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

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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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.

Conditions
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Anaplastic Astrocytoma, Glioblastoma

Intervention / Treatment
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* Drug: trabedersen
* Drug: temozolomide
* Device: Drug delivery system for administration of AP 12009
* Procedure: Placement of Drug Delivery System
* Drug: carmustine
* Drug: lomustine


Participation Criteria
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Eligibility Criteria
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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: Adequate renal function determined by serum creatinine and urea < 2 times the upper limit of normal Adequate liver function with ALT, AST and AP < 3 times the upper limit of normal, and bilirubin < 2.5 mg/dL INR < 1.5 and aPTT < 1.5 x ULN Hemoglobin > 9 g/dL Platelet count > 100 x 10E9/L WBC > 3 x 10E9/L 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: Lung function: vital capacity ≤ 70% Status following sequential or concomitant thoracic irradiation 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: trabedersen 10 µM<br>10 µM trabedersen (AP 12009), intratumoral infusion, every other week, 11 cycles, maximum 21 weeks | Drug: trabedersen<br> <br> * Other names: AP 12009;Device: Drug delivery system for administration of AP 12009<br>* 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).<br>Procedure: Placement of Drug Delivery System<br>* Surgery for placement of intratumoral catheter and subcutaneous port access system as per routine clinical practice. Stereotactical catheter placement controlled by CT.<br>|
| Active Comparator: Chemotherapy<br>temozolomide: capsules, up to 200 mg/sqm/day, 5 days per cycle, up to 26 cycles; carmustine: i.v. administration, up to 200 mg/sqm/day, 1 day per cycle, up to 8 cycles; lomustine: capsules, 110 mg/sqm/day, 1 day per cycle, up to 8 cycles. Only 1 of these 3 drugs/interventions is administered per patient in the comparator arm. | Drug: temozolomide<br> <br> * Other names: TMZ;Drug: carmustine<br> <br> * Other names: Carmubris;Drug: lomustine<br> <br> * Other names: CeeNU;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anaplastic astrocytoma, Glioblastoma, Antisense, Cancer, Transforming Growth Factor beta 2, Targeted therapy, Brain tumor, Glioma, Central Nervous System (CNS), Convection Enhanced Delivery (CED), Intratumoral administration