Loss of Chromosome 17p, Recurrent Plasma Cell Myeloma
Conditions
Brief summary
This phase I/II trial studies the side effects and best dose of idasanutlin and ixazomib citrate when given together with dexamethasone in treating patients with multiple myeloma that has returned after a period of improvement. Drugs used in chemotherapy, such as idasanutlin and dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Ixazomib citrate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving idasanutlin, ixazomib citrate, and dexamethasone together may work better in treating patients with multiple myeloma.
Detailed description
PRIMARY OBJECTIVES: I. To determine the maximum tolerated doses (MTD) of idasanutlin and ixazomib (ixazomib citrate) to be used in combination with dexamethasone in patients with relapsed or refractory multiple myeloma with TP53 (17p) deletion. (Phase I) II. To evaluate the confirmed response rate of ixazomib and idasanutlin used in combination with dexamethasone in patients with relapsed or refractory multiple myeloma with TP53 (17p) deletion. (Phase II) SECONDARY OBJECTIVES: I. To describe the toxicities and the confirmed response rate associated with the combination of idasanutlin, ixazomib and dexamethasone. (Phase I) II. To describe the toxicities associated with the combination of idasanutlin, ixazomib and dexamethasone. (Phase II) III. To describe the complete response (CR) and very good partial response (VGPR) rates. (Phase II) IV. To assess progression-free and overall survival. (Phase II) TERTIARY OBJECTIVES: I. Assess murine double minute 2 (MDM2) inhibition in bone marrow plasma cells. II. Identify potential biomarkers associated with response. III. To explore the pharmacodynamic effects of idasanutlin. OUTLINE: This is a phase I, dose-escalation study of idasanutlin and ixazomib citrate followed by a phase II study. Patients receive ixazomib citrate orally (PO) on days 1, 8, and 15 and idasanutlin PO once daily (QD) on days 1-5 every 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive dexamethasone PO on days 1, 8, 15, and 22 every 28 days for 12 courses at the discretion of the treating physician. After completion of study treatment, patients are followed up for 30 days, every 3 months, and then every 6 months.
Interventions
DRUGDexamethasone
Given PO
DRUGIdasanutlin
Given PO
DRUGIxazomib Citrate
Given PO
OTHERLaboratory Biomarker Analysis
Correlative studies
OTHERPharmacological Study
Correlative studies
Sponsors
Mayo Clinic
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of multiple myeloma (MM) with deletion 17p (del17p) or monosomy 17 by fluorescence in situ hybridization (FISH) who have received at least one line of therapy * Calculated creatinine clearance (using Cockcroft-Gault equation) \>= 30 mL/min * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 3.0 x upper limit of normal (ULN) * Total bilirubin =\< 1.5 x the upper limit of the normal range (ULN) * Absolute neutrophil count (ANC) \>= 1500/mm\^3 * Platelet count \>= 75,000/mm\^3 * Hemoglobin \>= 8.0 g/dL * NOTE: white blood count and platelet count criteria must be met without any transfusion or growth factor support * Patients with measurable disease defined as at least one of the following: * Serum monoclonal protein \>= 1.0 g/dL by protein electrophoresis * \> 200 mg of monoclonal protein in the urine on 24-hour electrophoresis * Serum immunoglobulin free light chain \>= 10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio * Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2 * Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information * Negative pregnancy test done =\< 7 days prior to registration, for women of childbearing potential only * Willing to follow strict birth control measures as suggested below * Female patients: if they are of childbearing potential (except if postmenopausal for at least 1 year before the screening visit, OR are surgically sterile), agree to one of the following: * Practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 90 days after the last dose of study drug, OR * Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject; (periodic abstinence \[eg, calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal are not acceptable methods of contraception) * Male patients: even if surgically sterilized (ie, status post-vasectomy), must agree to one of the following: * Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR * Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject; (periodic abstinence \[eg, calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal are not acceptable methods of contraception) * Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study) * Willing to provide bone marrow and blood samples for correlative research purposes
Exclusion criteria
* Other malignancy requiring active therapy * EXCEPTIONS: Non-melanoma skin cancer, ductal carcinoma in situ (DCIS) or carcinoma-in-situ of the cervix * NOTE: if there is a history of prior malignancy, they must not be receiving other specific treatment for their cancer * Other co-morbidity which would interfere with patient's ability to participate in trial, e.g. uncontrolled infection, uncompensated heart or lung disease * Other concurrent chemotherapy, radiotherapy, or any ancillary therapy considered investigational * NOTE: bisphosphonates are considered to be supportive care rather than therapy, and are thus allowed while on protocol treatment * Patient has \>= grade 2 peripheral neuropathy, or grade 1 with pain on clinical examination during the screening period * Major surgery =\< 14 days before study registration * All CYP2C8 inhibitors, inducers, and substrates should be discontinued \>= 7 days prior to registration; systemic treatment with CYP2C8 inhibitors (anastrozole, montelukast, quercetin, trimethoprim, gemfibrozil, rosiglitazone, pioglitazone), inducers (carbamazepine, phenytoin, rifabutin, rifampin), or substrates (amiodarone, repaglinide, rosiglitazone, sorafenib, torsemide) should be discontinued \>= 7 days prior to registration * Systemic treatment with strong inhibitors of CYP3A4 (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A4 inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital, Gingko biloba, St. John's wort) are not allowed =\< 14 days before registration * Evidence of current uncontrolled cardiovascular conditions, including cardiac arrhythmias, congestive heart failure, angina, or myocardial infarction within the past 6 months; Note: prior to study entry, any electrocardiogram (ECG) abnormality at screening must be documented by the investigator as not medically relevant * Corrected QT (QTc) \> 470 milliseconds (msec) on a 12-lead ECG obtained during the Screening period * Note: If a machine reading is above this value, the ECG should be reviewed by a qualified reader and confirmed on a subsequent ECG * Known human immunodeficiency virus (HIV) positive * Known hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection * Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol * Known allergy to any of the study medications, their analogues or excipients in the various formulations * Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib or idasanutlin including difficulty swallowing * Diarrhea \> grade 1, based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grading, or currently taking antidiarrheals * Need for ongoing therapeutic anticoagulation * Female patients who are lactating or have a positive serum pregnancy test during the screening period * Patients that have previously been treated with ixazomib, or who participated in a blinded study with ixazomib (whether treated with ixazomib or not)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Confirmed Response, Defined as a Patient Who Has Achieved a Stringent Complete Response (sCR), Complete Response (CR), Very Good Partial Response (VGPR), or Partial Response (PR) on Two Consecutive Evaluations (Phase II) | Up to 6 months | Responses will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease in this patient population. The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true success proportion will be calculated. |
| The Number of Participants Who Experienced Dose Limiting Toxicities. Maximum Tolerated Dose (MTD) of Ixazomib Citrate and Idasanutlin in Combination With Dexamethasone (Phase I) | 28 days | Defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) in at least one-third of patients (at least 2 of a maximum of 6 new patients). DLT is graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase II) | Up to 6 months | The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. |
| Overall Survival (Phase II) | Up to 3 years | The distribution of overall survival will be estimated using the method of Kaplan-Meier. |
| Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | 30 days after the last dose of study treatment, up to 3 years | Overall toxicity incidence as well as toxicity profiles by dose level, patient and tumor site will be explored and summarized. Frequency distributions, graphical techniques and other descriptive measures will form the basis of these analyses. |
| Progression Free Survival (Phase II) | Up to 3 years | The distribution of progression-free survival will be estimated using the method of Kaplan-Meier. |
| Rate of Complete Response (CR) (Phase II) | Up to 6 months | The rate of CR will be estimated by the number of patients with a sCR or CR or divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true success proportions will be calculated. |
| Rate of Partial Response (PR) (Phase II) | Up to 6 months | The rate of PR will be estimated by the number of patients with a VGPR or PR divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true success proportions will be calculated. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Changes in Macrophage Inhibitory Cytokine-1 (MIC) Levels | Baseline up to 6 months | Effect of inhibition of mdm2 will be assessed by measuring MIC levels. MIC levels at each time point and changes after treatment will be both graphically and quantitatively summarized and explored. Changes from baseline will be evaluated using Wilcoxon's signed rank test. |
| Impact of MDM2 Inhibition on Activation of p53 and Clonal Selection | Up to 6 months | Impact of MDM2 inhibition on activation of p53 and clonal selection examined using gene expression profiling and exome sequencing |
| Potential Biomarkers Associated With Response Determined Using Gene Expression Profiling | Up to 6 months | Potential biomarkers associated with response will be assessed in an exploratory manner. Potential markers will be determined using gene expression profiling. The correlation between potential biomarkers and response (responders vs. non-responders) will be evaluated using Fisher's exact and Wilcoxon rank sum tests, where appropriate. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase 1: Dose Level 0 Phase 1: Ixazomib 4.0 mg, Idasanutlin 100 mg, and Dexamethasone 40 mg | 4 |
| Phase 1: Dose Level 1 Phase 1: Ixazomib 4.0 mg, Idasanutlin 200 mg, and Dexamethasone 40 mg | 7 |
| Phase 1: Dose Level 2 Phase 1: Ixazomib 4.0 mg, Idasanutlin 250 mg, and Dexamethasone 40 mg | 4 |
| Phase 2: Dose Level 1 Phase 2: Ixazomib 4.0 mg, Idasanutlin 200 mg, and Dexamethasone 40 mg | 18 |
| Total | 33 |
Baseline characteristics
| Characteristic | Phase 1: Dose Level 0 | Phase 1: Dose Level 1 | Phase 1: Dose Level 2 | Phase 2: Dose Level 1 | Total |
|---|---|---|---|---|---|
| Age, Continuous | 67.3 years STANDARD_DEVIATION 6.6 | 60.9 years STANDARD_DEVIATION 8.69 | 63.0 years STANDARD_DEVIATION 12.03 | 65.0 years STANDARD_DEVIATION 7.65 | 64.2 years STANDARD_DEVIATION 8.19 |
| Disease category Refractory | 0 Participants | 3 Participants | 3 Participants | 3 Participants | 9 Participants |
| Disease category Relapsed | 4 Participants | 4 Participants | 1 Participants | 15 Participants | 24 Participants |
| ECOG Performance Status (PS) 0 | 1 Participants | 2 Participants | 2 Participants | 6 Participants | 11 Participants |
| ECOG Performance Status (PS) 1 | 3 Participants | 4 Participants | 2 Participants | 10 Participants | 19 Participants |
| ECOG Performance Status (PS) 2 | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 7 Participants | 4 Participants | 16 Participants | 31 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| (If serum M-spike), parameter followed for serum M-spike Missing | 0 Participants | 3 Participants | 2 Participants | 12 Participants | 17 Participants |
| (If serum M-spike), parameter followed for serum M-spike SPEP measurement | 4 Participants | 4 Participants | 2 Participants | 6 Participants | 16 Participants |
| Mayo Clinic Stratification for Myeloma and Risk-Adapted Therapy (mSMART) High Risk | 4 Participants | 6 Participants | 4 Participants | 14 Participants | 28 Participants |
| Mayo Clinic Stratification for Myeloma and Risk-Adapted Therapy (mSMART) Standard Risk | 0 Participants | 1 Participants | 0 Participants | 4 Participants | 5 Participants |
| Parameter for response Serum immunoglobulin free light chain >= 10 mg/dL | 0 Participants | 3 Participants | 2 Participants | 4 Participants | 9 Participants |
| Parameter for response Serum M-spike >= 1 g/dL and urine M-spike >= 200 mg/24 hours | 1 Participants | 2 Participants | 0 Participants | 2 Participants | 5 Participants |
| Parameter for response Serum M-spike >= 1 g/dL only | 3 Participants | 2 Participants | 2 Participants | 4 Participants | 11 Participants |
| Parameter for response Urine M-spike >= 200 mg/24 hours only | 0 Participants | 0 Participants | 0 Participants | 8 Participants | 8 Participants |
| Prior transplant related to this cancer No | 1 Participants | 1 Participants | 1 Participants | 4 Participants | 7 Participants |
| Prior transplant related to this cancer Yes | 3 Participants | 6 Participants | 3 Participants | 14 Participants | 26 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 0 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 5 Participants | 4 Participants | 15 Participants | 27 Participants |
| Revised International Staging System I | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 3 Participants |
| Revised International Staging System II | 2 Participants | 5 Participants | 4 Participants | 14 Participants | 25 Participants |
| Revised International Staging System III | 2 Participants | 1 Participants | 0 Participants | 2 Participants | 5 Participants |
| Serum Creatinine (mg/dL) | 0.8 mg/dL STANDARD_DEVIATION 0.24 | 1.1 mg/dL STANDARD_DEVIATION 0.6 | 0.9 mg/dL STANDARD_DEVIATION 0.19 | 1.2 mg/dL STANDARD_DEVIATION 0.53 | 1.1 mg/dL STANDARD_DEVIATION 0.49 |
| Serum LDH (U/L) | 201.3 (U/L) STANDARD_DEVIATION 43.94 | 198.7 (U/L) STANDARD_DEVIATION 162.89 | 349.0 (U/L) STANDARD_DEVIATION 239.56 | 259.6 (U/L) STANDARD_DEVIATION 119.45 | 249.5 (U/L) STANDARD_DEVIATION 144.49 |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 1 Participants | 5 Participants | 8 Participants |
| Sex: Female, Male Male | 3 Participants | 6 Participants | 3 Participants | 13 Participants | 25 Participants |
| What was the International Staging System myeloma stage? Missing | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| What was the International Staging System myeloma stage? Stage I | 2 Participants | 3 Participants | 3 Participants | 7 Participants | 15 Participants |
| What was the International Staging System myeloma stage? Stage II | 0 Participants | 2 Participants | 1 Participants | 5 Participants | 8 Participants |
| What was the International Staging System myeloma stage? Stage III | 2 Participants | 1 Participants | 0 Participants | 2 Participants | 5 Participants |
| What was the International Staging System myeloma stage? Unknown | 0 Participants | 0 Participants | 0 Participants | 4 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 7 | 0 / 4 | 2 / 17 |
| other Total, other adverse events | 4 / 4 | 7 / 7 | 4 / 4 | 17 / 17 |
| serious Total, serious adverse events | 0 / 4 | 3 / 7 | 0 / 4 | 6 / 17 |
Outcome results
Primary
Rate of Confirmed Response, Defined as a Patient Who Has Achieved a Stringent Complete Response (sCR), Complete Response (CR), Very Good Partial Response (VGPR), or Partial Response (PR) on Two Consecutive Evaluations (Phase II)
Responses will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease in this patient population. The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true success proportion will be calculated.
Time frame: Up to 6 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1: Dose Level 0 | Rate of Confirmed Response, Defined as a Patient Who Has Achieved a Stringent Complete Response (sCR), Complete Response (CR), Very Good Partial Response (VGPR), or Partial Response (PR) on Two Consecutive Evaluations (Phase II) | PR | 2 Participants |
| Phase 1: Dose Level 0 | Rate of Confirmed Response, Defined as a Patient Who Has Achieved a Stringent Complete Response (sCR), Complete Response (CR), Very Good Partial Response (VGPR), or Partial Response (PR) on Two Consecutive Evaluations (Phase II) | SD | 6 Participants |
| Phase 1: Dose Level 0 | Rate of Confirmed Response, Defined as a Patient Who Has Achieved a Stringent Complete Response (sCR), Complete Response (CR), Very Good Partial Response (VGPR), or Partial Response (PR) on Two Consecutive Evaluations (Phase II) | NA | 14 Participants |
| Phase 1: Dose Level 0 | Rate of Confirmed Response, Defined as a Patient Who Has Achieved a Stringent Complete Response (sCR), Complete Response (CR), Very Good Partial Response (VGPR), or Partial Response (PR) on Two Consecutive Evaluations (Phase II) | CR | 0 Participants |
| Phase 1: Dose Level 0 | Rate of Confirmed Response, Defined as a Patient Who Has Achieved a Stringent Complete Response (sCR), Complete Response (CR), Very Good Partial Response (VGPR), or Partial Response (PR) on Two Consecutive Evaluations (Phase II) | VGPR | 0 Participants |
| Phase 1: Dose Level 0 | Rate of Confirmed Response, Defined as a Patient Who Has Achieved a Stringent Complete Response (sCR), Complete Response (CR), Very Good Partial Response (VGPR), or Partial Response (PR) on Two Consecutive Evaluations (Phase II) | sCR | 0 Participants |
Primary
The Number of Participants Who Experienced Dose Limiting Toxicities. Maximum Tolerated Dose (MTD) of Ixazomib Citrate and Idasanutlin in Combination With Dexamethasone (Phase I)
Defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) in at least one-third of patients (at least 2 of a maximum of 6 new patients). DLT is graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1: Dose Level 0 | The Number of Participants Who Experienced Dose Limiting Toxicities. Maximum Tolerated Dose (MTD) of Ixazomib Citrate and Idasanutlin in Combination With Dexamethasone (Phase I) | 0 Participants |
| Phase 1: Dose Level 1 | The Number of Participants Who Experienced Dose Limiting Toxicities. Maximum Tolerated Dose (MTD) of Ixazomib Citrate and Idasanutlin in Combination With Dexamethasone (Phase I) | 0 Participants |
| Phase 1: Dose Level 2 | The Number of Participants Who Experienced Dose Limiting Toxicities. Maximum Tolerated Dose (MTD) of Ixazomib Citrate and Idasanutlin in Combination With Dexamethasone (Phase I) | 2 Participants |
| Phase 2: Dose Level 1 | The Number of Participants Who Experienced Dose Limiting Toxicities. Maximum Tolerated Dose (MTD) of Ixazomib Citrate and Idasanutlin in Combination With Dexamethasone (Phase I) | 1 Participants |
Secondary
Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I)
Overall toxicity incidence as well as toxicity profiles by dose level, patient and tumor site will be explored and summarized. Frequency distributions, graphical techniques and other descriptive measures will form the basis of these analyses.
Time frame: 30 days after the last dose of study treatment, up to 3 years
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1: Dose Level 0 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 3+ Adverse Events, Regardless of Attribution | 3 Participants |
| Phase 1: Dose Level 0 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 5 Heme Adverse Events, At Least Possibly Related | 0 Participants |
| Phase 1: Dose Level 0 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 3+ Heme Adverse Events, Regardless of Attribution | 3 Participants |
| Phase 1: Dose Level 0 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 4+ Non-heme Adverse Events, At Least Possibly Related | 0 Participants |
| Phase 1: Dose Level 0 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 5 Heme Adverse Events, Regardless of Attribution | 0 Participants |
| Phase 1: Dose Level 0 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 3+ Heme Adverse Events, At Least Possibly Related | 2 Participants |
| Phase 1: Dose Level 0 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 4+ Adverse Events, Regardless of Attribution | 0 Participants |
| Phase 1: Dose Level 0 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 4+ Heme Adverse Events, At Least Possibly Related | 0 Participants |
| Phase 1: Dose Level 0 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 4+ Heme Adverse Events, Regardless of Attribution | 0 Participants |
| Phase 1: Dose Level 0 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 5 Non-heme Adverse Events, At Least Possibly Related | 0 Participants |
| Phase 1: Dose Level 0 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 4+ Non-heme Adverse Events, Regardless of Attribution | 0 Participants |
| Phase 1: Dose Level 0 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 4+ Adverse Events, At Least Possibly Related | 0 Participants |
| Phase 1: Dose Level 0 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 5 Non-heme Adverse Events, Regardless of Attribution | 0 Participants |
| Phase 1: Dose Level 0 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 3+ Non-heme Adverse Events, At Least Possibly Related | 1 Participants |
| Phase 1: Dose Level 0 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 5 Adverse Events, Regardless of Attribution | 0 Participants |
| Phase 1: Dose Level 0 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 3+ Adverse Events, At Least Possibly Related | 2 Participants |
| Phase 1: Dose Level 0 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 3+ Non-heme Adverse Events, Regardless of Attribution | 1 Participants |
| Phase 1: Dose Level 0 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 5 Adverse Events, At Least Possibly Related | 0 Participants |
| Phase 1: Dose Level 1 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 4+ Adverse Events, At Least Possibly Related | 1 Participants |
| Phase 1: Dose Level 1 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 3+ Adverse Events, Regardless of Attribution | 4 Participants |
| Phase 1: Dose Level 1 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 3+ Adverse Events, At Least Possibly Related | 4 Participants |
| Phase 1: Dose Level 1 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 4+ Adverse Events, Regardless of Attribution | 1 Participants |
| Phase 1: Dose Level 1 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 4+ Non-heme Adverse Events, Regardless of Attribution | 0 Participants |
| Phase 1: Dose Level 1 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 5 Adverse Events, Regardless of Attribution | 0 Participants |
| Phase 1: Dose Level 1 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 5 Adverse Events, At Least Possibly Related | 0 Participants |
| Phase 1: Dose Level 1 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 3+ Heme Adverse Events, Regardless of Attribution | 4 Participants |
| Phase 1: Dose Level 1 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 3+ Heme Adverse Events, At Least Possibly Related | 4 Participants |
| Phase 1: Dose Level 1 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 4+ Heme Adverse Events, Regardless of Attribution | 1 Participants |
| Phase 1: Dose Level 1 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 4+ Heme Adverse Events, At Least Possibly Related | 1 Participants |
| Phase 1: Dose Level 1 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 5 Heme Adverse Events, Regardless of Attribution | 0 Participants |
| Phase 1: Dose Level 1 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 5 Heme Adverse Events, At Least Possibly Related | 0 Participants |
| Phase 1: Dose Level 1 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 3+ Non-heme Adverse Events, Regardless of Attribution | 2 Participants |
| Phase 1: Dose Level 1 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 3+ Non-heme Adverse Events, At Least Possibly Related | 1 Participants |
| Phase 1: Dose Level 1 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 4+ Non-heme Adverse Events, At Least Possibly Related | 0 Participants |
| Phase 1: Dose Level 1 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 5 Non-heme Adverse Events, Regardless of Attribution | 0 Participants |
| Phase 1: Dose Level 1 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 5 Non-heme Adverse Events, At Least Possibly Related | 0 Participants |
| Phase 1: Dose Level 2 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 3+ Adverse Events, Regardless of Attribution | 3 Participants |
| Phase 1: Dose Level 2 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 5 Heme Adverse Events, At Least Possibly Related | 0 Participants |
| Phase 1: Dose Level 2 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 5 Adverse Events, Regardless of Attribution | 0 Participants |
| Phase 1: Dose Level 2 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 5 Non-heme Adverse Events, At Least Possibly Related | 0 Participants |
| Phase 1: Dose Level 2 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 3+ Non-heme Adverse Events, Regardless of Attribution | 0 Participants |
| Phase 1: Dose Level 2 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 4+ Adverse Events, At Least Possibly Related | 2 Participants |
| Phase 1: Dose Level 2 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 5 Non-heme Adverse Events, Regardless of Attribution | 0 Participants |
| Phase 1: Dose Level 2 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 3+ Non-heme Adverse Events, At Least Possibly Related | 0 Participants |
| Phase 1: Dose Level 2 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 4+ Adverse Events, Regardless of Attribution | 3 Participants |
| Phase 1: Dose Level 2 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 3+ Adverse Events, At Least Possibly Related | 3 Participants |
| Phase 1: Dose Level 2 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 4+ Heme Adverse Events, Regardless of Attribution | 3 Participants |
| Phase 1: Dose Level 2 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 3+ Heme Adverse Events, At Least Possibly Related | 3 Participants |
| Phase 1: Dose Level 2 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 4+ Non-heme Adverse Events, Regardless of Attribution | 0 Participants |
| Phase 1: Dose Level 2 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 4+ Heme Adverse Events, At Least Possibly Related | 2 Participants |
| Phase 1: Dose Level 2 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 3+ Heme Adverse Events, Regardless of Attribution | 3 Participants |
| Phase 1: Dose Level 2 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 4+ Non-heme Adverse Events, At Least Possibly Related | 0 Participants |
| Phase 1: Dose Level 2 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 5 Heme Adverse Events, Regardless of Attribution | 0 Participants |
| Phase 1: Dose Level 2 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I) | Grade 5 Adverse Events, At Least Possibly Related | 0 Participants |
Secondary
Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase II)
The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration.
Time frame: Up to 6 months
Population: Participants who had adverse events fitting the criteria
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1: Dose Level 0 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase II) | Grade 5 Heme Adverse Events, At Least Possibly Related | 0 Participants |
| Phase 1: Dose Level 0 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase II) | Grade 3+ Non-heme Adverse Events, Regardless of Attribution | 5 Participants |
| Phase 1: Dose Level 0 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase II) | Grade 5 Non-heme Adverse Events, Regardless of Attribution | 2 Participants |
| Phase 1: Dose Level 0 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase II) | Grade 3+ Adverse Events, Regardless of Attribution | 14 Participants |
| Phase 1: Dose Level 0 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase II) | Grade 3+ Adverse Events, At Least Possibly Related | 13 Participants |
| Phase 1: Dose Level 0 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase II) | Grade 4+ Adverse Events, Regardless of Attribution | 10 Participants |
| Phase 1: Dose Level 0 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase II) | Grade 4+ Adverse Events, At Least Possibly Related | 9 Participants |
| Phase 1: Dose Level 0 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase II) | Grade 5 Adverse Events, Regardless of Attribution | 2 Participants |
| Phase 1: Dose Level 0 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase II) | Grade 5 Adverse Events, At Least Possibly Related | 0 Participants |
| Phase 1: Dose Level 0 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase II) | Grade 3+ Heme Adverse Events, Regardless of Attribution | 13 Participants |
| Phase 1: Dose Level 0 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase II) | Grade 3+ Heme Adverse Events, At Least Possibly Related | 13 Participants |
| Phase 1: Dose Level 0 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase II) | Grade 4+ Heme Adverse Events, Regardless of Attribution | 9 Participants |
| Phase 1: Dose Level 0 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase II) | Grade 4+ Heme Adverse Events, At Least Possibly Related | 9 Participants |
| Phase 1: Dose Level 0 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase II) | Grade 5 Heme Adverse Events, Regardless of Attribution | 0 Participants |
| Phase 1: Dose Level 0 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase II) | Grade 3+ Non-heme Adverse Events, At Least Possibly Related | 3 Participants |
| Phase 1: Dose Level 0 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase II) | Grade 4+ Non-heme Adverse Events, Regardless of Attribution | 4 Participants |
| Phase 1: Dose Level 0 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase II) | Grade 4+ Non-heme Adverse Events, At Least Possibly Related | 2 Participants |
| Phase 1: Dose Level 0 | Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase II) | Grade 5 Non-heme Adverse Events, At Least Possibly Related | 0 Participants |
Secondary
Overall Survival (Phase II)
The distribution of overall survival will be estimated using the method of Kaplan-Meier.
Time frame: Up to 3 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Dose Level 0 | Overall Survival (Phase II) | 21.0 months |
Secondary
Progression Free Survival (Phase II)
The distribution of progression-free survival will be estimated using the method of Kaplan-Meier.
Time frame: Up to 3 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Dose Level 0 | Progression Free Survival (Phase II) | 3.8 months |
Secondary
Rate of Complete Response (CR) (Phase II)
The rate of CR will be estimated by the number of patients with a sCR or CR or divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true success proportions will be calculated.
Time frame: Up to 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1: Dose Level 0 | Rate of Complete Response (CR) (Phase II) | 0 Participants |
Secondary
Rate of Partial Response (PR) (Phase II)
The rate of PR will be estimated by the number of patients with a VGPR or PR divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true success proportions will be calculated.
Time frame: Up to 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1: Dose Level 0 | Rate of Partial Response (PR) (Phase II) | 2 Participants |
Other Pre-specified
Changes in Macrophage Inhibitory Cytokine-1 (MIC) Levels
Effect of inhibition of mdm2 will be assessed by measuring MIC levels. MIC levels at each time point and changes after treatment will be both graphically and quantitatively summarized and explored. Changes from baseline will be evaluated using Wilcoxon's signed rank test.
Time frame: Baseline up to 6 months
Other Pre-specified
Impact of MDM2 Inhibition on Activation of p53 and Clonal Selection
Impact of MDM2 inhibition on activation of p53 and clonal selection examined using gene expression profiling and exome sequencing
Time frame: Up to 6 months
Other Pre-specified
Potential Biomarkers Associated With Response Determined Using Gene Expression Profiling
Potential biomarkers associated with response will be assessed in an exploratory manner. Potential markers will be determined using gene expression profiling. The correlation between potential biomarkers and response (responders vs. non-responders) will be evaluated using Fisher's exact and Wilcoxon rank sum tests, where appropriate.
Time frame: Up to 6 months