Efficacy and Safety of AP 12009 in Patients With Recurrent or Refractory Anaplastic Astrocytoma or Secondary Glioblastoma

Glioblastoma Clinical Trial

— SAPPHIRE  

Official title:

Efficacy and Safety of AP 12009 in Adult Patients With Recurrent or Refractory Anaplastic Astrocytoma or Secondary Glioblastoma as Compared to Standard Chemotherapy Treatment: A Randomized, Actively Controlled, Open Label Clinical Phase III Study.

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00761280
• Other study ID #: AP 12009-G005
• Status: Terminated
• Phase: Phase 3
• First received: September 26, 2008
• Last updated: November 4, 2014
• Start date: December 2008
• Est. completion date: June 2012

Study information

• Verified date: November 2014
• Source: Isarna Therapeutics GmbH
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

In this multinational Phase III study the efficacy and safety of 10 µM AP 12009 is compared to standard chemotherapy (temozolomide or BCNU or CCNU) in adult patients with confirmed recurrent or refractory anaplastic astrocytoma (WHO grade III) or secondary glioblastoma (WHO grade IV).

Description:

The purpose of this study is to compare the safety and efficacy of the 10 µM concentration of AP 12009 and standard chemotherapy (temozolomide, BCNU, CCNU) in adult patients with recurrent or refractory anaplastic astrocytoma (AA, WHO grade III) or secondary glioblastoma (GBM, WHO grade IV). AP 12009 (trabedersen) is a phosphorothioate antisense oligodeoxynucleotide specific for the mRNA of human Transforming Growth Factor beta 2 (TGF-beta-2), which is applied intratumorally. The growth factor TGF-beta plays a key role in malignant progression of various tumors by inducing proliferation, invasion, metastasis, angiogenesis, and escape from immunosurveillance. In patients with high-grade glioma, the TGF-beta-2 overexpression is associated with disease stage, clinical prognosis, and the immunodeficient state of the patients. Main objective of the study is to determine survival (rate) and tumor response.

Important note: Due to early trial termination, resulting in limited data availability, all analyses remain descriptive by nature, only. No conclusive endpoint analysis can be performed.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 27
• Est. completion date: June 2012
• Est. primary completion date: February 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• The patient has provided written informed consent prior to any study-related procedure.

• The patient is at least 18 years of age and equal to or below 70 years.

• The patient has a present diagnosis of AA or secondary GBM.

• The patient has a measurable lesion (> 1 ccm in volume, central MRI review).

• The lesion (or sum of lesions) does not exceed 50 ccm in volume (central MRI review).

• The tumor is localized supratentorially (central MRI review).

• All patients have recurrent or refractory disease, i.e. disease has progressed after prior surgery and radiotherapy at any time of the disease course or stage. Secondary GBM patients have progressed after a previous diagnosis of A and/or AA.

• The patient has not received more than one chemotherapy regimen. Radiation with concomitant chemotherapy, followed by adjuvant chemotherapy, is considered as one chemotherapy regimen.

• The patient is eligible for chemotherapy.

• The patient is on a maximum dose of 4 mg/day dexamethasone or equivalent doses for other corticosteroids, which has been stable or decreasing for at least 3 weeks prior to Screening.

• The patient is male or a non-pregnant, non-lactating female.

• Females of childbearing potential must have a negative beta-HCG pregnancy test at Screening.

• Females of childbearing potential and males must practice strict birth control.

• The patient must have recovered from acute toxicity caused by any previous therapy.

• The patient has a life expectancy of at least 3 months.

• The patient has a Karnofsky Performance Status of at least 70%.

• The patient shows adequate organ functions as assessed by the following screening laboratory values:

1. Adequate renal function determined by serum creatinine and urea < 2 times the upper limit of normal

2. Adequate liver function with ALT, AST and AP < 3 times the upper limit of normal, and bilirubin < 2.5 mg/dL

3. INR < 1.5 and aPTT < 1.5 x ULN

4. Hemoglobin > 9 g/dL

5. Platelet count > 100 x 10E9/L

6. WBC > 3 x 10E9/L

7. ANC > 1.5 x 10E9/L (or WBC > 3.0 x 10E9/L)

Exclusion Criteria:

• Patient unable or not willing to comply with the protocol regulations.

• The investigator deems it necessary to surgically (re-)resect the present tumor (NOTE:

the patient might still be eligible for randomization at a later timepoint).

• Tumor surgery, tumor debulking, or other neurosurgery within 3 months prior to randomization. If a =48-hour routine post-surgery MRI (in accordance with study specifications) qualifies the patient for study participation, the patient can be randomized 30 ± 7 days post-surgery.

• Radiotherapy or stereotactic (gamma knife) radiosurgery within 3 months prior to randomization.

• Prior interstitial brachytherapy of the brain with permanent implants. Prior interstitial brachytherapy of the brain with removable implants within 3 months prior to randomization.

• Chemotherapy, hormone therapy, or any other therapy with established or suggested anti-tumor effects within 4 weeks (nitrosoureas: 6 weeks) prior to randomization.

• Prior anti-TGF-beta 2 targeted therapy.

• Screening MRI shows a mass effect caused by the tumor defined as significant compression of the ventricular system and/or a midline shift (= 3 mm, central MRI review). Compression of the ventricular system and/or a midline shift = 3 mm only due to the presence of (a) cyst(s) or scarring processes does not exclude an individual from the study.

• Participation in another clinical study with another investigational medicinal product within 30 days prior to randomization.

• History of a second independent malignant disorder within 5 years, except for carcinoma in situ of the cervix and basal cell carcinoma.

• Presence of poorly controlled seizures.

• Clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure, unstable angina, or poorly controlled arrhythmia. Myocardial infarction within 6 months prior to randomization.

• Known HIV, HBV or HCV infection.

• Acute viral, bacterial, or fungal infection.

• Acute medical problems that may be considered to become an unacceptable risk, or any conditions, which might be contraindications for starting study treatment.

• Presence of high risk for pulmonary toxicities, defined as:

1. Lung function: vital capacity = 70%

2. Status following sequential or concomitant thoracic irradiation

3. Increased risk for a pulmonary toxicity induced by BCNU (Carmustine) or CCNU (Lomustine). Risk factors include smoking, presence of a respiratory condition, pre-existing radiographic pulmonary abnormalities, exposure to agents that cause lung damage.

• History of allergies to reagents used in this study, history of celiac disease.

• Drug abuse or extensive use of alcohol.

• Clinically relevant psychiatric disorders / legal incapacity or a limited legal capacity.

• Concomitant treatment with yellow fever vaccine.

Related Conditions & MeSH terms

• Anaplastic Astrocytoma
• Astrocytoma
• Glioblastoma

Intervention

Drug:
• trabedersen

• temozolomide

Device:
• Drug delivery system for administration of AP 12009
Drug delivery system for Convection Enhanced Delivery consists of a portable pump (Pegasus vario or Pega vario) with drug reservoir (Pega Bag) and infusion line (Pega Line). Main implanted parts are the port access system (PORT-A-CATH) and the intratumoral catheter (Medtronic ventricular catheter).

Procedure:
• Placement of Drug Delivery System
Surgery for placement of intratumoral catheter and subcutaneous port access system as per routine clinical practice. Stereotactical catheter placement controlled by CT.

Drug:
• carmustine

• lomustine

Locations

Country	Name	City	State
Argentina	FLENI	Ciudad Autónoma de Buenos Aires
Argentina	Hospital Británico	Ciudad Autónoma de Buenos Aires
Argentina	Sanatorio Allende	Córdoba
Austria	Universitätsklinik Innsbruck, Abteilung für Neurologie	Innsbruck
Austria	AKH Wien, Klinik für Neurochirurgie	Wien
Brazil	Hospital de Câncer de Barretos	Barretos / SP
Brazil	Centro Goiano de Oncologia (CGO)	Goiania
Brazil	Hospital Sao Vicente de Paulo	Passo Fundo
Brazil	Hospital de Clínicas de Porto Alegre	Porto Alegre
Brazil	Hospital Sao Lucas da PUCRS	Porto Alegre
Brazil	Hospital do Servidor Público Estadual	Sao Paulo
Canada	Foothills Medical Centre	Calgary
Canada	ECOGENE-21 Centre d'études cliniques	Chicoutimi	Quebec
Canada	Montreal Neurological Institute and Hospital	Montreal
France	La Timone University Hospital	Marseille
Germany	Klinik und Poliklinik für Neurochirurgie	Frankfurt/M.
Germany	Universitätsklinikum Freiburg	Freiburg
Germany	Neurochirurgische Klinik an der Universität Ulm am Bezirkskrankenhaus Günzburg	Günzburg
Germany	Universitätklinikum Hamburg-Eppendorf, Klinik für Neurochirurgie	Hamburg
Germany	Medizinische Hochschule Hannover Neurochirurgische Klinik	Hannover
Germany	Universitätsklinik Heidelberg Neurologische Klinik	Heidelberg
Germany	Universitätsklinikum Leipzig, Neurochirurgische Klinik	Leipzig
Germany	Otto-von-Guericke-Universität, Klinik für Neurochirurgie	Magdeburg
Germany	Klinik und Poliklinik für Neurochirurgie	Münster
Germany	Klinik und Poliklinik für Neurologie	Regensburg
Hungary	Szegedi Tudományegyetem Szent-Györgyi Albert Klinikai Központ	Szeged
India	BGS Global Hospital	Bangalore
India	Manipal Hospital & Manipal Institute for Neurological Disorders	Bangalore
India	NIMHANS	Bangalore
India	Postgraduate Institute of Medical Education & Research (PGIMER)	Chandigarh
India	Apollo Speciality Hospitals	Chennai
India	Amrita Institute of Medical Sciences Research Center	Cochin
India	Care Hospitals	Hyderabaad
India	AMRI Hospitals	Kolkata
India	SGPGI of Medical Sciences	Lucknow
India	Advanced Centre for Treatment Research and Education in Cancer (ACTREC)	Mumbai
India	All India Institute of Medical Sciences (AIIMS)	New Delhi
India	SCTIMST, Dept. of Neurosurgery	Thiruvananthapuram
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Kangnam St. Mary's Hospital	Seoul
Korea, Republic of	Severance Hospital, Yonsei University College of Medicine	Seoul
Mexico	Hospital San Javier	Guadalajara
Mexico	Hospital General de Mexico	Mexico City
Mexico	Medica Sur	Mexico City
Poland	Wojskowy Szpital Kliniczny, Klinika Neurochirurgii	Bydgoszcz
Poland	Akademickie Centrum Kliniczne	Gdansk
Poland	SP ZOZ Uniwersytecki Szpital Kliniczny nr 1, Klinika Neurochirurgii	Lódz
Poland	Samodzielny Publiczny Szpital Kliniczny nr 4, Klinika Neurochirurgii i Neurochirurgii Dzieciecej	Lublin
Poland	Kliniczny Oddzial Neurochirurgii SUM w Sosnowcu Wojewódzki Szpital Specjalistyczny nr 5	Sosnowiec
Poland	Centrum Onkologii - Instytut Im. Marii Sklodowskiej-Curie	Warszawa
Russian Federation	Chelyabinsk City Hospital #3; Department of Neurosurgery	Chelyabinsk
Russian Federation	State Institution Russian Oncology Research Center N.N. Blokhin	Moscow
Russian Federation	Samara Region Clinical Hospital M.I. Kalinin	Samara
Russian Federation	Military Medical Academy, Neurosurgery Dept	St. Petersburg
Russian Federation	Russian Scientific Research Neurosurgical Institute A.L. Polenov	St. Petersburg
Spain	Hospital de Cruces	Baracaldo
Spain	Hospital Universitario Vall d'Hebron	Barcelona
Spain	Hospital Doce de Octubre	Madrid
Spain	Hospital Universitario Marqués de Valdecilla	Santander
Spain	Hospital Universitario Virgen del Rocío	Sevilla
Taiwan	China Medical University Hospital	Taichung
Taiwan	Taichung Veterans General Hospital	Taichung
Taiwan	Tri-Service General Hospital	Taipei City
United Kingdom	Edinburgh Centre for Neuro-Oncology, Western General Hospital	Edinburgh
United Kingdom	The National Hospital for Neurology and Neurosurgery	London
United States	NJ Neuroscience Institute; JFK Medical Center	Edison	New Jersey
United States	Winthrop University Hospital	Mineola	New York
United States	University of Rochester Medical Center	Rochester	New York

Sponsors (1)

Lead Sponsor	Collaborator
Isarna Therapeutics GmbH

Countries where clinical trial is conducted

United States,  Argentina,  Austria,  Brazil,  Canada,  France,  Germany,  Hungary,  India,  Korea, Republic of,  Mexico,  Poland,  Russian Federation,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Survival Rate at 24 Months in the Intent-to-treat Population - Percentage of Participants (Descriptive Analysis, Only)	Survival rate was defined as the proportion of participants known to be alive at 24 months from randomization. If a participant's status was unknown and there was no follow-up information available, they were categorized as 'Died' for the purposes of the analysis.	24 months
Primary	Survival at 24 Months in the Intent-to-treat Population - Number of Participants	Survival status was assessed at 24 months from randomization. Participants with unknown or missing status were considered treatment failures, i.e., assumed to be dead. The category "Lost to / insufficient follow-up" includes participants who were alive at last data collection point but did not yet have enough follow-up time to reach the 24 month time point.	24 months
Secondary	Survival Rate at 12, 18, and 21 Months in the Intent-to-treat Population - Percentage of Participants (Descriptive Analysis, Only)	Survival rate was defined as the proportion of participants known to be alive at each time-point from randomization. Participants with unknown or missing status were considered treatment failures, i.e., assumed to be dead.	12, 18, and 21 months
Secondary	Survival at 12, 18, and 21 Months in the Intent-to-treat Population - Number of Participants	Survival status was assessed at each time-point from randomization. Participants with unknown or missing status were considered treatment failures, i.e., assumed to be dead. The category "Lost to follow-up" for each time-point includes participants who were alive at the last data collection point but did not yet have enough follow-up time to reach the time point.	12, 18, and 21 months
Secondary	Median Overall Survival (Days) From Randomization in the Intent-to-treat Population (Descriptive Analysis, Only)	Median overall survival was defined as the date of randomization to the date of death. If a participant's status was unknown and there was no follow-up information available, they were categorized as 'Died' for the purposes of the analysis. Analysis was by Kaplan-Meier estimation.	Up to 24 months
Secondary	Response Category by Independent Review in the Intent-to-treat Population - Number of Participants	Tumor response was classified based on the (neuro-)radiologist's evaluation according to the Macdonald Response Criteria for bidimensionally measurable disease as outlined below: Complete Response (CR): Disappearance of all enhancing tumor on consecutive MRI scans at least 1 month apart, off steroids, neurologically stable or improved.; Partial Response (PR): =50% reduction in size of enhancing tumor on consecutive MRI scans at least 1 month apart, steroids stable or reduced, neurologically stable or improved.; Progressive Disease (PD): =25% increase in size of enhancing tumor or any new tumor on MRI scans, steroids stable or increased, neurologically worse.; Stable Disease (SD): all other situations.; Two qualified neuro-radiologists reviewed scans at each MRI time point, with adjudication of discrepancies by a third reviewer. Their findings and clinical information were independently reviewed by a neuro-oncologist, who made the assessment of overall response.	Up to 24 months
Secondary	Overall Response Rate (CR+PR) by Independent Review in the Intent-to-treat Population - Percentage of Participants (Descriptive Analysis, Only)	Overall response rate was the proportion of participants with a best response of Complete Response (CR) or Partial Response (PR) observed from the start of treatment until disease progression.	Up to 24 months
Secondary	Tumor Control Rate (CR+PR+SD) by Independent Review in the Intent-to-treat Population - Percentage of Participants (Descriptive Analysis, Only)	Tumor control rate was defined as the proportion of participants assessed as having Complete Response (CR), Partial Response (PR), or Stable Disease (SD). Participants with unknown or missing response were treated as non-responders.	Up to 24 months
Secondary	Median Duration of Response (Days) by Independent Review (Descriptive Analysis, Only)	Duration of response was defined as the time from the first documentation of confirmed response (Complete Response, CR, or Partial Response, PR) to the first signs of Progressive Disease (PD), as assessed by the study neuro-oncologist. Median Duration of Response was calculated by Kaplan-Meier estimate.; Censoring rules were: at the date of randomization -- participants without baseline assessments, or for those with no post-baseline timor assessments who were discontinued for other than progressive disease or death.; at the date of last tumor assessment -- discontinuation other than PD or death, or if a new treatment was started prior to disease progression; at the date of death or last tumor assessment -- death or PD after one missed tumor assessment; at the date of last tumor assessment -- death or PD after more than one missed tumor assessment; at the date of last tumor assessment -- participants on ongoing treatment at data cut-off	Up to 24 months
Secondary	Disease Progression at 10, 12, 14, 16, 18, 21, and 24 Months by Independent Review in the Intent-to-treat Population - Number of Participants	Tumor response was classified based on the (neuro-)radiologist's evaluation: Complete Response (CR): Disappearance of all enhancing tumor on consecutive MRI scans at least 1 month apart, off steroids, neurologically stable or improved.; Partial Response (PR): =50% reduction in size of enhancing tumor on consecutive MRI scans at least 1 month apart, steroids stable or reduced, neurologically stable or improved.; Progressive Disease (PD): =25% increase in size of enhancing tumor or any new tumor on MRI scans, steroids stable or increased, neurologically worse.; Stable Disease (SD): all other situations.; Based on clinical and imaging data, an independent neuro-oncologist made the final assessment of "Progressed" versus "Not Progressed". Participants who had MRI assessment results missing or unknown were "UNK or missing", and were treated as "Progressed" for the purposes of the calculation.	10, 12, 14, 16, 18, 21, and 24 months
Secondary	Disease Progression Rate at 10, 12, 14, 16, 18, 21, and 24 Months by Independent Review in the Intent-to-treat Population - Percentage of Participants (Descriptive Analysis, Only)	Tumor response was classified based on the (neuro-)radiologist's evaluation: Complete Response (CR): Disappearance of all enhancing tumor on consecutive MRI scans at least 1 month apart, off steroids, neurologically stable or improved.; Partial Response (PR): =50% reduction in size of enhancing tumor on consecutive MRI scans at least 1 month apart, steroids stable or reduced, neurologically stable or improved.; Progressive Disease (PD): =25% increase in size of enhancing tumor or any new tumor on MRI scans, steroids stable or increased, neurologically worse.; Stable Disease (SD): all other situations.; Based on clinical and imaging data, an independent neuro-oncologist made the final assessment of "Progressed" versus "Not Progressed". Participants who had MRI assessment results missing or unknown were "UNK or missing", and were treated as "Progressed" for the purposes of the calculation.	10, 12, 14, 16, 18, 21 and 24 months
Secondary	Median Time to Progression (Days) by Independent Review for the Intent-to-treat Population (Descriptive Analysis, Only)	Time to progression was calculated from the date of randomization to the date of the first documented tumor progression. Participants who did not progress or died were censored at the last tumor assessment date or the date of start of a new anti-tumor treatment or death.	Up to 24 months