Solid Malignancies
Conditions
Brief summary
The purpose of this study is to determine the dose limiting toxicities, minimum tolerated dose and recommended dose for Phase II studies.
Interventions
DRUGIxabepilone
Intravenous (IV) Infusion; 10, 20, 30, 35, 40 & 45 mg/m2, once every 21 days (1 cycle), up to 9 cycles
Sponsors
R-Pharm
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* confirmed diagnosis of a primary solid tumor * measurable or non-measurable disease * progressive disease * men and women greater or equal to 18 years of age.
Exclusion criteria
* women of child bearing potential who are not using birth control * women who are pregnant or breast feeding * women with a positive pregnancy test on enrollment * patients with brain metastasis * prior treatment with Ixabepilone * known history of human immunodeficiency virus (HIV)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicities at Dose Level | Measures taken at Cycle 01 (21-day cycle) | Dose limiting toxicities=any of the following events attributed to Ixabepilone occuring during the first cycle: grade 3/4 nausea, vomiting, or diarrhea despite medical intervention and/or prophylaxis; other Grade ≥3 nonhematological toxicity; any toxicity requiring study therapy discontinuation; delayed recovery from study therapy-related toxicity which delays scheduled re-treatment for \>14 days; Grade 4 neutropenia for ≥5 consecutive days; grade 3/4 neutropenia with sepsis or a fever ≥38.5 C; thrombocytopenia \<25,000 cells/mm3 or bleeding requiring a platelet transfusion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Related Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | From time of screening through post study follow-up at a maximum of 21 9-day cycles. Toxicity assessments occured at least every 4 weeks until all study drug related toxicities. | Adverse events (AEs) and Serious AEs (SAEs) considered possibly, probably, or certainly related to study treatment, graded according to Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 (Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death). |
| Hematology Results - Worst On-Study Grade | Baseline (within 2 weeks of dosing), weekly, and within 72 hours prior to each subsequent 21-day cycle. If CTC Grade 4 hematologic toxicity is observed, complete blood count plus differential and platelets repeated every 3 days until resolution. | Worst on-study grade based on laboratory values graded according to Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. (Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death). |
| Mean Plasma Concentration of Ixabepilone at 40 mg/m2 Dose Level | through 72 hours after start of infusion | Mean concentrations over full time period for the 40 mg/mg2 dose level, established as the Maximum Tolerated Dose. (The Maximum Tolerated Dose was established as 40 mg/m2, based on an investiagtion of Dose Limiting Toxicities, which consisted of Febrile Neutropenia (at 40 mg/m2) in 1 participant and Grade 4 neutropenia lasting ≥5 days (at 45 mg/m2)in 2 participants.) |
| Best Tumor Response, According to Response Evaluation Criteria in Solid Tumors (RECIST) | At Baseline (up to 2 weeks prior to starting therapy), after every 2nd cycle, and at post study follow-upn after a maximum of 9 cycles. | RECIST criteria, wherein complete response = disappearance of all target lesions; partial response = 30% decrease in the sum of the longest diameter of target lesions; progressive disease = 20% increase in the sum of the longest diameter of target lesions, and stable disease = small changes that do not meet above criteria. |
Countries
United States
Participant flow
Pre-assignment details
A total of 39 participants enrolled and 4 participants were never treated (2 reported serious adverse events \[SAEs\] prior to the first dose of study medication and were never treated; 1 had rapid decline in performance status and died prior to the first dose of study medication; no reason was given for the remaining participant).
Participants by arm
| Arm | Count |
|---|---|
| 10 mg/m2 Ixabepilone | 4 |
| 20 mg/m2 Ixabepilone | 3 |
| 30 mg/m2 Ixabepilone | 8 |
| 35 mg/m2 Ixabepilone | 4 |
| 40 mg/m2 Ixabepilone | 11 |
| 45 mg/m2 Ixabepilone | 5 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Death | 1 |
| Overall Study | Disease Progression/Relapse | 23 |
| Overall Study | Investigator Request | 5 |
| Overall Study | Study Drug Toxicity | 4 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Total | 45 mg/m2 | 40 mg/m2 | 20 mg/m2 | 10 mg/m2 | 35 mg/m2 | 30 mg/m2 |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 59.0 years | 52.0 years | 58.0 years | 59.0 years | 63.5 years | 59.5 years | 61.5 years |
| Karnofsky Performance Status 0 to 60 | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Karnofsky Performance Status 70 to 80 | 13 participants | 2 participants | 4 participants | 1 participants | 2 participants | 2 participants | 2 participants |
| Karnofsky Performance Status 90 to 100 | 22 participants | 3 participants | 7 participants | 2 participants | 2 participants | 2 participants | 6 participants |
| Race/Ethnicity, Customized Asian | 4 participants | 1 participants | 1 participants | 0 participants | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Black | 5 participants | 2 participants | 1 participants | 1 participants | 0 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized White | 26 participants | 2 participants | 9 participants | 2 participants | 3 participants | 3 participants | 7 participants |
| Sex: Female, Male Female | 16 Participants | 3 Participants | 5 Participants | 0 Participants | 1 Participants | 2 Participants | 5 Participants |
| Sex: Female, Male Male | 19 Participants | 2 Participants | 6 Participants | 3 Participants | 3 Participants | 2 Participants | 3 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 |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 4 | 3 / 3 | 8 / 8 | 4 / 4 | 11 / 11 | 5 / 5 |
| serious Total, serious adverse events | 2 / 4 | 2 / 3 | 4 / 8 | 1 / 4 | 5 / 11 | 2 / 5 |
Outcome results
Primary
Number of Participants With Dose Limiting Toxicities at Dose Level
Dose limiting toxicities=any of the following events attributed to Ixabepilone occuring during the first cycle: grade 3/4 nausea, vomiting, or diarrhea despite medical intervention and/or prophylaxis; other Grade ≥3 nonhematological toxicity; any toxicity requiring study therapy discontinuation; delayed recovery from study therapy-related toxicity which delays scheduled re-treatment for \>14 days; Grade 4 neutropenia for ≥5 consecutive days; grade 3/4 neutropenia with sepsis or a fever ≥38.5 C; thrombocytopenia \<25,000 cells/mm3 or bleeding requiring a platelet transfusion.
Time frame: Measures taken at Cycle 01 (21-day cycle)
Population: All treated participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 10 mg/m2 | Number of Participants With Dose Limiting Toxicities at Dose Level | 0 participants |
| 20 mg/m2 | Number of Participants With Dose Limiting Toxicities at Dose Level | 0 participants |
| 30 mg/m2 | Number of Participants With Dose Limiting Toxicities at Dose Level | 0 participants |
| 35 mg/m2 | Number of Participants With Dose Limiting Toxicities at Dose Level | 0 participants |
| 40 mg/m2 | Number of Participants With Dose Limiting Toxicities at Dose Level | 1 participants |
| 45 mg/m2 | Number of Participants With Dose Limiting Toxicities at Dose Level | 2 participants |
Secondary
Best Tumor Response, According to Response Evaluation Criteria in Solid Tumors (RECIST)
RECIST criteria, wherein complete response = disappearance of all target lesions; partial response = 30% decrease in the sum of the longest diameter of target lesions; progressive disease = 20% increase in the sum of the longest diameter of target lesions, and stable disease = small changes that do not meet above criteria.
Time frame: At Baseline (up to 2 weeks prior to starting therapy), after every 2nd cycle, and at post study follow-upn after a maximum of 9 cycles.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 10 mg/m2 | Best Tumor Response, According to Response Evaluation Criteria in Solid Tumors (RECIST) | Partial Response | 0 Participants |
| 10 mg/m2 | Best Tumor Response, According to Response Evaluation Criteria in Solid Tumors (RECIST) | Complete Response | 0 Participants |
| 10 mg/m2 | Best Tumor Response, According to Response Evaluation Criteria in Solid Tumors (RECIST) | Stable Disease | 14 Participants |
| 10 mg/m2 | Best Tumor Response, According to Response Evaluation Criteria in Solid Tumors (RECIST) | Progressive Disease | 15 Participants |
| 10 mg/m2 | Best Tumor Response, According to Response Evaluation Criteria in Solid Tumors (RECIST) | Unable to Determine | 6 Participants |
Secondary
Hematology Results - Worst On-Study Grade
Worst on-study grade based on laboratory values graded according to Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. (Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death).
Time frame: Baseline (within 2 weeks of dosing), weekly, and within 72 hours prior to each subsequent 21-day cycle. If CTC Grade 4 hematologic toxicity is observed, complete blood count plus differential and platelets repeated every 3 days until resolution.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 10 mg/m2 | Hematology Results - Worst On-Study Grade | White Blood Cells | 5 Participants |
| 10 mg/m2 | Hematology Results - Worst On-Study Grade | Absolute Neutrophil Count | 8 Participants |
| 10 mg/m2 | Hematology Results - Worst On-Study Grade | Hemoglobin | 1 Participants |
| 10 mg/m2 | Hematology Results - Worst On-Study Grade | Platelets | 21 Participants |
| 20 mg/m2 | Hematology Results - Worst On-Study Grade | Absolute Neutrophil Count | 5 Participants |
| 20 mg/m2 | Hematology Results - Worst On-Study Grade | White Blood Cells | 5 Participants |
| 20 mg/m2 | Hematology Results - Worst On-Study Grade | Platelets | 9 Participants |
| 20 mg/m2 | Hematology Results - Worst On-Study Grade | Hemoglobin | 14 Participants |
| 30 mg/m2 | Hematology Results - Worst On-Study Grade | Absolute Neutrophil Count | 6 Participants |
| 30 mg/m2 | Hematology Results - Worst On-Study Grade | Hemoglobin | 13 Participants |
| 30 mg/m2 | Hematology Results - Worst On-Study Grade | White Blood Cells | 8 Participants |
| 30 mg/m2 | Hematology Results - Worst On-Study Grade | Platelets | 0 Participants |
| 35 mg/m2 | Hematology Results - Worst On-Study Grade | White Blood Cells | 10 Participants |
| 35 mg/m2 | Hematology Results - Worst On-Study Grade | Absolute Neutrophil Count | 5 Participants |
| 35 mg/m2 | Hematology Results - Worst On-Study Grade | Platelets | 3 Participants |
| 35 mg/m2 | Hematology Results - Worst On-Study Grade | Hemoglobin | 7 Participants |
| 40 mg/m2 | Hematology Results - Worst On-Study Grade | Platelets | 2 Participants |
| 40 mg/m2 | Hematology Results - Worst On-Study Grade | Hemoglobin | 0 Participants |
| 40 mg/m2 | Hematology Results - Worst On-Study Grade | White Blood Cells | 7 Participants |
| 40 mg/m2 | Hematology Results - Worst On-Study Grade | Absolute Neutrophil Count | 11 Participants |
Secondary
Mean Plasma Concentration of Ixabepilone at 40 mg/m2 Dose Level
Mean concentrations over full time period for the 40 mg/mg2 dose level, established as the Maximum Tolerated Dose. (The Maximum Tolerated Dose was established as 40 mg/m2, based on an investiagtion of Dose Limiting Toxicities, which consisted of Febrile Neutropenia (at 40 mg/m2) in 1 participant and Grade 4 neutropenia lasting ≥5 days (at 45 mg/m2)in 2 participants.)
Time frame: through 72 hours after start of infusion
Population: All participants treated at the 40 mg/m2 dose level.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 10 mg/m2 | Mean Plasma Concentration of Ixabepilone at 40 mg/m2 Dose Level | Hour 0.00 (n=11) | 0 ng/mL | Standard Deviation 0 |
| 10 mg/m2 | Mean Plasma Concentration of Ixabepilone at 40 mg/m2 Dose Level | Hour 1.00 (n=11) | 20.79 ng/mL | Standard Deviation 14.12 |
| 10 mg/m2 | Mean Plasma Concentration of Ixabepilone at 40 mg/m2 Dose Level | Hour 2.00 (n=11) | 24.31 ng/mL | Standard Deviation 13.64 |
| 10 mg/m2 | Mean Plasma Concentration of Ixabepilone at 40 mg/m2 Dose Level | Hour 4.00 (n=11) | 33.15 ng/mL | Standard Deviation 32.75 |
| 10 mg/m2 | Mean Plasma Concentration of Ixabepilone at 40 mg/m2 Dose Level | Hour 8.00 (n=11) | 32.04 ng/mL | Standard Deviation 16.2 |
| 10 mg/m2 | Mean Plasma Concentration of Ixabepilone at 40 mg/m2 Dose Level | Hour 12.00 (n=11) | 35.25 ng/mL | Standard Deviation 11.96 |
| 10 mg/m2 | Mean Plasma Concentration of Ixabepilone at 40 mg/m2 Dose Level | Hour 16.00 (n=11) | 44.47 ng/mL | Standard Deviation 13.8 |
| 10 mg/m2 | Mean Plasma Concentration of Ixabepilone at 40 mg/m2 Dose Level | Hour 20.00 (n=11) | 55.05 ng/mL | Standard Deviation 29.41 |
| 10 mg/m2 | Mean Plasma Concentration of Ixabepilone at 40 mg/m2 Dose Level | Hour 24.00 (n=11) | 54.71 ng/mL | Standard Deviation 23.63 |
| 10 mg/m2 | Mean Plasma Concentration of Ixabepilone at 40 mg/m2 Dose Level | Hour 25.00 (n=10) | 35.59 ng/mL | Standard Deviation 24.51 |
| 10 mg/m2 | Mean Plasma Concentration of Ixabepilone at 40 mg/m2 Dose Level | Hour 26.00 (n=10) | 33.70 ng/mL | Standard Deviation 17.17 |
| 10 mg/m2 | Mean Plasma Concentration of Ixabepilone at 40 mg/m2 Dose Level | Hour 27.00 (n=10) | 35.15 ng/mL | Standard Deviation 20.47 |
| 10 mg/m2 | Mean Plasma Concentration of Ixabepilone at 40 mg/m2 Dose Level | Hour 72.00 (n=10) | 27.45 ng/mL | Standard Deviation 47.71 |
Secondary
Treatment Related Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation
Adverse events (AEs) and Serious AEs (SAEs) considered possibly, probably, or certainly related to study treatment, graded according to Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 (Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death).
Time frame: From time of screening through post study follow-up at a maximum of 21 9-day cycles. Toxicity assessments occured at least every 4 weeks until all study drug related toxicities.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 10 mg/m2 | Treatment Related Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Nausea | 16 Participants |
| 10 mg/m2 | Treatment Related Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Fatigue | 14 Participants |
| 10 mg/m2 | Treatment Related Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Alopecia | 12 Participants |
| 10 mg/m2 | Treatment Related Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Diarrhea | 11 Participants |
| 10 mg/m2 | Treatment Related Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Peripheral sensory neuropathy | 9 Participants |
| 10 mg/m2 | Treatment Related Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Stomatitis | 9 Participants |
| 10 mg/m2 | Treatment Related Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Any SAE | 0 Participants |
| 10 mg/m2 | Treatment Related Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Death within 30 days of last dose | 0 Participants |
| 10 mg/m2 | Treatment Related Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Any AE leading to discontinuation | 0 Participants |
| 10 mg/m2 | Treatment Related Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Any Treatment-Related AE | 12 Participants |
| 20 mg/m2 | Treatment Related Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Any AE leading to discontinuation | 5 Participants |
| 20 mg/m2 | Treatment Related Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Nausea | 0 Participants |
| 20 mg/m2 | Treatment Related Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Peripheral sensory neuropathy | 0 Participants |
| 20 mg/m2 | Treatment Related Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Stomatitis | 0 Participants |
| 20 mg/m2 | Treatment Related Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Fatigue | 2 Participants |
| 20 mg/m2 | Treatment Related Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Any Treatment-Related AE | 21 Participants |
| 20 mg/m2 | Treatment Related Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Death within 30 days of last dose | 1 Participants |
| 20 mg/m2 | Treatment Related Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Alopecia | 0 Participants |
| 20 mg/m2 | Treatment Related Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Any SAE | 16 Participants |
| 20 mg/m2 | Treatment Related Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Diarrhea | 0 Participants |
| 30 mg/m2 | Treatment Related Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Death within 30 days of last dose | 1 Participants |
| 30 mg/m2 | Treatment Related Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Diarrhea | 11 Participants |
| 30 mg/m2 | Treatment Related Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Peripheral sensory neuropathy | 9 Participants |
| 30 mg/m2 | Treatment Related Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Stomatitis | 9 Participants |
| 30 mg/m2 | Treatment Related Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Any AE leading to discontinuation | 5 Participants |
| 30 mg/m2 | Treatment Related Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Any SAE | 16 Participants |
| 30 mg/m2 | Treatment Related Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Nausea | 16 Participants |
| 30 mg/m2 | Treatment Related Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Any Treatment-Related AE | 33 Participants |
| 30 mg/m2 | Treatment Related Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Fatigue | 16 Participants |
| 30 mg/m2 | Treatment Related Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Alopecia | 12 Participants |