Clinical Trial of PM00104 (Zalypsis®) in Patients With Advanced and/or Metastatic Endometrial or Cervical Cancer Previously Treated With One Line of Systemic Chemotherapy

• Sponsor: PharmaMar (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00900562
• Collaborator: (none)
• Enrollment: 19
• Locations: 4
• Arm: 1
• Duration (Months): 25
• Patients Per Site: 4.8
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Uterine Cervical Cancer; Endometrial Cancer	Drug: Zalypsis ( PM00104)	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 19 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: Aug 1, 2009
• Actual Primary Completion Date: Sep 1, 2011
• Actual Study Completion Date: Sep 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1 Zalypsis (PM00104)	Drug: Zalypsis ( PM00104); Zalypsis (PM00104) (2.5 mg/vial) is provided as a powder for concentrate for solution for infusion

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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

2. 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

3. 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

4. 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

5. 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

6. 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.

7. 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

8. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts 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.

1. 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.

1. 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).

2. 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.

3. Age ≥ 18 years.

4. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 1.

5. Life expectancy ≥ 3 months.

6. 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.

1. Left ventricular ejection fraction (LVEF) within normal limits (LVEF of at least 50%).

2. 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.

1. 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.

2. 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.

3. 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.

4. 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.

1. Evidence of progressive or symptomatic central nervous system (CNS) metastases or leptomeningeal metastases.

2. 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).

1. 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.

2. 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.

3. Treatment with any investigational product within 30 days prior to inclusion in the study.

4. Known hypersensitivity to any component of PM00104.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital Cancer Center	Boston	Massachusetts	United States	02114-2617
2	UNM (University of New Mexico) Cancer Center	Albuquerque	New Mexico	United States	87131
3	OU Cancer Institute	Oklahoma City	Oklahoma	United States	73104
4	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111-2497

Sponsors and Collaborators

• PharmaMar

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Sep 30, 2010
• Statistical Analysis Plan - Jul 28, 2009

More Information

Publications

None provided.

• Responsible Party: PharmaMar
• ClinicalTrials.gov Identifier: NCT00900562
• Other Study ID Numbers: PM104-B-001-09
• First Posted: May 13, 2009
• Last Update Posted: Oct 28, 2021
• Last Verified: Jul 1, 2021

• Keywords provided by PharmaMar: Zalypsis; Cancer; Endometrial; Uterine Cervical; PharmaMar
• Additional relevant MeSH terms: Uterine Cervical Neoplasms; Endometrial Neoplasms

Study Results

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

Arm/Group Title	Endometrial Cancer	Cervical Cancer
Arm/Group Description	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	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
Period Title: Overall Study
STARTED	12	7
COMPLETED	0	0
NOT COMPLETED	12	7

Baseline Characteristics

Arm/Group Title	Endometrial Cancer	Cervical Cancer	Total
Arm/Group Description	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	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	Total of all reporting groups
Overall Participants	12	7	19
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	9 75%	7 100%	16 84.2%
>=65 years	3 25%	0 0%	3 15.8%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	61.5	38	59
Sex: Female, Male (Count of Participants)
Female	12 100%	7 100%	19 100%
Male	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
Caucasian	6 50%	4 57.1%	10 52.6%
Hispanic	3 25%	0 0%	3 15.8%
African American	0 0%	1 14.3%	1 5.3%
Black	3 25%	1 14.3%	4 21.1%
Other	0 0%	1 14.3%	1 5.3%
Region of Enrollment (participants) [Number]
United States	12 100%	7 100%	19 100%
Eastern Cooperative Oncology Group Performance Status (Count of Participants)
0	5 41.7%	1 14.3%	6 31.6%
1	7 58.3%	6 85.7%	13 68.4%
Histology (Count of Participants)
Adenocarcinoma	0 0%	1 14.3%	1 5.3%
Adenosquamous	0 0%	3 42.9%	3 15.8%
Clear cell	1 8.3%	0 0%	1 5.3%
Endometrioid	4 33.3%	0 0%	4 21.1%
Mixed	3 25%	0 0%	3 15.8%
Other	1 8.3%	1 14.3%	2 10.5%
Papillary serous	3 25%	0 0%	3 15.8%
Squamous cell carcinoma	0 0%	2 28.6%	2 10.5%
Extent of disease (Count of Participants)
Metastatic	10 83.3%	7 100%	17 89.5%
Locally advanced	2 16.7%	0 0%	2 10.5%
Histology grade (Count of Participants)
Poorly differentiated	10 83.3%	6 85.7%	16 84.2%
Moderately differentiated	1 8.3%	1 14.3%	2 10.5%
Unknown	1 8.3%	0 0%	1 5.3%
Sites involved (Count of Participants)
1	6 50%	1 14.3%	7 36.8%
2	2 16.7%	2 28.6%	4 21.1%
3	2 16.7%	2 28.6%	4 21.1%
>3	2 16.7%	2 28.6%	4 21.1%
Time from diagnosis to first infusion (months) [Median (Full Range) ]
Median (Full Range) [months]	18.2	10.7	16.6
Time from last progression to first infusion (months) [Median (Full Range) ]
Median (Full Range) [months]	0.9	0.8	0.8
Prior Surgery (Count of Participants)
Count of Participants [Participants]	11 91.7%	6 85.7%	17 89.5%
Prior Systemic anticancer therapy (Count of Participants)
Count of Participants [Participants]	12 100%	7 100%	19 100%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate (ORR)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Endometrial Cancer	Cervical Cancer
Arm/Group Description	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	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
Measure Participants	10	7
Count of Participants [Participants]	0 0%	0 0%

2. Secondary Outcome

Title	Best Tumor Response
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Endometrial Cancer	Cervical Cancer
Arm/Group Description	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	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
Measure Participants	10	7
SD ≥ 4 months	1 8.3%	0 0%
PD	9 75%	7 100%

3. Secondary Outcome

Title	Progression Free Survival
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Endometrial Cancer	Cervical Cancer
Arm/Group Description	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	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
Measure Participants	10	7
Median (95% Confidence Interval) [months]	1.8	1.5

4. Secondary Outcome

Title	Progression Free Survival Rate at 4 Months
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Endometrial Cancer	Cervical Cancer
Arm/Group Description	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	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
Measure Participants	10	7
Number (95% Confidence Interval) [percentage of participants]	10 83.3%	0 0%

5. Secondary Outcome

Title	Overall Survival
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Endometrial Cancer	Cervical Cancer
Arm/Group Description	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	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
Measure Participants	10	7
Median (95% Confidence Interval) [months]	5.5	5.6

6. Secondary Outcome

Title	PM00104 Plasma PK Parameters (Cmax) at First Infusion
Description	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)

Outcome Measure Data

Analysis Population Description

All treated patients

Arm/Group Title	PM00104
Arm/Group Description	Zalypsis (PM00104): Zalypsis (PM00104) (2.5 mg/vial) is provided as a powder for concentrate for solution for infusion
Measure Participants	19
Mean (Standard Deviation) [μg/l]	26.47 (11.98)

7. Secondary Outcome

Title	PM00104 Plasma PK Parameters (AUC) at First Infusion
Description	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)

Outcome Measure Data

Analysis Population Description

All treated patients

Arm/Group Title	PM00104
Arm/Group Description	Zalypsis (PM00104): Zalypsis (PM00104) (2.5 mg/vial) is provided as a powder for concentrate for solution for infusion
Measure Participants	19
Mean (Standard Deviation) [h*μg/l]	80.88 (37.41)

8. Secondary Outcome

Title	PM00104 Plasma PK Parameters (Cmax) at Second Infusion
Description	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)

Outcome Measure Data

Analysis Population Description

All treated patients with second infusion

Arm/Group Title	PM00104
Arm/Group Description	Zalypsis (PM00104): Zalypsis (PM00104) (2.5 mg/vial) is provided as a powder for concentrate for solution for infusion
Measure Participants	16
Mean (Standard Deviation) [μg/l]	35.02 (21.06)

9. Secondary Outcome

Title	PM00104 Plasma PK Parameters (AUC) at Second Infusion
Description	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)

Outcome Measure Data

Analysis Population Description

All treated patients with Second infusion

Arm/Group Title	PM00104
Arm/Group Description	Zalypsis (PM00104): Zalypsis (PM00104) (2.5 mg/vial) is provided as a powder for concentrate for solution for infusion
Measure Participants	16
Mean (Standard Deviation) [h*μg/l]	86.55 (40.41)

Adverse Events

Time Frame	From first infusion to study termination, up to 2 years
Arm/Group Title	Endometrial Cancer		Cervical Cancer
Arm/Group Description	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		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
All Cause Mortality
	Endometrial Cancer		Cervical Cancer
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/12 (75%)		5/7 (71.4%)
Serious Adverse Events
	Endometrial Cancer		Cervical Cancer
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/12 (41.7%)		3/7 (42.9%)
Blood and lymphatic system disorders
Disseminated intravascular coagulation	1/12 (8.3%)	1	0/7 (0%)	0
Anaemia	0/12 (0%)	0	1/7 (14.3%)	1
Cardiac disorders
Endocarditis noninfective	1/12 (8.3%)	1	0/7 (0%)	0
Gastrointestinal disorders
Diarrhoea	1/12 (8.3%)	1	1/7 (14.3%)	1
Nausea	1/12 (8.3%)	1	1/7 (14.3%)	1
Vomiting	1/12 (8.3%)	1	1/7 (14.3%)	1
Abdominal pain	0/12 (0%)	0	1/7 (14.3%)	3
Constipation	0/12 (0%)	0	1/7 (14.3%)	2
General disorders
Pyrexia	1/12 (8.3%)	1	0/7 (0%)	0
Infections and infestations
Escherichia bacteraemia	1/12 (8.3%)	1	0/7 (0%)	0
Enterobacter infection	0/12 (0%)	0	1/7 (14.3%)	1
Pneumonia	0/12 (0%)	0	1/7 (14.3%)	1
Investigations
Troponin I increased	1/12 (8.3%)	1	0/7 (0%)	0
Blood creatinine increased	0/12 (0%)	0	1/7 (14.3%)	1
Metabolism and nutrition disorders
Anorexia	1/12 (8.3%)	1	0/7 (0%)	0
Dehydration	1/12 (8.3%)	1	0/7 (0%)	0
Hyperkalaemia	0/12 (0%)	0	1/7 (14.3%)	1
Nervous system disorders
Cerebral ischaemia	1/12 (8.3%)	1	0/7 (0%)	0
Renal and urinary disorders
Hydronephrosis	1/12 (8.3%)	1	0/7 (0%)	0
Renal failure	0/12 (0%)	0	1/7 (14.3%)	1
Respiratory, thoracic and mediastinal disorders
Atelectasis	1/12 (8.3%)	1	0/7 (0%)	0
Pleural effusion	1/12 (8.3%)	1	0/7 (0%)	0
Productive cough	1/12 (8.3%)	1	0/7 (0%)	0
Vascular disorders
Deep vein thrombosis	2/12 (16.7%)	3	0/7 (0%)	0
Hypotension	1/12 (8.3%)	1	0/7 (0%)	0
Other (Not Including Serious) Adverse Events
	Endometrial Cancer		Cervical Cancer
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/12 (100%)		7/7 (100%)
Blood and lymphatic system disorders
Anaemia	2/12 (16.7%)	3	4/7 (57.1%)	9
Thrombocytopenia	1/12 (8.3%)	1	0/7 (0%)	0
Cardiac disorders
Cardio-respiratory arrest	1/12 (8.3%)	1	0/7 (0%)	0
Sinus tachycardia	0/12 (0%)	0	1/7 (14.3%)	1
Tachycardia	1/12 (8.3%)	1	0/7 (0%)	0
Ventricular tachycardia	1/12 (8.3%)	1	0/7 (0%)	0
Ear and labyrinth disorders
Ear pain	1/12 (8.3%)	1	0/7 (0%)	0
Tinnitus	2/12 (16.7%)	3	0/7 (0%)	0
Eye disorders
Vision blurred	2/12 (16.7%)	3	0/7 (0%)	0
Visual disturbance	2/12 (16.7%)	3	1/7 (14.3%)	1
Gastrointestinal disorders
Abdominal distension	2/12 (16.7%)	2	0/7 (0%)	0
Abdominal pain	2/12 (16.7%)	3	2/7 (28.6%)	3
Constipation	7/12 (58.3%)	13	5/7 (71.4%)	13
Diarrhoea	5/12 (41.7%)	5	2/7 (28.6%)	2
Dyspepsia	3/12 (25%)	3	0/7 (0%)	0
Dysphagia	1/12 (8.3%)	2	1/7 (14.3%)	1
Gastritis	0/12 (0%)	0	1/7 (14.3%)	1
Mouth ulceration	1/12 (8.3%)	1	0/7 (0%)	0
Nausea	7/12 (58.3%)	16	4/7 (57.1%)	6
Vomiting	3/12 (25%)	3	4/7 (57.1%)	6
General disorders
Asthenia	2/12 (16.7%)	4	1/7 (14.3%)	1
Chest pain	2/12 (16.7%)	2	1/7 (14.3%)	1
Chills	3/12 (25%)	4	0/7 (0%)	0
Fatigue	7/12 (58.3%)	15	6/7 (85.7%)	12
Generalised oedema	0/12 (0%)	0	1/7 (14.3%)	1
Mucosal inflammation	0/12 (0%)	0	1/7 (14.3%)	1
Oedema	1/12 (8.3%)	1	0/7 (0%)	0
Oedema peripheral	2/12 (16.7%)	3	0/7 (0%)	0
Pain	0/12 (0%)	0	1/7 (14.3%)	1
Pyrexia	4/12 (33.3%)	4	0/7 (0%)	0
Infections and infestations
Catheter related infection	0/12 (0%)	0	2/7 (28.6%)	2
Fungal infection	1/12 (8.3%)	1	0/7 (0%)	0
Sepsis syndrome	1/12 (8.3%)	1	0/7 (0%)	0
Urinary tract infection	3/12 (25%)	3	2/7 (28.6%)	2
Injury, poisoning and procedural complications
Fall	1/12 (8.3%)	1	0/7 (0%)	0
Investigations
Alanine aminotransferase increased	0/12 (0%)	0	1/7 (14.3%)	1
Aspartate aminotransferase increased	0/12 (0%)	0	1/7 (14.3%)	1
Neutrophil count decreased	1/12 (8.3%)	1	0/7 (0%)	0
Weight decreased	2/12 (16.7%)	2	0/7 (0%)	0
Metabolism and nutrition disorders
Anorexia	5/12 (41.7%)	8	3/7 (42.9%)	5
Decreased appetite	1/12 (8.3%)	1	0/7 (0%)	0
Dehydration	0/12 (0%)	0	1/7 (14.3%)	1
Hypercalcaemia	0/12 (0%)	0	1/7 (14.3%)	1
Hypokalaemia	0/12 (0%)	0	2/7 (28.6%)	4
Musculoskeletal and connective tissue disorders
Arthralgia	2/12 (16.7%)	2	0/7 (0%)	0
Back pain	0/12 (0%)	0	1/7 (14.3%)	1
Bone pain	1/12 (8.3%)	1	0/7 (0%)	0
Muscular weakness	0/12 (0%)	0	1/7 (14.3%)	3
Myalgia	2/12 (16.7%)	2	0/7 (0%)	0
Pain in extremity	0/12 (0%)	0	1/7 (14.3%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain	2/12 (16.7%)	5	2/7 (28.6%)	3
Nervous system disorders
Cerebrovascular accident	1/12 (8.3%)	1	0/7 (0%)	0
Dizziness	0/12 (0%)	0	1/7 (14.3%)	1
Dysgeusia	1/12 (8.3%)	2	0/7 (0%)	0
Headache	1/12 (8.3%)	1	1/7 (14.3%)	1
Hypoaesthesia	0/12 (0%)	0	1/7 (14.3%)	1
Memory impairment	1/12 (8.3%)	1	0/7 (0%)	0
Neuropathy peripheral	1/12 (8.3%)	1	1/7 (14.3%)	1
Paraesthesia	1/12 (8.3%)	2	1/7 (14.3%)	1
Peripheral sensory neuropathy	1/12 (8.3%)	1	0/7 (0%)	0
Psychiatric disorders
Depression	0/12 (0%)	0	1/7 (14.3%)	1
Insomnia	1/12 (8.3%)	1	0/7 (0%)	0
Mental disorder	1/12 (8.3%)	1	0/7 (0%)	0
Mood altered	1/12 (8.3%)	1	0/7 (0%)	0
Renal and urinary disorders
Dysuria	1/12 (8.3%)	1	0/7 (0%)	0
Haematuria	1/12 (8.3%)	1	1/7 (14.3%)	1
Pollakiuria	1/12 (8.3%)	1	0/7 (0%)	0
Urinary retention	0/12 (0%)	0	1/7 (14.3%)	1
Reproductive system and breast disorders
Vaginal discharge	0/12 (0%)	0	1/7 (14.3%)	1
Vaginal haemorrhage	1/12 (8.3%)	1	2/7 (28.6%)	4
Respiratory, thoracic and mediastinal disorders
Cough	2/12 (16.7%)	2	0/7 (0%)	0
Dyspnoea	5/12 (41.7%)	5	2/7 (28.6%)	2
Epistaxis	1/12 (8.3%)	1	0/7 (0%)	0
Hiccups	1/12 (8.3%)	1	0/7 (0%)	0
Pleural effusion	1/12 (8.3%)	1	0/7 (0%)	0
Skin and subcutaneous tissue disorders
Alopecia	1/12 (8.3%)	1	1/7 (14.3%)	1
Nail disorder	0/12 (0%)	0	1/7 (14.3%)	1
Night sweats	3/12 (25%)	3	1/7 (14.3%)	1
Vascular disorders
Deep vein thrombosis	0/12 (0%)	0	1/7 (14.3%)	1
Jugular vein thrombosis	1/12 (8.3%)	1	0/7 (0%)	0
Vena cava thrombosis	1/12 (8.3%)	1	0/7 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days from the time submitted to the sponsor for review.