FOLFOX or CAPOX (up to 8 weeks)
Title
Incidence of grade 3 or higher treatment emergent adverse events (TEAEs) during FOLFOX or CAPOX treatment
Description
The incidence of grade 3 or higher TEAEs during FOLFOX or CAPOX chemotherapy will be assessed using the FOLFOX/CAPOX analysis set.
Time Frame
Up to end of FOLFOX or CAPOX (up to 16 weeks)
Other Pre-specified Outcome Measures:
Title
Rate of complete response (CR) by magnetic resonance imaging (MRI) after chemo-radiation therapy (CRT)
Description
MRI report after CRT will be collected from medical records. Discrepancies will be resolved with the diagnostic radiology investigators of the research team. Complete response based on MRI will be tabulated as proportions and analyzed descriptively using the CRT analysis sets.
Time Frame
Prior to starting FOLFOX or CAPOX regimen (up to 8 weeks)
Title
Rate of CR by endoscopic exam after CRT
Description
Endoscopic exam report after CRT will be collected from medical records (as available). Discrepancies will be resolved with the surgical oncology investigators of the research team. Complete response based on endoscopic exam will be tabulated as proportions and analyzed descriptively using the CRT analysis sets.
Time Frame
Prior to starting FOLFOX or CAPOX regimen (up to 8 weeks)
Title
Rate of clinical complete response (cCR) by MRI and endoscopic response after CRT
Description
cCR requires CR for MRI and CR for endoscopic responses. The number of cCR after CRT will be tabulated as proportions using the CRT analysis sets, respectively.
Time Frame
Prior to starting FOLFOX or CAPOX regimen (up to 8 weeks)
Title
Rate of CR by MRI after CRT and FOLFOX or CAPOX
Description
MRI report after CRT + FOLFOX or CAPOX will be collected from medical records. Discrepancies will be resolved with the diagnostic radiology investigators of the research team. Complete response based on MRI will be tabulated as proportions and analyzed descriptively using the CRT and the FOLFOX/CAPOX analysis sets, respectively.
Time Frame
At end of chemotherapy visit (up to 21 weeks)
Title
Rate of CR by endoscopic exam after CRT and FOLFOX or CAPOX
Description
Endoscopic exam report after CRT + FOLFOX or CAPOX will be collected from medical records (as available). Discrepancies will be resolved with the surgical oncology investigators of the research team. Complete response based on endoscopic exam will be tabulated as proportions and analyzed descriptively using the CRT and the FOLFOX/CAPOX analysis sets, respectively.
Time Frame
At end of chemotherapy visit (up to 21 weeks)
Title
Rate of cCR by MRI and endoscopic response after CRT and FOLFOX or CAPOX
Description
cCR requires CR for MRI and CR for endoscopic responses. The number of cCR after CRT and after CRT + FOLFOX or CAPOX will be tabulated as proportions using the CRT and the FOLFOX/CAPOX analysis sets, respectively.
Time Frame
At end of chemotherapy visit (up to 21 weeks)
Title
Rate of pathologic complete response after standard total mesorectal excision (TME)
Description
Pathology report after standard TME will be collected from medical records. Discrepancies will be resolved with the surgical oncology and pathology investigators of the research team. Complete response based on pathology will be tabulated as proportions and analyzed descriptively using the TME population.
Time Frame
At resection (up to 29 weeks)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
All races and ethnic groups will be included
Histologically confirmed diagnosis of adenocarcinoma of the rectum
Clinical stage II (T3-4aN0M0) and stage III (T1-4aN1+M0) based on MRI
Resectable primary rectal tumor at baseline
No evidence of distant metastases
No prior pelvic radiation therapy
No prior chemotherapy or surgery for rectal cancer
No active infections requiring systemic antibiotic treatment (oral antibiotics are acceptable at the discretion of the treating physician)
Eastern Cooperative Oncology Group (ECOG) performance status 0-1
Leukocytes >= 3,000/uL
Absolute neutrophil count >= 1,500/uL
Hemoglobin >= 9.0 gm/dL
Platelets >= 100,000/uL
Total bilirubin within normal institutional limits
Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal (ULN)
Creatinine within normal institutional limits, OR creatinine clearance >= 60 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal
Female participants of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. A female of childbearing potential is defined of one who is biologically capable of becoming pregnant. Reliable contraception should be used starting from trial screening and must be continued throughout the study
Females of childbearing potential must agree to use effective contraceptive method starting with the first dose of study therapy through 6 months after the last dose of study therapy
Male participants must agree to use an effective method of contraception starting with the first dose of study therapy through 6 months after the last dose of study therapy
Participants must read, have the ability to understand, agree to, and sign a statement of Informed Consent prior to participation in this study
Participants must, as part of their planned treatment per institutional guidelines, be:
Scheduled to receive preoperative FOLFOX or CAPOX chemotherapy, which requires a central venous access device for administration
Able to undergo planned TME of the rectal tumor per institutional standards
Exclusion Criteria:
Recurrent rectal cancer
Primary unresectable rectal cancer. A tumor is considered unresectable when invading adjacent organs (T4b disease) and an en bloc resection will not achieve negative margins. Rectal cancer presenting with concurrent or overlapping sites in the colon is eligible if these sites could be removed with surgery
Distant nodal disease (retroperitoneal nodes), or any metastatic disease by computed tomography (CT) or positron emission tomography (PET)
Creatinine > 1.5 x ULN
History of peripheral neuropathy > grade 2
History of malabsorption syndromes or inflammatory bowel disease
Use of immunosuppressive or myelosuppressive medications including but not limited to adalimumab, azathioprine, BCG, clozapine, cyclosporine, deferiprone, etanercept, fingolimod, hydroxyurea, interferon, leflunomide, methotrexate, mycophenolate, natalizumab, pimecrolimus, rituximab, sirolimus, and tacrolimus
Inability to take oral medications
Participants who received prior pelvic radiotherapy
Use of induction chemotherapy prior to chemo-radiation of rectal cancer
Use of other chemotherapy regimens other than FOLFOX or CAPOX
Participants who are unable to undergo an MRI
Participants who are unable to undergo TME
Refusal of standard-of-care TME of the rectal tumor if there is persistent disease after neoadjuvant treatment
Participants with a history of any arterial thrombotic event within the past 6 months, including angina (stable or unstable), myocardial infarction (MI), transient ischemic attack (TIA), or cerebrovascular accident (CVA)
Participants with a recent history of venous thrombotic episodes such as deep venous thrombosis and pulmonary embolism within the past 3 months. If these episodes occurred more than three months prior to enrollment, they may be considered for protocol participation, provided they are on stable doses of anticoagulant therapy. Similarly, participants who are anticoagulated for atrial fibrillation or other conditions may participate, provided they are on stable doses of anticoagulant therapy
Febrile illness within 7 days of study enrollment
History of allergic reactions attributed to compounds of similar chemical or biologic composition to TAS-102 or other agents used in this study
Other anticancer or experimental therapy. No other experimental therapies including for other disease indications are allowed while the participant is receiving study treatment
Women who are pregnant or breast-feeding
Participants with any other concurrent medical or psychiatric condition or disease which, in the investigator's judgment, would make them inappropriate candidates for entry into this study
Participants with a history of a prior malignancy within the past 5 years, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
OHSU Knight Cancer Clinical Trials Hotline
Phone
503-494-1080
Email
trials@ohsu.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Charles D Lopez, MD, PhD
Organizational Affiliation
OHSU Knight Cancer Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
OHSU Knight Cancer Institute
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
OHSU Knight Cancer Clinical Trials Hotline
Phone
503-494-1080
Email
trials@ohsu.edu
First Name & Middle Initial & Last Name & Degree
Emerson Y. Chen, MD
Email
cheem@ohsu.edu
First Name & Middle Initial & Last Name & Degree
Charles D. Lopez, MD, PhD
First Name & Middle Initial & Last Name & Degree
Emerson Y. Chen, MD
First Name & Middle Initial & Last Name & Degree
Nima Nabavizadeh, MD
12. IPD Sharing Statement
Learn more about this trial
TAS-102 With Concurrent Radiation for the Treatment of Untreated Resectable Stage II-III Rectal Cancer
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