Dovitinib for Patients With Tumor Pathway Activations Inhibited by Dovitinib

This was a phase II, open label study to determine the efficacy and safety of treatment with dovitinib (TKI258) in patients with a diagnosis of select solid tumors or hematological malignancies that have been pre-identified (prior to study consent) to have mutations, translocations or amplifications and whose disease has progressed on or after standard treatment.

Genomic profiling is becoming more accessible to patients and their physicians. As such, more patients have been identified with potentially-actionable mutations, translocations or amplifications but do not have access to targeted drug treatment. This is a signal-seeking study to match patients with tumor pathway activations inhibited by dovitinib to the RTK inhibitor dovitinib. Pre-identification of mutations, translocations, or amplifications will be performed locally at a CLIA certified laboratory prior to participation on the trial.

For the purpose of this study, genomic profiling is not considered part of screening. Informed consent must be signed before any screening activities take place. Once eligibility (screening criteria met) has been confirmed by Novartis, the patient will initiate therapy with dovitinib single-agent. The patient may not receive any additional anti-cancer therapy during treatment with dovitinib.

Patients received study treatment until disease progression (assessed by investigator per RECIST 1.1 or appropriate hematologic response criteria), unacceptable toxicity, death or discontinuation from study treatment for any other reason (e.g., withdrawal of consent, start of a new anti-neoplastic therapy or at the discretion of the investigator), otherwise known as End of Treatment. All patients who discontinue from study treatment due to disease progression must have their progression clearly documented.

Disease assessment (by RECIST 1.1 or appropriate hematological response criteria) will be performed every 8 weeks (±4 days) after first dose of study drug (Day 1 of every odd cycle), until disease progression or end of treatment, whichever occurs first. The frequency of disease assessment may be reduced to every 12 weeks for patients who have at least 4 post-baseline disease assessments and are clinically stable (except AML patients). Scans was assessed locally by the investigator. After discontinuation of treatment, patients, regardless of reason for treatment discontinuation, will be followed for safety for 30 days after the last dose.

All patients will be followed for survival status every 3 months for 2 years after the last patient has enrolled in the study,regardless of treatment discontinuation reason (except if consent is withdrawn or patient is lost to follow-up)

Key Inclusion Criteria:

Patients eligible for inclusion in this study had to meet all of the following criteria:

• Patient's age was ≥ 18 years of age at the time of signing informed consent.
• 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.
• 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
• 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:

• FGFR 1-3 (amplifications were also allowed)
• PDGFRα or PDGFRβ
• VEGFR1-2 (KDR)
• FLT3, cKIT (amplifications are also allowed),
• RET, TrkA (NTRK1), or CSF-1R
• 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.
• 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.
• 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
• Patients with measurable disease as per appropriate guidelines:

a. Solid Tumors: by RECIST 1.1

• 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.
• Leukemia only: Relapsed/refractory leukemia for which no standard therapy options were anticipated to result in a durable remission:

• 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.
• 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.
• For patients with Chronic Myeloid Leukemia (CML) only accelerated and blast phase CML were allowed.
• Patient with an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
• Patient with a life expectancy of at least 16 weeks
• All Patients were having adequate bone marrow as described below:

• Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L (not applicable for leukemia patients).
• Platelets (PLT) ≥ 75 x 109/L (no platelet transfusion within past 14 days) (not applicable for leukemia patients).
• Hemoglobin (Hgb) ≥ 9 g/dl (not applicable for leukemia patients).
• International Normalized Ratio (INR) ≤ 1.5.
• Serum amylase and lipase ≤ upper limit of normal (ULN).
• All patients had adequate organ function defined as described below:

• 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.
• 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)
• Alanine aminotransferase (AST) and/or aspartate aminotransferase (ALT) ≤ 3.0 x upper limit of normal range (ULN)
• Total serum bilirubin within normal range (or ≤ 1.5 x ULN)
• 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.
• 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:

• Patients who received prior treatment with dovitinib (TKI258).
• Patients with a known hypersensitivity to dovitinib (TKI258) or to its excipients.
• Patients with brain metastasis or history of brain metastasis or leptomeningeal carcinomatosis.
• Patients with diarrhea ≥ CTCAE grade 2.
• Patients with neuropathy ≥ CTCAE grade 2.
• Patients with acute or chronic pancreatitis.
• Patients with external biliary drains.
• 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.
• Patients with 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 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).
• 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).
• 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.
• Patients with uncontrolled diabetes mellitus.
• Patients with clinical evidence of active CNS leukemia.
• Patient who received Allogeneic stem cell transplant and/or had active has graft-versus host disease (GVHD).
• Patient received Autologous stem cell transplant within last 4 weeks.
• 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).
• 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.
• 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.
• 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.
• 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.
• Patients not able to discontinue their current anti-cancer therapy prior to first dose of study drug.
• 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).
• 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.
• 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.
• 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.
• 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:

• 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).
• 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.
• Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing was not mandatory).
• Patients who received investigational agents within ≤ 5t1/2 of the agent (or ≤ 4 weeks when half-life was unknown) prior to starting study drug.
• Patient with history of non-compliance to medical regimen.
• 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.
• 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):

• Placement of an intrauterine device (IUD) or intrauterine system (IUS)
• Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
• 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.
• 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.
• 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.