Dovitinib Lactate, Gemcitabine Hydrochloride, and Paclitaxel Albumin-Stabilized Nanoparticle Formulation in Treating Patients With Advanced Solid Tumors or Pancreatic Cancer

Study Overview
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Brief Summary
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This phase I trial studies the highest and safest doses of dovitinib lactate, paclitaxel albumin-stabilized nanoparticle formulation, and gemcitabine hydrochloride when given together. Dovitinib lactate disrupts the activity of fibroblast growth factor receptors and reduces cancer growth and spread. Gemcitabine hydrochloride and paclitaxel albumin-stabilized nanoparticle formulation are anti-cancer drugs for treating many cancer types.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose and recommended phase II dose of dovitinib (dovitinib lactate) when administered concurrently with gemcitabine (gemcitabine hydrochloride) and nab-paclitaxel (paclitaxel albumin-stabilized nanoparticle formulation) in patients with advanced solid malignancies. II. To characterize the safety profile of dovitinib, gemcitabine and nab-paclitaxel combination in patients with advanced solid malignancies. SECONDARY OBJECTIVES: I. To characterize the pharmacokinetic profile of dovitinib, nab-paclitaxel, gemcitabine and their metabolites when administered concurrently in patients with advanced solid malignancies. II. To determine the preliminary efficacy of the study combination in patients with advanced solid tumors and pancreas adenocarcinoma. III. To explore serum and tumor biomarkers predictive of efficacy to the study combination. OUTLINE: This is a dose-escalation study of dovitinib lactate. Patients receive dovitinib lactate orally (PO) once daily (QD) 5 days per week, paclitaxel albumin-stabilized nanoparticle formulation intravenously (IV) over 30 minutes, and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 4 weeks.

Official Title
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A Phase Ib Study of Dovitinib in Combination With Gemcitabine and Nab-Paclitaxel in Patients With Advanced Solid Tumors and Pancreatic Cancer

Conditions
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Duct Cell Adenocarcinoma of the Pancreas, Recurrent Pancreatic Cancer, Stage III Pancreatic Cancer, Stage IV Pancreatic Cancer, Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
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* Drug: dovitinib lactate
* Drug: gemcitabine hydrochloride
* Drug: paclitaxel albumin-stabilized nanoparticle formulation
* Other: pharmacological study
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Part A and Part B2: Histologically or cytologically confirmed solid tumors that are advanced or metastatic that gemcitabine and/or nab-paclitaxel containing treatment is considered a rational option Part Bl: Histologically or cytologically confirmed adenocarcinoma of the pancreas that is locally advanced or metastatic Part Bl: At least one malignant lesion not previously irradiated that can be safely biopsied, and patient is agreeable to undergo fresh tumor biopsy Patients with at least one measurable site of disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1 that has not been previously irradiated Eastern Cooperative Oncology Group (ECOG) performance status =< 1 Life expectancy >= 3 months Absolute neutrophil count (ANC) >= 1,500 cells/mm^3 (SI units 1.5 x 10^9/L) Platelets >= 100,000 cells/mm^3 (SI units 100 x 10^9/L) Hemoglobin >= 9 g/dL (SI units 90 g/L) Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (SGPT) =< 1.5 x upper limit of normal (ULN) Bilirubin =< 1.5 x ULN Serum creatinine =< 1.5 x ULN International normalized ratio (INR) =< 1.5 (anticoagulation is allowed if target INR =< 1.5 on a stable dose of warfarin or on a stable dose of LMW heparin for > 2 weeks at the first dose of study agent) If urinalysis shows proteinuria, 24 hour urine collection is to be performed and the 24 hour urine protein is to be < 2 grams to be eligible Willing and able to comply with scheduled visits, treatment plan and laboratory tests Ability to understand and willingness to sign a written informed consent; a signed informed consent must be obtained prior to any study specific procedures Exclusion Criteria: Patients who have received the last administration of an anti-cancer therapy including chemotherapy, immunotherapy, hormonal therapy and monoclonal antibodies (but excluding nitrosourea, mitomycin-C, targeted therapy and radiation) =< 4 weeks prior to starting study drug, or who have not recovered from side effects of such therapy Patients who have received the last administration of nitrosourea or mitomycin-C =< 6 weeks prior to starting study drug, or who have not recovered from the side effects of such therapy 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 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), or who have not recovered from radiotherapy toxicities Patients who have undergone major surgery (e.g., intra-thoracic, intra-abdominal or intrapelvic), 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 Impaired cardiac function or clinically significant cardiac diseases, including any of the following: History or presence of serious uncontrolled ventricular arrhythmias or presence of serious uncontrolled atrial fibrillation, Clinically significant resting bradycardia Known left ventricular ejection fraction (LVEF) assessed by 2-dimensional (2-D) echocardiogram (ECHO) < 50% or lower limit of normal (whichever is higher) or multiple gated acquisition scan (MUGA) < 45% or lower limit of normal (whichever is higher), Any of the following within 6 months prior to study entry: 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 systolic blood pressure (SBP) >= 160 mmHg and/or diastolic blood pressure (DBP) >= 100 mm Hg, with or without anti-hypertensive medication Previous pericarditis; clinically significant pleural effusion in the previous 12 months or current ascites requiring two or more interventions/month Any active gastrointestinal (GI) impairment which, in the opinion of the investigator, would impair or alter the absorption of dovitinib (e.g., ulcerative colitis, or Crohn's disease) Positive hemoccult test result within 14 days prior to the start of study treatment Cirrhosis, chronic active hepatitis or chronic persistent hepatitis Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory) Patients who are currently receiving oral anticoagulation treatment with therapeutic doses of warfarin with goal INR > 1.5; patients receiving anticoagulation by subcutaneous injection such as heparin, enoxaparin, fondaparinux that are not expected to interact with study medications will be eligible History of alcoholism, drug addiction, or any psychiatric or psychological condition which, in the opinion of the investigator, would impair study compliance Uncontrolled diarrhea >= Common Terminology Criteria for Adverse Events (CTCAE) grade 2 Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g., active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol Pregnant or breast-feeding women 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 (e.g., who has had menses any time in the preceding 12 consecutive months), must have a negative serum pregnancy test =< 3 days prior to starting study treatment Women of child-bearing potential, who are biologically able to conceive, not employing 2 forms of highly effective contraception; male not using at least at least one form of highly effective contraception will be excluded; highly effective contraception (e.g., male condom with spermicide, diaphragm with spermicide, intra-uterine device) must be used by both sexes during the study and must be continued for 8 weeks after the end of study treatment; oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, and are therefore not considered effective for this study Patients with known brain metastases or who have signs/symptoms attributable to brain metastases and have not been assessed with radiologic imaging to rule out the presence of brain metastases

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (dovitinib, gemcitabine, nab-paclitaxel)<br>Patients receive dovitinib lactate PO QD 5 days per week, paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: dovitinib lactate<br>* Given PO<br>* Other names: TKI258;Drug: gemcitabine hydrochloride<br>* Given IV<br>* Other names: Gemzar;Drug: paclitaxel albumin-stabilized nanoparticle formulation<br>* Given IV<br>* Other names: nanoparticle albumin-bound paclitaxel;Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose of dovitinib lactate, defined as the highest dose level at which < 33% of patients experience study treatment-related dose-limiting toxicity, graded using the National Cancer Institute (NCI) CTCAE version 4.0 |  | 28 days | 
| Incidence of adverse events graded by NCI CTCAE version 4.0 | Characterized by type, frequency, timing, seriousness and relationship to study treatment. All toxicities and adverse events will be summarized with frequencies and descriptive measures, and tabulated according to body system, severity and relation to treatment. Demographic data and baseline disease characteristics will be displayed, and summary statistics will be used to describe patient population. | Up to 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma pharmacokinetic (PK) parameters of dovitinib lactate | Pharmacokinetic parameters will be summarized for each cohort of patients. Comparison of PK parameters among the dose levels will be performed using non-parametric statistical methods for K-independent samples. Drug-drug interaction will be examined comparing PK parameters using nonparametric statistical methods. | Pre-dose, 0.5, 1-2,4-5, 6-8, 24 hours post-dose day 1 of course 2; pre-dose trough day 8 of course 2 | 
| Plasma PK parameters of gemcitabine hydrochloride | Pharmacokinetic parameters will be summarized for each cohort of patients. Comparison of PK parameters among the dose levels will be performed using non-parametric statistical methods for K-independent samples. Drug-drug interaction will be examined comparing PK parameters using nonparametric statistical methods. | Prior to end of infusion, and 0.5, 1-2, and 4-6 hours post-end of infusion day 1 of course 2; prior to infusion of IV chemotherapy day 8 of course 2 | 
| Plasma PK parameters of paclitaxel albumin-stabilized nanoparticle formulation | Pharmacokinetic parameters will be summarized for each cohort of patients. Comparison of PK parameters among the dose levels will be performed using non-parametric statistical methods for K-independent samples. Drug-drug interaction will be examined comparing PK parameters using nonparametric statistical methods. | Prior to end of infusion, and 0.5, 1-2, and 4-6 hours post-end of infusion day 1 of course 2; prior to infusion of IV chemotherapy day 8 of course 2 | 
| Survival (expansion cohort) | Overall survival will be estimated using Kaplan-Meier method. | 6 months | 
| Response rate, defined according to RECIST 1.1 (expansion cohort) |  | Up to 4 weeks | 
| Progression-free survival (expansion cohort) |  | Up to 4 weeks | 
| Biomarker expression levels in tumor specimens | Differences in biomarkers between responders and non-responders will be explored with frequencies and summary statistics. Tests for differences in continuously measured biomarkers will be done with standard two-sample testing procedures. Categorical biomarkers will be tested with Fisher's exact test. | Baseline |