Clinical Trials /

TAS-102 With Concurrent Radiation for the Treatment of Untreated Resectable Stage II-III Rectal Cancer

NCT04104139

Description:

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.

Related Conditions:
  • Rectal Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • 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 (Lonsurf®) With Concurrent Radiation in Previously Untreated Resectable Stage II and Stage III Rectal Cancer (FIERCE Study)

Clinical Trial IDs

  • ORG STUDY ID: STUDY00019576
  • SECONDARY ID: NCI-2019-06387
  • SECONDARY ID: SOL-19069-L
  • SECONDARY ID: P30CA069533
  • NCT ID: NCT04104139

Conditions

  • 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

Interventions

DrugSynonymsArms
Trifluridine and Tipiracil Hydrochloride (TAS-102)Lonsurf®, 733030-01-8, TAS-102, TAS 102, Thymidine, Alpha,alpha,alpha-trifluoro-, Mixt. with 5-Chloro-6-((2-imino-1-pyrrolidinyl)methyl)-2,4(1H,3H)-pyrimidinedione Monohydrochloride, Lonsurf, Tipiracil Hydrochloride Mixture with Trifluridine, Trifluridine/Tipiracil, Trifluridine/Tipiracil Hydrochloride Combination Agent TAS-102Treatment (TAS-102, IMRT, 3D-CRT)

Purpose

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 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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (TAS-102, IMRT, 3D-CRT)ExperimentalPatients 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.
  • Trifluridine and Tipiracil Hydrochloride (TAS-102)

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)

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Proportion of dose limiting toxicity (DLT)s for TAS-102 at the maximum tolerated dose (MTD)
Time Frame:Up to end of week 8
Safety Issue:
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.

Secondary Outcome Measures

Measure:Incidence of adverse events (AEs) (all grade) for TAS-102 concurrent with radiation therapy (RT)
Time Frame:Up to start of fluorouracil/leucovorin calcium/oxaliplatin (FOLFOX) (up to 8 weeks)
Safety Issue:
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.
Measure:Incidence of grade 3 or higher treatment emergent adverse events (TEAEs) during FOLFOX treatment
Time Frame:End of FOLFOX regimen (up to 16 weeks)
Safety Issue:
Description:The incidence of grade 3 or higher TEAEs during FOLFOX chemotherapy will be assessed using the FOLFOX analysis set.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:OHSU Knight Cancer Institute

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