Endometrial Cancer, Uterine Cervical Cancer
Conditions
Keywords
Zalypsis, Cancer, Endometrial, Uterine Cervical, PharmaMar
Brief summary
This study is a phase II clinical and pharmacokinetic trial of PM00104 (Zalypsis®) in patients with advanced and/or metastatic endometrial or cervical cancer previously treated with one line of systemic chemotherapy to evaluate the antitumor activity and to determine the safety profile, the pharmacokinetic profile and the pharmacogenomic profile.
Interventions
DRUGZalypsis ( PM00104)
Zalypsis (PM00104) (2.5 mg/vial) is provided as a powder for concentrate for solution for infusion
Sponsors
PharmaMar
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Voluntary written informed consent, obtained from the patient before the beginning of any specific study procedures. 2. Group 1 (endometrial cancer): * Histologically confirmed advanced and/or metastatic endometrial cancer (any grade, including endometrioid, clear cell, serous and mixed types) with documented disease progression as per RECIST at study entry. * Patients must have failed one prior systemic chemotherapy line for advanced/metastatic disease (excluding chemosensitizing chemotherapy); prior hormone therapy and biological therapy are allowed. 3. Group 2 (cervical cancer): * Histologically confirmed advanced and/or metastatic cervical cancer with documented disease progression as per RECIST at study entry. * Patients must have failed one prior systemic chemotherapy line for advanced/metastatic disease (excluding chemosensitizing chemotherapy); prior hormone therapy and biological therapy are allowed. 4. Complete recovery from the effects of prior radiotherapy and from any drug-related adverse events (AEs) derived from previous treatments, excluding alopecia and grade 1 peripheral neuropathy according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE, v.3.0). 5. At least one measurable lesion (target lesion according to the RECIST), located in a non-irradiated area and adequately measured less than four weeks before study entry. Tumors within a previously irradiated field will be designated as nontarget lesions unless progression is clearly documented or biopsy proven. 6. Age ≥ 18 years. 7. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 1. 8. Life expectancy ≥ 3 months. 9. Appropriate bone marrow reserve, renal and hepatic functions: * Platelet count ≥ 100 x 109/l, hemoglobin ≥ 9 g/dl and absolute neutrophil count (ANC) ≥ 1.5 x 109/l. * Alkaline phosphatase (AP) ≤ 2.5 x upper limit of normality (ULN) (≤ 5 x ULN in case of extensive bone metastases). * Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤ 2.5 x ULN (≤ 5 x ULN in case of hepatic metastases). * Total bilirubin ≤ 1.5 x ULN, unless due to Gilbert's syndrome. * Renal function: patients with calculated creatinine clearance (using Cockcroft and Gault formula) ≥ 30 ml/min. * Albumin ≥ 2.5 g/dl. 10. Left ventricular ejection fraction (LVEF) within normal limits (LVEF of at least 50%). 11. Women of childbearing potential must have a negative serum pregnancy test before study entry. In case of childbearing potential, the patients and their partners must agree to use a medically acceptable method of contraception.
Exclusion criteria
1. Prior therapy with PM00104. 2. Uterine sarcomas, adenosarcoma, and malignant Mullerian tumors. 3. Cervical neuroendocrine or small cell carcinomas, nonepithelial cervical neoplasms such as sarcomas. 4. Patients who have isolated recurrences (vaginal, pelvic or paraaortic) potentially curative with radiation therapy or surgery. 5. Pregnant or lactating women, or in case of childbearing potential, women not using an appropriate contraceptive method. 6. Less than three weeks from prior radiation therapy, biological therapy or chemotherapy, AND * Less than six weeks from prior nitrosourea, mitomycin C, high-dose chemotherapy or radiotherapy involving the whole pelvis or over 50% of the spine, provided that acute effects of radiation treatment have resolved. * Hormonal therapy and palliative radiation therapy (i.e., for control of pain from bone metastases) must be discontinued before study entry. 7. Group 1 (endometrial cancer): more than one line of prior systemic chemotherapy for advanced/metastatic disease (excluding chemosensitizing chemotherapy), but not less than three weeks before. 8. Group 2 (cervical cancer): more than one line of prior systemic chemotherapy for advanced/metastatic disease (excluding chemosensitizing chemotherapy, but not less than three weeks before. 9. Patients with a prior invasive malignancy (except nonmelanoma skin cancer) who have had any evidence of disease within the last five years or whose prior malignancy treatment contraindicates the current protocol therapy. 10. Patients with serious non-healing wound, ulcer, or bone fracture. * This includes history of: abdominal fistula, gastrointestinal perforation or intra-abdominal abscess for which an interval of three to six months must pass before study entry. * In addition, the patient must have undergone correction (or spontaneous healing) of the perforation/fistula and/or the underlying process causing the fistula/perforation. * Patients with granulating incisions healing by secondary intention with no evidence of fascial dehiscence or infection are eligible but require weekly wound examinations. 11. Evidence of progressive or symptomatic central nervous system (CNS) metastases or leptomeningeal metastases. 12. Other diseases or serious conditions: * Increased cardiac risk as defined by: * Unstable angina or myocardial infarction within 12 months before inclusion in the study. * New York Heart Association (NYHA) grade II or greater congestive heart failure. * Symptomatic arrhythmia or any arrhythmia requiring ongoing treatment. * Abnormal electrocardiogram (ECG), i.e., patients with the following are excluded: QT prolongation - QTc \> 480 msec; signs of cardiac enlargement or hypertrophy; bundle branch block; partial blocks;signs of ischemia or necrosis, and Wolff Parkinson White patterns. * History or presence of valvular heart disease. * Uncontrolled arterial hypertension despite optimal medical therapy. * Previous mediastinal radiotherapy. * Previous treatment with doxorubicin at cumulative doses exceeding 400 mg/m2. * History of significant neurological or psychiatric disorders. * Active infection requiring systemic treatment. * Significant non-neoplastic liver disease (e.g., cirrhosis, active chronic hepatitis). * Immunocompromised patients, including those known to be infected with the human immunodeficiency virus (HIV). * Uncontrolled (i.e., requiring relevant changes in medication within the last month or hospital admission within the last three months) endocrine diseases (e.g., diabetes mellitus, hypo- or hyperthyroidism, adrenal disorder). 13. Any other major illness that, in the Investigator's judgment, will substantially increase the risk associated with the patient's participation in the study. The investigator should feel free to consult the Study Coordinator or the Sponsor for uncertainty in this regard. 14. Limitation of the patient's ability to comply with the treatment or to follow-up at a participating center. Patients enrolled into this trial must be treated and followed at a participating center. 15. Treatment with any investigational product within 30 days prior to inclusion in the study. 16. Known hypersensitivity to any component of PM00104.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | At baseline and every other cycle (± 1 week) until evidence of PD, up to 2 years | Overall Response Rate defined as the percentage of patients with either complete response (CR) or partial response (PR) according to RECIST v.1.0. CR, complete response: disappearance of all lesions; PD, disease progression: ≥10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: ≥10% decrease in target lesion size or ≥15% decrease in tumor density; SD, stable disease: none of the CR, PR, or PD criteria met; RECIST, Response Evaluation Criteria in Solid Tumors |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | From the date of first infusion of study treatment to the date of progression or death, up to 2 years | Progression-free survival (PFS) was defined as the time from the date of first infusion of study treatment to the date of progression or death (due to any cause). If progression or death had not occurred at the time of the analysis, PFS was censored on the date of last tumor evaluation. PD, disease progression: ≥10% increase in target lesion size and does not meet tumor density criteria of PR density |
| Progression Free Survival Rate at 4 Months | At 4 months | Progression-free survival rate at 4 months was defined as the percentage of patients who did not progress and were alive at 4 months. PD, disease progression: ≥10% increase in target lesion size and does not meet tumor density criteria of PR density |
| Overall Survival | From the date of first infusion to the date of death, up to 2 years | Overall survival (OS) was defined as the time from the date of first infusion of study treatment to the date of death (due to any cause). Patients with no documented death were censored at the last date they were known to be alive |
| Best Tumor Response | At baseline and every other cycle (± 1 week) until evidence of PD, up to 2 years | Best tumor response was defined as the best response achieved during the study according to RECIST v1.0 CR, complete response: disappearance of all lesions; PD, disease progression: ≥10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: ≥10% decrease in target lesion size or ≥15% decrease in tumor density; SD, stable disease: none of the CR, PR, or PD criteria met; RECIST, Response Evaluation Criteria in Solid Tumors |
| PM00104 Plasma PK Parameters (AUC) at First Infusion | 0 (Pre-infusion) and 1, 1.5, 3, 7, 24, 48, 168 hours after the end of first infusion (Day 1) | AUC Area under the plasma concentration-time curve from time zero to infinity. |
| PM00104 Plasma PK Parameters (Cmax) at Second Infusion | 0 (Pre-infusion) and 1, 1.5, 3, 7, 24, 48, 168 hours after the end of second infusion (Day 8) | Cmax Maximum plasma concentration, directly determined from the experimental data |
| PM00104 Plasma PK Parameters (AUC) at Second Infusion | 0 (Pre-infusion) and 1, 1.5, 3, 7, 24, 48, 168 hours after the end of second infusion (Day 8) | AUC Area under the plasma concentration-time curve from time zero to infinity |
| PM00104 Plasma PK Parameters (Cmax) at First Infusion | 0 (Pre-infusion) and 1, 1.5, 3, 7, 24, 48, 168 hours after the end of first infusion (Day 1) | Cmax Maximum plasma concentration, directly determined from the experimental data |
Countries
United States
Participant flow
Recruitment details
Endometrial Cancer: 12 patients were recruited and treated at 4 sites in the US. Patients participated between 14/08/2009 (first consent signed (CS)) and 22/2/2010 (last CS). The first dose was administered on 26/08/2009 and the last dose on 2/4/2010. Cervical Cancer: 7 patients were recruited and treated at 3 sites in the US. Patients participated in the study between 19/8/2009 (first CS) and 22/12/2010 (last CS). The first dose was administered on 26/10/2009 and the last dose on 10/03/2011
Participants by arm
| Arm | Count |
|---|---|
| Endometrial Cancer Patients with Endometrial Cancer. A treatment cycle consisted of the administration of i.v. 1-hour infusions of PM00104 on Day 1, Day 8 and Day 15, and all study evaluations done before the next cycle. Treatment cycles were to be repeated every four weeks.
Study treatment was administered to patients by a central catheter and by specialized on-site study personnel. A central catheter was mandatory as some cases of infusion site reactions were observed in the phase I trials | 12 |
| Cervical Cancer Patients with Cervical Cancer A treatment cycle consisted of the administration of i.v. 1-hour infusions of PM00104 on Day 1, Day 8 and Day 15, and all study evaluations done before the next cycle. Treatment cycles were to be repeated every four weeks.
Study treatment was administered to patients by a central catheter and by specialized on-site study personnel. A central catheter was mandatory as some cases of infusion site reactions were observed in the phase I trials | 7 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 1 |
| Overall Study | Progressive disease | 9 | 5 |
| Overall Study | Toxicity | 1 | 0 |
| Overall Study | Unrelated adverse event | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Endometrial Cancer | Cervical Cancer |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 3 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants | 9 Participants | 7 Participants |
| Age, Continuous | 59 years | 61.5 years | 38 years |
| Eastern Cooperative Oncology Group Performance Status 0 | 6 Participants | 5 Participants | 1 Participants |
| Eastern Cooperative Oncology Group Performance Status 1 | 13 Participants | 7 Participants | 6 Participants |
| Extent of disease Locally advanced | 2 Participants | 2 Participants | 0 Participants |
| Extent of disease Metastatic | 17 Participants | 10 Participants | 7 Participants |
| Histology Adenocarcinoma | 1 Participants | 0 Participants | 1 Participants |
| Histology Adenosquamous | 3 Participants | 0 Participants | 3 Participants |
| Histology Clear cell | 1 Participants | 1 Participants | 0 Participants |
| Histology Endometrioid | 4 Participants | 4 Participants | 0 Participants |
| Histology Mixed | 3 Participants | 3 Participants | 0 Participants |
| Histology Other | 2 Participants | 1 Participants | 1 Participants |
| Histology Papillary serous | 3 Participants | 3 Participants | 0 Participants |
| Histology Squamous cell carcinoma | 2 Participants | 0 Participants | 2 Participants |
| Histology grade Moderately differentiated | 2 Participants | 1 Participants | 1 Participants |
| Histology grade Poorly differentiated | 16 Participants | 10 Participants | 6 Participants |
| Histology grade Unknown | 1 Participants | 1 Participants | 0 Participants |
| Prior Surgery | 17 Participants | 11 Participants | 6 Participants |
| Prior Systemic anticancer therapy | 19 Participants | 12 Participants | 7 Participants |
| Race/Ethnicity, Customized African American | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Black | 4 Participants | 3 Participants | 1 Participants |
| Race/Ethnicity, Customized Caucasian | 10 Participants | 6 Participants | 4 Participants |
| Race/Ethnicity, Customized Hispanic | 3 Participants | 3 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment United States | 19 participants | 12 participants | 7 participants |
| Sex: Female, Male Female | 19 Participants | 12 Participants | 7 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Sites involved 1 | 7 Participants | 6 Participants | 1 Participants |
| Sites involved 2 | 4 Participants | 2 Participants | 2 Participants |
| Sites involved 3 | 4 Participants | 2 Participants | 2 Participants |
| Sites involved >3 | 4 Participants | 2 Participants | 2 Participants |
| Time from diagnosis to first infusion | 16.6 months | 18.2 months | 10.7 months |
| Time from last progression to first infusion | 0.8 months | 0.9 months | 0.8 months |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 9 / 12 | 5 / 7 |
| other Total, other adverse events | 12 / 12 | 7 / 7 |
| serious Total, serious adverse events | 5 / 12 | 3 / 7 |
Outcome results
Primary
Overall Response Rate (ORR)
Overall Response Rate defined as the percentage of patients with either complete response (CR) or partial response (PR) according to RECIST v.1.0. CR, complete response: disappearance of all lesions; PD, disease progression: ≥10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: ≥10% decrease in target lesion size or ≥15% decrease in tumor density; SD, stable disease: none of the CR, PR, or PD criteria met; RECIST, Response Evaluation Criteria in Solid Tumors
Time frame: At baseline and every other cycle (± 1 week) until evidence of PD, up to 2 years
Population: Two patients were not evaluable for efficacy: One patient received only one PM00104 infusion in Cycle 1 and had to be withdrawn from the study due to a troponin I increase, which occurred seven days after the first infusion of PM00104 and was considered serious (SAE) and related to PM00104; One patient only received one PM00104 infusion and was withdrawn from the study due to drug-unrelated marantic endocarditis
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Endometrial Cancer | Overall Response Rate (ORR) | 0 Participants |
| Cervical Cancer | Overall Response Rate (ORR) | 0 Participants |
Secondary
Best Tumor Response
Best tumor response was defined as the best response achieved during the study according to RECIST v1.0 CR, complete response: disappearance of all lesions; PD, disease progression: ≥10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: ≥10% decrease in target lesion size or ≥15% decrease in tumor density; SD, stable disease: none of the CR, PR, or PD criteria met; RECIST, Response Evaluation Criteria in Solid Tumors
Time frame: At baseline and every other cycle (± 1 week) until evidence of PD, up to 2 years
Population: Two patients were not evaluable for efficacy: One patient received only one PM00104 infusion in Cycle 1 and had to be withdrawn from the study due to a troponin I increase, which occurred seven days after the first infusion of PM00104 and was considered serious (SAE) and related to PM00104; One patient only received one PM00104 infusion and was withdrawn from the study due to drug-unrelated marantic endocarditis
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Endometrial Cancer | Best Tumor Response | SD ≥ 4 months | 1 Participants |
| Endometrial Cancer | Best Tumor Response | PD | 9 Participants |
| Cervical Cancer | Best Tumor Response | SD ≥ 4 months | 0 Participants |
| Cervical Cancer | Best Tumor Response | PD | 7 Participants |
Secondary
Overall Survival
Overall survival (OS) was defined as the time from the date of first infusion of study treatment to the date of death (due to any cause). Patients with no documented death were censored at the last date they were known to be alive
Time frame: From the date of first infusion to the date of death, up to 2 years
Population: Two patients were not evaluable for efficacy: One patient received only one PM00104 infusion in Cycle 1 and had to be withdrawn from the study due to a troponin I increase, which occurred seven days after the first infusion of PM00104 and was considered serious (SAE) and related to PM00104; One patient only received one PM00104 infusion and was withdrawn from the study due to drug-unrelated marantic endocarditis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Endometrial Cancer | Overall Survival | 5.5 months |
| Cervical Cancer | Overall Survival | 5.6 months |
Secondary
PM00104 Plasma PK Parameters (AUC) at First Infusion
AUC Area under the plasma concentration-time curve from time zero to infinity.
Time frame: 0 (Pre-infusion) and 1, 1.5, 3, 7, 24, 48, 168 hours after the end of first infusion (Day 1)
Population: All treated patients
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Endometrial Cancer | PM00104 Plasma PK Parameters (AUC) at First Infusion | 80.88 h*μg/l | Standard Deviation 37.41 |
Secondary
PM00104 Plasma PK Parameters (AUC) at Second Infusion
AUC Area under the plasma concentration-time curve from time zero to infinity
Time frame: 0 (Pre-infusion) and 1, 1.5, 3, 7, 24, 48, 168 hours after the end of second infusion (Day 8)
Population: All treated patients with Second infusion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Endometrial Cancer | PM00104 Plasma PK Parameters (AUC) at Second Infusion | 86.55 h*μg/l | Standard Deviation 40.41 |
Secondary
PM00104 Plasma PK Parameters (Cmax) at First Infusion
Cmax Maximum plasma concentration, directly determined from the experimental data
Time frame: 0 (Pre-infusion) and 1, 1.5, 3, 7, 24, 48, 168 hours after the end of first infusion (Day 1)
Population: All treated patients
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Endometrial Cancer | PM00104 Plasma PK Parameters (Cmax) at First Infusion | 26.47 μg/l | Standard Deviation 11.98 |
Secondary
PM00104 Plasma PK Parameters (Cmax) at Second Infusion
Cmax Maximum plasma concentration, directly determined from the experimental data
Time frame: 0 (Pre-infusion) and 1, 1.5, 3, 7, 24, 48, 168 hours after the end of second infusion (Day 8)
Population: All treated patients with second infusion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Endometrial Cancer | PM00104 Plasma PK Parameters (Cmax) at Second Infusion | 35.02 μg/l | Standard Deviation 21.06 |
Secondary
Progression Free Survival
Progression-free survival (PFS) was defined as the time from the date of first infusion of study treatment to the date of progression or death (due to any cause). If progression or death had not occurred at the time of the analysis, PFS was censored on the date of last tumor evaluation. PD, disease progression: ≥10% increase in target lesion size and does not meet tumor density criteria of PR density
Time frame: From the date of first infusion of study treatment to the date of progression or death, up to 2 years
Population: Two patients were not evaluable for efficacy: One patient received only one PM00104 infusion in Cycle 1 and had to be withdrawn from the study due to a troponin I increase, which occurred seven days after the first infusion of PM00104 and was considered serious (SAE) and related to PM00104; One patient only received one PM00104 infusion and was withdrawn from the study due to drug-unrelated marantic endocarditis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Endometrial Cancer | Progression Free Survival | 1.8 months |
| Cervical Cancer | Progression Free Survival | 1.5 months |
Secondary
Progression Free Survival Rate at 4 Months
Progression-free survival rate at 4 months was defined as the percentage of patients who did not progress and were alive at 4 months. PD, disease progression: ≥10% increase in target lesion size and does not meet tumor density criteria of PR density
Time frame: At 4 months
Population: Two patients were not evaluable for efficacy: One patient received only one PM00104 infusion in Cycle 1 and had to be withdrawn from the study due to a troponin I increase, which occurred seven days after the first infusion of PM00104 and was considered serious (SAE) and related to PM00104; One patient only received one PM00104 infusion and was withdrawn from the study due to drug-unrelated marantic endocarditis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Endometrial Cancer | Progression Free Survival Rate at 4 Months | 10 percentage of participants |
| Cervical Cancer | Progression Free Survival Rate at 4 Months | 0 percentage of participants |