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.
PRIMARY OBJECTIVES:
I. To determine the recommended phase 2 dose of TAS-102 per the proportion of grade 3 or
higher adverse events during chemo-radiation (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) 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 pathological complete response (pCR) after standard
total mesorectal excision (TME).
IV. To evaluate the cellular and molecular biology of rectal cancer and associated
Circulating Hybrid Cells (CHCs).
V. Determine how cellular and molecular biology of rectal cancer and associated CHCs are
temporally altered following cancer-directed therapies.
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.
After completion of study treatment, patients are followed for up to a total of 8 weeks (2
months) from end of FOLFOX treatment until rectal cancer surgery or death, whichever occurs
first.
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)
- ECOG performance status 0-1
- Participants must have normal organ and marrow function as defined below:
- Leukocytes >=3,000/µL
- Absolute neutrophil count >=1,500/µL
- Hemoglobin > 9.0 gm/dL
- Platelets >=100,000/µL
- Total bilirubin within normal institutional limits
- AST(SGOT)/ALT(SGPT) <=2.5 × institutional upper limit of normal (ULN)
- Creatinine within normal institutional limits, OR Creatinine clearance >=60
mL/min/1.73 m2 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
(Appendix B) 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 (Appendix B)
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 chemotherapy, which requires a central
venous access device for administration
- Scheduled 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
- Distant nodal disease (retroperitoneal nodes), or any metastatic disease by CT or 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
- 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
- Participants with a history of any arterial thrombotic event within the past 6 months,
including angina (stable or unstable), MI, TIA, or 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
