Clinical Trials /

Cabozantinib in Combination With Cetuximab in Patients With Recurrent or Metastatic Head and Neck Squamous Cell Cancer

NCT03667482

Description:

The purpose of this study is to test the safety of cabozantinib, at different doses, in combination with cetuximab to find out what effects, if any, this combined treatment has on people with HNSCC.

Related Conditions:
  • Head and Neck Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Cabozantinib in Combination With Cetuximab in Patients With Recurrent or Metastatic Head and Neck Squamous Cell Cancer
  • Official Title: A Phase 1 Study of Concurrent Cabozantinib and Cetuximab in Recurrent or Metastatic Head and Neck Squamous Cell Cancer

Clinical Trial IDs

  • ORG STUDY ID: 18-303
  • NCT ID: NCT03667482

Conditions

  • Head and Neck Squamous Cell Cancer
  • Recurrent Head and Neck Squamous Cell Cancer
  • Metastatic Head and Neck Squamous Cell Cancer

Interventions

DrugSynonymsArms
CabozantinibCabozantinib in Combination With Cetuximab
CetuximabCabozantinib in Combination With Cetuximab

Purpose

The purpose of this study is to test the safety of cabozantinib, at different doses, in combination with cetuximab to find out what effects, if any, this combined treatment has on people with HNSCC.

Trial Arms

NameTypeDescriptionInterventions
Cabozantinib in Combination With CetuximabExperimentalTreatment will be initiated with a 400 mg/m2 loading dose of cetuximab followed by 240 mg/m2 cetuximab IV weekly. Cabozantinib will be initiated at 40 mg PO daily, with subsequent 20 mg or 40 mg doses as tolerated per the study design.
  • Cabozantinib
  • Cetuximab

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically or cytologically confirmed diagnosis of squamous cell carcinoma of the
             head and neck.

          -  Disease must be considered incurable. Incurable is defined as metastatic disease or a
             local or regional recurrence in a previously irradiated site that is unresectable (or
             patient declines resection).

          -  Measurable disease defined as lesions that can be accurately measured in at least one
             dimension (longest diameter to be recorded) as >10 mm with CT scan, as >20 mm by chest
             x-ray, or >10 mm with calipers by clinical exam.

          -  Patients in the expansion phase (only) must be cetuximab refractory. Cetuximab
             refractory patients are those who have received either single agent cetuximab or
             cetuximab in combination with chemotherapy and have progressed after treatment.

          -  Cetuximab refractory patients are those who have received either single agent
             cetuximab or cetuximab in combination with chemotherapy and have progressed after
             treatment.

          -  Measurable disease per RECIST v1.1 as determined by the investigator;

          -  The subject has had an assessment of all known disease sites e.g., by computerized
             tomography (CT) scan, magnetic resonance imaging (MRI), bone scan as appropriate,
             within 28 days before the first dose of cabozantinib.

          -  The subject is ≥ 18 years old on the day of consent.

          -  The subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0
             or 1.

          -  Recovery to baseline or ≤ Grade 1 CTCAE v.5.0 from toxicities related to any prior
             treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive
             therapy.

          -  The subject has organ and marrow function and laboratory values as follows within 14
             days before the first dose of cabozantinib.

               1. The ANC ≥ 1500/mm3 without colony stimulating factor support.

               2. White blood cell count ≥ 2500/mm3 (≥ 2.5 GI/L).

               3. Platelets ≥ 100,000/mm3;

               4. Hemoglobin ≥ 9 g/dL;

               5. Bilirubin ≤ 1.5 x the ULN. For subjects with known Gilbert's disease, bilirubin ≤
                  3.0 mg/dL;

               6. Albumin ≥ 2.8 g/dl;

               7. Creatinine ≤ 2.0 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min. For creatinine
                  clearance estimation, the Cockcroft and Gault equation should be used:

             i. Male: CrCl (mL/min) = (140 - age) × wt (kg) / (creatinine × 72); h. Female:
             Multiply above result by 0.85; Alanine aminotransferase (ALT), aspartate
             aminotransferase (AST), and alkaline phosphatase (ALP) ≤ 3 x upper limit of normal
             (ULN). ALP ≤ 5 x ULN with documented bone metastases.

             i. Lipase < 2.0 x the upper limit of normal and no radiologic or clinical evidence of
             pancreatitis.

             j. UPCR ≤ 1. k. Phosphorus, calcium, magnesium and potassium ≥ LLN.

          -  The subject is capable of understanding and complying with the protocol requirements
             and has signed the informed consent document;

          -  Sexually active subjects (men and women) must agree to use medically accepted barrier
             methods of contraception (e.g., male or female condom) during the course of the study
             and for 4 months after the last dose of study drug(s), even if oral contraceptives are
             also used. All subjects of reproductive potential must agree to use both a barrier
             method and a second method of birth control during the course of the study and for 4
             months after the last dose of study drug(s).

          -  Female subjects of childbearing potential must not be pregnant at screening. Females
             of childbearing potential are defined as premenopausal females capable of becoming
             pregnant (i.e., females who have had any evidence of menses in the past 12 months,
             with the exception of those who had prior hysterectomy). However, women who have been
             amenorrheic for 12 or more months are still considered to be of childbearing potential
             if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, low body
             weight, ovarian suppression or other reasons.

          -  No Grade 3-4 hypersensitivity reaction to cetuximab.

        Exclusion Criteria:

          -  Any patient with incurable disease who has not received cetuximab (for expansion phase
             portion of study only).

          -  Any patient who has received >70 Gy of XRT to the neck in the same radiation field. No
             head and neck radiation within 2 months prior to initiation. Treatment areas should be
             healed with no sequelae from RT that would predispose to fistula formation.

          -  A history of other malignancy ≤ 5 years previous with the exception of basal cell or
             squamous cell carcinoma of the skin which were treated with local resection only,
             carcinoma in situ of the cervix, synchronous H&N primaries or low grade tumors deemed
             cured and not treated with systemic therapy. Other cancers that will not affect the
             study outcome may be included with the consent of the PI (Dr. Michel) as long as it
             would not affect the study outcome (e.g., low grade prostate cancer on surveillance
             alone).

          -  Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy
             (including investigational) within 4 weeks before first dose of study treatment with
             the exception of cetuximab and small molecule kinase inhibitors (kinase inhibitors
             must be stopped within 2 weeks of first dose of study treatment.

          -  Prior treatment with cabozantinib.

          -  Radiation therapy for bone metastasis within 2 weeks, any other external radiation
             therapy within 4 weeks before the 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.;

          -  Receipt of any type of small molecule kinase inhibitor (including investigational
             kinase inhibitor) within 14 days before the first dose of study treatment. Note:
             Subjects with prostate cancer currently receiving LHRH or GnRH agonists may be
             maintained on these agents.

          -  The subject has received any other type of investigational agent within 28 days before
             the 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
             before the first dose of study treatment. Eligible subjects must be neurologically
             asymptomatic and without corticosteroid treatment at the time of the start of study
             treatment.

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

          -  Concomitant anticoagulation with oral anticoagulants (e.g., warfarin, direct thrombin
             and Factor Xa inhibitors) or platelet inhibitors (e.g., clopidogrel).

        Allowed anticoagulants are the following:

          1. Low-dose aspirin for cardioprotection (per local applicable guidelines) is permitted.

          2. Low-dose low molecular weight heparins (LMWH) are permitted.

          3. Anticoagulation with therapeutic doses of LMWH is allowed in subjects without known
             brain metastases who are on a stable dose of LMWH for at least 6 weeks before first
             dose of study treatment, and who have had no clinically significant hemorrhagic
             complications from the anticoagulation regimen or the tumor.

               -  The subject has experienced any of the following:

        a. clinically-significant GI bleeding within 6 months before the first dose of study
        treatment; b. hemoptysis of ≥ 0.5 teaspoon (2.5ml) of red blood within 3 months before the
        first dose of study treatment;

          -  Any other signs indicative of pulmonary hemorrhage within 3 months before the first
             dose of study treatment. 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.

          -  The subject has radiographic evidence of cavitating pulmonary lesion(s);

          -  The subject has tumor invading or encasing any major blood vessels.

          -  The subject has evidence of tumor invading the GI tract (esophagus, stomach, small or
             large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor
             within 28 days before the first dose of cabozantinib.

          -  Known brain metastases or cranial epidural disease unless adequately treated with
             radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks
             before the first dose of study treatment. Eligible subjects must be neurologically
             asymptomatic and without corticosteroid treatment at the time of the start of study
             treatment.

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

          -  Concomitant anticoagulation with oral anticoagulants (e.g., warfarin, direct thrombin
             and Factor Xa inhibitors) or platelet inhibitors (e.g., clopidogrel). Allowed
             anticoagulants are the following:

               1. Low-dose aspirin for cardioprotection (per local applicable guidelines) is
                  permitted.

               2. Low-dose low molecular weight heparins (LMWH) are permitted.

               3. Anticoagulation with therapeutic doses of LMWH is allowed in subjects without
                  known brain metastases who are on a stable dose of LMWH for at least 6 weeks
                  before first dose of study treatment, and who have had no clinically significant
                  hemorrhagic complications from the anticoagulation regimen or the tumor.

          -  The subject has experienced any of the following:

               1. clinically-significant GI bleeding within 6 months before the first dose of study
                  treatment;

               2. hemoptysis of ≥ 0.5 teaspoon (2.5ml) of red blood within 3 months before the
                  first dose of study treatment;

          -  any other signs indicative of pulmonary hemorrhage within 3 months before the first
             dose of study treatment. 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.

          -  The subject has radiographic evidence of cavitating pulmonary lesion(s).

          -  The subject has tumor invading or encasing any major blood vessels.

          -  The subject has evidence of tumor invading the GI tract (esophagus, stomach, small or
             large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor
             within 28 days before the first dose of cabozantinib.

          -  The subject has uncontrolled, significant intercurrent or recent illness including,
             but not limited to, the following conditions:

             a. Cardiovascular disorders including: i. Congestive heart failure (CHF): New York
             Heart Association (NYHA) Class III (moderate) or Class IV (severe) at the time of
             screening; ii. Concurrent uncontrolled hypertension defined as sustained blood
             pressure (BP) > 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal
             antihypertensive treatment within 7 days of the first dose of study treatment; iii.
             Any history of congenital long QT syndrome; iv. Any of the following within 6 months
             before the first dose of study

               -  treatment: unstable angina pectoris;

               -  clinically-significant cardiac arrhythmias;

               -  stroke (including transient ischemic attack (TIA), or other ischemic event);

               -  myocardial infarction;

               -  thromboembolic event requiring therapeutic anticoagulation (Note: subjects with a
                  venous filter (e.g., vena cava filter) are not eligible for this study).

          -  GI disorders particularly those associated with a high risk of perforation or fistula
             formation including: i. Tumors invading the GI tract, active peptic ulcer disease,
             inflammatory bowel disease (e.g., Crohn's disease), diverticulitis, cholecystitis,
             symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of
             the pancreatic duct or common bile duct, or gastric outlet obstruction. Abdominal
             fistula, GI perforation, bowel obstruction, intra-abdominal abscess within 6 months
             before randomization

               -  Note: Complete healing of an intra-abdominal abscess must be confirmed prior to
                  randomization ii.

        ii. No pre-existing fistula of the head and neck. No pre-existing osteonecrosis of the jaw.

          -  Other clinically significant disorders that would preclude safe study participation;

          -  Major surgery (e.g., GI surgery, removal or biopsy of brain metastasis) within 8 weeks
             before first dose of study treatment. Complete wound healing from major surgery must
             have occurred 1 month before first dose and from minor surgery (e.g., simple excision,
             tooth extraction) at least 10 days before first dose. Subjects with clinically
             relevant ongoing complications from prior surgery are not eligible.

          -  QTcF > 500 msec within 1 month before the first dose of study treatment:

             a. Three ECGs must be performed for eligibility determination. If the average of these
             three consecutive results for QTcF is ≤ 500 msec, the subject meets eligibility in
             this regard.

          -  Pregnant or lactating females;

          -  Inability to swallow intact tablets;

          -  Previously identified allergy or hypersensitivity to components of the study treatment
             formulations;

          -  The subject requires chronic concomitant treatment with strong CYP3A4 inducers (e.g.,
             phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St.

        John's Wort).

          -  Other clinically significant disorders that would preclude safe study participation.

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

               2. Symptomatic hypothyroidism.

               3. Moderate to severe hepatic impairment (Child-Pugh B or C).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:maximum tolerated dose (MTD)
Time Frame:2 years
Safety Issue:
Description:from 3 testing dose levels: 20, 40, and 60. Three patients will be enrolled at the dose level 0 of 40 mg. The dose escalation scheme is as follows: If none of the initial three patients at a given dose level experience DLT within 4 weeks, the next dose level will be studied. If one of the initial three patients at a given dose level experiences DLT, three additional patients will be treated at the same dose level. Escalation will continue only if there is no additional DLT observed.If two or more patients experience DLT at a given dose, the previous dose level will be studied. Should two or more patients experience the DLT at the lowest dose level (20 mg), the study will be halted, and alternative dosing will be considered. 4. The highest dose level with no more than one DLT among six patients will be declared as the MTD. If only three patients were treated at a dose under consideration as the MTD, an additional three patients will be treated at that level.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Memorial Sloan Kettering Cancer Center

Trial Keywords

  • Cabozantinib
  • Cetuximab
  • 18-303

Last Updated