Clinical Trials Register

Summary
EudraCT Number:	2011-003715-28
Sponsor's Protocol Code Number:	HALO-109-201
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2011-11-14
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Czechia - SUKL

A.2

EudraCT number

2011-003715-28

A.3

Full title of the trial

A Phase 1b/2 Multicenter, International, Randomized, Double Blind, Placebo-Controlled, Study of Gemcitabine Combined with PEGPH20 (PEGylated Recombinant Human Hyaluronidase) Compared to Gemcitabine Combined with Placebo in Patients with Stage IV Previously Untreated Pancreatic Cancer

Mezinárodní multicentrická dvojitě zaslepená placebem kontrolovaná klinická studie fáze 1b/2 hodnotící použití gemcitabinu v kombinaci s PEGPH20 (pegylovaná rekombinantní lidská hyaluronidáza) u pacientů se čtvrtým stadiem dříve neléčeného karcinomu pankreatu ve srovnání s použitím gemcitabinu v kombinaci s placebem

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Multicenter, International, Randomized, Double Blind, Placebo-Controlled, Study of Gemcitabine Combined with PEGPH20 Compared to Gemcitabine Combined with Placebo in Patients with Stage IV Previously untreated Pancreatic Cancer, a Phase 1b/2

A.4.1

Sponsor's protocol code number

HALO-109-201

A.5.4

Other Identifiers

Name:

IND

Number:

102770

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Halozyme, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Halozyme, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Halozyme, Inc.
B.5.2	Functional name of contact point	Sam Dychter
B.5.3	Address:
B.5.3.1	Street Address	11388 Sorrento Valley Road
B.5.3.2	Town/ city	San Diego
B.5.3.3	Post code	CA 92121
B.5.3.4	Country	United States
B.5.4	Telephone number	+1858794 8889
B.5.5	Fax number	+1858704 8315
B.5.6	E-mail	sdychter@halozyme.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	PEGylated Recombinant Human Hyaluronidase
D.3.2	Product code	PEGPH20
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	PEGPH20
D.3.9.3	Other descriptive name	PEGylated recombinant human hyaluronidase; H201; rHuPH20
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	3.5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	Yes
D.3.11.13.1	Other medicinal product type	PEGPH20 is a multi-site PEGylated enzyme generated by conjugating N-hydroxysuccinimidyl ester of methoxypoly(ethylene glycol)-butanoic acid (MSBA-30K or PEG) and rHuPH20.
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	GEMCITABINE HYDROCHLORIDE
D.3.9.1	CAS number	122111-03-9
D.3.9.4	EV Substance Code	SUB02324MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1000
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Metastatic Pancreatic Cancer

E.1.1.1

Medical condition in easily understood language

Metastatic Pancreatic Cancer

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10033605
E.1.2	Term	Pancreatic cancer metastatic
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Phase 1b
•To assess the safety and tolerability, and select a safe dose of PEGPH20 in combination with gemcitabine
Phase 2 (in EU sites)
• To compare the Overall Survival (OS) of PEGPH20 in combination with gemcitabine versus gemcitabine in combination with placebo in patients with previously untreated Stage IV pancreatic cancer.

E.2.2

Secondary objectives of the trial

Phase 1
•To characterize plasma pharmacokinetics of PEGPH20 when used in combination with gemcitabine
•To assess the Objective Response Rate (ORR) by RECIST 1.1 criteria
•To assess PEGPH20 pharmacodynamic activities including hyaluronan (HA) catabolites in serum and urine, HA staining changes in tumor biopsies, as well as PEGPH20 effect on vascular perfusion and metabolic activities of the tumor using DCE-MRI and FDG-PET/CT
•To explore the PEGPH20 effect on CA19-9 changes in relation to: 1)intensity of tumor-associated HA staining, 2)DCE-MRI perfusion, and/or 3)FDG-PET/CT perfusion, anatomic data and metabolic activity.
Phase 2
To compare the change in CA19-9 levels in the PEGPH20 plus gemcitabine with gemcitabine plus placebo treatment groups
• To compare the Objective Response Rate (ORR) between the two groups by RECIST 1.1 criteria
•To compare Progression-free Survival between the two groups

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Newly diagnosed, previously untreated, histologically confirmed Stage IV pancreatic ductal adenocarcinoma with documented disseminated neoplasm to the liver and/or the lung. Prior to enrollment, confirmation of the following must be obtained:
o Pathology report of the tissue biopsy reviewed and approved by the Sponsor medical monitor
o Available tumor tissue block or a minimum of 5 unstained core biopsy slides that meet specific tissue sample requirements (see Study Laboratory Manual). Note: Fine needle aspirates (FNA) or brushing biopsies will not be acceptable.
• One or more metastatic tumors measurable on CT scan per RECIST 1.1 criteria
• Karnofsky Performance Status ≥ 70%
• Life expectancy of at least 3 months
• Age ≥ 18 years
• Signed, written IRB/EC-approved Informed Consent Form
• A negative serum pregnancy test, if female
• Ejection fraction ≥ 50% by either Echocardiogram (Echo) or multi-gated acquisition (MUGA) Scan
• Acceptable liver function:
− Bilirubin ≤ 1.5 times upper limit of normal
− AST (SGOT) and ALT (SGPT) ≤ 2.5 times upper limit of normal, (if liver metastases are present, then ≤ 5 times upper limit of normal is allowed)
• Acceptable renal function:
− Serum creatinine within normal limits, OR calculated creatinine clearance ≥ 40 mL/min/1.73 m2 for patients with creatinine levels above normal
• Acceptable hematologic status:
− ANC ≥ 1,500 cells/mm3
− Platelet count ≥ 100,000 plt/mm3
− Hemoglobin ≥ 9 g/dL
Acceptable coagulation status:
− PT/INR within normal limits or INR 2.0-3.0 if on warfarin
− PTT within normal limits, or within 1.2xULN if on warfarin
• For men and women of child-producing potential, agreement to use an effective contraceptive method from the time of screening and throughout their time on study

E.4

Principal exclusion criteria

•Locally advanced Pancreatic Ductal Adenocarcinoma (PDA)
• Known central nervous system involvement or brain metastases
• New York Heart Association Class III or IV cardiac disease (Appendix C), or myocardial infarction within the past 12 months
• Active, uncontrolled bacterial, viral, or fungal infection requiring systemic therapy
• Known infection with HIV, hepatitis B, or hepatitis C
• Known allergy to hyaluronidase
• Women currently pregnant or breast feeding
• Heparin therapy administered IV
• Intolerant to dexamethasone
• History of another primary cancer within the last 3 years with the exception of skin cancer (other than melanoma) or curatively-treated cervical carcinoma in-situ
• Any other disease, metabolic dysfunction, physical examination finding or clinical laboratory finding that leads to reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, that may affect the interpretation of the results or render the patient at high risk from treatment complications
• Other unspecified reasons that, in the opinion of the Investigator or Sponsor, make the patient unsuitable for the study

E.5 End points

E.5.1

Primary end point(s)

•For the Phase 1b portion of the study, the primary objectives are to assess the safety and tolerability, and select a safe dose of PEGPH20 in combination with gemcitabine for Phase 2.

• For Phase 2, OS is the primary endpoint. The ITT population will be used for the analysis of OS. The hazard ratio (PEGPH20/placebo) and its 95% confidence interval will be estimated using a Cox proportional hazards regression model. Kaplan-Meier curves will be calculated for each group and the median survivals estimated.

E.5.1.1

Timepoint(s) of evaluation of this end point

As per Study schedule of events (included in the Study protocol)

E.5.2

Secondary end point(s)

•The distributions of the change in CA19-9 from baseline to Week 8 of Cycle 1 between the groups will be compared. Additionally, the percent of patients achieving a ≥ 25%, ≥ 50%, and ≥ 75% decline in CA19-9 from baseline to Week 8 of Cycle 1 and their 95% confidence intervals will be calculated for each treatment group.
• An objective response as defined by RECIST 1.1 criteria will be evaluated. The proportion of patients achieving an objective response (the objective response rate [ORR]) (either a complete response [CR] or a partial response [PR]), and its 95% confidence interval will be estimated for each group. The Fisher’s exact test will be used to test the difference in the ORR between groups.
• PFS will be analyzed using the ITT population. The hazard ratio (PEGPH20/placebo) and its 95% confidence interval will be estimated using a Cox proportional hazards regression model. Kaplan-Meier curves will be calculated for each group and the median progression free survivals estimated.
•Duration of Response (DOR) is defined as the interval from the demonstration of an objective response (CR+PR) to the earliest of documented evidence of recurrent or progressive disease or the date of death due to any cause. DOR will be described using Kaplan-Meier curves for patients in each treatment group who achieved an objective response.
• The proportions of patients achieving a complete response [CR], a partial response [PR], and who have stable disease [SD] and their 95% confidence intervals will be calculated and reported.
• The proportion of patients in each group achieving an objective response as defined by the CHOI criteria and their 95% confidence intervals will be calculated.
• Change in pain assessment score will be reported using descriptive statistics, by time and treatment group.
• Estimates of OS and PFS at Months 3, 6, 9, and 12 will be calculated from the Kaplan-Meier curves, and reported by treatment group.

E.5.2.1

Timepoint(s) of evaluation of this end point

As per protocol.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Phase 1b (not in EU sites)

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Phase 1b - open label, Phase 2-double blind

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

PEGPH20+gemcitabine vs. Placebo+gemcitabine

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Czech Republic

Hungary

Romania

Russian Federation

Slovakia

Ukraine

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LSLV

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

155

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

198

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

As per study protocol

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2012-04-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-11-14

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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