Solid Tumors
Conditions
Keywords
solid tumors, relapsed, advanced, metastatic, small cell lung cancer, ovarian cancer, refractory
Brief summary
The purpose of this study is to determine the safety and tolerability of ME-344 when given in combination with Hycamtin® in patients with solid tumors
Interventions
DRUGME-344
Part 1: ME-344 IV at 10 mg/kg on Days 1, 8, 15, and 22 of each 28-day cycle. Part 2: ME-344 IV at the dose defined in Part 1 on Days 1, 8, 15, and 22 of each 28 day cycle. Patients will be allowed to continue receiving ME-344 infusions weekly according to the assigned dose level as long as there is clinical benefit to the patient as assessed by the Investigator.
DRUGTopotecan
Part 1: Topotecan 4 mg/m2 i.v. weekly on Days 1, 8 and 15 of each 28-day cycle. Part 2: Topotecan 4 mg/m2 i.v. weekly on Days 1, 8 and 15 of each 28-day cycle.
Sponsors
SCRI Development Innovations, LLC
MEI Pharma, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologic or cytologic confirmed locally advanced or metastatic small cell lung cancer, ovarian cancer, or cervical cancer (Part 1); small cell lung cancer and ovarian cancer (Part 2) * Patients with ovarian and small cell lung cancer must have failed initial therapy * Patients with carcinoma of the cervix must have advanced disease not amenable to curative surgery and/or radiation therapy * Patients may not have received more than 4 prior regimens of therapy * Patients may not previously have received irinotecan, topotecan or other topoisomerase I inhibitor * ECOG Performance status 0-1 (Appendix B) * A minimum life expectancy of 12 weeks * Adequate bone marrow, hepatic and renal function as evidenced by: * Absolute neutrophil count (ANC) \> 1.5 x 109/L * Platelet count \> 100 x 109/L * Hemoglobin \> 9.0 g/dL * Serum bilirubin \< 1.5 x ULN * AST/ALT (SGOT/SGPT) \< 2.5 x ULN for the reference laboratory or \< 5 x --ULN in the presence of liver metastases * Serum creatinine \< 1.5 x ULN or creatinine clearance ≥ 60 mL/min as measured by institutional standards * At least 21 days must have elapsed prior to Day 1 Cycle 1, since any radiotherapy, immunotherapy or following major surgery; any surgical incision should be completely healed. At least 14 days must have elapsed prior to Day 1 Cycle 1 since limited palliative radiotherapy, defined as a course of therapy encompassing \<25% total bone marrow volume and not exceeding 30 GY.
Exclusion criteria
* Patients with tumor involvement of the Central Nervous System (CNS). SCLC patients with previously treated CNS lesions must have stable CNS disease for at least 4 weeks * Patients with uncontrolled infection or systemic disease * Patients with clinically significant cardiac disease not well controlled with medication (e.g., congestive heart failure, symptomatic coronary artery disease e.g. angina, and cardiac arrhythmias) or myocardial infarction within the last 12 months * Patients who have toxicity from last prior therapy that has not recovered to at least Grade 1, with the exception of Grade 2 alopecia * Patients who have had any chemotherapy regimens, biologic, or targeted therapies within the 2 weeks prior to Cycle 1 Day 1 * Patients with any neuropathy \> Grade 1 * Patients with known hypersensitivity to any components of ME-344 or topotecan study drug product * Patients with known human immunodeficiency virus (HIV) or Hepatitis B or C (active, previously treated or both) * Patients with a history of solid organ transplantation * Patients with presence of concurrent or active malignant disease (other than disease under study) within the last 12 months with the exception of adequately treated in-situ carcinomas, basal or squamous cell carcinoma, or non-melanomatous skin cancer. Patients with any psychiatric disorder or social or geographic situation that would preclude study participation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Adverse Events | Through study completion- an average of 2 years | The AE Profile will be determined by the number of AEs regardless of severity |
| Number of Serious Adverse Events | Through study completion- an average of 2 years | The SAE Profile will be determined by the number of SAEs |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Minimum Plasma Concentration (Cmin) of ME-344 | Cycle 1 Day 1, at 0, .5, 1, 2, 4, 6 and 24 hours post-dose and Day 15 at 0 and end of infusion | Various pharmacokinetic parameters for ME-344 in plasma were calculated based on the plasma concentration data. |
| Mean Terminal Half-life (t 1/2) | Cycle 1 Day 1, at 0, .5, 1, 2, 4, 6 and 24 hours post-dose and Day 15 at 0 and end of infusion | Various pharmacokinetic parameters for ME-344 in plasma were calculated based on the plasma concentration data. |
| Maximum Plasma Concentration (Cmax) | Cycle 1 Day 1, at 0, .5, 1, 2, 4, 6 and 24 hours post-dose and Day 15 at 0 and end of infusion | Peak Plasma Concentration (Cmax) of ME-344 in combination with topotecan |
| Estimate the Overall Survival (OS) | Up to 2 years | 41 subjects were analysed. Overall survival is defined as the first day of study drug administration to death. |
| Estimate Overall Response Rate for ME-344 Given in Combination With Topotecan | Response was assessed throughout the trial up to 13 months | Overall response rate was defined as the total number of patients with Complete Response plus Partial Response. All efficacy assessments were to include a baseline assessment and follow-up assessments at a minimum of every 8 weeks for the first 6 cycles, then every 12 weeks thereafter, while receiving study drug. Tumor response and progression-free survival were assessed using RECIST 1.1 criteria or GCIG criteria for CA-125 levels. |
| Time to Maximum Plasma Concentration for ME-344 (Tmax) | Cycle 1 Day 1, at 0, .5, 1, 2, 4, 6 and 24 hours post-dose and Day 15 at 0 and end of infusion | Various pharmacokinetic parameters for ME-344 in plasma were calculated based on the plasma concentration data. |
Countries
United Kingdom, United States
Participant flow
Recruitment details
This study was open to recruitment from April 30, 2014 through December 7, 2015 at 7 investigational sites in the USA and 2 sites in the United Kingdom. Forty-six patients were enrolled. The study was conducted in two parts. Fourteen (14) patients enrolled in Part 1 and 32 subjects were enrolled in Part 2.
Pre-assignment details
Fifty-eight (58) potential participants were screened; 46 subjects passed screening and were enrolled in the study.
Participants by arm
| Arm | Count |
|---|---|
| ME-344 ME-344 IV, 10 mg/kg on Days 1, 8, 15 and 22 of each 28 day cycle Topotecan IV, 4 mg/m2 on Days 1, 8 and 15 of each 28 day cycle
ME-344: Part 1: ME-344 IV at 10 mg/kg on Days 1, 8, 15, and 22 of each 28-day cycle.
Part 2: ME-344 IV at the dose defined in Part 1 on Days 1, 8, 15, and 22 of each 28 day cycle.
Patients will be allowed to continue receiving ME-344 infusions weekly according to the assigned dose level as long as there is clinical benefit to the patient as assessed by the Investigator.
Topotecan: Part 1: Topotecan 4 mg/m2 i.v. weekly on Days 1, 8 and 15 of each 28-day cycle.
Part 2: Topotecan 4 mg/m2 i.v. weekly on Days 1, 8 and 15 of each 28-day cycle. | 46 |
| Total | 46 |
Baseline characteristics
| Characteristic | ME-344 |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 12 Participants |
| Age, Categorical Between 18 and 65 years | 34 Participants |
| Age, Continuous | 59.5 Years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 41 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants |
| Race/Ethnicity, Customized Other | 1 Participants |
| Race/Ethnicity, Customized White | 42 Participants |
| Region of Enrollment United Kingdom | 8 participants |
| Region of Enrollment United States | 38 participants |
| Sex: Female, Male Female | 40 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 6 / 46 |
| other Total, other adverse events | 46 / 46 |
| serious Total, serious adverse events | 17 / 46 |
Outcome results
Primary
Number of Adverse Events
The AE Profile will be determined by the number of AEs regardless of severity
Time frame: Through study completion- an average of 2 years
Population: 46 subjects received \> 2 doses of ME-344 and topotecan and were eligible for DLT analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ME-344 | Number of Adverse Events | 595 adverse events |
Primary
Number of Serious Adverse Events
The SAE Profile will be determined by the number of SAEs
Time frame: Through study completion- an average of 2 years
Population: 46 subjects received \> 2 doses of ME-344 and topotecan and were eligible for DLT analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ME-344 | Number of Serious Adverse Events | 23 SAEs |
Secondary
Estimate Overall Response Rate for ME-344 Given in Combination With Topotecan
Overall response rate was defined as the total number of patients with Complete Response plus Partial Response. All efficacy assessments were to include a baseline assessment and follow-up assessments at a minimum of every 8 weeks for the first 6 cycles, then every 12 weeks thereafter, while receiving study drug. Tumor response and progression-free survival were assessed using RECIST 1.1 criteria or GCIG criteria for CA-125 levels.
Time frame: Response was assessed throughout the trial up to 13 months
Population: Part 1 (N =12), Part 2 (N=29)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ME-344 | Estimate Overall Response Rate for ME-344 Given in Combination With Topotecan | 1 participants |
Secondary
Estimate the Overall Survival (OS)
41 subjects were analysed. Overall survival is defined as the first day of study drug administration to death.
Time frame: Up to 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ME-344 | Estimate the Overall Survival (OS) | 3.7 months |
Secondary
Maximum Plasma Concentration (Cmax)
Peak Plasma Concentration (Cmax) of ME-344 in combination with topotecan
Time frame: Cycle 1 Day 1, at 0, .5, 1, 2, 4, 6 and 24 hours post-dose and Day 15 at 0 and end of infusion
Population: Pharmacokinetic parameters for ME-344 in plasma were calculated based on the plasma concentration data from 13 patients who received treatment in Part 1 of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ME-344 | Maximum Plasma Concentration (Cmax) | 20880 ng/mL | Standard Deviation 8201.3 |
Secondary
Mean Terminal Half-life (t 1/2)
Various pharmacokinetic parameters for ME-344 in plasma were calculated based on the plasma concentration data.
Time frame: Cycle 1 Day 1, at 0, .5, 1, 2, 4, 6 and 24 hours post-dose and Day 15 at 0 and end of infusion
Population: Samples were collected from patients in Part 1 of the study for measurement of plasma concentration of ME-344. Samples were collected from 13 patients in Part 1.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ME-344 | Mean Terminal Half-life (t 1/2) | 5.301 hours | Standard Deviation 2.0114 |
Secondary
Minimum Plasma Concentration (Cmin) of ME-344
Various pharmacokinetic parameters for ME-344 in plasma were calculated based on the plasma concentration data.
Time frame: Cycle 1 Day 1, at 0, .5, 1, 2, 4, 6 and 24 hours post-dose and Day 15 at 0 and end of infusion
Population: Samples were collected from patients in Part 1 of the study for measurement of plasma concentration of ME-344. Samples were collected from 13 patients in Part 1.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ME-344 | Minimum Plasma Concentration (Cmin) of ME-344 | 25.3 ng/mL | Standard Deviation 12.824 |
Secondary
Time to Maximum Plasma Concentration for ME-344 (Tmax)
Various pharmacokinetic parameters for ME-344 in plasma were calculated based on the plasma concentration data.
Time frame: Cycle 1 Day 1, at 0, .5, 1, 2, 4, 6 and 24 hours post-dose and Day 15 at 0 and end of infusion
Population: Samples were collected from patients in Part 1 of the study for measurement of plasma concentration of ME-344. Samples were collected from 13 patients in Part 1
| Arm | Measure | Value (MEAN) |
|---|---|---|
| ME-344 | Time to Maximum Plasma Concentration for ME-344 (Tmax) | 0.5 hours |