Dovitinib for Patients With Tumor Pathway Activations Inhibited by Dovitinib
Condition: Tumor Pathway Activations Inhibited by Dovitinib
MeSH terms: Neoplasms
Intervention: Dovitinib (TKI258)
Intervention description: Dovitinib (TKI) will be dosed on a flat scale of 500 mg on a 5 days on/2 days off dosing schedule.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 80.0
Sex: All
Minimum age: 18 Years
Maximum age: 100 Years
Healthy volunteers: No
Keywords: Solid tumor malignancy; hematologic malignancy; mutation; translocations; FGFR; PDGFR; VEGF; cKIT; FLT3; CSR1; Trk; RET; TKI258; dovitinib; signature; AML; acute myelogenous leukemia; GIST; gastrointestinal stromal tumor; Head and Neck cancer; Melanoma; NSCLC; non-small cell lung carcinoma; lung cancer; ovarian cancer; thyroid cancer; amplification

Summary:

      The purpose of this signal seeking study was to determine whether treatment with dovitinib
      (TKI258) demonstrated sufficient efficacy in select pathway-activated solid tumors and/or
      hematologic malignancies to warrant further study.
    

Eligibility criteria:

        Key Inclusion Criteria:

        Patients eligible for inclusion in this study had to meet all of the following criteria:

          1. Patient's age was ≥ 18 years of age at the time of signing informed consent.

          2. Patient had a confirmed diagnosis of a selected solid tumor (except for primary
             diagnosis of urothelial tumors, hepatocellular carcinoma (HCC), endometrial carcinoma,
             metastatic breast cancer (mBC), squamous NSCLC, and renal cell carcinoma (RCC)) or
             hematologic malignancies (except for primary diagnosis of FLT3 AML and multiple
             myeloma). Additional tumor types could be excluded during the course of the study in
             the case of early futility or success based upon an interim analysis or at the
             discretion of Novartis.

          3. Patient was in need of treatment because of progression or relapse defined as:

               -  radiological progression for solid tumor and lymphoma

               -  for hematologic malignancies, measureable progression or relapse by appropriate
                  criteria

          4. Patients had pre-identified tumor with a mutation and/or translocation of one of the
             known kinase targets of dovitinib. The qualifying alteration were assessed and
             reported by a CLIA-certified laboratory. The mutations included:

               1. FGFR 1-3 (amplifications were also allowed)

               2. PDGFRα or PDGFRβ

               3. VEGFR1-2 (KDR)

               4. FLT3, cKIT (amplifications are also allowed),

               5. RET, TrkA (NTRK1), or CSF-1R

          5. Patient had archival tissue available for submission to allow for molecular testing
             related to pathway activation. If the tissue was not available or not of sufficient
             quantity the patient was willing to undergo a fresh tumor biopsy to allow for this
             analysis. The sample was submitted prior to first study dose unless agreed upon
             between Novartis and the investigator.

          6. Patient received at least one prior treatment for recurrent, metastatic and /or
             locally advanced disease and for whom no standard therapy options were anticipated to
             result in a durable remission.

          7. Diffuse large B cell lymphoma only: Patient received or was ineligible for autologous
             or allogeneic stem cell transplant. This did not apply to patients with Mantle cell
             lymphoma or follicular lymphoma

          8. Patients with measurable disease as per appropriate guidelines:

             a. Solid Tumors: by RECIST 1.1

          9. Lymphoma: Patient had at least one measurable nodal lesion (≥2 cm) according to Cheson
             criteria (Cheson 2007). In case where the patient had no measurable nodal lesions ≥ 2
             cm in the long axis at screening, then the patient had at least one measurable
             extra-nodal lesion.

         10. Leukemia only: Relapsed/refractory leukemia for which no standard therapy options were
             anticipated to result in a durable remission:

               1. Acute myelogenous leukemia (AML) by World Health Organization (WHO)
                  classification (except FLT3) or acute lymphoblastic leukemia (ALL) relapsed or
                  refractory to standard chemotherapy; unsuitable for standard chemotherapy or
                  unwilling to undergo standard chemotherapy. Philadelphia chromosome (Ph) positive
                  ALL eligible if failed prior tyrosine-kinase inhibitor therapy.

               2. Age > 60 years with AML (except FLT3) not candidates for or have refused standard
                  chemotherapy, excluding patients with acute promyelocytic leukemia (APL) or with
                  favorable cytogenetic abnormalities.

               3. For patients with Chronic Myeloid Leukemia (CML) only accelerated and blast phase
                  CML were allowed.

         11. Patient with an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1

         12. Patient with a life expectancy of at least 16 weeks

         13. All Patients were having adequate bone marrow as described below:

               1. Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L (not applicable for leukemia
                  patients).

               2. Platelets (PLT) ≥ 75 x 109/L (no platelet transfusion within past 14 days) (not
                  applicable for leukemia patients).

               3. Hemoglobin (Hgb) ≥ 9 g/dl (not applicable for leukemia patients).

               4. International Normalized Ratio (INR) ≤ 1.5.

               5. Serum amylase and lipase ≤ upper limit of normal (ULN).

         14. All patients had adequate organ function defined as described below:

               1. Potassium, calcium (corrected for serum albumin) and magnesium within normal
                  limits (WNL). Supplementation was allowed to meet eligibility requirements.
                  Bisphosphonates to treat malignant hypercalcemia WERE NOT allowed.

               2. Serum creatinine ≤ 1.5 x ULN or Serum creatinine >1.5 - 3 x ULN if

                    -  creatinine clearance by 24-hr urine was ≥ 30 mL/min/1.73m2 (≥50
                       mL/min/1.73m2 in the presence of proteinuria as defined by inclusion
                       criterion #16 or

                    -  calculated creatinine clearance (CrCl) was ≥ 30 mL/min using the Cockroft-
                       Gault equation CrCl = (140 - age in years) x (weight in kg) / (72 x serum
                       creatinine in mg/dL) (if female, multiply the number by 0.85)

               3. Alanine aminotransferase (AST) and/or aspartate aminotransferase (ALT) ≤ 3.0 x
                  upper limit of normal range (ULN)

               4. Total serum bilirubin within normal range (or ≤ 1.5 x ULN)

         15. Urine dipstick reading: Negative for proteinuria or, if documentation of +1 results
             for protein on dipstick reading, then total urinary protein ≤ 500 mg and measured
             creatinine clearance ≥ 50 mL/min/1.73m2 from a 24 hour urine collection.

         16. For Leukemia patients, peripheral blast counts < 50,000 blasts/mm3

        Key Exclusion Criteria:

        Patients eligible for this study did not meet any of the following criteria:

          1. Patients who received prior treatment with dovitinib (TKI258).

          2. Patients with a known hypersensitivity to dovitinib (TKI258) or to its excipients.

          3. Patients with brain metastasis or history of brain metastasis or leptomeningeal
             carcinomatosis.

          4. Patients with diarrhea ≥ CTCAE grade 2.

          5. Patients with neuropathy ≥ CTCAE grade 2.

          6. Patients with acute or chronic pancreatitis.

          7. Patients with external biliary drains.

          8. Patients with a history of pulmonary embolism (PE), or untreated deep venous
             thrombosis (DVT) ≤ 6 months prior to starting study drug. Note: Patients with recent
             DVT who were treated with therapeutic anti-coagulant agents for at least 6 weeks are
             eligible.

          9. Patients with impaired cardiac function or clinically significant cardiac diseases,
             including any of the following:

               1. History or presence of serious uncontrolled ventricular arrhythmias.

               2. Clinically significant resting bradycardia.

               3. LVEF assessed by either 2-D echocardiogram (ECHO) < 50% or lower limit of normal
                  (whichever was the higher), or 2-D multiple gated acquisition scan (MUGA) < 45%
                  or lower limit of normal (whichever was the higher).

               4. 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).

               5. Uncontrolled hypertension defined by a SBP ≥ 160 mm Hg and/or DBP ≥ 100 mm Hg,
                  with or without anti-hypertensive medication(s). Initiation or adjustment of
                  antihypertensive medication(s) was allowed prior to study entry.

         10. Patients with uncontrolled diabetes mellitus.

         11. Patients with clinical evidence of active CNS leukemia.

         12. Patient who received Allogeneic stem cell transplant and/or had active has
             graft-versus host disease (GVHD).

         13. Patient received Autologous stem cell transplant within last 4 weeks.

         14. Impairment of GI function or GI disease that could significantly alter the absorption
             of dovitinib (e.g. severe ulcerative diseases, uncontrolled nausea, vomiting,
             diarrhea, malabsorption syndrome, or small bowel resection).

         15. Any other condition that was, in the Investigator's judgment, contraindicate patient's
             participation in the clinical study due to safety concerns or compliance with clinical
             study procedures, e.g. infection/inflammation, intestinal obstruction, unable to
             swallow oral medication, social/psychological complications.

         16. Patients who were treated with any hematopoietic colony-stimulating growth factors
             (e.g.,G-CSF, GM-CSF) ≤ 2 weeks prior to starting study drug. Erythropoietin or
             darbepoetin therapy, if initiated at least 2 weeks prior to enrollment, could be
             continued. Restriction was not applicable for patients with Leukemia.

         17. Patient who received chemotherapy or other anticancer therapy ≤ 4 weeks (6 weeks for
             nitrosourea, monoclonal antibodies or mitomycin-C) prior to starting study drug or who
             had not recovered to a grade 1 from side effects of such therapy (except for alopecia
             and neuropathy). Patients with leukemia could receive therapy with hydroxyurea and/or
             steroids for the purpose of cytoreduction but must discontinue use prior to first dose
             of study drug.

         18. Patients who received the last administration of an anticancer small molecule therapy
             (e.g. sunitinib, sorafenib, pazopanib, axitinib, everolimus, temsirolimus,
             ridaforolimus) ≤ 2 weeks prior to starting study drug, or who had not recovered from
             the side effects of such therapy.

         19. Patients not able to discontinue their current anti-cancer therapy prior to first dose
             of study drug.

         20. Patients who received radiotherapy ≤ 4 weeks prior to starting the study drug or who
             had not recovered from radiotherapy-related toxicities (note: palliative radiotherapy
             for bone lesions ≤ 2 weeks prior to starting study drug is allowed).

         21. Patients who had undergone major surgery (e.g., intra-thoracic, intra-abdominal,
             intrapelvic) ≤ 4 weeks prior to starting study treatment or who had not recovered from
             side effects of such surgery.

         22. Patient was currently receiving antiplatelet therapy of prasugrel or clopidogrel, or
             full dose anticoagulation treatment with therapeutic doses of warfarin. However,
             treatment with low doses of warfarin (e.g., ≤ 2 mg/day) or locally accepted low doses
             of acetylsalicylic acid (up to 100 mg daily) to prevent cardiovascular events or
             strokes was allowed.

         23. Patients with another primary malignancy within 3 years prior to starting study
             treatment, with the exception of adequately treated basal cell carcinoma, squamous
             cell carcinoma or other non-melanomatous skin cancer, or in-situ carcinoma of the
             uterine cervix.

         24. Cirrhosis of the liver or known hepatitis B or C infection that was either acute or
             was considered chronic because the virus did not become undetectable:

               1. Hepatitis C Virus (HCV) infection: acute or chronic infection as depicted by a
                  positive HCV RNA testing (note: in a patient with known anti-HCV but with a
                  negative test for HCV RNA, re-testing for HCV RNA 4-6 months later was requested
                  to confirm the resolution of HCV infection).

               2. Hepatitis B Virus (HBV) infection: acute infection (HBsAg+ with or without HBeAg+
                  or detectable serum HBV DNA), HBV carriers as evidence by ongoing presence of
                  HBsAg and detectable serum HBV DNA levels.

         25. Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing was not
             mandatory).

         26. Patients who received investigational agents within ≤ 5t1/2 of the agent (or ≤ 4 weeks
             when half-life was unknown) prior to starting study drug.

         27. Patient with history of non-compliance to medical regimen.

         28. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
             female after conception and until the termination of gestation, confirmed by a
             positive hCG laboratory test.

         29. Women of child-bearing potential, defined as all women physiologically capable of
             becoming pregnant, unless they were using highly effective methods of contraception
             (defined below). Highly effective contraception had to be used by both sexes (female
             patients and their male partners) during study treatment and for 30 days after the
             last doseof study medication.

             Highly effective contraception methods included:

               -  Total abstinence (when this was in line with the preferred and usual lifestyle of
                  the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal,
                  post- ovulation methods) and withdrawal were not acceptable methods of
                  contraception

               -  Female sterilization (have had surgical bilateral oophorectomy with or without
                  hysterectomy) or tubal ligation at least six weeks before taking study treatment.

             In case of oophorectomy alone, only when the reproductive status of the woman was
             confirmed by follow up hormone level assessment

               -  Male sterilization (at least 6 months prior to screening). For female patients on
                  the study the vasectomized male partner was the sole partner for that subject.

               -  Combination of the following (a+b):

                    1. Placement of an intrauterine device (IUD) or intrauterine system (IUS)

                    2. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or
                       cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal
                       suppository

         30. Oral, implantable, or injectable hormone contraceptives might be affected by
             cytochrome P450 interactions, and were therefore not considered effective for this
             study Women of child-bearing potential (sexually mature women) who had not undergone a
             hysterectomy or who were not naturally postmenopausal for at least 12 consecutive
             months (i.e., who has had menses any time in the preceding 12 consecutive months),
             were required to have a negative serum pregnancy test ≤ 14 days prior to starting
             study drug.

         31. Post-menopausal women were allowed to participate in this study. Women were considered
             post-menopausal and not of child bearing potential if they have had 12 months of
             natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age
             appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea
             with serum FSH levels > 40 mIU/mL or have had surgical bilateral oophorectomy (with or
             without hysterectomy) at least six weeks prior to entry in the study. In the case of
             oophorectomy alone, only when the reproductive status of the woman was confirmed by
             follow up hormone level assessment, then she was considered not of child bearing
             potential.

         32. Fertile males not willing to use contraception. Fertile males must use condom with
             spermicide. Highly effective contraception, as defined above, was to be used by both
             sexes (male patients and their female partners) during study treatment and for 90 days
             after the last dose of study medication and was not to father a child in this period.
             A condom was required to be used also by vasectomized men in order to prevent delivery
             of the drug via seminal fluid.