Clinical Trials /

Phase 1b/2 Study of Rivoceranib and Trifluridine/Tipiracil for Metastatic Colorectal Cancer

NCT04073615

Description:

Comparing the efficacy of rivoceranib and trifluridine/tipiracil administered individually as monotherapies, as well as a rivocernib plus trifluridine/tipiracil combination therapy in the treatment of mCRC that is unresponsive to traditional chemotherapies.

Related Conditions:
  • Colorectal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase 1b/2 Study of Rivoceranib and Trifluridine/Tipiracil for Metastatic Colorectal Cancer
  • Official Title: Phase 1b/2 Open-label Study to Evaluate the Safety, Tolerability and Efficacy of Rivoceranib and Trifluridine/Tipiracil as Monotherapies and as Combination Therapy in Subjects With Metastatic Colorectal Cancer

Clinical Trial IDs

  • ORG STUDY ID: RM-110
  • NCT ID: NCT04073615

Conditions

  • CRC

Interventions

DrugSynonymsArms
RivoceranibRivoceranib Mesylate, apatinib mesylateRivoceranib
Trifluridine/TipiracilLonsurfTrifluridine/tipiracil

Purpose

Comparing the efficacy of rivoceranib and trifluridine/tipiracil administered individually as monotherapies, as well as a rivocernib plus trifluridine/tipiracil combination therapy in the treatment of mCRC that is unresponsive to traditional chemotherapies.

Detailed Description

      This a multicenter open-label study comparing safety, tolerability and efficacy of
      rivoceranib monotherapy, trifluridine/tipiracil monotherapy and the combination of
      rivoceranib plus trifluridine/tipiracil in subjects with mCRC. Subjects with histologically
      or cytologically definitive adenocarcinoma of the colon or rectum who have progressed
      following standard of care therapy for colorectal cancer will be randomly assigned (1:1:2) to
      rivoceranib, trifluridine/tipiracil or rivoceranib plus trifluridine/tipiracil treatment
      groups.

      The study will consist of an initial phase 1b portion to assess the safety of and determine
      the RP2D of rivoceranib in combination with trifluridine/tipiracil. A subsequent phase 2
      portion will assess the primary endpoint of PFS by investigator assessment.
    

Trial Arms

NameTypeDescriptionInterventions
RivoceranibExperimentalRivoceranib, 700 mg po, qd
  • Rivoceranib
Trifluridine/tipiracilActive Comparator35 mg/m2 po, bid
  • Trifluridine/Tipiracil
Rivoceranib and trifluridine/tipiracilExperimentalRivoceranib, recommended phase 2 dose (RP2D) Trifluridine/Tipiracil, 35 mg/m2, po, bid
  • Rivoceranib
  • Trifluridine/Tipiracil

Eligibility Criteria

        Inclusion Criteria:

          -  Subjects are eligible to be included in the study only if all the following criteria
             apply:

        Disease related

          1. Histological or cytological confirmation of the diagnosis of mCRC

          2. Failure to respond or be intolerant of at least 2 prior regimens of standard
             anti-cancer treatments (study treatment must be 3rd-line or greater for mCRC).

             Failed prior treatments may include:

               -  Fluoropyrimidines-based chemotherapy

               -  Irinotecan-based chemotherapy

               -  Oxaliplatin-based chemotherapy

               -  Anti-Vascular Endothelial Growth Factor (VEGF) biological therapy

               -  Anti-Epidermal Growth Factor Receptor (EGFR) therapy, if RAS wild-type

               -  Immunotherapy (e.g., nivolumab, pembrolizumab and ipilimumab), in patients with
                  Microsatellite Instability High/Deficient Mismatch Repair (MSI-H/dMMR) Subjects
                  who had received adjuvant chemotherapy and had recurrence during or within 6
                  months of completion of the adjuvant chemotherapy would be considered as 1 prior
                  line of therapy

          3. Have progressed based on imaging during or within 3 months of the last administration
             of most recent standard therapy

          4. Have measurable disease, as defined by RECIST v1.1

             Laboratory

          5. Adequate bone marrow, renal, and hepatic function, as evidenced by the following
             within 7 days prior to study treatment

               -  Absolute neutrophil count (ANC) ≥1,500/mm3

               -  Platelets ≥75,000/mm3

               -  Hemoglobin ≥9.0 g/dL

               -  Creatinine clearance (according to Cockcroft-Gault Equation or by 24 hr urine
                  collection) > 50 mL/min and serum creatinine <1.0× ULN

               -  AST and ALT ≤3.0x ULN (≤5.0 × ULN for subjects with liver involvement of their
                  cancer)

               -  Bilirubin ≤1.5 × ULN

               -  Alkaline phosphatase ≤2.5 × ULN (≤5 × ULN with liver involvement of their cancer)

               -  INR/PTT ≤1.5 × ULN (Subjects currently under treatment with anti-thrombotic
                  agents such as warfarin or heparin with no abnormal coagulation values can
                  participate in this study)

          6. Urinary protein <2+ on dipstick or routine urinalysis. If urine dipstick or routine
             analysis indicates proteinuria ≥ 2+, a 24-hour urine or urine protein/creatinine ratio
             must be collected and must demonstrate <2 g of protein in 24 hours to allow
             participation in the study.

             Demographic

          7. Men and women at least 18 years of age at the time of study entry (or age of majority,
             if higher per local regulations)

          8. Have an Eastern Cooperative Oncology Group (ECOG) status of 0 or 1 Ethical/Other

          9. Able to understand and willing to provide written informed consent prior to enrollment
             in the study

         10. Female subjects who are of non-reproductive potential (i.e., post menopausal by
             history - no menses for ≥1 year; OR history of hysterectomy; OR history of bilateral
             tubal ligation; OR history of bilateral oophorectomy). Female subjects of childbearing
             potential must have a negative serum pregnancy test upon study entry.

         11. Male and female subjects of reproductive potential who agree to use both a highly
             effective method of birth control (eg, implants, injectables, combined oral
             contraceptives, some intrauterine devices, complete abstinence, or sterilized partner)
             and a barrier method (eg, condoms, cervical ring, sponge, etc.) during the period of
             therapy and for 3 months after the final dose of study drugs for male subjects and 6
             months after the final dose of study drugs for female subjects. Female subjects should
             also refrain from breastfeeding and egg donation and males should refrain from sperm
             donation throughout this period.

         12. In the assessment of the Investigator, subject is willing and able to comply with the
             protocol for the duration of the study including undergoing treatment and scheduled
             visits and examinations including follow up.

        Exclusion Criteria:

          -  Subjects will be excluded from the study if any of the following criteria apply:

        Disease-related

          1. Prior treatment with rivoceranib or trifluridine/tipiracil

          2. Prior treatment with other VEGFR small molecule inhibitors (eg, regorafenib)

          3. Packed red blood cell transfusion or erythropoietin therapy within 14 days prior to
             first dose of study drug

          4. History of another malignancy within 3 years prior to Cycle 1 Day 1. A subject with
             the following malignancies is eligible for this study if, in the opinion of the
             Investigator, they do not pose a significant risk to life expectancy:

               -  Carcinoma of the skin without melanomatous features

               -  Curatively treated cervical carcinoma in situ

               -  Bladder tumors considered superficial such as noninvasive (T1a) and carcinoma in
                  situ (Tis)

               -  Thyroid papillary cancer with prior treatment

               -  Prostate cancer which has been surgically or medically treated and not likely to
                  recur within 3 years

          5. Prior chemotherapy, radiation therapy or major surgery within 4 weeks prior to first
             dose of study drug or presence of any non-healing wound (a procedure such as catheter
             placement is not considered to be major surgery). Prior immunotherapy within 12 weeks
             prior to first dose of study drug. Palliative radiotherapy to non-target lesions
             within 2 weeks prior to first dose of study drug or biopsy within 1 week prior to
             first dose of study drug is permitted

          6. Active renal dysfunction that requires dialysis treatments

          7. Active cardiac disease including any of the following:

               -  Congestive heart failure New York Heart Association (NYHA) ≥Class 2

               -  Myocardial infarction less than 6 months before the start of Cycle 1 Day 1 of
                  treatment

          8. Cardiac arrhythmias requiring antiarrhythmic therapy (beta-blockers or digoxin are
             permitted)

          9. History of uncontrolled hypertension (blood pressure ≥140/90 mmHg and/or change in
             antihypertensive medication within 7 days prior to first dose of study drug)

         10. History of antiangiogenic drug class-related severe adverse reactions, including
             uncontrolled hypertension or others related to prior therapy discontinuation and/or
             those that may indicate a higher risk to a subject's safety, in the Investigator's
             opinion, if provided further antiangiogenic treatment.

         11. History of vascular disease including arterial or venous embolic events (pulmonary
             embolism), other than hypertension, within 6 months prior to Cycle 1 Day 1 (eg,
             hypertensive crisis, hypertensive encephalopathy, stroke or transient ischemic attack
             [TIA], or significant peripheral vascular diseases) that, in the Investigator's
             opinion, may pose a risk to the subject on VEGF inhibitor therapy.

         12. History of clinically significant thrombosis within 3 months prior to first dose of
             study drug that, in the Investigator's opinion, may place the subject at risk of side
             effects from antiangiogenics medications

         13. History of bleeding diathesis or clinically significant bleeding within 14 days prior
             to first dose of study drug

         14. Therapy with systemic anticoagulant or antithrombotic agents within 7 days prior to
             first dose of study drug that in the Investigator's opinion could interfere with
             clotting. The maximum allowable daily dose of aspirin is 325 mg

         15. Subjects with unstable seizure disorder requiring medication changes within 3 months
             of Cycle 1 Day 1 treatment

         16. Untreated or active central nervous system (CNS) or leptomeningeal metastases.
             Subjects are eligible if metastases have been treated and subjects are neurologically
             returned to baseline or neurologically stable (expect for residual signs and symptoms
             related to the CNS treatment) for at least 4 weeks prior to first dose of study drug.
             In addition, subjects must be either off corticosteroids, or on a stable dose or
             decreasing dose of ≤ 20 mg daily prednisone or prednisone-equivalent. A baseline
             radiological assessment of the brain will be performed on subjects who have prior
             history of metastases with CNS involvement

         17. History of clinically significant glomerulonephritis, biopsy-proven nephritis, crystal
             nephropathy or other renal insufficiencies

         18. Unresolved adverse reactions >Grade 1 excluding peripheral neuropathy or treatment
             related myelosuppression

         19. Known hypersensitivity to any of the study drugs, study drug classes, or any
             components of study drug formulations

         20. Inability to swallow oral medications

         21. An active malabsorption condition, or any other condition that in the opinion of the
             Investigator might affect the absorption of study drug Ethical/Other

         22. Psychiatric illness/social situations that would limit compliance with study
             requirements

         23. History of drug or alcohol abuse within past 5 years

         24. Known seropositive requiring antiviral therapy for human immunodeficiency virus (HIV)
             infection

         25. Known seropositive requiring antiviral therapy for hepatitis B virus (HBV) infection
             OR evidence of active hepatitis B infection by detectable viral load if the antibody
             tests are positive.

             NOTE: A positive-HBcAb subject with an undetectable surface antigen and negative
             hepatitis B DNA test (eg, polymerase chain reaction [PCR] test) can be enrolled

         26. Known seropositive requiring anti-viral therapy for hepatitis C virus (HCV) infection
             OR subjects with positive hepatitis C virus antibody (Ab).

             NOTE: A positive Anti-HCV subject with an undetectable/negative hepatitis C RNA test
             can be enrolled

         27. Participation in another clinical study with any investigational medication or product
             administered within 28 days prior to first dose of study drug

         28. Female subjects who are pregnant or breast-feeding

         29. Subjects unable or unwilling to discontinue excluded medications for at least 2 weeks
             prior to first dose of study drug

         30. Other serious conditions, in the Investigator's opinion
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:(Phase 1b) Determine Recommended Phase 2 Dose (RP2D)
Time Frame:3-6 months
Safety Issue:
Description:Determine RP2D of rivoceranib when used in combination with trifluridine/tipiracil in subjects with mCRC

Secondary Outcome Measures

Measure:(Phase 1b) OS
Time Frame:3-6 months
Safety Issue:
Description:Determine the overall survival (OS) in subjects with mCRC taking rivoceranib in combination with trifluridine/tipiracil
Measure:(Phase 1b) Safety Assessments
Time Frame:3-6 months
Safety Issue:
Description:Evaluate safety and tolerability (eg, new AEs, AEs present at baseline that worsen in severity during the study, and clinically significant laboratory abnormalities) of rivoceranib when used in combination with trifluridine/tipiracil in subjects with mCRC
Measure:(Phase 2) OS
Time Frame:30-33 months
Safety Issue:
Description:Determine the overall survival (OS) in subjects with mCRC taking rivoceranib in combination with trifluridine/tipiracil
Measure:(Phase 2) PFS
Time Frame:30-33 months
Safety Issue:
Description:Determine the Progression Free Survival (PFS) in subjects with mCRC taking rivoceranib in combination with trifluridine/tipiracil
Measure:(Phase 2) ORR
Time Frame:30-33 months
Safety Issue:
Description:The Overall Response Rate (ORR) (complete response [CR] + partial response [PR] per RECIST v1.1 in subjects with mCRC taking rivoceranib in combination with trifluridine/tipiracil
Measure:(Phase 2) DCR
Time Frame:30-33 months
Safety Issue:
Description:The Disease Control Rate (DCR) (CR + PR + stable disease) per RECIST v1.1 in subjects with mCRC taking rivoceranib in combination with trifluridine/tipiracil
Measure:(Phase 2) Safety assessments
Time Frame:30-33 months
Safety Issue:
Description:Evaluate safety and tolerability (eg, new AEs, AEs present at baseline that worsen in severity during the study, and clinically significant laboratory abnormalities) of rivoceranib when used in combination with trifluridine/tipiracil in subjects with mCRC

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:LSK BioPartners Inc.

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