Advanced Solid Tumors, Hematologic Malignancies
Conditions
Brief summary
This is a phase 1, 2-part, pharmacokinetic study in patients with advanced solid tumors or hematologic malignancies and varying degrees of liver dysfunction (normal function, moderate hepatic impairement or severe hepatic impairment) as defined by the National Cancer Institute (NCI) Organ Dysfunction Working Group.
Interventions
DRUGIXAZOMIB
Sponsors
Millennium Pharmaceuticals, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 18 years or older * Patients must have a diagnosis of an advanced malignant solid tumor or hematologic malignancy for which standard, curative, or life-prolonging treatment does not exist or is no longer effective * Total bilirubin and aspartate aminotransferase (AST) levels consistent with normal hepatic function (total bilirubin and AST ≤ the upper limit of normal), moderate hepatic impairment (total bilirubin \> 1.5 to 3x the upper limit of normal with any AST level) or severe hepatic impairment (total bilirubin \> 3x the upper limit of normal with any AST level) * Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 * Female patients who are postmenopausal for at least 1 year OR are surgically sterile OR if of childbearing potential, agree to practice 2 effective methods of contraception at the same time during the entire study through 90 days after the last dose of study drug OR agree to practice true abstinence * Male patients who agree to practice effective barrier contraception during the entire study and through 90 days after the last dose of study drug OR agree to practice true abstinence * Voluntary written consent * Suitable venous access for the conduct of blood sampling * Appropriate clinical laboratory values as specified in the protocol
Exclusion criteria
* Systemic treatment with strong and moderate inhibitors of CYP1A2, strong and moderate inhibitors of CYP3A, or clinically significant CYP3A inducers or use of Ginkgo biloba or St. John's wort within 14 days before the first dose of study drug * Use of any nicotine-containing products within 14 days before the first dose of study drug * Central Nervous System Involvement or Symptomatic brain metastasis. Patients with brain metastases: must have stable neurologic status following local therapy (surgery or radiation) for at least 2 weeks after completion of the definitive therapy; and must be without neurologic dysfunction that would confound the evaluation of neurologic and other AEs * Female patients who are lactating or breastfeeding or have a positive serum pregnancy test * Serious medical or psychiatric illness that could interfere with participation in the study * Treatment with any investigational products or radiotherapy within 21 days before the first dose of study drug * Systemic anticancer therapy within 14 days before the first dose of study drug * Exposure to nitrosoureas or mitomycin C within 6 weeks before the first dose of study drug * Treatment with therapeutic monoclonal antibodies or antibody-drug conjugates within 60 days before the first dose of study drug * Radiotherapy or major surgery within the 14 days preceding the first dose of study drug * Infection requiring systemic intravenous antibiotic therapy or other serious infection within 14 days before the first dose of study drug * Life-threatening illness unrelated to cancer * Severe CNS, pulmonary, or renal disease not related to the patient's cancer * Known human immunodeficiency virus (HIV) positive * Evidence of uncontrolled cardiovascular conditions * QTc \> 500 milliseconds (msec) on a 12-lead ECG obtained during the Screening period * Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of IXAZOMIB * Known allergy to the study medication, its analogues, or excipients in the formulation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Unbound AUC(0-last): Unbound Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib | Part A, Day 1: Pre-dose and at multiple timepoints (up to 336 hours) post-dose | — |
| Unbound Cmax: Unbound Maximum Observed Plasma Concentration for Ixazomib | Part A, Day 1: Pre-dose and at multiple timepoints (up to 336 hours) post-dose | — |
| Tmax- Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | Part A, Day 1: Pre-dose and at multiple timepoints (up to 336 hours) post-dose | — |
| Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | Baseline up to 30 days after last dose of study drug (Day 45 for each treatment cycle for up to a maximum of 12 cycles [28 days treatment cycles]) | An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. |
| Number of Participants Reporting Clinically Significant Change From Baseline in Laboratory Values | Baseline up to Day 15 for each treatment cycle (28 days treatment cycle for up to a maximum of 12 cycles) | The number of participants with any markedly abnormal standard safety laboratory values collected throughout study. |
| Number of Participants Reporting Clinically Significant Change From Baseline in Vital Signs | Baseline up to Day 15 for each treatment cycle (28 days treatment cycle for up to a maximum of 12 cycles) | Vital signs included body temperature (oral or tympanic measurement), sitting blood pressure (after the participant has rested for at least 5 minutes), and pulse (bpm). |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 4 investigative sites in the United States from 27 August 2013 to 25 March 2015.
Pre-assignment details
Participants with diagnosis of advanced solid tumors or hematologic malignancies having varying degrees of liver dysfunction enrolled in 1 of 3 treatment groups to receive ixazomib 4 mg (normal hepatic function), 2.3 mg (moderate impairment), 1.5 mg (severe impairment) on Day 1 (Part A, 15 day cycle) and on Days 1,8 and 15(Part B, 28 day cycle).
Participants by arm
| Arm | Count |
|---|---|
| Normal Hepatic Function (Ixazomib 4 mg) Ixazomib 4 mg, capsule, orally, on Day 1 in the pharmacokinetic part (Part A, 15-day cycle) and once on Days 1, 8 and 15 in the 28 day treatment cycle part (Part B) in participants with normal hepatic function. | 13 |
| Moderate Hepatic Impairment (Ixazomib 2.3 mg) Ixazomib 2.3 mg, capsule, orally, on Day 1 in the pharmacokinetic part (Part A, 15-day cycle) and once on Days 1, 8 and 15 in the 28 day treatment cycle part (Part B) in participants with moderate hepatic impairment. | 15 |
| Severe Hepatic Impairment (Ixazomib 1.5 mg) Ixazomib 1.5 mg, capsule, orally, on Day 1 in the pharmacokinetic part (Part A, 15-day cycle) and once on Days 1, 8 and 15 in the 28 day treatment cycle part (Part B) in participants with severe hepatic impairment. | 20 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Part A: Pharmacokinetic Period | Not evaluable for PK analyses | 1 | 2 | 2 |
| Part B: Treatment Period | Adverse Event | 1 | 2 | 3 |
| Part B: Treatment Period | Progressive disease | 10 | 12 | 15 |
| Part B: Treatment Period | Withdrawal by Subject | 2 | 1 | 2 |
Baseline characteristics
| Characteristic | Normal Hepatic Function (Ixazomib 4 mg) | Total | Severe Hepatic Impairment (Ixazomib 1.5 mg) | Moderate Hepatic Impairment (Ixazomib 2.3 mg) |
|---|---|---|---|---|
| Age, Continuous | 58.8 years STANDARD_DEVIATION 15.19 | 56.2 years STANDARD_DEVIATION 14.45 | 54.5 years STANDARD_DEVIATION 13.84 | 56.2 years STANDARD_DEVIATION 15.26 |
| Baseline aspartate aminotransferase (AST) | 21.04 units per liter (U/L) STANDARD_DEVIATION 6.884 | 141.09 units per liter (U/L) STANDARD_DEVIATION 167.256 | 197.48 units per liter (U/L) STANDARD_DEVIATION 198.211 | 169.97 units per liter (U/L) STANDARD_DEVIATION 147.433 |
| Baseline Eastern Cooperative Oncology Group (ECOG) performance status 0 | 1 participants | 2 participants | 1 participants | 0 participants |
| Baseline Eastern Cooperative Oncology Group (ECOG) performance status 1 | 12 participants | 46 participants | 19 participants | 15 participants |
| Baseline total bilirubin | 7.43 micro mole per liter (mcmol/L) STANDARD_DEVIATION 3.092 | 59.85 micro mole per liter (mcmol/L) STANDARD_DEVIATION 66.249 | 108.61 micro mole per liter (mcmol/L) STANDARD_DEVIATION 78.372 | 40.25 micro mole per liter (mcmol/L) STANDARD_DEVIATION 5.594 |
| Disease type at diagnosis Other | 3 participants | 6 participants | 2 participants | 1 participants |
| Disease type at diagnosis Solid tumor | 10 participants | 42 participants | 18 participants | 14 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 4 Participants | 0 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 39 Participants | 20 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 5 Participants | 0 Participants | 2 Participants |
| Height | 168.6 centimeter (cm) STANDARD_DEVIATION 6.79 | 169.0 centimeter (cm) STANDARD_DEVIATION 19.01 | 169.6 centimeter (cm) STANDARD_DEVIATION 27.54 | 168.6 centimeter (cm) STANDARD_DEVIATION 12.56 |
| Months from initial diagnosis to first dose of ixazomib | 56.5 months STANDARD_DEVIATION 43.4 | 37.4 months STANDARD_DEVIATION 32.56 | 35.2 months STANDARD_DEVIATION 28.73 | 23.7 months STANDARD_DEVIATION 16.59 |
| Participants with prior antineoplastic therapy | 13 participants | 48 participants | 20 participants | 15 participants |
| Participant with prior radiation Had no prior radiation | 7 participants | 25 participants | 9 participants | 9 participants |
| Participant with prior radiation Had prior radiation | 6 participants | 23 participants | 11 participants | 6 participants |
| Participant with prior surgery Had no prior surgery | 1 participants | 4 participants | 2 participants | 1 participants |
| Participant with prior surgery Had prior surgery | 12 participants | 44 participants | 18 participants | 14 participants |
| Race/Ethnicity, Customized Asian | 0 participants | 2 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Black or African American | 2 participants | 10 participants | 6 participants | 2 participants |
| Race/Ethnicity, Customized Other | 0 participants | 4 participants | 0 participants | 4 participants |
| Race/Ethnicity, Customized White | 11 participants | 32 participants | 13 participants | 8 participants |
| Sex: Female, Male Female | 7 Participants | 20 Participants | 6 Participants | 7 Participants |
| Sex: Female, Male Male | 6 Participants | 28 Participants | 14 Participants | 8 Participants |
| Weight | 74.42 kilogram (kg) STANDARD_DEVIATION 16.788 | 76.27 kilogram (kg) STANDARD_DEVIATION 18.431 | 76.94 kilogram (kg) STANDARD_DEVIATION 23.498 | 76.97 kilogram (kg) STANDARD_DEVIATION 12.05 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 12 / 13 | 14 / 15 | 17 / 20 |
| serious Total, serious adverse events | 6 / 13 | 10 / 15 | 15 / 20 |
Outcome results
Primary
Number of Participants Reporting Clinically Significant Change From Baseline in Laboratory Values
The number of participants with any markedly abnormal standard safety laboratory values collected throughout study.
Time frame: Baseline up to Day 15 for each treatment cycle (28 days treatment cycle for up to a maximum of 12 cycles)
Population: The safety analysis population was defined as participants who received at least 1 dose of ixazomib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Normal Hepatic Function (Ixazomib 4 mg) | Number of Participants Reporting Clinically Significant Change From Baseline in Laboratory Values | 0 participants |
| Moderate Hepatic Impairment (Ixazomib 2.3 mg) | Number of Participants Reporting Clinically Significant Change From Baseline in Laboratory Values | 0 participants |
| Severe Hepatic Impairment (Ixazomib 1.5 mg) | Number of Participants Reporting Clinically Significant Change From Baseline in Laboratory Values | 0 participants |
Primary
Number of Participants Reporting Clinically Significant Change From Baseline in Vital Signs
Vital signs included body temperature (oral or tympanic measurement), sitting blood pressure (after the participant has rested for at least 5 minutes), and pulse (bpm).
Time frame: Baseline up to Day 15 for each treatment cycle (28 days treatment cycle for up to a maximum of 12 cycles)
Population: The safety analysis population was defined as participants who received at least 1 dose of ixazomib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Normal Hepatic Function (Ixazomib 4 mg) | Number of Participants Reporting Clinically Significant Change From Baseline in Vital Signs | 0 participants |
| Moderate Hepatic Impairment (Ixazomib 2.3 mg) | Number of Participants Reporting Clinically Significant Change From Baseline in Vital Signs | 0 participants |
| Severe Hepatic Impairment (Ixazomib 1.5 mg) | Number of Participants Reporting Clinically Significant Change From Baseline in Vital Signs | 0 participants |
Primary
Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAE) and Serious Adverse Events (SAE)
An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.
Time frame: Baseline up to 30 days after last dose of study drug (Day 45 for each treatment cycle for up to a maximum of 12 cycles [28 days treatment cycles])
Population: The safety analysis population was defined as participants who received at least 1 dose of ixazomib.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Normal Hepatic Function (Ixazomib 4 mg) | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | TEAE | 13 participants |
| Normal Hepatic Function (Ixazomib 4 mg) | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | SAE | 6 participants |
| Moderate Hepatic Impairment (Ixazomib 2.3 mg) | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | TEAE | 15 participants |
| Moderate Hepatic Impairment (Ixazomib 2.3 mg) | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | SAE | 10 participants |
| Severe Hepatic Impairment (Ixazomib 1.5 mg) | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | TEAE | 20 participants |
| Severe Hepatic Impairment (Ixazomib 1.5 mg) | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | SAE | 15 participants |
Primary
Tmax- Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib
Time frame: Part A, Day 1: Pre-dose and at multiple timepoints (up to 336 hours) post-dose
Population: The PK analysis population was defined as participants who received the single dose of ixazomib in Part A of the study, did not receive any excluded concomitant medications through the completion of PK sampling, and had sufficient concentration-time data to permit the reliable estimation of PK parameters by noncompartmental analysis methods.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Normal Hepatic Function (Ixazomib 4 mg) | Tmax- Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | 0.950 hours |
| Moderate Hepatic Impairment (Ixazomib 2.3 mg) | Tmax- Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | 1.500 hours |
| Severe Hepatic Impairment (Ixazomib 1.5 mg) | Tmax- Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | 1.205 hours |
Primary
Unbound AUC(0-last): Unbound Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib
Time frame: Part A, Day 1: Pre-dose and at multiple timepoints (up to 336 hours) post-dose
Population: The PK analysis population was defined as participants who received the single dose of ixazomib in Part A of the study, did not receive any excluded concomitant medications through the completion of PK sampling, and had sufficient concentration-time data to permit the reliable estimation of PK parameters by noncompartmental analysis methods.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Hepatic Function (Ixazomib 4 mg) | Unbound AUC(0-last): Unbound Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib | 9.6476 nanogram*hours per milliliter (ng*hr/mL) | Standard Deviation 5.39885 |
| Moderate Hepatic Impairment (Ixazomib 2.3 mg) | Unbound AUC(0-last): Unbound Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib | 7.3292 nanogram*hours per milliliter (ng*hr/mL) | Standard Deviation 5.35269 |
| Severe Hepatic Impairment (Ixazomib 1.5 mg) | Unbound AUC(0-last): Unbound Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib | 4.4383 nanogram*hours per milliliter (ng*hr/mL) | Standard Deviation 4.21266 |
Primary
Unbound Cmax: Unbound Maximum Observed Plasma Concentration for Ixazomib
Time frame: Part A, Day 1: Pre-dose and at multiple timepoints (up to 336 hours) post-dose
Population: The PK analysis population was defined as participants who received the single dose of ixazomib in Part A of the study, did not receive any excluded concomitant medications through the completion of PK sampling, and had sufficient concentration-time data to permit the reliable estimation of PK parameters by noncompartmental analysis methods.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Hepatic Function (Ixazomib 4 mg) | Unbound Cmax: Unbound Maximum Observed Plasma Concentration for Ixazomib | 0.50893 nanogram per milliliter (ng/mL) | Standard Deviation 0.271928 |
| Moderate Hepatic Impairment (Ixazomib 2.3 mg) | Unbound Cmax: Unbound Maximum Observed Plasma Concentration for Ixazomib | 0.37245 nanogram per milliliter (ng/mL) | Standard Deviation 0.385113 |
| Severe Hepatic Impairment (Ixazomib 1.5 mg) | Unbound Cmax: Unbound Maximum Observed Plasma Concentration for Ixazomib | 0.23176 nanogram per milliliter (ng/mL) | Standard Deviation 0.271358 |