Lung Cancer, Unspecified Adult Solid Tumor, Protocol Specific
Conditions
Keywords
unspecified adult solid tumor, protocol specific, recurrent non-small cell lung cancer, stage IIIA non-small cell lung cancer, stage IIIB non-small cell lung cancer, stage IV non-small cell lung cancer
Brief summary
RATIONALE: Drugs used in chemotherapy, such as vinorelbine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. PURPOSE: This pilot trial is studying the side effects and best dose of vinorelbine in treating patients with advanced solid tumors that have not responded to treatment and liver dysfunction.
Detailed description
OBJECTIVES: * To correlate indocyanine green and lidocaine metabolism with vinorelbine ditartrate pharmacokinetics in patients with advanced, refractory solid tumors and varying degrees of liver dysfunction. * To determine the pharmacokinetics of vinorelbine ditartrate in these patients. * To test a plan of dose adjustment for vinorelbine ditartrate administration in these patients. OUTLINE: Patients are stratified according to extent of clinical liver dysfunction (normal vs mild vs moderate vs severe). Patients receive dose-adjusted vinorelbine ditartrate IV over 10 minutes once weekly in the absence of disease progression or unacceptable toxicity. Patients achieving an objective complete response receive 2 additional courses of study therapy. Patients undergo blood sample collection periodically during study for pharmacokinetic and pharmacodynamic correlative studies. Blood is also collected after patients receive lidocaine IV push and indocyanine green (ICG) IV push. Samples are analyzed for whole blood and plasma concentrations of vinorelbine ditartrate and its metabolites by high performance liquid chromatography (15) or by liquid chromatography/tandem mass spectrometry assay. Samples are also analyzed for ICG clearance and lidocaine hydrochloride metabolic capacity by fluorescent polarization immunoassay. After completion of study therapy, patients are followed periodically.
Interventions
OTHERmass spectrometry
Used to determine concentrations of vinorelbine and its metabolites
OTHERpharmacological study
Determination of concentrations of vinorelbine and its metabolites
DRUGindocyanine green
0.5 mg/kg will be administered by IV push to determine clearance
DRUGlidocaine
1 mg/kg will be administered to determine metabolic capacity
Varying doses ranging from 30 mg/m2 to 7.5 mg/m2 will be administered based upon liver function
OTHERhigh performance liquid chromatography
Used to determine plasma concentrations of vinorelbine
OTHERintracellular fluorescence polarization analysis
Used to determine concentration of lidocaine metabolic capacity
Used to determine concentrations of vinorelbine and its metabolites
Sponsors
National Cancer Institute (NCI)
City of Hope Medical Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically confirmed advanced solid tumor * Any histology allowed * Refractory to standard therapy OR no standard therapy exists * Previously untreated non-small cell lung cancer allowed, provided abnormal liver function is present, defined as moderate (group 3) or severe (group 4) * Measurable disease not required * Present measurable disease requires baseline measurements within 4 weeks of study entry * Patients with acute hepatitis from viral or drug etiologies should recover to a stable baseline prior to study therapy * History of brain metastasis allowed, provided the following criteria are met: * Metastasis has been controlled by radiotherapy or surgery * Patient is not currently on corticosteroids * Neurologic status is stable PATIENT CHARACTERISTICS: * Karnofsky performance status 70-100% * Life expectancy ≥ 2 months * ANC = 1,500/mm³ * Platelet count = 100,000/mm³ * Hemoglobin = 10 g/dL (transfusion to this level allowed) * Creatinine \< 1.5 mg/dL OR creatinine clearance \> 60 mL/ min * Patients with EKG evidence of first- or second-degree AV block or left or right bundle branch block are ineligible for the lidocaine bolus, but may otherwise be treated on this protocol * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * No concurrent illness (e.g., cardiovascular, pulmonary, or central nervous system) that is poorly controlled or of such severity that the investigator deems unwise to enter the patient on protocol * Must have ability to comply with study treatment and required tests * Obstructive jaundice requires a drainage procedure prior to study treatment PRIOR CONCURRENT THERAPY: * See Disease Characteristics * Recovered from prior therapy * At least 3 weeks since prior chemotherapy (6 weeks for mitomycin or nitrosourea therapy) * No prior radiotherapy to \> 30% of the bone marrow or more than standard adjuvant pelvic radiotherapy for rectal cancer
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve | 2 months post treatment | Pharmacokinetics were evaluated in patients with sufficient dosing information and plasma concentration versus time data over 0-24 hours following vinorelbine infusion to allow calculation of area-under-the-curve from zero to 24 hours after infusion (AUC0-24). Furthermore, dose-normalization of AUC0-24 to the standard 30 mg/m2 dose was performed to allow evaluation of the relationship between liver function and AUC of vinorelbine. Data were collected at 0 and 24 hours post-dose. |
| Number of Participants With Grade 3 and 4 Toxicities | 3 weeks after the stop of treatment | Grade 3 & 4 toxicities at least possible related to study drugs during any cycle of treatment. Toxicity graded according to Common Terminology Criteria for Adverse Events version 2.0. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Patients All patients with treatment-refractory solid tumors enrolled on the study. | 47 |
| Total | 47 |
Baseline characteristics
| Characteristic | All Patients |
|---|---|
| Age, Continuous | 58 years |
| Race/Ethnicity, Customized African American | 2 Participants |
| Race/Ethnicity, Customized Asian | 9 Participants |
| Race/Ethnicity, Customized Caucasian | 23 Participants |
| Race/Ethnicity, Customized Hispanic | 13 Participants |
| Region of Enrollment United States | 47 participants |
| Sex: Female, Male Female | 23 Participants |
| Sex: Female, Male Male | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 11 / 11 | 1 / 1 | 3 / 3 | 2 / 2 | 8 / 8 | 10 / 10 | 7 / 7 | 5 / 5 |
| other Total, other adverse events | 11 / 11 | 1 / 1 | 3 / 3 | 2 / 2 | 7 / 8 | 10 / 10 | 7 / 7 | 5 / 5 |
| serious Total, serious adverse events | 0 / 11 | 0 / 1 | 0 / 3 | 0 / 2 | 3 / 8 | 0 / 10 | 4 / 7 | 0 / 5 |
Outcome results
Primary
Area Under the Curve
Pharmacokinetics were evaluated in patients with sufficient dosing information and plasma concentration versus time data over 0-24 hours following vinorelbine infusion to allow calculation of area-under-the-curve from zero to 24 hours after infusion (AUC0-24). Furthermore, dose-normalization of AUC0-24 to the standard 30 mg/m2 dose was performed to allow evaluation of the relationship between liver function and AUC of vinorelbine. Data were collected at 0 and 24 hours post-dose.
Time frame: 2 months post treatment
Population: Vinorelbine plasma AUC0-24 data were available for a total of 30 subjects.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Normal | Area Under the Curve | 271 ng/ml x hr |
| Mild | Area Under the Curve | 537 ng/ml x hr |
| Moderate | Area Under the Curve | 341 ng/ml x hr |
| Severe | Area Under the Curve | 324 ng/ml x hr |
Primary
Number of Participants With Grade 3 and 4 Toxicities
Grade 3 & 4 toxicities at least possible related to study drugs during any cycle of treatment. Toxicity graded according to Common Terminology Criteria for Adverse Events version 2.0.
Time frame: 3 weeks after the stop of treatment
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Normal | Number of Participants With Grade 3 and 4 Toxicities | Confusion | 0 Participants |
| Normal | Number of Participants With Grade 3 and 4 Toxicities | Thrombocytopenia | 0 Participants |
| Normal | Number of Participants With Grade 3 and 4 Toxicities | Diarrhea | 1 Participants |
| Normal | Number of Participants With Grade 3 and 4 Toxicities | Elevated INR | 0 Participants |
| Normal | Number of Participants With Grade 3 and 4 Toxicities | Hypophosphatemia | 0 Participants |
| Normal | Number of Participants With Grade 3 and 4 Toxicities | Fatigue | 1 Participants |
| Normal | Number of Participants With Grade 3 and 4 Toxicities | Hypertension | 0 Participants |
| Normal | Number of Participants With Grade 3 and 4 Toxicities | Edema | 0 Participants |
| Normal | Number of Participants With Grade 3 and 4 Toxicities | Anorexia/weight loss | 0 Participants |
| Normal | Number of Participants With Grade 3 and 4 Toxicities | Pulmonary hemorrhage | 0 Participants |
| Normal | Number of Participants With Grade 3 and 4 Toxicities | Cerebrovascular ischemia | 0 Participants |
| Normal | Number of Participants With Grade 3 and 4 Toxicities | Petechiae/purpura | 0 Participants |
| Normal | Number of Participants With Grade 3 and 4 Toxicities | Thromboembolism | 0 Participants |
| Normal | Number of Participants With Grade 3 and 4 Toxicities | Dehydration | 1 Participants |
| Normal | Number of Participants With Grade 3 and 4 Toxicities | Hypokalemia | 0 Participants |
| Normal | Number of Participants With Grade 3 and 4 Toxicities | Ascites | 0 Participants |
| Normal | Number of Participants With Grade 3 and 4 Toxicities | Dyspnea | 0 Participants |
| Normal | Number of Participants With Grade 3 and 4 Toxicities | Hypotension | 1 Participants |
| Normal | Number of Participants With Grade 3 and 4 Toxicities | Constipation | 0 Participants |
| Normal | Number of Participants With Grade 3 and 4 Toxicities | Pain | 1 Participants |
| Normal | Number of Participants With Grade 3 and 4 Toxicities | Hypercalcemia | 0 Participants |
| Normal | Number of Participants With Grade 3 and 4 Toxicities | Generalized weakness | 0 Participants |
| Normal | Number of Participants With Grade 3 and 4 Toxicities | Neuropathy | 0 Participants |
| Normal | Number of Participants With Grade 3 and 4 Toxicities | Anemia | 1 Participants |
| Normal | Number of Participants With Grade 3 and 4 Toxicities | Hyponatremia | 0 Participants |
| Normal | Number of Participants With Grade 3 and 4 Toxicities | Neutropenia | 4 Participants |
| Normal | Number of Participants With Grade 3 and 4 Toxicities | Hyperglycemia | 3 Participants |
| Normal | Number of Participants With Grade 3 and 4 Toxicities | Hyperkalemia | 0 Participants |
| Normal | Number of Participants With Grade 3 and 4 Toxicities | Abnormal LFTs | 0 Participants |
| Normal | Number of Participants With Grade 3 and 4 Toxicities | Hallucinations | 0 Participants |
| Normal | Number of Participants With Grade 3 and 4 Toxicities | Lymphopenia | 1 Participants |
| Normal | Number of Participants With Grade 3 and 4 Toxicities | Infection (including febrile neutropenia) | 0 Participants |
| Mild | Number of Participants With Grade 3 and 4 Toxicities | Pulmonary hemorrhage | 0 Participants |
| Mild | Number of Participants With Grade 3 and 4 Toxicities | Hallucinations | 0 Participants |
| Mild | Number of Participants With Grade 3 and 4 Toxicities | Edema | 0 Participants |
| Mild | Number of Participants With Grade 3 and 4 Toxicities | Dehydration | 0 Participants |
| Mild | Number of Participants With Grade 3 and 4 Toxicities | Pain | 0 Participants |
| Mild | Number of Participants With Grade 3 and 4 Toxicities | Fatigue | 0 Participants |
| Mild | Number of Participants With Grade 3 and 4 Toxicities | Hyperglycemia | 1 Participants |
| Mild | Number of Participants With Grade 3 and 4 Toxicities | Generalized weakness | 0 Participants |
| Mild | Number of Participants With Grade 3 and 4 Toxicities | Neutropenia | 1 Participants |
| Mild | Number of Participants With Grade 3 and 4 Toxicities | Infection (including febrile neutropenia) | 0 Participants |
| Mild | Number of Participants With Grade 3 and 4 Toxicities | Petechiae/purpura | 0 Participants |
| Mild | Number of Participants With Grade 3 and 4 Toxicities | Thrombocytopenia | 0 Participants |
| Mild | Number of Participants With Grade 3 and 4 Toxicities | Abnormal LFTs | 1 Participants |
| Mild | Number of Participants With Grade 3 and 4 Toxicities | Hypophosphatemia | 0 Participants |
| Mild | Number of Participants With Grade 3 and 4 Toxicities | Hypokalemia | 0 Participants |
| Mild | Number of Participants With Grade 3 and 4 Toxicities | Anorexia/weight loss | 0 Participants |
| Mild | Number of Participants With Grade 3 and 4 Toxicities | Ascites | 0 Participants |
| Mild | Number of Participants With Grade 3 and 4 Toxicities | Thromboembolism | 0 Participants |
| Mild | Number of Participants With Grade 3 and 4 Toxicities | Cerebrovascular ischemia | 0 Participants |
| Mild | Number of Participants With Grade 3 and 4 Toxicities | Hyperkalemia | 0 Participants |
| Mild | Number of Participants With Grade 3 and 4 Toxicities | Hypertension | 0 Participants |
| Mild | Number of Participants With Grade 3 and 4 Toxicities | Elevated INR | 0 Participants |
| Mild | Number of Participants With Grade 3 and 4 Toxicities | Confusion | 0 Participants |
| Mild | Number of Participants With Grade 3 and 4 Toxicities | Lymphopenia | 0 Participants |
| Mild | Number of Participants With Grade 3 and 4 Toxicities | Constipation | 0 Participants |
| Mild | Number of Participants With Grade 3 and 4 Toxicities | Hypercalcemia | 0 Participants |
| Mild | Number of Participants With Grade 3 and 4 Toxicities | Hypotension | 0 Participants |
| Mild | Number of Participants With Grade 3 and 4 Toxicities | Anemia | 0 Participants |
| Mild | Number of Participants With Grade 3 and 4 Toxicities | Diarrhea | 0 Participants |
| Mild | Number of Participants With Grade 3 and 4 Toxicities | Neuropathy | 0 Participants |
| Mild | Number of Participants With Grade 3 and 4 Toxicities | Hyponatremia | 0 Participants |
| Mild | Number of Participants With Grade 3 and 4 Toxicities | Dyspnea | 0 Participants |
| Moderate | Number of Participants With Grade 3 and 4 Toxicities | Hypokalemia | 0 Participants |
| Moderate | Number of Participants With Grade 3 and 4 Toxicities | Dyspnea | 0 Participants |
| Moderate | Number of Participants With Grade 3 and 4 Toxicities | Confusion | 0 Participants |
| Moderate | Number of Participants With Grade 3 and 4 Toxicities | Neutropenia | 2 Participants |
| Moderate | Number of Participants With Grade 3 and 4 Toxicities | Diarrhea | 0 Participants |
| Moderate | Number of Participants With Grade 3 and 4 Toxicities | Generalized weakness | 0 Participants |
| Moderate | Number of Participants With Grade 3 and 4 Toxicities | Hypotension | 0 Participants |
| Moderate | Number of Participants With Grade 3 and 4 Toxicities | Hyponatremia | 0 Participants |
| Moderate | Number of Participants With Grade 3 and 4 Toxicities | Hyperglycemia | 1 Participants |
| Moderate | Number of Participants With Grade 3 and 4 Toxicities | Thromboembolism | 0 Participants |
| Moderate | Number of Participants With Grade 3 and 4 Toxicities | Constipation | 0 Participants |
| Moderate | Number of Participants With Grade 3 and 4 Toxicities | Edema | 0 Participants |
| Moderate | Number of Participants With Grade 3 and 4 Toxicities | Hyperkalemia | 0 Participants |
| Moderate | Number of Participants With Grade 3 and 4 Toxicities | Hallucinations | 0 Participants |
| Moderate | Number of Participants With Grade 3 and 4 Toxicities | Pulmonary hemorrhage | 0 Participants |
| Moderate | Number of Participants With Grade 3 and 4 Toxicities | Dehydration | 0 Participants |
| Moderate | Number of Participants With Grade 3 and 4 Toxicities | Lymphopenia | 0 Participants |
| Moderate | Number of Participants With Grade 3 and 4 Toxicities | Hypercalcemia | 0 Participants |
| Moderate | Number of Participants With Grade 3 and 4 Toxicities | Ascites | 0 Participants |
| Moderate | Number of Participants With Grade 3 and 4 Toxicities | Neuropathy | 0 Participants |
| Moderate | Number of Participants With Grade 3 and 4 Toxicities | Hypertension | 0 Participants |
| Moderate | Number of Participants With Grade 3 and 4 Toxicities | Hypophosphatemia | 0 Participants |
| Moderate | Number of Participants With Grade 3 and 4 Toxicities | Abnormal LFTs | 0 Participants |
| Moderate | Number of Participants With Grade 3 and 4 Toxicities | Elevated INR | 0 Participants |
| Moderate | Number of Participants With Grade 3 and 4 Toxicities | Anorexia/weight loss | 0 Participants |
| Moderate | Number of Participants With Grade 3 and 4 Toxicities | Anemia | 2 Participants |
| Moderate | Number of Participants With Grade 3 and 4 Toxicities | Cerebrovascular ischemia | 0 Participants |
| Moderate | Number of Participants With Grade 3 and 4 Toxicities | Infection (including febrile neutropenia) | 0 Participants |
| Moderate | Number of Participants With Grade 3 and 4 Toxicities | Fatigue | 0 Participants |
| Moderate | Number of Participants With Grade 3 and 4 Toxicities | Petechiae/purpura | 0 Participants |
| Moderate | Number of Participants With Grade 3 and 4 Toxicities | Pain | 0 Participants |
| Moderate | Number of Participants With Grade 3 and 4 Toxicities | Thrombocytopenia | 0 Participants |
| Severe | Number of Participants With Grade 3 and 4 Toxicities | Pain | 0 Participants |
| Severe | Number of Participants With Grade 3 and 4 Toxicities | Hyperkalemia | 0 Participants |
| Severe | Number of Participants With Grade 3 and 4 Toxicities | Abnormal LFTs | 0 Participants |
| Severe | Number of Participants With Grade 3 and 4 Toxicities | Hypercalcemia | 0 Participants |
| Severe | Number of Participants With Grade 3 and 4 Toxicities | Hyperglycemia | 0 Participants |
| Severe | Number of Participants With Grade 3 and 4 Toxicities | Neutropenia | 1 Participants |
| Severe | Number of Participants With Grade 3 and 4 Toxicities | Thrombocytopenia | 0 Participants |
| Severe | Number of Participants With Grade 3 and 4 Toxicities | Anorexia/weight loss | 0 Participants |
| Severe | Number of Participants With Grade 3 and 4 Toxicities | Ascites | 0 Participants |
| Severe | Number of Participants With Grade 3 and 4 Toxicities | Hypokalemia | 0 Participants |
| Severe | Number of Participants With Grade 3 and 4 Toxicities | Elevated INR | 0 Participants |
| Severe | Number of Participants With Grade 3 and 4 Toxicities | Cerebrovascular ischemia | 0 Participants |
| Severe | Number of Participants With Grade 3 and 4 Toxicities | Confusion | 0 Participants |
| Severe | Number of Participants With Grade 3 and 4 Toxicities | Pulmonary hemorrhage | 0 Participants |
| Severe | Number of Participants With Grade 3 and 4 Toxicities | Constipation | 0 Participants |
| Severe | Number of Participants With Grade 3 and 4 Toxicities | Dehydration | 0 Participants |
| Severe | Number of Participants With Grade 3 and 4 Toxicities | Diarrhea | 0 Participants |
| Severe | Number of Participants With Grade 3 and 4 Toxicities | Anemia | 0 Participants |
| Severe | Number of Participants With Grade 3 and 4 Toxicities | Petechiae/purpura | 0 Participants |
| Severe | Number of Participants With Grade 3 and 4 Toxicities | Dyspnea | 0 Participants |
| Severe | Number of Participants With Grade 3 and 4 Toxicities | Thromboembolism | 0 Participants |
| Severe | Number of Participants With Grade 3 and 4 Toxicities | Edema | 0 Participants |
| Severe | Number of Participants With Grade 3 and 4 Toxicities | Fatigue | 0 Participants |
| Severe | Number of Participants With Grade 3 and 4 Toxicities | Hyponatremia | 0 Participants |
| Severe | Number of Participants With Grade 3 and 4 Toxicities | Generalized weakness | 0 Participants |
| Severe | Number of Participants With Grade 3 and 4 Toxicities | Neuropathy | 0 Participants |
| Severe | Number of Participants With Grade 3 and 4 Toxicities | Hallucinations | 0 Participants |
| Severe | Number of Participants With Grade 3 and 4 Toxicities | Hypotension | 0 Participants |
| Severe | Number of Participants With Grade 3 and 4 Toxicities | Hypophosphatemia | 0 Participants |
| Severe | Number of Participants With Grade 3 and 4 Toxicities | Hypertension | 0 Participants |
| Severe | Number of Participants With Grade 3 and 4 Toxicities | Infection (including febrile neutropenia) | 0 Participants |
| Severe | Number of Participants With Grade 3 and 4 Toxicities | Lymphopenia | 0 Participants |
| Moderate (30mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Thromboembolism | 0 Participants |
| Moderate (30mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Hallucinations | 1 Participants |
| Moderate (30mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Dyspnea | 0 Participants |
| Moderate (30mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Petechiae/purpura | 0 Participants |
| Moderate (30mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Diarrhea | 0 Participants |
| Moderate (30mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Dehydration | 2 Participants |
| Moderate (30mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Constipation | 0 Participants |
| Moderate (30mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Pulmonary hemorrhage | 0 Participants |
| Moderate (30mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Hypercalcemia | 0 Participants |
| Moderate (30mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Hypotension | 1 Participants |
| Moderate (30mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Confusion | 0 Participants |
| Moderate (30mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Hypophosphatemia | 1 Participants |
| Moderate (30mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Hyperkalemia | 0 Participants |
| Moderate (30mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Hyponatremia | 0 Participants |
| Moderate (30mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Cerebrovascular ischemia | 0 Participants |
| Moderate (30mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Ascites | 0 Participants |
| Moderate (30mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Abnormal LFTs | 1 Participants |
| Moderate (30mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Hypertension | 1 Participants |
| Moderate (30mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Elevated INR | 0 Participants |
| Moderate (30mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Anorexia/weight loss | 0 Participants |
| Moderate (30mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Thrombocytopenia | 0 Participants |
| Moderate (30mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Hypokalemia | 3 Participants |
| Moderate (30mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Neutropenia | 7 Participants |
| Moderate (30mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Hyperglycemia | 0 Participants |
| Moderate (30mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Lymphopenia | 0 Participants |
| Moderate (30mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Generalized weakness | 0 Participants |
| Moderate (30mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Neuropathy | 0 Participants |
| Moderate (30mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Infection (including febrile neutropenia) | 2 Participants |
| Moderate (30mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Fatigue | 0 Participants |
| Moderate (30mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Edema | 0 Participants |
| Moderate (30mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Pain | 1 Participants |
| Moderate (30mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Anemia | 1 Participants |
| Moderate (15mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Petechiae/purpura | 0 Participants |
| Moderate (15mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Pulmonary hemorrhage | 0 Participants |
| Moderate (15mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Anemia | 3 Participants |
| Moderate (15mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Lymphopenia | 1 Participants |
| Moderate (15mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Neutropenia | 4 Participants |
| Moderate (15mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Thrombocytopenia | 1 Participants |
| Moderate (15mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Anorexia/weight loss | 1 Participants |
| Moderate (15mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Ascites | 0 Participants |
| Moderate (15mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Cerebrovascular ischemia | 1 Participants |
| Moderate (15mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Confusion | 0 Participants |
| Moderate (15mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Constipation | 1 Participants |
| Moderate (15mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Dehydration | 1 Participants |
| Moderate (15mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Diarrhea | 0 Participants |
| Moderate (15mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Dyspnea | 0 Participants |
| Moderate (15mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Edema | 0 Participants |
| Moderate (15mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Fatigue | 0 Participants |
| Moderate (15mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Generalized weakness | 0 Participants |
| Moderate (15mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Hallucinations | 0 Participants |
| Moderate (15mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Hypotension | 0 Participants |
| Moderate (15mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Hypertension | 0 Participants |
| Moderate (15mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Infection (including febrile neutropenia) | 1 Participants |
| Moderate (15mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Thromboembolism | 2 Participants |
| Moderate (15mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Abnormal LFTs | 3 Participants |
| Moderate (15mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Hypercalcemia | 1 Participants |
| Moderate (15mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Hyperglycemia | 0 Participants |
| Moderate (15mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Hyperkalemia | 1 Participants |
| Moderate (15mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Hypophosphatemia | 1 Participants |
| Moderate (15mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Neuropathy | 0 Participants |
| Moderate (15mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Pain | 0 Participants |
| Moderate (15mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Elevated INR | 0 Participants |
| Moderate (15mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Hypokalemia | 0 Participants |
| Moderate (15mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Hyponatremia | 0 Participants |
| Severe (20mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Petechiae/purpura | 1 Participants |
| Severe (20mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Generalized weakness | 2 Participants |
| Severe (20mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Hypotension | 1 Participants |
| Severe (20mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Dehydration | 0 Participants |
| Severe (20mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Constipation | 0 Participants |
| Severe (20mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Anemia | 1 Participants |
| Severe (20mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Confusion | 1 Participants |
| Severe (20mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Pulmonary hemorrhage | 1 Participants |
| Severe (20mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Neuropathy | 1 Participants |
| Severe (20mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Infection (including febrile neutropenia) | 3 Participants |
| Severe (20mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Cerebrovascular ischemia | 0 Participants |
| Severe (20mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Fatigue | 1 Participants |
| Severe (20mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Ascites | 1 Participants |
| Severe (20mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Hypophosphatemia | 1 Participants |
| Severe (20mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Edema | 1 Participants |
| Severe (20mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Elevated INR | 1 Participants |
| Severe (20mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Hyperkalemia | 0 Participants |
| Severe (20mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Anorexia/weight loss | 1 Participants |
| Severe (20mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Dyspnea | 1 Participants |
| Severe (20mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Thrombocytopenia | 2 Participants |
| Severe (20mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Neutropenia | 4 Participants |
| Severe (20mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Hyponatremia | 1 Participants |
| Severe (20mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Hypokalemia | 2 Participants |
| Severe (20mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Pain | 1 Participants |
| Severe (20mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Hypertension | 0 Participants |
| Severe (20mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Hypercalcemia | 0 Participants |
| Severe (20mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Hallucinations | 0 Participants |
| Severe (20mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Hyperglycemia | 1 Participants |
| Severe (20mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Diarrhea | 0 Participants |
| Severe (20mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Lymphopenia | 1 Participants |
| Severe (20mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Abnormal LFTs | 3 Participants |
| Severe (20mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Thromboembolism | 0 Participants |
| Severe (7.5mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Thromboembolism | 0 Participants |
| Severe (7.5mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Infection (including febrile neutropenia) | 0 Participants |
| Severe (7.5mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Hyperkalemia | 0 Participants |
| Severe (7.5mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Hypertension | 0 Participants |
| Severe (7.5mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Hypotension | 1 Participants |
| Severe (7.5mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Anemia | 0 Participants |
| Severe (7.5mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Hypophosphatemia | 0 Participants |
| Severe (7.5mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Hallucinations | 0 Participants |
| Severe (7.5mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Generalized weakness | 0 Participants |
| Severe (7.5mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Fatigue | 1 Participants |
| Severe (7.5mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Neuropathy | 0 Participants |
| Severe (7.5mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Edema | 0 Participants |
| Severe (7.5mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Dyspnea | 0 Participants |
| Severe (7.5mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Pain | 0 Participants |
| Severe (7.5mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Diarrhea | 0 Participants |
| Severe (7.5mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Constipation | 1 Participants |
| Severe (7.5mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Petechiae/purpura | 0 Participants |
| Severe (7.5mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Dehydration | 0 Participants |
| Severe (7.5mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Confusion | 1 Participants |
| Severe (7.5mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Pulmonary hemorrhage | 0 Participants |
| Severe (7.5mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Cerebrovascular ischemia | 0 Participants |
| Severe (7.5mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Ascites | 0 Participants |
| Severe (7.5mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Anorexia/weight loss | 0 Participants |
| Severe (7.5mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Hyponatremia | 0 Participants |
| Severe (7.5mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Elevated INR | 0 Participants |
| Severe (7.5mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Thrombocytopenia | 0 Participants |
| Severe (7.5mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Neutropenia | 0 Participants |
| Severe (7.5mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Hypokalemia | 0 Participants |
| Severe (7.5mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Hypercalcemia | 0 Participants |
| Severe (7.5mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Lymphopenia | 0 Participants |
| Severe (7.5mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Hyperglycemia | 2 Participants |
| Severe (7.5mg/m2) | Number of Participants With Grade 3 and 4 Toxicities | Abnormal LFTs | 3 Participants |