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Clinical Trial Results:
A phase II Controlled Study of PM01183 in Platinum-Resistant / Refractory Advanced Ovarian Cancer Patients.

Summary
EudraCT number	2011-002172-16
Trial protocol	ES
Global end of trial date	25 Sep 2014

Results information
Results version number	v1(current)
This version publication date	29 Jul 2016
First version publication date	29 Jul 2016
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

PM1183-B-002-11

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Pharma Mar, S.A.

Sponsor organisation address

Av de los Reyes 1, Poligono Industrial La Mina , Colmenar Viejo, Madrid, Spain, 28770

Public contact

Clinical DevelopmentDepartment of PharmaMar´s Oncology, Business Unit., Pharma Mar, S.A., 34 91846 60 00, clinicaltrials@pharmamar.com

Scientific contact

Clinical DevelopmentDepartment of PharmaMar´s Oncology, Business Unit., Pharma Mar, S.A., 34 91846 60 00, clinicaltrials@pharmamar.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

29 Jun 2016

Is this the analysis of the primary completion data?

Yes

Primary completion date

25 Sep 2014

Global end of trial reached?

Yes

Global end of trial date

25 Sep 2014

Was the trial ended prematurely?

Main objective of the trial

To evaluate the antitumor activity of PM01183 in patients with platinum-resistant / refractory advanced ovarian cancer.

Protection of trial subjects

This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki (as approved by the 59th World Medical Association General Assembly, held at Seoul in 2008) and was consistent with Good Clinical Practice (GCP) and applicable regulatory requirements. Study personnel involved in conducting this trial was qualified by education, training, and experience to perform their respective task(s). The Sponsor provided insurance or indemnity in accordance with the applicable regulatory requirements.

Background therapy

Patients were to receive standard antiemetic prophylaxis according to American Society of Clinical Oncology (ASCO) guidelines before each treatment administration: • Corticosteroids (dexamethasone i.v. or equivalent, at institutional standard antiemetic doses). • Serotonin (5-HT3) antagonists (ondansetron 8 mg i.v. or equivalent). If necessary, in addition to the above, 10 mg of metoclopramide every eight hours could be administered orally or the duration of treatment with 5-HT3 antagonists and/or dexamethasone could be extended (according to Investigator criteria). Additional antiemetics could be used after Cycle 1 upon agreement with the Sponsor.

Evidence for comparator

Actual start date of recruitment

19 Dec 2011

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

France: 45

Country: Number of subjects enrolled

Spain: 36

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Eighty-one patients were enrolled between 19 December 2011 and 22 March 2013 at nine study centers (France and Spain). There were 52 patients treated with PM01183 in the Experimental Arm: 22 in an unrandomized first stage; 30 in the randomized second stage. Twenty-nine patients were randomized to topotecan in the second stage Control Arm

Screening details

Sign IC;Age≥18 year;Histologically/cytologically confirmed epithelial ovarian, fallopian tube or primary peritoneal cancer;Platinum-resistant/refractory disease;FIGO stages IIC through IV and measurable disease as per RECIST v.1.1 or by GCIG criteria;Adequate hematological/renal/metabolic/hepatic function;At least 3 weeks since last prior therapy

Period 1 title

Overall period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Blinding implementation details

-First stage: 18 evaluable patients were to be given PM01183 to explore the activity of PM01183. If the minimum threshold of antitumor activity was met (at least two of the 18 patients with confirmed tumor responses) - Second stage: 60 evaluable patients were to be randomized (stratified according to platinum-resistance or refractoriness), 30 per arm, to an PM01183 Arm or to a Control Arm (Topotecan). Patients discontinuing topotecan could be considered for crossover to PM01183 treatment.

Are arms mutually exclusive

Yes

PM01183

Arm description

There were 52 patients treated with PM01183 in the Experimental Arm: 22 in an unrandomized first stage; 30 in the randomized second stage. All patients in this arm received PM01183 7.0 mg FD on Day 1 i.v. as a 1-h infusion q3wk (three weeks = one treatment cycle).

Arm type

Experimental

Investigational medicinal product name

PM01183

Investigational medicinal product code

PM01183

Other name

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

PM01183 was supplied as a lyophilized powder for concentrate for solution for infusion with two strengths: 1 mg/vial and 4 mg/vial. Before use, the 1-mg vial and 4-mg vial was reconstituted with 2 mL and 8 mL of water for injection respectively to give a solution containing 0.5 mg/mL of PM01183. For administration to patients as i.v. infusion, reconstituted vials were further diluted with glucose 50 mg/mL (5%) solution for infusion or sodium chloride 9 mg/mL (0.9%) solution for infusion. All patients in this arm received PM01183: 7.0 mg FD on Day 1 i.v. as a 1-h infusion q3wk (three weeks = one treatment cycle).

Topotecan

Arm description

During the second stage, patients were randomized the Control Arm: Topotecan. Topotecan was administered either as a standard (daily) or weekly regimen. The daily dose/regimen was based on approved topotecan dosing for relapsed ovarian cancer. The weekly regimen and dose/regimen was based on clinical practice reported in the literature.

Arm type

Active comparator

Investigational medicinal product name

Topotecan

Investigational medicinal product code

Topotecan

Other name

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Standard Daily Regimen: Topotecan: i.v. as a 30-min infusion daily on Days 1–5 q3wk (3 weeks = 1 treatment cycle). The starting topotecan dose depended on the patient’s ECOG PS, CrCL, and on the number of line of prior chemotherapy lines: -1.50 mg/m2/daily for patients with ECOG PS=0, CrCL≥60 mL/min and not more than one line. -1.25 mg/m2/daily for patients with ECOG PS=1 or 2, or CrCL 41–59 mL/min, or more than one line. -0.75 mg/m2/daily for patients with CrCL 30–40 mL/min. Weekly Regimen:- Topotecan: i.v. as a 30-min infusion weekly on Days 1, 8 and 15 q4wk (4 weeks = 1 treatment cycle). The starting topotecan dose depended on the patient’s ECOG PS and CrCL: -4.0 mg/m2 for patients with ECOG PS=0 or 1 and CrCL≥60 mL/min. -3.0 mg/m2 for patients with ECOG PS=2 or CrCL 41–59 ml/min. -2.4 mg/m2 for patients with calculated CrCL 30–40 mL/min. Regardless of the starting dose, patients received topotecan at the same schedule

Number of subjects in period 1	PM01183	Topotecan
Started	52	29
Completed	0	0
Not completed	52	29
Adverse event, serious fatal	-	1
Physician decision	5	3
Consent withdrawn by subject	4	2
Adverse event, non-fatal	5	-
Progressive disease	38	23

Baseline characteristics

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Reporting group title

PM01183

Reporting group description

Reporting group title

Topotecan

Reporting group description

Reporting group values	PM01183	Topotecan	Total
Number of subjects	52	29	81
Age categorical
Units: Subjects
18–49 years	7	6	13
50–69 years	37	12	49
≥ 70 years	8	11	19
Age continuous
Units: years
median (full range (min-max))	59 (35 to 81)	61 (35 to 80)	-
Gender categorical
Units: Subjects
Female	52	29	81
Male	0	0	0
ECOG PS
ECOG PS=Eastern Cooperative Oncology Group performance status
Units: Subjects
PS 0	26	11	37
PS 1	24	14	38
PS 2	2	4	6
Race
Units: Subjects
Caucasian	44	22	66
Unk	8	7	15
Primary tumor site
Units: Subjects
Ovarian	44	23	67
Peritoneal	7	4	11
Fallopian tube	1	2	3
Histology type
Units: Subjects
Papillary serous	38	19	57
Endometrioid	4	2	6
Undifferentiated carcinoma	4	2	6
Mixed epithelial ovarian	2	0	2
Mucinous	2	1	3
Clear cell	1	3	4
Unspecified/unknown	1	2	3
Histology grade
Units: Subjects
Well differentiated	8	0	8
Moderately differentiated	9	8	17
Poorly differentiated	24	9	33
Unknown	11	12	23
Disease stage at inclusion
Units: Subjects
Locally advanced	20	16	36
Metastatic	32	13	45
Visceral metastasis
Units: Subjects
Yes	20	8	28
No	32	21	53
Ascites
Units: Subjects
Yes	11	10	21
No	41	19	60
Platinum status
Platinum-resistant disease was defined as disease relapse or progression less than six months after last platinum-containing chemotherapy; platinum-refractory disease was defined as disease that did not respond during last platinum-containing chemotherapy
Units: Subjects
Refractory	19	13	32
Resistant	33	16	49
Platinum resistance
Units: Subjects
Primary resistance	30	18	48
Secondary resistance	22	11	33
Patients with PFI
PFI, platinum-free interval;
Units: Subjects
< 3 months	20	15	35
3–6 months	32	14	46
Disease evaluation
GCIG, Gynecological Cancer Intergroup criteria;RECIST, Response Evaluation Criteria in Solid Tumors v.1.1
Units: Subjects
RECIST (measurable disease)	43	22	65
GCIG (non-measurable disease)	9	7	16
Patients with CA-125
Units: Subjects
≥2× ULN	38	20	58
<2× ULN	14	9	23
Radiotherapy
Units: Subjects
Yes	2	0	2
No	50	29	79
Surgery (cytoreduction)
Units: Subjects
Yes	38	24	62
No	14	5	19
Chemotherapy lines
Units: Subjects
1 line	18	13	31
2 lines	26	12	38
3 lines	8	4	12
Best response to last prior therapy
Units: Subjects
Complete Response	7	1	8
Partial Response	11	11	22
Stable Disease	16	5	21
Progressive Disease	14	7	21
Unk	4	5	9
Weight
Units: Kg
median (full range (min-max))	64.5 (45 to 110)	62 (50 to 96)	-
BSA
BSA=body surface area
Units: m2
median (full range (min-max))	1.7 (1.44 to 2.27)	1.68 (1.47 to 2.05)	-
Signs and symptoms per patient
Units: number
median (full range (min-max))	1 (0 to 4)	1 (0 to 6)	-
Albumin
Units: g/dL
median (full range (min-max))	4 (2.8 to 4.8)	3.7 (3.1 to 4.4)	-
Alpha-1-acid glycoprotein
n=45 for the Experimental Arm; n=23 for the Control Arm
Units: mg/dL
median (full range (min-max))	114 (44 to 454)	135 (13.2 to 374)	-
Time from first diagnosis to first infusion
Units: months
median (full range (min-max))	18.8 (2.6 to 109.4)	14 (3.8 to 81.2)	-
Number of sites involved
Units: number
median (full range (min-max))	2 (1 to 6)	2 (1 to 5)	-
Platinum-free interval
Units: months
median (full range (min-max))	3.6 (0.1 to 6)	2.3 (0 to 5.9)	-
Time from last platinum to PM01183 treatment start
Units: months
median (full range (min-max))	6.9 (0.8 to 36.9)	5.8 (0.7 to 20.3)	-
CA-125
Units: IU/mL
median (full range (min-max))	218.3 (10.3 to 4013)	165 (9.3 to 14408)	-
TTP last regimen
Units: months
median (full range (min-max))	5.5 (0.2 to 24.8)	5.5 (1.1 to 11.1)	-

End points

Top of page

Reporting group title

PM01183

Reporting group description

Reporting group title

Topotecan

Reporting group description

Subject analysis set title

First stage - PM01183

Subject analysis set type

Intention-to-treat

Subject analysis set description

In the first stage, patients were to be given PM01183 as a 1-hour infusion q3wk to explore the activity of PM01183 in this setting. If the minimum threshold of antitumor activity was met (at least two patients of the first 18 evaluable patients with confirmed tumor responses by any of the standard response assessment criteria)

Subject analysis set title

Second stage - PM01183

Subject analysis set type

Intention-to-treat

Subject analysis set description

In the second stage, patients were to be randomized (stratified according to platinum-resistance or refractoriness), to an Experimental Arm PM01183 at the same dose and schedule as in the first stage.

Primary: Confirmed responses

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End point title

Confirmed responses

End point description

The overall response rate (ORR) was defined as the percentage of patients with a complete or partial response according to RECIST v.1.1 (or GCIG criteria in patients with disease not measurable per RECIST). CR=Complete response PR=Partial response SD=Stable disease PD=Progressive disease

End point type

Primary

End point timeframe

Overall period

End point values	PM01183	Topotecan	First stage - PM01183	Second stage - PM01183
Number of subjects analysed	52	29	22	30
Units: number of subjects
Complete response	1	0	0	1
Partial response	11	0	7	4
Stable disease	26	15	11	15
Progressive disease	13	14	4	9
Not evaluable	1	0	0	1

Differences between treatments

Comparison groups

PM01183 v Topotecan

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0033

Method

Fisher exact

Confidence interval

Secondary: Response by RECIST

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End point title

Response by RECIST

End point description

The overall response rate (ORR) was defined as the percentage of patients with a complete or partial response according to RECIST v.1.1

End point type

Secondary

End point timeframe

Overall period

End point values	PM01183	Topotecan	First stage - PM01183	Second stage - PM01183
Number of subjects analysed	43 ^[1]	22 ^[2]	17 ^[3]	26 ^[4]
Units: number of subjects
CR+PR	10	0	5	5

Notes
[1] - % patients (95%CI): 23.3% (11.8–38.6%)
[2] - % patients (95%CI): 0.0% (0.0-15.4%)
[3] - % patients (95%CI): 29.4% (10.3-56%)
[4] - % patients (95%CI): 19.2% (6.6-39.4%)

No statistical analyses for this end point

Secondary: Clinical benefit

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End point title

Clinical benefit

End point description

Clinical benefit was defined as CR+PR+SD≥ 4 months.

End point type

Secondary

End point timeframe

Overall period

End point values	PM01183	Topotecan	First stage - PM01183	Second stage - PM01183
Number of subjects analysed	52 ^[5]	29 ^[6]	22 ^[7]	30 ^[8]
Units: number of subjects
CR+PR+SD≥ 4 months	22	4	10	12

Notes
[5] - % patients (95%CI): 42.3% (28.7–56.8%)
[6] - % patients (95%CI): 13.8% (3.9–31.7%)
[7] - % patients (95%CI): 45.5% (24.4–67.8%)
[8] - % patients (95%CI): 40.0% (22.7–59.4%)

No statistical analyses for this end point

Secondary: Duration of Response

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End point title

Duration of Response

End point description

Duration of response (DR), defined as the time from the date when the response criteria (PR or CR, whichever was reached first) were fulfilled, to the first date when PD, recurrence or death was documented.

End point type

Secondary

End point timeframe

Overall period

End point values	PM01183	Topotecan
Number of subjects analysed	12 ^[9]	0 ^[10]
Units: months
median (confidence interval 95%)	4.6 (2.5 to 6.9)	( to )

Notes
[9] - PM01183 responders Events: 9 (75.0%)
[10] - Topotecan responders

No statistical analyses for this end point

Secondary: Progression-free Survival

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End point title

Progression-free Survival

End point description

Progression-free survival (PFS), defined as the time from the date of first infusion to the date of PD, death (of any cause), or last tumor evaluation. Progression-free survival rate at six months (PFS6), defined as the Kaplan-Meier estimate of the percentage of patients who were alive and progression-free at six months after the first infusion.

End point type

Secondary

End point timeframe

Overall period

End point values	PM01183	Topotecan	First stage - PM01183	Second stage - PM01183
Number of subjects analysed	52 ^[11]	29 ^[12]	22 ^[13]	30 ^[14]
Units: months
median (confidence interval 95%)	4 (2.7 to 5.6)	2 (1.4 to 2.8)	4.5 (2.5 to 6.7)	3.9 (2.5 to 5.7)

Attachments

PFS

Notes
[11] - Events: 41 (78.8%) PFS6 (95%CI): 32.4% (18.7–46.2%)
[12] - Events: 26 (89.7%) PFS6 (95%CI): 7.4% (0–17.1%)
[13] - Events: 18 (81.8%) PFS6 (95%CI): 34.5% (12.8–56.1%)
[14] - Events: 23 (76.7%) PFS6 (95%CI): 31.0% (13.4–48.5%)

Progression-free survival

Comparison groups

Topotecan v Second stage - PM01183

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0067 ^[15]

Method

Logrank

Confidence interval

Notes
[15] - PM01183 second stage vs topotecan

Secondary: Overall Survival

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End point title

Overall Survival

End point description

Overall survival (OS), defined as the time from the date of first infusion to the date of death (of any cause) or last patient contact. Overall survival rate at six months (OS6), defined as the Kaplan-Meier estimate of the percentage of patients who were alive at six months after the first infusion. Overall survival rate at 12 months (OS12), defined as the Kaplan-Meier estimate of the percentage of patients who were alive at 12 months after the first infusion. Fifteen patients in Control Arm subsequently crossed over and received PM01183

End point type

Secondary

End point timeframe

Overall period

End point values	PM01183	Topotecan	First stage - PM01183	Second stage - PM01183
Number of subjects analysed	52 ^[16]	29 ^[17]	22 ^[18]	30 ^[19]
Units: months
median (confidence interval 95%)	10.6 (9.5 to 18.1)	8.5 (3.3 to 15.6)	12.6 (9.2 to 22)	9.7 (7.7 to 19.3)

Attachments

Notes
[16] - Events: 43 (82.7%) OS6 (95%CI): 84.5% (74.7–94.4%) OS12 (95%CI): 47.2% (33.5–60.9%)
[17] - Events: 23 (79.3%) OS6 (95%CI): 55.2% (37.1–73.3%) OS12 (95%CI): 36.9% (19.1–54.8%)
[18] - Events: 20 (90.9%) OS6 (95%CI): 86.4% (72.0–100%) OS12 (95%CI): 50.0% (29.1–70.9%)
[19] - Events: 23 (76.7%) OS6 (95%CI): 83.1% (69.5–96.6%) OS12 (95%CI): 45.0% (26.9–63.1%)

Differences between treatments

Comparison groups

Topotecan v Second stage - PM01183

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2871 ^[20]

Method

Logrank

Confidence interval

Notes
[20] - PM01183 second stage vs topotecan

Secondary: PM01183 Pharmacokinetic parameters

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End point title

PM01183 Pharmacokinetic parameters

End point description

The complete plasma concentration-time profiles of PM01183 were analyzed by standard non-compartmental methods (NCA). AUC, area under the concentration-time curve from time zero to infinity

End point type

Secondary

End point timeframe

Blood samples (4 mL) for the analysis of PM01183 were collected prior to, during, and after Day 1 of the first and second cycles in all available patients

End point values	First stage - PM01183
Number of subjects analysed	22
Units: units
median (full range (min-max))
Cycle 1 at 7.0 mg dose: Cmax (μg/L)	145 (57.7 to 468)
Cycle 1 at 7.0 mg dose: AUC (h*μg/L)	697.9 (346.5 to 2648)
Cycle 2 at 7.0 mg dose: Cmax (μg/L)	131 (91.6 to 587)
Cycle 2 at 7.0 mg dose: AUC (h*μg/L)	716 (387.1 to 2936)
Cycle 2 at 5.5 mg dose: Cmax (μg/L)	181 (143 to 266)
Cycle 2 at 5.5 mg dose: AUC (h*μg/L)	746.6 (733.7 to 1703)

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Overall period

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

14.1

Reporting group title

Topotecan

Reporting group description

In the second-stage Control Arm, topotecan was administered as a 30-min i.v. infusion either in a dose range of 0.75–1.50 mg/m2 on Days 1 to 5 q3wk (standard regimen, referred to as ‘daily’) or 2.4–4.0 mg/m2 on Days 1, 8 and 15 every four weeks (q4wk) (weekly regimen) according to the Investigator’s preference.

Reporting group title

PM01183

Reporting group description

PM01183 was administered as a 7.0 mg flat dose (FD) 1-h intravenous (i.v.) infusion every three weeks (q3wk) in both stages.

Serious adverse events	Topotecan	PM01183
Total subjects affected by serious adverse events
subjects affected / exposed	12 / 29 (41.38%)	18 / 52 (34.62%)
number of deaths (all causes)	23	43
number of deaths resulting from adverse events	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant ascites
subjects affected / exposed	1 / 29 (3.45%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tumour pain
subjects affected / exposed	1 / 29 (3.45%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 29 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 29 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood bilirubin increased
subjects affected / exposed	0 / 29 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Wound evisceration
subjects affected / exposed	0 / 29 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 29 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	3 / 29 (10.34%)	2 / 52 (3.85%)
occurrences causally related to treatment / all	3 / 3	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	3 / 29 (10.34%)	8 / 52 (15.38%)
occurrences causally related to treatment / all	3 / 3	8 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	4 / 29 (13.79%)	6 / 52 (11.54%)
occurrences causally related to treatment / all	7 / 7	13 / 13
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	1 / 29 (3.45%)	5 / 52 (9.62%)
occurrences causally related to treatment / all	1 / 1	9 / 9
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	1 / 29 (3.45%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fatigue
subjects affected / exposed	0 / 29 (0.00%)	2 / 52 (3.85%)
occurrences causally related to treatment / all	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 29 (3.45%)	3 / 52 (5.77%)
occurrences causally related to treatment / all	0 / 1	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Ascites
subjects affected / exposed	1 / 29 (3.45%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	1 / 29 (3.45%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	2 / 29 (6.90%)	2 / 52 (3.85%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal perforation
subjects affected / exposed	1 / 29 (3.45%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Proctalgia
subjects affected / exposed	1 / 29 (3.45%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 29 (0.00%)	2 / 52 (3.85%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	0 / 29 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism
subjects affected / exposed	2 / 29 (6.90%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Rhabdomyolysis
subjects affected / exposed	0 / 29 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Device related infection
subjects affected / exposed	1 / 29 (3.45%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infection
subjects affected / exposed	1 / 29 (3.45%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Aspergillosis
subjects affected / exposed	0 / 29 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchopnemonia
subjects affected / exposed	0 / 29 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 29 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
postoperative wound infection
subjects affected / exposed	0 / 29 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 29 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 29 (0.00%)	2 / 52 (3.85%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypercalcaemia
subjects affected / exposed	1 / 29 (3.45%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	1 / 29 (3.45%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	1 / 29 (3.45%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	0 / 29 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dehydration
subjects affected / exposed	0 / 29 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	0 / 29 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Topotecan	PM01183
Total subjects affected by non serious adverse events
subjects affected / exposed	28 / 29 (96.55%)	51 / 52 (98.08%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain
subjects affected / exposed	2 / 29 (6.90%)	0 / 52 (0.00%)
occurrences all number	9	0
Vascular disorders
Phlebitis
subjects affected / exposed	0 / 29 (0.00%)	3 / 52 (5.77%)
occurrences all number	0	3
General disorders and administration site conditions
Fatigue
subjects affected / exposed	18 / 29 (62.07%)	48 / 52 (92.31%)
occurrences all number	53	255
Mucosal inflammation
subjects affected / exposed	1 / 29 (3.45%)	4 / 52 (7.69%)
occurrences all number	2	5
Oedema peripheral
subjects affected / exposed	4 / 29 (13.79%)	4 / 52 (7.69%)
occurrences all number	13	19
Pyrexia
subjects affected / exposed	3 / 29 (10.34%)	10 / 52 (19.23%)
occurrences all number	3	12
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	4 / 29 (13.79%)	9 / 52 (17.31%)
occurrences all number	8	22
Cough
subjects affected / exposed	0 / 29 (0.00%)	4 / 52 (7.69%)
occurrences all number	0	9
Psychiatric disorders
Anxiety
subjects affected / exposed	3 / 29 (10.34%)	4 / 52 (7.69%)
occurrences all number	4	12
Insomnia
subjects affected / exposed	1 / 29 (3.45%)	3 / 52 (5.77%)
occurrences all number	1	4
Investigations
Weight decreased
subjects affected / exposed	1 / 29 (3.45%)	5 / 52 (9.62%)
occurrences all number	2	16
Cardiac disorders
Tachycardia
subjects affected / exposed	3 / 29 (10.34%)	1 / 52 (1.92%)
occurrences all number	6	1
Nervous system disorders
Dysgeusia
subjects affected / exposed	1 / 29 (3.45%)	4 / 52 (7.69%)
occurrences all number	3	9
Headache
subjects affected / exposed	2 / 29 (6.90%)	7 / 52 (13.46%)
occurrences all number	3	12
Neurotoxicity
subjects affected / exposed	2 / 29 (6.90%)	1 / 52 (1.92%)
occurrences all number	2	10
Peripheral sensory neuropathy
subjects affected / exposed	5 / 29 (17.24%)	4 / 52 (7.69%)
occurrences all number	16	21
Neuropathy peripheral
subjects affected / exposed	0 / 29 (0.00%)	3 / 52 (5.77%)
occurrences all number	0	20
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	11 / 29 (37.93%)	24 / 52 (46.15%)
occurrences all number	35	64
Neutropenia
subjects affected / exposed	9 / 29 (31.03%)	11 / 52 (21.15%)
occurrences all number	11	14
Thrombocytopenia
subjects affected / exposed	4 / 29 (13.79%)	7 / 52 (13.46%)
occurrences all number	9	9
Febrile neutropenia
subjects affected / exposed	0 / 29 (0.00%)	3 / 52 (5.77%)
occurrences all number	0	3
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	18 / 29 (62.07%)	23 / 52 (44.23%)
occurrences all number	46	53
Ascites
subjects affected / exposed	5 / 29 (17.24%)	7 / 52 (13.46%)
occurrences all number	11	30
Constipation
subjects affected / exposed	14 / 29 (48.28%)	30 / 52 (57.69%)
occurrences all number	30	89
Diarrhoea
subjects affected / exposed	7 / 29 (24.14%)	7 / 52 (13.46%)
occurrences all number	12	9
Dyspepsia
subjects affected / exposed	2 / 29 (6.90%)	4 / 52 (7.69%)
occurrences all number	2	4
Intestinal obstruction
subjects affected / exposed	1 / 29 (3.45%)	3 / 52 (5.77%)
occurrences all number	1	5
Nausea
subjects affected / exposed	13 / 29 (44.83%)	36 / 52 (69.23%)
occurrences all number	22	127
Vomiting
subjects affected / exposed	12 / 29 (41.38%)	33 / 52 (63.46%)
occurrences all number	17	78
Abdominal pain upper
subjects affected / exposed	0 / 29 (0.00%)	5 / 52 (9.62%)
occurrences all number	0	12
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	5 / 29 (17.24%)	7 / 52 (13.46%)
occurrences all number	20	18
Dry skin
subjects affected / exposed	3 / 29 (10.34%)	0 / 52 (0.00%)
occurrences all number	3	0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	3 / 29 (10.34%)	2 / 52 (3.85%)
occurrences all number	5	8
Musculoskeletal pain
subjects affected / exposed	2 / 29 (6.90%)	3 / 52 (5.77%)
occurrences all number	4	4
Myalgia
subjects affected / exposed	1 / 29 (3.45%)	3 / 52 (5.77%)
occurrences all number	1	11
Arthralgia
subjects affected / exposed	0 / 29 (0.00%)	3 / 52 (5.77%)
occurrences all number	0	9
Infections and infestations
Nasopharyngitis
subjects affected / exposed	0 / 29 (0.00%)	3 / 52 (5.77%)
occurrences all number	0	4
Urinary tract infection
subjects affected / exposed	2 / 29 (6.90%)	2 / 52 (3.85%)
occurrences all number	2	3
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	5 / 29 (17.24%)	13 / 52 (25.00%)
occurrences all number	7	31
Hypokalaemia
subjects affected / exposed	2 / 29 (6.90%)	3 / 52 (5.77%)
occurrences all number	2	12

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Were there any global substantial amendments to the protocol? Yes

20 Feb 2012

The protocol amendment included the following changes: 1) Due to the global shortage of pegylated liposomal doxorubicin (PLD) which resulted in a lack of PLD supplies for clinical use worldwide, topotecan substituted PLD in the planned Control Arm. 2) Some data suggested that the weekly topotecan schedule was better tolerated and less myelotoxic than the standard schedule. Investigators were able to choose which topotecan schedule to administer to patients allocated to the Control Arm during the second stage of the study. 3) In order to improve patient safety in the Control Arm, the criteria for defining the starting dose of the daily topotecan regimen was slightly modified, the ECOG PS requirement was made stricter, and the extent of prior chemotherapy was taken into account to allocate the daily topotecan starting dose. 4) The exclusion criterion #1b was modified to clarify that patients with grade ≥ 3 ascites were not eligible. 5) Albumin level requirements at inclusion were changed to a minimum of 3.0 g/dL (inclusion criteria #8e).

04 Dec 2013

The protocol amendment included the following changes: • Planned end-of-study date was extended to 18 months after accrual of the last evaluable patient. • The follow-up assessments of patients showing documented disease progression or starting a new antitumor therapy were updated: every three months until the clinical cut-off, with the purpose of collecting information on survival. • A new secondary endpoint (overall survival rate at 12 months [OS12]) was included. • Exploratory analysis of Homologous Recombination Deficiency (HRD Assay) could be performed on patients responding to treatment, if considered relevant. • Polymorphisms and somatic mutations of genes involved in DNA repair mechanisms, or related to the mechanism of action of PM01183 or to the disease, could also be analyzed in tumor tissue, if relevant.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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A phase II Controlled Study of PM01183 in Platinum-Resistant / Refractory Advanced Ovarian Cancer Patients.

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Clinical Trial Results: A phase II Controlled Study of PM01183 in Platinum-Resistant / Refractory Advanced Ovarian Cancer Patients.

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Primary: Confirmed responses

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Substantial protocol amendments (globally)

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Clinical Trial Results:
A phase II Controlled Study of PM01183 in Platinum-Resistant / Refractory Advanced Ovarian Cancer Patients.