Neoplasms
Conditions
Brief summary
Single-agent, open-label, multi-center sequential dose escalation and expansion study of BAL101553, administered as an intravenous (IV) infusion over 48 hours to adults with advanced or recurrent solid tumors or recurrent glioblastoma.
Detailed description
This is the first study of prolonged intravenous infusion of BAL101553 (lisavanbulin). BAL101553 will be administered as an intravenous infusion over 48 hours, to adults with advanced or recurrent solid tumors or recurrent glioblastoma who have failed standard therapy, or for whom no effective standard therapy is available. The primary goal of the study is to find the highest dose of BAL101553 that can safely be given to humans and to assess what side effects occur. The study will start by treating patients with a low dose. Once it has been shown that this low dose is well tolerated, new patients will be treated at higher dose levels (dose escalation). Once the highest, well tolerated dose is identified, up to 20 new patients with platinum-resistant/refractory ovarian cancer and up to 20 new patients with recurrent glioblastoma will be treated at that dose (this part is called dose expansion) to further assess as secondary goal the tolerability and potential anticancer activity of BAL101553. A further secondary goal of this study is to assess the pharmacokinetics of BAL101553.
Interventions
DRUGBAL101553
BAL101553 48-hour infusion on day 1, 8, and 15 of each 28-day cycle; oral capsule daily for one week during Cycle 2 (study days 15-21)
DRUGBAL101553 at MTD
BAL101553 48-hour infusion on day 1, 8, and 15 of each 28-day cycle; treatment with maximum tolerated dose (MTD)
Sponsors
Basilea Pharmaceutica
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥ 18 years 2. Phase 1: Patients with either histologically or cytologically confirmed advanced or recurrent solid tumor, who failed standard therapy or for whom no effective standard therapy is available. Phase 2a: Patients with platinum-resistant/refractory ovarian, fallopian tube or primary peritoneal cancer (high-grade serous, endometrioid, or carcinosarcoma histotypes) or glioblastoma in first relapse. 3. Patients with solid tumors must have measurable disease according to Response Evaluation Criteria in Solid Tumors \[RECIST\] v1.1. Patients with recurrent glioblastoma must have measurable disease defined by contrast-enhancing magnetic resonance imaging. 4. Life expectancy ≥ 12 weeks 5. Acceptable organ and marrow function at baseline (protocol defined laboratory parameters) 6. Patients with solid tumors must have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 and patients with recurrent glioblastoma must have an ECOG performance status ≤ 2. 7. Other protocol-defined inclusion criteria may apply.
Exclusion criteria
1. Patients with solid tumors who have received chemotherapy, radiotherapy, immunotherapy, or investigational agents within 4 weeks prior to starting study drug or who have not recovered from side effects of prior therapies. Patients with recurrent glioblastoma who have: received radiotherapy within 12 weeks, unless there is a new area of enhancement consistent with recurrent tumor outside the radiation field, or there is histological confirmation of unequivocal tumor progression; received administration of prior antitumor chemotherapy within 4 weeks, or within 6 weeks for nitrosoureas; undergone surgical resection within 4 weeks or a stereotactic biopsy/core biopsy within 1 week prior to starting study drug, or have been treated previously with bevacizumab. 2. Patients who have had prior exposure to BAL101553. 3. Peripheral neuropathy ≥ CTCAE grade 2. 4. Uncontrolled intercurrent illness that would unduly increase the risk of toxicity or limit compliance with study requirements 5. Systolic blood pressure (SBP) ≥ 140 mmHg or diastolic blood pressure (DBP) ≥ 90 mmHg at the screening visit. 6. Blood pressure (BP) combination treatment with more than two antihypertensive medications. 7. Women who are pregnant or breast-feeding. Men or women of reproductive potential who are not willing to apply effective birth control. 8. Other protocol-defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) of BAL101553 | 28 day cycle | First 28-day treatment cycle dose limiting toxicities (DLT) graded according to CTCAE in the MTD-determining population in Phase 1 based on the number of participants with adverse effects as measure of tolerability at various dose levels |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC of BAL101553 and BAL27862 | 0 to 168 hours post-dose at Day 1 of Cycle 1 and Cycle 2 in each cohort in Phase 1, 28-day cycles | Pharmacokinetic parameter Area under the plasma concentration versus time curve AUC0-last (of BAL101553 and BAL27862 has been assessed after a 48-hour IV infusion. Lisavanbulin (BAL101553) is the prodrug of avanbulin (BAL27862). |
| Cmax of BAL101553 and BAL27862 | Pre-dose, and 0.5, 1, 2, 4, 8, 24, 30, 48, 52, 54, 72 h, and 168 h after the start of study-drug infusion on Day 1 of Cycle 1 and pre-dose, and 0.5, 1, 2, 4, 8, 24, 30, 48, 72 h, and 168 h after the start of study-drug infusion on Day 1 of Cycle 2. | Pharmacokinetic parameter Peak Plasma Concentration Cmax of BAL101553 and BAL27862. Lisavanbulin (BAL101553) is the prodrug of avanbulin (BAL27862). |
| Safety and Tolerability of BAL101553 Treatment Based on Number of Patients With Related Treatment-emergent Adverse Events (TEAEs) in the Phase 1 and Phase 2a Safety Population at Various Dose Levels and Indication | TEAEs with onset on or after Day 1 of the study and until 28 days after the last dose | TEAEs are defined as all events occurring after BAL101553 treatment begins, up to 28 days after last study drug administration according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 |
| Bioavailability of Daily Oral BAL101553 Measured by BAL27862 in Phase 1 | Relative oral bioavailability, calculated as dose-normalized AUC0-τ following oral administration on Cycle 2 Day 21 divided by dose normalized AUC0-∞ following IV administration on Cycle 1 Day 1 for each cohort. | Ratio of AUCs of avanbulin after oral and IV administration (relative bioavailability) of BAL101553 (lisavanbulin) which is the prodrug of avanbulin (BAL27862) |
| Anti-tumor Activity of BAL101553 by Best Response Rate Per RECIST / RANO Criteria | 28 day cycles | The objective response rate (ORR) was calculated using the efficacy evaluable populations (EEPs in Phase 2a) and the full analysis population (FAP in Phase 1 and Phase 2a) based on RECIST v1.1 guidelines (defines criteria for the radiological assessment in tumor response) for patients with solid tumors (excluding GBM (glioblastoma)) and RANO criteria (assessment Incorporating MRI and clinical factors) for patients with GBM. ORR = Rate of complete and partial responses |
| Tmax of BAL101553 and BAL27862 | Pre-dose, and 0.5, 1, 2, 4, 8, 24, 30, 48, 52, 54, 72 h, and 168 h after the start of study-drug infusion on Day 1 of Cycle 1 and pre-dose, and 0.5, 1, 2, 4, 8, 24, 30, 48, 72 h, and 168 h after the start of study-drug infusion on Day 1 of Cycle 2. | Pharmacokinetic parameter Time to Peak Plasma Concentration Tmax of BAL101553 and BAL27862 |
Countries
Switzerland
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 30 mg/m² Cohort BAL101553 30 mg/m² intravenously over 48 hours on Days 1, 8 and 15 of each (at least one) 28-day treatment cycle. During cycle 2, oral BAL101553 was administered on study days 15-21. The oral dose was selected to match the weekly IV dose of 30 mg/m². | 4 |
| 45 mg/m² Cohort BAL101553 45 mg/m² intravenously over 48 hours on Days 1, 8 and 15 of each (at least one) 28-day treatment cycle. During cycle 2, oral BAL101553 was administered on study days 15-21. The oral dose was selected to match the weekly IV dose of 45 mg/m². | 3 |
| 70 mg/m² Cohort BAL101553 70 mg/m² intravenously over 48 hours on Days 1, 8 and 15 of each (at least one) 28-day treatment cycle. During cycle 2, oral BAL101553 was administered on study days 15-21. The oral dose was selected to match the weekly IV dose of 70 mg/m². | 9 |
| 90 mg/m² Cohort BAL101553 90 mg/m² intravenously over 48 hours on Days 1, 8 and 15 of each (at least one) 28-day treatment cycle. During cycle 2, oral BAL101553 was administered on study days 15-21. The oral dose was selected to match the weekly IV dose of 90 mg/m². | 4 |
| Phase 2a - Ovarian Cancer Cohort BAL101553 at 70 mg/m² (MTD) BAL101553 48-hour infusion on day 1, 8, and 15 of each 28-day cycle | 11 |
| Phase 2a - Recurrent Glioblastoma Cohort BAL101553 at 70 mg/m² (MTD) BAL101553 48-hour infusion on day 1, 8, and 15 of each 28-day cycle | 12 |
| Total | 43 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Phase 1 - 30 mg/m² Cohort | Progressive disease | 4 | 0 | 0 | 0 | 0 | 0 |
| Phase 1 - 45 mg/m² Cohort | Progressive disease | 0 | 3 | 0 | 0 | 0 | 0 |
| Phase 1 - 70 mg/m² Cohort | Adverse Event | 0 | 0 | 2 | 0 | 0 | 0 |
| Phase 1 - 70 mg/m² Cohort | Progressive disease | 0 | 0 | 7 | 0 | 0 | 0 |
| Phase 1 - 90 mg/m² Cohort | Progressive disease | 0 | 0 | 0 | 4 | 0 | 0 |
| Phase 2a | Adverse Event | 0 | 0 | 0 | 0 | 0 | 1 |
| Phase 2a | Progressive disease | 0 | 0 | 0 | 0 | 11 | 11 |
Baseline characteristics
| Characteristic | 30 mg/m² Cohort | Total | Phase 2a - Recurrent Glioblastoma Cohort | Phase 2a - Ovarian Cancer Cohort | 90 mg/m² Cohort | 70 mg/m² Cohort | 45 mg/m² Cohort |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 54.3 Years STANDARD_DEVIATION 3.3 | 60.7 Years STANDARD_DEVIATION 8.25 | 59.3 Years STANDARD_DEVIATION 7.45 | 64.7 Years STANDARD_DEVIATION 8.78 | 63.0 Years STANDARD_DEVIATION 7.26 | 59.6 Years STANDARD_DEVIATION 10.53 | 61.0 Years STANDARD_DEVIATION 0 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 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 | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 43 Participants | 12 Participants | 11 Participants | 4 Participants | 9 Participants | 3 Participants |
| Region of Enrollment Switzerland | 4 participants | 43 participants | 12 participants | 11 participants | 4 participants | 9 participants | 3 participants |
| Sex: Female, Male Female | 2 Participants | 27 Participants | 3 Participants | 11 Participants | 3 Participants | 6 Participants | 2 Participants |
| Sex: Female, Male Male | 2 Participants | 16 Participants | 9 Participants | 0 Participants | 1 Participants | 3 Participants | 1 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 | 0 / 4 | 0 / 3 | 3 / 9 | 0 / 4 | 3 / 11 | 2 / 12 |
| other Total, other adverse events | 4 / 4 | 3 / 3 | 9 / 9 | 4 / 4 | 11 / 11 | 11 / 12 |
| serious Total, serious adverse events | 1 / 4 | 1 / 3 | 7 / 9 | 1 / 4 | 4 / 11 | 5 / 12 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) of BAL101553
First 28-day treatment cycle dose limiting toxicities (DLT) graded according to CTCAE in the MTD-determining population in Phase 1 based on the number of participants with adverse effects as measure of tolerability at various dose levels
Time frame: 28 day cycle
Population: MTD-determining population in Phase 1: All patients who meet the following minimum criteria during the first 28-day treatment cycle (Cycle 1)~* received at least one partial or complete dose of BAL101553 and has experienced a DLT;~* received all three doses of BAL101553 without experiencing a DLT (including the ability to initiate treatment Cycle 2), have been observed for ≥ 28 days following the first dose, and have been evaluated for safety.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MTD-determining Population in Phase 1 | Maximum Tolerated Dose (MTD) of BAL101553 | 70 mg/m² |
Secondary
Anti-tumor Activity of BAL101553 by Best Response Rate Per RECIST / RANO Criteria
The objective response rate (ORR) was calculated using the efficacy evaluable populations (EEPs in Phase 2a) and the full analysis population (FAP in Phase 1 and Phase 2a) based on RECIST v1.1 guidelines (defines criteria for the radiological assessment in tumor response) for patients with solid tumors (excluding GBM (glioblastoma)) and RANO criteria (assessment Incorporating MRI and clinical factors) for patients with GBM. ORR = Rate of complete and partial responses
Time frame: 28 day cycles
Population: FAP:~Patients who receive at least one partial or complete dose of BAL101553.~EEP:~Patients with progressive disease who completed at least Cycle 1 dosing and at least one on-study tumor assessment (clinical or radiological by RECIST v1.1 or RANO criteria) Patients with stable disease, partial or complete response, based on a radiological assessment by RECIST v1.1 or RANO criteria at the end of Cycle 2, with at least 4 doses of study drug in the first two cycles.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MTD-determining Population in Phase 1 | Anti-tumor Activity of BAL101553 by Best Response Rate Per RECIST / RANO Criteria | Progressive disease | 15 Participants |
| MTD-determining Population in Phase 1 | Anti-tumor Activity of BAL101553 by Best Response Rate Per RECIST / RANO Criteria | Complete response | 1 Participants |
| MTD-determining Population in Phase 1 | Anti-tumor Activity of BAL101553 by Best Response Rate Per RECIST / RANO Criteria | Missing | 1 Participants |
| MTD-determining Population in Phase 1 | Anti-tumor Activity of BAL101553 by Best Response Rate Per RECIST / RANO Criteria | Partial response | 0 Participants |
| MTD-determining Population in Phase 1 | Anti-tumor Activity of BAL101553 by Best Response Rate Per RECIST / RANO Criteria | Stable disease | 3 Participants |
| Phase 1 - 45 mg/m² Cohort | Anti-tumor Activity of BAL101553 by Best Response Rate Per RECIST / RANO Criteria | Progressive disease | 7 Participants |
| Phase 1 - 45 mg/m² Cohort | Anti-tumor Activity of BAL101553 by Best Response Rate Per RECIST / RANO Criteria | Stable disease | 4 Participants |
| Phase 1 - 45 mg/m² Cohort | Anti-tumor Activity of BAL101553 by Best Response Rate Per RECIST / RANO Criteria | Partial response | 0 Participants |
| Phase 1 - 45 mg/m² Cohort | Anti-tumor Activity of BAL101553 by Best Response Rate Per RECIST / RANO Criteria | Missing | 0 Participants |
| Phase 1 - 45 mg/m² Cohort | Anti-tumor Activity of BAL101553 by Best Response Rate Per RECIST / RANO Criteria | Complete response | 0 Participants |
| Phase 1 - 70 mg/m² Cohort | Anti-tumor Activity of BAL101553 by Best Response Rate Per RECIST / RANO Criteria | Stable disease | 3 Participants |
| Phase 1 - 70 mg/m² Cohort | Anti-tumor Activity of BAL101553 by Best Response Rate Per RECIST / RANO Criteria | Complete response | 0 Participants |
| Phase 1 - 70 mg/m² Cohort | Anti-tumor Activity of BAL101553 by Best Response Rate Per RECIST / RANO Criteria | Partial response | 0 Participants |
| Phase 1 - 70 mg/m² Cohort | Anti-tumor Activity of BAL101553 by Best Response Rate Per RECIST / RANO Criteria | Progressive disease | 5 Participants |
| Phase 1 - 70 mg/m² Cohort | Anti-tumor Activity of BAL101553 by Best Response Rate Per RECIST / RANO Criteria | Missing | 0 Participants |
| Phase 1 - 90 mg/m² Cohort | Anti-tumor Activity of BAL101553 by Best Response Rate Per RECIST / RANO Criteria | Missing | 0 Participants |
| Phase 1 - 90 mg/m² Cohort | Anti-tumor Activity of BAL101553 by Best Response Rate Per RECIST / RANO Criteria | Complete response | 0 Participants |
| Phase 1 - 90 mg/m² Cohort | Anti-tumor Activity of BAL101553 by Best Response Rate Per RECIST / RANO Criteria | Progressive disease | 9 Participants |
| Phase 1 - 90 mg/m² Cohort | Anti-tumor Activity of BAL101553 by Best Response Rate Per RECIST / RANO Criteria | Stable disease | 2 Participants |
| Phase 1 - 90 mg/m² Cohort | Anti-tumor Activity of BAL101553 by Best Response Rate Per RECIST / RANO Criteria | Partial response | 1 Participants |
| Phase 2a - Ovarian Cancer Cohort | Anti-tumor Activity of BAL101553 by Best Response Rate Per RECIST / RANO Criteria | Stable disease | 1 Participants |
| Phase 2a - Ovarian Cancer Cohort | Anti-tumor Activity of BAL101553 by Best Response Rate Per RECIST / RANO Criteria | Progressive disease | 6 Participants |
| Phase 2a - Ovarian Cancer Cohort | Anti-tumor Activity of BAL101553 by Best Response Rate Per RECIST / RANO Criteria | Complete response | 0 Participants |
| Phase 2a - Ovarian Cancer Cohort | Anti-tumor Activity of BAL101553 by Best Response Rate Per RECIST / RANO Criteria | Missing | 0 Participants |
| Phase 2a - Ovarian Cancer Cohort | Anti-tumor Activity of BAL101553 by Best Response Rate Per RECIST / RANO Criteria | Partial response | 1 Participants |
Secondary
AUC of BAL101553 and BAL27862
Pharmacokinetic parameter Area under the plasma concentration versus time curve AUC0-last (of BAL101553 and BAL27862 has been assessed after a 48-hour IV infusion. Lisavanbulin (BAL101553) is the prodrug of avanbulin (BAL27862).
Time frame: 0 to 168 hours post-dose at Day 1 of Cycle 1 and Cycle 2 in each cohort in Phase 1, 28-day cycles
Population: The PK analysis set includes all patients who received at least one partial or complete dose of study drug and had at least one post-baseline PK assessment.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| MTD-determining Population in Phase 1 | AUC of BAL101553 and BAL27862 | BAL101553 | 1430 h*ng/mL | Geometric Coefficient of Variation 43.9 |
| MTD-determining Population in Phase 1 | AUC of BAL101553 and BAL27862 | BAL27862 | 1730 h*ng/mL | Geometric Coefficient of Variation 37.8 |
| Phase 1 - 45 mg/m² Cohort | AUC of BAL101553 and BAL27862 | BAL101553 | 1310 h*ng/mL | Geometric Coefficient of Variation 47.6 |
| Phase 1 - 45 mg/m² Cohort | AUC of BAL101553 and BAL27862 | BAL27862 | 2250 h*ng/mL | Geometric Coefficient of Variation 58.2 |
| Phase 1 - 70 mg/m² Cohort | AUC of BAL101553 and BAL27862 | BAL101553 | 2260 h*ng/mL | Geometric Coefficient of Variation 43.9 |
| Phase 1 - 70 mg/m² Cohort | AUC of BAL101553 and BAL27862 | BAL27862 | 3440 h*ng/mL | Geometric Coefficient of Variation 45.1 |
| Phase 1 - 90 mg/m² Cohort | AUC of BAL101553 and BAL27862 | BAL101553 | 1890 h*ng/mL | Geometric Coefficient of Variation 13.3 |
| Phase 1 - 90 mg/m² Cohort | AUC of BAL101553 and BAL27862 | BAL27862 | 3920 h*ng/mL | Geometric Coefficient of Variation 57.7 |
| Phase 2a - Ovarian Cancer Cohort | AUC of BAL101553 and BAL27862 | BAL101553 | 3560 h*ng/mL | Geometric Coefficient of Variation 45.9 |
| Phase 2a - Ovarian Cancer Cohort | AUC of BAL101553 and BAL27862 | BAL27862 | 7720 h*ng/mL | Geometric Coefficient of Variation 44.6 |
| Phase 2a - Recurrent Glioblastoma Cohort | AUC of BAL101553 and BAL27862 | BAL101553 | 3550 h*ng/mL | Geometric Coefficient of Variation 43.1 |
| Phase 2a - Recurrent Glioblastoma Cohort | AUC of BAL101553 and BAL27862 | BAL27862 | 6640 h*ng/mL | Geometric Coefficient of Variation 49.3 |
| 90 mg/m² Cycle 1 Day 1 | AUC of BAL101553 and BAL27862 | BAL27862 | 10400 h*ng/mL | Geometric Coefficient of Variation 37.2 |
| 90 mg/m² Cycle 1 Day 1 | AUC of BAL101553 and BAL27862 | BAL101553 | 4810 h*ng/mL | Geometric Coefficient of Variation 74 |
| 90 mg/m² Cycle 2 Day 1 | AUC of BAL101553 and BAL27862 | BAL101553 | 4150 h*ng/mL | Geometric Coefficient of Variation 67.5 |
| 90 mg/m² Cycle 2 Day 1 | AUC of BAL101553 and BAL27862 | BAL27862 | 10700 h*ng/mL | Geometric Coefficient of Variation 39.3 |
Secondary
Bioavailability of Daily Oral BAL101553 Measured by BAL27862 in Phase 1
Ratio of AUCs of avanbulin after oral and IV administration (relative bioavailability) of BAL101553 (lisavanbulin) which is the prodrug of avanbulin (BAL27862)
Time frame: Relative oral bioavailability, calculated as dose-normalized AUC0-τ following oral administration on Cycle 2 Day 21 divided by dose normalized AUC0-∞ following IV administration on Cycle 1 Day 1 for each cohort.
Population: Patients with both Cycle 1 Day 1 AUC0-∞ and Cycle 2 Day 1 AUC0-τ evaluations
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MTD-determining Population in Phase 1 | Bioavailability of Daily Oral BAL101553 Measured by BAL27862 in Phase 1 | 1.11 Ratio | Standard Deviation 0 |
| Phase 1 - 45 mg/m² Cohort | Bioavailability of Daily Oral BAL101553 Measured by BAL27862 in Phase 1 | 1.32 Ratio | Standard Deviation 0 |
| Phase 1 - 70 mg/m² Cohort | Bioavailability of Daily Oral BAL101553 Measured by BAL27862 in Phase 1 | 0.796 Ratio | Standard Deviation 18.9 |
| Phase 1 - 90 mg/m² Cohort | Bioavailability of Daily Oral BAL101553 Measured by BAL27862 in Phase 1 | 0.893 Ratio | Standard Deviation 0 |
Secondary
Cmax of BAL101553 and BAL27862
Pharmacokinetic parameter Peak Plasma Concentration Cmax of BAL101553 and BAL27862. Lisavanbulin (BAL101553) is the prodrug of avanbulin (BAL27862).
Time frame: Pre-dose, and 0.5, 1, 2, 4, 8, 24, 30, 48, 52, 54, 72 h, and 168 h after the start of study-drug infusion on Day 1 of Cycle 1 and pre-dose, and 0.5, 1, 2, 4, 8, 24, 30, 48, 72 h, and 168 h after the start of study-drug infusion on Day 1 of Cycle 2.
Population: The PK analysis set includes all patients who received at least one partial or complete dose of study drug and had at least one post-baseline PK assessment.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| MTD-determining Population in Phase 1 | Cmax of BAL101553 and BAL27862 | BAL27862 | 45.7 ng/mL | Geometric Coefficient of Variation 30.2 |
| MTD-determining Population in Phase 1 | Cmax of BAL101553 and BAL27862 | BAL101553 | 43.0 ng/mL | Geometric Coefficient of Variation 22.9 |
| Phase 1 - 45 mg/m² Cohort | Cmax of BAL101553 and BAL27862 | BAL27862 | 52.7 ng/mL | Geometric Coefficient of Variation 45.8 |
| Phase 1 - 45 mg/m² Cohort | Cmax of BAL101553 and BAL27862 | BAL101553 | 44.2 ng/mL | Geometric Coefficient of Variation 15.8 |
| Phase 1 - 70 mg/m² Cohort | Cmax of BAL101553 and BAL27862 | BAL27862 | 76.8 ng/mL | Geometric Coefficient of Variation 18.6 |
| Phase 1 - 70 mg/m² Cohort | Cmax of BAL101553 and BAL27862 | BAL101553 | 69.3 ng/mL | Geometric Coefficient of Variation 19.3 |
| Phase 1 - 90 mg/m² Cohort | Cmax of BAL101553 and BAL27862 | BAL101553 | 60.9 ng/mL | Geometric Coefficient of Variation 4.3 |
| Phase 1 - 90 mg/m² Cohort | Cmax of BAL101553 and BAL27862 | BAL27862 | 76.2 ng/mL | Geometric Coefficient of Variation 43.1 |
| Phase 2a - Ovarian Cancer Cohort | Cmax of BAL101553 and BAL27862 | BAL27862 | 144 ng/mL | Geometric Coefficient of Variation 25.7 |
| Phase 2a - Ovarian Cancer Cohort | Cmax of BAL101553 and BAL27862 | BAL101553 | 119 ng/mL | Geometric Coefficient of Variation 34.5 |
| Phase 2a - Recurrent Glioblastoma Cohort | Cmax of BAL101553 and BAL27862 | BAL101553 | 111 ng/mL | Geometric Coefficient of Variation 34.9 |
| Phase 2a - Recurrent Glioblastoma Cohort | Cmax of BAL101553 and BAL27862 | BAL27862 | 120 ng/mL | Geometric Coefficient of Variation 41.2 |
| 90 mg/m² Cycle 1 Day 1 | Cmax of BAL101553 and BAL27862 | BAL101553 | 174 ng/mL | Geometric Coefficient of Variation 63.6 |
| 90 mg/m² Cycle 1 Day 1 | Cmax of BAL101553 and BAL27862 | BAL27862 | 223 ng/mL | Geometric Coefficient of Variation 44.7 |
| 90 mg/m² Cycle 2 Day 1 | Cmax of BAL101553 and BAL27862 | BAL27862 | 199 ng/mL | Geometric Coefficient of Variation 40.4 |
| 90 mg/m² Cycle 2 Day 1 | Cmax of BAL101553 and BAL27862 | BAL101553 | 198 ng/mL | Geometric Coefficient of Variation 76.8 |
Secondary
Safety and Tolerability of BAL101553 Treatment Based on Number of Patients With Related Treatment-emergent Adverse Events (TEAEs) in the Phase 1 and Phase 2a Safety Population at Various Dose Levels and Indication
TEAEs are defined as all events occurring after BAL101553 treatment begins, up to 28 days after last study drug administration according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03
Time frame: TEAEs with onset on or after Day 1 of the study and until 28 days after the last dose
Population: All patients who receive at least one full or partial dose of BAL101553 and had at least one post-baseline safety assessment is included in the safety analysis population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MTD-determining Population in Phase 1 | Safety and Tolerability of BAL101553 Treatment Based on Number of Patients With Related Treatment-emergent Adverse Events (TEAEs) in the Phase 1 and Phase 2a Safety Population at Various Dose Levels and Indication | Patients with CTCAE Grade 3/4 or severe related AE | 0 Participants |
| MTD-determining Population in Phase 1 | Safety and Tolerability of BAL101553 Treatment Based on Number of Patients With Related Treatment-emergent Adverse Events (TEAEs) in the Phase 1 and Phase 2a Safety Population at Various Dose Levels and Indication | Patients with ≥1 related AE | 2 Participants |
| MTD-determining Population in Phase 1 | Safety and Tolerability of BAL101553 Treatment Based on Number of Patients With Related Treatment-emergent Adverse Events (TEAEs) in the Phase 1 and Phase 2a Safety Population at Various Dose Levels and Indication | Patients with ≥1 related serious AE | 0 Participants |
| Phase 1 - 45 mg/m² Cohort | Safety and Tolerability of BAL101553 Treatment Based on Number of Patients With Related Treatment-emergent Adverse Events (TEAEs) in the Phase 1 and Phase 2a Safety Population at Various Dose Levels and Indication | Patients with CTCAE Grade 3/4 or severe related AE | 0 Participants |
| Phase 1 - 45 mg/m² Cohort | Safety and Tolerability of BAL101553 Treatment Based on Number of Patients With Related Treatment-emergent Adverse Events (TEAEs) in the Phase 1 and Phase 2a Safety Population at Various Dose Levels and Indication | Patients with ≥1 related AE | 2 Participants |
| Phase 1 - 45 mg/m² Cohort | Safety and Tolerability of BAL101553 Treatment Based on Number of Patients With Related Treatment-emergent Adverse Events (TEAEs) in the Phase 1 and Phase 2a Safety Population at Various Dose Levels and Indication | Patients with ≥1 related serious AE | 0 Participants |
| Phase 1 - 70 mg/m² Cohort | Safety and Tolerability of BAL101553 Treatment Based on Number of Patients With Related Treatment-emergent Adverse Events (TEAEs) in the Phase 1 and Phase 2a Safety Population at Various Dose Levels and Indication | Patients with CTCAE Grade 3/4 or severe related AE | 2 Participants |
| Phase 1 - 70 mg/m² Cohort | Safety and Tolerability of BAL101553 Treatment Based on Number of Patients With Related Treatment-emergent Adverse Events (TEAEs) in the Phase 1 and Phase 2a Safety Population at Various Dose Levels and Indication | Patients with ≥1 related AE | 8 Participants |
| Phase 1 - 70 mg/m² Cohort | Safety and Tolerability of BAL101553 Treatment Based on Number of Patients With Related Treatment-emergent Adverse Events (TEAEs) in the Phase 1 and Phase 2a Safety Population at Various Dose Levels and Indication | Patients with ≥1 related serious AE | 2 Participants |
| Phase 1 - 90 mg/m² Cohort | Safety and Tolerability of BAL101553 Treatment Based on Number of Patients With Related Treatment-emergent Adverse Events (TEAEs) in the Phase 1 and Phase 2a Safety Population at Various Dose Levels and Indication | Patients with CTCAE Grade 3/4 or severe related AE | 2 Participants |
| Phase 1 - 90 mg/m² Cohort | Safety and Tolerability of BAL101553 Treatment Based on Number of Patients With Related Treatment-emergent Adverse Events (TEAEs) in the Phase 1 and Phase 2a Safety Population at Various Dose Levels and Indication | Patients with ≥1 related AE | 3 Participants |
| Phase 1 - 90 mg/m² Cohort | Safety and Tolerability of BAL101553 Treatment Based on Number of Patients With Related Treatment-emergent Adverse Events (TEAEs) in the Phase 1 and Phase 2a Safety Population at Various Dose Levels and Indication | Patients with ≥1 related serious AE | 1 Participants |
| Phase 2a - Ovarian Cancer Cohort | Safety and Tolerability of BAL101553 Treatment Based on Number of Patients With Related Treatment-emergent Adverse Events (TEAEs) in the Phase 1 and Phase 2a Safety Population at Various Dose Levels and Indication | Patients with CTCAE Grade 3/4 or severe related AE | 3 Participants |
| Phase 2a - Ovarian Cancer Cohort | Safety and Tolerability of BAL101553 Treatment Based on Number of Patients With Related Treatment-emergent Adverse Events (TEAEs) in the Phase 1 and Phase 2a Safety Population at Various Dose Levels and Indication | Patients with ≥1 related AE | 9 Participants |
| Phase 2a - Ovarian Cancer Cohort | Safety and Tolerability of BAL101553 Treatment Based on Number of Patients With Related Treatment-emergent Adverse Events (TEAEs) in the Phase 1 and Phase 2a Safety Population at Various Dose Levels and Indication | Patients with ≥1 related serious AE | 0 Participants |
| Phase 2a - Recurrent Glioblastoma Cohort | Safety and Tolerability of BAL101553 Treatment Based on Number of Patients With Related Treatment-emergent Adverse Events (TEAEs) in the Phase 1 and Phase 2a Safety Population at Various Dose Levels and Indication | Patients with ≥1 related AE | 4 Participants |
| Phase 2a - Recurrent Glioblastoma Cohort | Safety and Tolerability of BAL101553 Treatment Based on Number of Patients With Related Treatment-emergent Adverse Events (TEAEs) in the Phase 1 and Phase 2a Safety Population at Various Dose Levels and Indication | Patients with ≥1 related serious AE | 0 Participants |
| Phase 2a - Recurrent Glioblastoma Cohort | Safety and Tolerability of BAL101553 Treatment Based on Number of Patients With Related Treatment-emergent Adverse Events (TEAEs) in the Phase 1 and Phase 2a Safety Population at Various Dose Levels and Indication | Patients with CTCAE Grade 3/4 or severe related AE | 1 Participants |
Secondary
Tmax of BAL101553 and BAL27862
Pharmacokinetic parameter Time to Peak Plasma Concentration Tmax of BAL101553 and BAL27862
Time frame: Pre-dose, and 0.5, 1, 2, 4, 8, 24, 30, 48, 52, 54, 72 h, and 168 h after the start of study-drug infusion on Day 1 of Cycle 1 and pre-dose, and 0.5, 1, 2, 4, 8, 24, 30, 48, 72 h, and 168 h after the start of study-drug infusion on Day 1 of Cycle 2.
Population: The PK analysis set includes all patients who received at least one partial or complete dose of study drug and had at least one post-baseline PK assessment.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| MTD-determining Population in Phase 1 | Tmax of BAL101553 and BAL27862 | BAL101553 | 39.0 hours |
| MTD-determining Population in Phase 1 | Tmax of BAL101553 and BAL27862 | BAL27862 | 48.0 hours |
| Phase 1 - 45 mg/m² Cohort | Tmax of BAL101553 and BAL27862 | BAL27862 | 48.0 hours |
| Phase 1 - 45 mg/m² Cohort | Tmax of BAL101553 and BAL27862 | BAL101553 | 30.0 hours |
| Phase 1 - 70 mg/m² Cohort | Tmax of BAL101553 and BAL27862 | BAL101553 | 29.0 hours |
| Phase 1 - 70 mg/m² Cohort | Tmax of BAL101553 and BAL27862 | BAL27862 | 48.0 hours |
| Phase 1 - 90 mg/m² Cohort | Tmax of BAL101553 and BAL27862 | BAL27862 | 47.5 hours |
| Phase 1 - 90 mg/m² Cohort | Tmax of BAL101553 and BAL27862 | BAL101553 | 27.1 hours |
| Phase 2a - Ovarian Cancer Cohort | Tmax of BAL101553 and BAL27862 | BAL27862 | 47.6 hours |
| Phase 2a - Ovarian Cancer Cohort | Tmax of BAL101553 and BAL27862 | BAL101553 | 4.00 hours |
| Phase 2a - Recurrent Glioblastoma Cohort | Tmax of BAL101553 and BAL27862 | BAL101553 | 1.56 hours |
| Phase 2a - Recurrent Glioblastoma Cohort | Tmax of BAL101553 and BAL27862 | BAL27862 | 46.6 hours |
| 90 mg/m² Cycle 1 Day 1 | Tmax of BAL101553 and BAL27862 | BAL101553 | 2.53 hours |
| 90 mg/m² Cycle 1 Day 1 | Tmax of BAL101553 and BAL27862 | BAL27862 | 46.2 hours |
| 90 mg/m² Cycle 2 Day 1 | Tmax of BAL101553 and BAL27862 | BAL27862 | 47.4 hours |
| 90 mg/m² Cycle 2 Day 1 | Tmax of BAL101553 and BAL27862 | BAL101553 | 1.17 hours |