A Broad Multi-histology Phase II Study of the Multi-Kinase Inhibitor R935788 (Fostamatinib Disodium) in Advanced Colorectal, Non-small Cell Lung, Head and Neck Hepatocellular and Renal Cell Carcinomas, and Pheochromocytoma and Thyroid Tumors (Multi-H...
Condition: Head and Neck Neoplasms; Pheochromocytoma; Colorectal Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma, Renal Cell
MeSH terms: Carcinoma; Neoplasms; Carcinoma, Renal Cell; Colorectal Neoplasms; Carcinoma, Non-Small-Cell Lung; Head and Neck Neoplasms; Pheochromocytoma
Intervention: Fostamatinib disodium
Intervention description: 200 mg BID was the administered dose for the initial part of the study and then a phase I dose escalation was added with 100 mg as the starting dose.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 37.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Multi-Kinase Inhibitor; Neoplasms; Advanced Cancer; Kidney Cancer; Liver Cancer; Pheochromocytoma; Non-Small Cell Lung Cancer; Colorectal Cancer; Head and Neck Cancer

Summary:

      Background:

        -  The drug R935788 (fostamatanib disodium) is a kinase inhibitor (i.e., it interferes with
           cell communication and growth and may prevent tumor growth).

        -  R935788 has shown promising activity in NCI-60 (a panel of 60 diverse human cancer cell
           lines) against colon cancer, non-small cell lung cancer, and renal cell carcinoma cell
           lines, as well as in two renal cell xenograft models.

        -  This is an open-label, Phase II study of R935788. Phase I studies in patients with
           immune thrombocytopenic purpura, rheumatoid arthritis, and lymphoma have demonstrated
           safety with a continuous dosing schedule, and a maximum tolerated dose has been
           established.

      Objectives:

        -  To test an experimental drug called R935788 (fostamatinib disodium) for its ability to
           stop cancer growth signals, thus slowing the growth of cancer cells in laboratory
           testing.

        -  To determine the clinical response of R935788 administered orally twice a day on a
           continuous schedule in patients with colorectal carcinoma, pheochromocytoma, follicular
           or papillary thyroid cancer, non-small cell lung cancer, hepatocellular, carcinoma of
           the head and neck, and renal cell carcinoma.

        -  To evaluate the effects, safety, and biochemical response of R935788 therapy.

      Eligibility:

        -  Patients with colorectal carcinoma, pheochromocytoma, follicular or papillary thyroid
           cancer, non-small cell lung cancer (excluding squamous cell histology), hepatocellular
           cancer, carcinoma of the head and neck, and renal cell carcinoma whose disease has
           progressed after any therapy or who have no acceptable standard treatment options.

        -  Patients must have recovered from toxicities of prior therapies to at least eligibility
           levels.

        -  Patients who have received radiation or chemotherapy within 4 weeks of study enrollment
           are not eligible.

        -  Women who are pregnant or breastfeeding are not eligible.

      Design:

        -  Researchers will conduct the following tests and procedures during the study:

             -  Clinic visits with a physical exam, including vital signs and blood pressure, every
                other week during cycle 1, and once a month starting with cycle 2.

             -  Blood will be drawn weekly during cycle 1, every other week during cycle 2, and
                once a month starting with cycle 3; urine tests will be conducted depending on
                results of blood tests.

             -  Imaging tests, such as computed tomography (CT) scans (a series of x-rays) or
                ultrasound (an examination using sound waves), will be done every 8 weeks while the
                patient is receiving R935788.

        -  R935788 will be administered orally twice a day for 28 days (one cycle). Imaging studies
           will be obtained every two cycles. Patients will fill in a diary to show when they took
           the medication and to note any side effects. The 28-day treatment cycle will be repeated
           as long as the patient is tolerating R935788 and the cancer is either stable or getting
           better.

        -  Researchers will conduct the following additional tests to see how the study is
           affecting the patient:

             -  Other research blood samples will be collected before treatment, at cycle 1 week 3,
                at the beginning of cycle 2, and at 8 weeks.

             -  Optional tumor biopsies will be requested before starting treatment, at cycle 1 day
                28.

             -  Patients with specific lesions or tumors may be asked for an optional tumor biopsy
                on day 8.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  3.1.1 Subjects must have histologically documented solid tumors: pheochromocytoma,
             follicular or papillary thyroid, colorectal, non-small cell lung (excluding squamous
             cell histology), hepatocellular, head and neck or renal cell origin, whose disease has
             progressed after any number of prior therapies or who have no acceptable standard
             treatment options.

          -  Patients with follicular or papillary thyroid cancer will be eligible if they have
             metastatic or unresectable, locally advanced disease which is refractory to, or not
             suitable for, I therapy.

          -  Diagnosis of malignancy must be confirmed by the Laboratory of Pathology at the
             Clinical Center, National Institutes of Health (NIH), prior to patient enrollment.

          -  3.1.2 Patients must have measurable disease, defined as at least one lesion that can
             be accurately measured in at least one dimension (longest diameter to be recorded) as
             greater than or equal to 20 mm with conventional techniques or as greater than or
             equal to 10 mm with spiral computed tomography (CT) scan.

          -  3.1.3 Life expectancy of greater than 3 months.

          -  3.1.4 Eastern Cooperative Oncology Group (ECOG) performance status less than or equal
             to 2 (Karnofsky greater than or equal to 60%).

          -  3.1.5 Subjects must have normal organ and marrow function as defined below:

          -  absolute neutrophil count greater than or equal to 1,500/mcL

          -  platelets greater than or equal to 100,000/mcL

          -  total bilirubin within less than or equal to 1.5 institutional upper limit of normal
             (ULN)

          -  aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase(SGOT),alanine
             aminotransferase (ALT)/serum glutamic pyruvic transaminase(SGPT) less than or equal to
             2.5 times ULN

          -  creatinine < 1.5 times ULN

        OR

          -  creatinine clearance greater than or equal to 60 mL/min/1.73 m^2 for patients with
             creatinine levels greater than or equal to 1.5 times institutional upper limit of
             normal.

          -  3.1.6 The effects of R935788 on the developing human fetus 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 or abstinence) prior to
             study entry, for the duration of study participation, and for 1 month after
             discontinuation of the study. Women of child bearing potential must have a negative
             pregnancy test in order to be eligible. Should a participant or a participant's
             partner become pregnant or suspect she is pregnant while participating in this study,
             the participant should inform the Research Team immediately.

          -  3.1.7 Ability to understand and the willingness to sign a written informed consent
             document.

          -  3.1.8 Age greater than or equal to 18 years. Because no dosing or adverse event data
             are currently available on the use of R935788 in patients < 18 years of age, children
             are excluded from this study, but may be eligible for future pediatric Phase I trials.

          -  3.1.9 Patients with diagnosis of hypertension should have their blood pressure
             adequately controlled by medical therapy (adequate control of hypertension for the
             purposes of this trial is defined as systolic blood pressure < 150 mmHg or diastolic
             pressure < 90 mmHg).

          -  3.1.10 Patients with head and neck cancer who are unable to swallow and who are
             gastrostomy tube (G-tube) dependent will have the tablets dissolved in water or orange
             juice followed by a free water or orange juice flush.

        EXCLUSION CRITERIA:

          -  3.2.1 Subjects who have had chemotherapy, biotherapy, or radiotherapy within 4 weeks
             prior to entering the study, or those who have not recovered from adverse events due
             to prior therapy.

          -  A time period of greater than or equal to 2 weeks must have elapsed since a patient
             was administered any investigational agent as part of a Phase 0 study (also referred
             to as an early Phase I study or pre-Phase I study where a sub-therapeutic dose of drug
             is administered) at the principal investigator's (PI's) discretion, and patients
             should have recovered from any toxicity from prior therapy to eligibility levels.

          -  3.2.2 Patients must not have other current malignancies, other than basal cell skin
             cancer, squamous cell skin cancer, in situ cervical cancer, ductal or lobular
             carcinoma in situ of the breast.

          -  Patients who have undergone primary therapy for a prior diagnosis of cancer and are
             disease free for at least 3 years prior to study entry will be included in the trial.

          -  3.2.3 Patients may not be receiving any other investigational agents.

          -  3.2.4 Subjects with known brain metastases are excluded with the exception of those
             whose brain metastatic disease status has remained stable for at least 3 months since
             treatment of the brain metastases without steroids (except for maintenance replacement
             doses) or antiseizure medications.

          -  Patients cannot be taking enzyme-inducing anti-seizure medications (e.g., phenytoin,
             carbamazepine, phenobarbital, primidone, oxcarbamazepine); other seizure medications
             that are not considered enzyme-inducing would be permissible.

          -  3.2.5 Because there is an unknown but potential risk for adverse events in nursing
             infants secondary to exposure to this agent, women who are breast feeding are
             ineligible for this study.

          -  3.2.6 Patients receiving medications known to induce/inhibit cytochrome P450 3A4
             (CYP3A4) will be excluded from this study.

          -  Patients who must initiate treatment with a CYP3A4 inhibitor while receiving R935788
             will be carefully monitored.

          -  Inhibitors of CYP3A4 include but are not limited to:

          -  amiodarone,

          -  clarithromycin,

          -  erythromycin,

          -  imatinib,

          -  troleandomycin,

          -  ritonavir,

          -  indinavir,

          -  fluconazole,

          -  itraconazole,

          -  and ketoconazole.

          -  Patients should also avoid grapefruit and grapefruit juice during participation in the
             study.

          -  Patients will also be required to keep a study diary to record any side effects that
             occur during the study and any other medications taken.

          -  3.2.7 Subjects with clinically significant illnesses which would compromise
             participation in the study, including, but not limited to: unstable or serious medical
             conditions (ongoing or active infection, symptomatic congestive heart failure [AHA
             Class II or worse], unstable angina pectoris, cardiac arrhythmia, or psychiatric
             illness/social situations that would limit compliance with study requirements) are
             excluded due to the possibility that the underlying condition may obscure the
             attribution of effect and adverse events with respect to the study medication and may
             limit study compliance.

          -  3.2.8 Patients with hepatocellular cancer (HCC) may have underlying chronic infectious
             hepatitis as long as there is no evidence of hepatic failure and they meet the
             eligibility criteria.

          -  3.2.9 Human immunodeficiency virus (HIV)-positive patients on combination
             antiretroviral therapy are ineligible because of the potential for pharmacokinetic
             interactions with R935788.