Clinical Trials /

Study of Cabozantinib Plus TAS102 in mCRC as Salvage Therapy

NCT04868773

Description:

This is a phase I clinical trial assessing the safety and recommended phase II dose of cabozantinib in combination with trifluridine/tipiracil (TAS102) in patients with metastatic colorectal carcinoma (mCRC).

Related Conditions:
  • Colorectal Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of Cabozantinib Plus TAS102 in mCRC as Salvage Therapy
  • Official Title: A Phase 1 Study of the Combination of Cabozantinib With Trifluridine/Tipiracil (TAS-102) in Patients With Metastatic Colorectal Adenocarcinoma (mCRC)

Clinical Trial IDs

  • ORG STUDY ID: UCI 20-134 [HS# 2021-6481]
  • SECONDARY ID: 2021-6481
  • NCT ID: NCT04868773

Conditions

  • Colorectal Cancer
  • Colorectal Carcinoma
  • Metastatic Cancer
  • CRC

Interventions

DrugSynonymsArms
CabozantinibCABOMETYX®, COMETRIQCabozantinib in Combination with TAS-102 (trifluridine/tipiracil)
TAS-102trifluridine and tipiracilCabozantinib in Combination with TAS-102 (trifluridine/tipiracil)

Purpose

This is a phase I clinical trial assessing the safety and recommended phase II dose of cabozantinib in combination with trifluridine/tipiracil (TAS102) in patients with metastatic colorectal carcinoma (mCRC).

Detailed Description

      Patients with histologically proven colorectal adenocarcinoma not amenable to curative
      treatment will be eligible to participate for this study. After meeting the eligibility
      criteria, patients will be given a IP regimen consisting of cabozantinib 20 - 40 mg given
      orally everyday for 28 days, trifluridine/tipiracil (TAS102) 25 - 35 mg/m2 on Days 1 - 5 and
      Days 8 - 12 every 28 days, and peg-filgrastim 6 mg subcutaneously on Day 13 every 28 days.
      Tumor assessments will be completed by CT/MRI every 8 weeks during the first year of
      treatment and every 3 months after the first year until patient comes off treatment.
    

Trial Arms

NameTypeDescriptionInterventions
Cabozantinib in Combination with TAS-102 (trifluridine/tipiracil)ExperimentalSubjects will receive cabozantinib in combination with TAS-102. Patients will receive cabozantinib on Days 1 - 28 and TAS-102 on Days 1-5 and Days 8-12, for a cycle length of 28 days.
  • Cabozantinib
  • TAS-102

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically or cytologically confirmed colorectal adenocarcinoma

          -  Must have locally advanced, recurrent, or metastatic disease not amenable to curative
             intent surgery or radiation.

          -  Must have progressed, or not tolerated, a fluoropyrimidine, irinotecan, oxaliplatin,
             and cetuximab or panitumumab (only for RAS wild-type). Prior exposure to bevacizumab
             or ramucirumab is allowed. Patients who have exhausted all other standard of care
             options are also eligible.

          -  Age ≥ 18 years

          -  Performance status: ECOG performance status ≤2 (Appendix A).

          -  Life expectancy of greater than 3 months

          -  Adequate organ and marrow function as defined below:

               1. leukocytes ≥ 3,000/mcL

               2. absolute neutrophil count ≥ 1,500/mcL

               3. platelets ≥ 100,000/mcl

               4. total bilirubin within normal institutional limits

               5. AST(SGOT)/ALT(SPGT) ≤ 3 X institutional upper limit of normal or ≤ 5 X if liver
                  metastases are present

               6. creatinine <1.5 ULN

               7. hemoglobin ≥ 8 g/dL

               8. Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg

               9. (PT)/INR or partial thromboplastin time (PTT) test < 1.3 x ULN

          -  The effects of cabozantinib on the developing human fetus at the recommended
             therapeutic dose are unknown. For this reason, women of child-bearing potential and
             men must agree to use adequate contraception (hormonal or barrier method of birth
             control; abstinence) prior to study entry, for the duration of study participation,
             and for 4 months following completion of therapy. Should a woman become pregnant or
             suspect she is pregnant while participating in this study, she should inform her
             treating physician immediately.

             1. A female of child-bearing potential is any woman (regardless of sexual orientation,
             having undergone a tubal ligation, or remaining celibate by choice) who meets the
             following criteria: Has not undergone a hysterectomy or bilateral oophorectomy; or has
             not been naturally postmenopausal for at least 12 consecutive months (i.e., has had
             menses at any time in the preceding 12 consecutive months).

          -  Ability to swallow tablets

          -  Ability to understand and the willingness to sign a written informed consent.

        Exclusion Criteria:

          -  Patients who have chemotherapy within 2 weeks prior to entering the study

          -  All toxicities attributed to prior anti-cancer therapy other than alopecia must have
             resolved to grade 1 or baseline

          -  Patients may not be receiving any other investigational agents.

          -  Receipt of any type of small molecule kinase inhibitor (including investigational
             kinase inhibitor) within 2 weeks before first dose of study treatment.

          -  Known brain metastases or cranial epidural disease unless adequately treated with
             radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks
             prior to first dose of study treatment after radiotherapy or at least 4 weeks prior to
             first dose of study treatment after major surgery (e.g., removal or biopsy of brain
             metastasis). Subjects must have complete wound healing from major surgery or minor
             surgery before first dose of study treatment. Eligible subjects must be neurologically
             asymptomatic and without corticosteroid treatment at the time of first dose of study
             treatment.

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to TAS-102, cabozantinib or other agents used in study.

          -  Uncontrolled intercurrent illness including, but not limited to, the following
             conditions:

               1. ongoing or active infection

               2. Cardiovascular disorders: Congestive heart failure New York Heart Association
                  Class 3 or 4, unstable angina pectoris, serious cardiac arrhythmias; uncontrolled
                  hypertension defined as sustained blood pressure (BP) > 140 mm Hg systolic or >
                  90 mm Hg diastolic despite optimal antihypertensive treatment; Stroke (including
                  transient ischemic attack [TIA]), myocardial infarction (MI), or other ischemic
                  event, or thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism)
                  within 6 months before first dose. Subjects with a diagnosis of incidental,
                  subsegmental PE or DVT within 6 months are allowed if stable, asymptomatic, and
                  treated with a stable dose of permitted anticoagulation (see exclusion criterion
                  #3.2.8) for at least 1 week before first dose of study treatment.

               3. Gastrointestinal (GI) disorders including those associated with a high risk of
                  perforation or fistula formation:The subject has evidence of tumor invading the
                  GI tract, active peptic ulcer disease, inflammatory bowel disease (e.g., Crohn's
                  disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis,
                  acute pancreatitis, acute obstruction of the pancreatic duct or common bile duct,
                  or gastric outlet obstruction. Abdominal fistula, GI perforation, bowel
                  obstruction, or intra-abdominal abscess within 6 months before first dose of
                  study treatment. Note: Complete healing of an intra-abdominal abscess must be
                  confirmed before first dose of study treatment.

               4. Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon
                  (2.5 ml) of red blood, or other history of significant bleeding (e.g., pulmonary
                  hemorrhage) within 12 weeks before first dose of study treatment.

               5. Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease
                  manifestation.

               6. Lesions invading any major blood vessels. Subjects with lesions invading the
                  intrahepatic vasculature, including portal vein, hepatic vein, and hepatic
                  artery, are eligible.

               7. Other clinically significant disorders that would preclude safe study
                  participation:

               1. Active infection requiring systemic treatment (based on investigator assessment).
                  Acute or chronic hepatitis B or C infection, known human immunodeficiency virus
                  (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness, or known
                  positive test for tuberculosis infection where there is clinical or radiographic
                  evidence of active mycobacterial infection.

               2. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced
                  pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on
                  screening chest CT scan.

               3. Serious non-healing wound/ulcer/bone fracture

               4. Malabsorption syndrome

               5. Uncompensated/symptomatic hypothyroidism

               6. Moderate to severe hepatic impairment (Child-Pugh B or C)

               7. Requirement for hemodialysis or peritoneal dialysis

               8. History of solid organ or allogenic stem cell transplant

          -  Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin
             inhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or platelet
             inhibitors (e.g., clopidogrel). Allowed anticoagulants are the following:

               1. Prophylactic use of low-dose aspirin for cardio-protection (per local applicable
                  guidelines) and low-dose low molecular weight heparins (LMWH).

               2. Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors
                  rivaroxaban, edoxaban, or apixaban in subjects without known brain metastases who
                  are on a stable dose of the anticoagulant for at least 1 week before first dose
                  of study treatment without clinically significant hemorrhagic complications from
                  the anticoagulation regimen or the tumor.

          -  The subject has prothrombin time (PT)/INR or partial thromboplastin time (PTT) test ≥
             1.5 x the laboratory ULN within 7 days before the first dose of study treatment.

          -  Major surgery (e.g., laparoscopic nephrectomy, GI surgery, removal or biopsy of brain
             metastasis) within 2 weeks before first dose of study treatment. Minor surgeries
             within 10 days before first dose. Subjects must have complete wound healing from major
             surgery or minor surgery before first dose of study treatment. Subjects with
             clinically relevant ongoing complications from prior surgery are not eligible.

          -  Prior treatment with cabozantinib

          -  Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per
             electrocardiogram (ECG) within 14 days before first dose of study treatment.
             Furthermore, subjects with a history of additional risk factors for torsades de
             pointes (e.g., long QT syndrome) are also excluded. Note: If a single ECG shows a QTcF
             with an absolute value > 500 ms, two additional ECGs at intervals of approximately 3
             min must be performed within 30 min after the initial ECG, and the average of these
             three consecutive results for QTcF will be used to determine eligibility.

        Corrected QT (QTc) = QT / ∛RR QT: duration of QT interval RR: duration of RR interval

          -  History of another primary cancer within the last 3 years with the exception of
             non-melanoma skin cancer, early-stage prostate cancer, or curatively treated cervical
             carcinoma in-situ.

          -  Inability to comply with study and follow-up procedures as judged by the Investigator

          -  Radiation therapy for bone metastasis within 2 weeks, any other radiation therapy
             within 4 weeks before first dose of study treatment. Systemic treatment with
             radionuclides within 6 weeks before the first dose of study treatment. Subjects with
             clinically relevant ongoing complications from prior radiation therapy are not
             eligible.

          -  Has received a live vaccine within 30 days prior to the first dose of study
             intervention.

          -  Has severe hypersensitivity (Grade ≥ 3) to TAS-102 or cabozantinib and/or any of their
             excipients.

          -  Has a history or current evidence of any condition (eg, known deficiency of the enzyme
             dihydropyrimidine dehydrogenase), therapy, or laboratory abnormality that might
             confound the results of the study, interfere with the participant's participation for
             the full duration of the study, or is not in the best interest of the participant to
             participate, in the opinion of the treating investigator.

          -  Pregnant or lactating females.

          -  Previously identified allergy or hypersensitivity to components of the study treatment
             formulations or history of severe infusion-related reactions to monoclonal antibodies.
             Subjects with rare hereditary problems of galactose intolerance, the Lapp lactase
             deficiency or glucose-galactose malabsorption are also excluded.
      
Maximum Eligible Age:100 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose Limiting Toxicity [DLT]
Time Frame:From the start date of treatment until 4 weeks after the last patient has started treatment, an average of 1 year.
Safety Issue:
Description:To determine the Dose Limiting Toxicity (DLT) at Cycle 1 Day 28. A DLT is defined as the occurrence of specific toxicities within the DLT treatment period if judged by the Investigator to be possibly, probably, or definitely related to cabozantinib or TAS-102.

Secondary Outcome Measures

Measure:Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
Time Frame:From the start date of treatment until 4 weeks after removal of treatment due to disease progression, toxicity, delay of treatment, or withdrawal of treatment, whichever came first, an average of 1 year.
Safety Issue:
Description:To evaluate the tolerability of administering cabozantinib in combination with TAS-102 in patients with metastatic colorectal cancer from the start of treatment, duration of treatment and up to 4 weeks after completion of study treatment. Toxicity and adverse events are based on the CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 5.0.
Measure:Progression-Free Survival of Patients who Received Cabozantinib with TAS-102
Time Frame:From the start date of treatment until 4 weeks after removal of treatment due to disease progression, toxicity, delay of treatment, or withdrawal of treatment, whichever came first, an average of 1 year.
Safety Issue:
Description:Progression-free survival (PFS) is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.
Measure:Overall Survival of Patients who Received Cabozantinib with TAS-102
Time Frame:From date of registration for up to 18 months after last patient is enrolled or until death from any cause, whichever came first
Safety Issue:
Description:To evaluate overall survival in patients with metastatic colorectal cancer receiving cabozantinib in combination with TAS-102.
Measure:Number of Participants with Objective Response Rate
Time Frame:From the start date of treatment until 4 weeks after removal of treatment due to disease progression, toxicity, delay of treatment, or withdrawal of treatment, whichever came first, an average of 1 year.
Safety Issue:
Description:The ORR is determined by Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) in patients with measurable disease, progression-free, safety regardless of grade and overall survival.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of California, Irvine

Last Updated

July 21, 2021