Study of Dovitinib (TKI258) in Adenoid Cystic Carcinoma
Condition: Adenoid Cystic Carcinoma
MeSH terms: Carcinoma; Carcinoma, Adenoid Cystic
Intervention: Dovitinib (TKI258)
Intervention description: 500 mg orally on a 5-days on/2-days off schedule each week of a 4-week (28-day) cycle. Treatment will continue until progression as defined by RECIST, unacceptable adverse events, patient refusal to continue on study, or physician's decision to withdraw the patient.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 35.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      The purpose of this study is to improve survival of patients with recurrent or metastatic
      Adenoid Cystic Carcinoma (ACC). This study will test the efficacy of the investigational
      drug, TKI258, in treating ACC.
    

Eligibility criteria:

        Inclusion Criteria:

        Patients eligible for inclusion in this study have to meet all of the following criteria:

          1. Patients must have histology or cytology studies that confirm the diagnosis of adenoid
             cystic carcinoma. (Note: Subsequent central review of the pathology slides will be
             provided by Drs. Christopher Moskaluk or Henry Frierson, Department of Pathology at
             the University of Virginia Health Sciences Center).

          2. Patients must have recurrent and/or metastatic disease that is not amenable to
             potentially curative surgical resection or radiotherapy.

          3. 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 >10
             mm with spiral CT scan (or >20 mm with conventional techniques). Pathologic lymph
             nodes are measured by shortest diameter as per RECIST.

          4. Patients must have serial imaging that allows measurement of tumor growth rates by
             change point analysis:

        1. The remote baseline study scan must be within six calendar months of the immediate
        pre-study scan.

        2. The remote baseline scan must have measurable disease ≥ 10 mm for non-pulmonary lesions
        or ≥ 4 mm for pulmonary metastases that show subsequent progression.

        3. Comparison of the remote baseline and subsequent studies must show progressive disease
        in 1-5 selected target lesions based on the following:

          1. Modified RECIST criteria (i.e. proportional increase of 1.2 or the appearance of new
             lesions) AND/OR

          2. Progression by change point analysis with an increase in the slope of the average
             tumor measurements of at least 0.22 b

        a = "remote baseline scan" refers to scan done prior to pre-study scan which is used to
        determine pre-treatment tumor growth rate.

        b = the estimated mean minus one standard deviation based on analysis of progressive tumors
        from untreated patients with ACC.

        5. Life expectancy > 16 weeks.

        6. ECOG (WHO) performance status 0-2

        7. Age ≥ 18 years old

        8. Patients must have the following laboratory values:

          -  Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

          -  Platelets ≥ 100 x 109/L

          -  Hemoglobin (Hgb) > 9 g/dL

          -  Serum total bilirubin: ≤ 1.5 x ULN

          -  ALT and AST ≤ 3.0 x ULN

          -  Serum creatinine ≤ 1.5 x ULN or serum creatinine >1.5 - 3 x ULN if calculated
             creatinine clearance (CrCl) is ≥ 30 mL/min using the Cockroft-Gault equation, see
             formula below:

        CrCl = [140-age (years)] x weight (kg) / [72 x serum Cr (mg/dL)] (if patient is female
        multiply the above by 0.85)

        9. Patients who give a written informed consent obtained according to local guidelines

        Exclusion Criteria:

        Patients are ineligible for this study if he or she has any of the following:

          1. Patients with brain metastases

          2. Patients with another primary malignancy within 3 years prior to starting study drug,
             with the exception of adequately treated in-situ carcinoma of the uterine cervix, or
             skin cancer (such as basal cell carcinoma, squamous cell carcinoma, or
             non-melanomatous skin cancer)

          3. Patients who have received the last administration of an anticancer therapy including
             chemotherapy, immunotherapy, hormonal therapy and monoclonal antibodies (but excluding
             nitrosurea, mitomycin-C, targeted therapy and radiation) ≤ 4 weeks prior to starting
             study drug, or who have not recovered from the side effects of such therapy

          4. Patients who have received the last administration of nitrosurea or mitomycin-C ≤ 6
             weeks prior to starting study drug, or who have not recovered from the side effects of
             such therapy

          5. Patients who have received targeted therapy (e.g. sunitinib, sorafenib, pazopanib) ≤ 2
             weeks prior to starting study drug, or who have not recovered from the side effects of
             such therapy

          6. Patients who have had radiotherapy ≤ 4 weeks prior to starting study drug or ≤ 2 weeks
             prior to starting study drug in the case of localized radiotherapy (e.g. for analgesic
             purpose or for lytic lesions at risk of fracture), if the measurable lesions are
             outside the radiation field. Also excluded would be those who have not recovered from
             toxicity radiotherapy.

          7. Patients who have undergone major surgery (e.g. intra-thoracic, intra-abdominal or
             intra-pelvic), open biopsy or significant traumatic injury ≤ 4 weeks prior to starting
             study drug, or patients who have had minor procedures, percutaneous biopsies or
             placement of vascular access device ≤ 1 week prior to starting study drug, or who have
             not recovered from side effects of such procedure or injury

          8. Patients with any of the following concurrent severe and/or uncontrolled medical
             conditions which could compromise participation in the study:

               -  Impaired cardiac function or clinically significant cardiac diseases, including
                  any of the following:

               -  History or presence of serious uncontrolled ventricular arrhythmias

               -  Clinically significant resting bradycardia

               -  LVEF assessed by 2-D echocardiogram (ECHO) or multiple gated acquisition scan
                  (MUGA) < 45%

               -  Any of the following within 6 months prior to starting study drug: myocardial
                  infarction (MI), severe/unstable angina, Coronary Artery Bypass Graft (CABG),
                  Congestive Heart Failure (CHF), Cerebrovascular Accident (CVA), Transient
                  Ischemic Attack (TIA), Pulmonary Embolism (PE)

               -  Uncontrolled hypertension defined by a SBP ≥ 160 mm Hg and/or DBP ≥ 100 mm Hg,
                  with or without anti-hypertensive medication(s)

                    1. Impairment of gastrointestinal (GI) function or GI disease that may
                       significantly alter the absorption of dovitinib (e.g. ulcerative diseases,
                       uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small
                       bowel resection)

                    2. Cirrhosis, chronic active hepatitis or chronic persistent hepatitis

                    3. Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing
                       is not mandatory)

                    4. Patients who are currently receiving anticoagulation treatment with
                       therapeutic doses of warfarin

                    5. Other concurrent severe and/or uncontrolled concomitant medical conditions
                       (e.g. active or uncontrolled infection, uncontrolled diabetes) that could
                       cause unacceptable safety risks or compromise compliance with the protocol

          9. Pregnant or breast-feeding women

         10. Women of child-bearing potential not employing an effective method of birth control.
             Two birth control methods must be used throughout the trial and one month after the
             last dose of study drug (e.g. condom with spermicidal jelly, foam suppository or film;
             diaphragm with spermicide; male condom and diaphragm with spermicide). Contraceptives
             that are affected by cytochrome P450 interactions (e.g. oral, implantable, injectable,
             or intrauterine hormonal contraceptives) are not considered effective for this study.
             Women of child-bearing potential, defined as sexually mature women who have not
             undergone a hysterectomy or who have not been naturally postmenopausal for at least 12
             consecutive months (i.e., who has had menses any time in the preceding 12 consecutive
             months), must have a negative serum pregnancy test ≤ 7 days prior to starting study
             drug.

         11. Fertile males not willing to use contraception, as stated above

         12. Patients unwilling or unable to comply with the protocol