Symptoms and General Pathology

All Conditions

Neoplasms

Skin and Connective Tissue Diseases

Infections

Rare Diseases

Recurrence

Melanoma

Virus Diseases

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

All Drugs and Chemicals

Antineoplastic Agents

Antibodies

Immunomodulating Agents

Ipilimumab

Immunoglobulins

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

1x10\^7 TCID50/mL TBI-1401(HF10) administered to a single or multiple eligible tumors in a total volume up to 5.0 mL (injection volume will be adjusted based on the size of tumor mass) by intratumoral injection and 3 mg/kg ipilimumab administered by intravenous infusions.

1x10\^7 TCID50/mL TBI-1401(HF10) (for a total of 6 injections; the first 4 injections at 1-week intervals; the remaining 2 injections at 3-week intervals).

Following combination therapy, patients may continue to receive the 1x10\^7 TCID50/mL TBI-1401(HF10) alone for up to an additional 13 injections (total of 19 injections = 1 year) if eligible for administration.

TBI-1401(HF10)

3 mg/kg ipilimumab (for a total of 4 intravenous infusions, each administered at 3-week intervals).

Naoya Yamazaki

The purpose of this study is to determine if TBI-1401(HF10) in combination with ipilimumab is effective in Japanese patients with stages IIIB, IIIC, or IV unresectable or metastatic melanoma.

The study is designed to assess efficacy and safety with repeated administration of intratumoral injections of TBI-1401(HF10) at 1x10\^7 TCID50/mL in combination with intravenous infusions of 3mg/kg ipilimumab in Japanese patients.

This is a single arm, open label Phase II study, to evaluate the efficacy and safety of TBI-1401(HF10) treatment in combination with the immunologic checkpoint inhibitor, ipilimumab (anti-CTLA-4 monoclonal antibody). The study population will include patients with Stage IIIB, IIIC or IV unresectable or metastatic malignant melanoma who are ipilimumab-eligible.

Patients will receive the dose of 1x10\^7 TCID50/mL TBI-1401(HF10) (for a total of 6 injections; the first 4 injections at 1-week intervals; the remaining 2 injections at 3-week intervals) + ipilimumab at 3 mg/kg (for a total of 4 intravenous infusions, each administered at 3-week intervals).

Following combination therapy, patients may continue to receive the 1x10\^7 TCID50/mL TBI-1401(HF10) alone for up to an additional 13 injections (total of 19 injections = 1 year) if they have tolerated the study treatment, are responding, have stable disease, or have progressive disease that is not clinically significant in the judgment of the Investigator.

A Study of Combination With TBI-1401(HF10) and Ipilimumab in Japanese Patients With Unresectable or Metastatic Melanoma

A Phase II Study of Combination Treatment With TBI-1401(HF10), a Replication-competent HSV-1 Oncolytic Virus, and Ipilimumab in Japanese Patients With Stage IIIB, IIIC, or IV Unresectable or Metastatic Malignant Melanoma

Evaluate the change of anti-HSV-1 antibody levels.

Analysis the change of cytokine profiles, antitumor T-cell reactivity and regulatory T-cell (Treg) population by immunoassay and flow cytometry.

Biopsies will be performed to evaluate the histopathological response with TBI-1401(HF10) administrated tumor.

Determine the efficacy of TBI-1401(HF10) in combination with Ipilimumab evaluated by irRC (immuno-related response criteria)

Determine the efficacy of TBI-1401(HF10) in combination with Ipilimumab evaluated by modified WHO (mWHO) response criteria

Determine the efficacy of TBI-1401(HF10) in combination with Ipilimumab evaluated by RECIST version 1.1

Overall tumor response evaluated by irRC in the measurable target lesion(s) and unmeasurable/evaluable target lesion(s).

Overall tumor response evaluated by mWHO response criteria in the measurable target lesion(s) and unmeasurable/evaluable target lesion(s).

Overall tumor response evaluated by RECIST version 1.1 in the measurable target lesion(s) and unmeasurable/evaluable target lesion(s).

Adverse events will be evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE version 4.0).

Evaluation the time to progression during and after the treatment.

Evaluation the length of time after a partial or complete response.

Determine the 1 year survival rate of patient who received treatment.

Takara Bio Inc.

Nervous System Diseases

Neoplasm Metastasis

Glioblastoma

Glioma

Brain Neoplasms

Astrocytoma

Neoplasms, Neuroepithelial

Neoplasms, Glandular and Epithelial

Anaplastic Astrocytoma

Temozolomide

Lomustine

Mitogens

Carmustine

Trabedersen

Antineoplastic Agents, Alkylating

Alkylating Agents

10 µM trabedersen (AP 12009), intratumoral infusion, every other week, 11 cycles, maximum 21 weeks

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.

trabedersen

temozolomide

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).

Drug delivery system for administration of AP 12009

Surgery for placement of intratumoral catheter and subcutaneous port access system as per routine clinical practice. Stereotactical catheter placement controlled by CT.

Placement of Drug Delivery System

carmustine

lomustine

Rolando Del Maestro, MD, PhD

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).

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

Isarna Therapeutics GmbH

Only treatment-emergent adverse events are listed, defined as any AE whose onset occurred or intensity worsened after undertaking the first study procedure or first dose of study drug (whichever occurred first) but less than 28 days after medication/procedures had stopped. Adverse events (including lab tests) were assessed at study visits.

10 µM trabedersen (AP 12009), intratumoral infusion, every other week, 11 cycles, maximum 21 weeks.

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).

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.

Trabedersen 10 µM

Temozolomide: capsules, up to 200 mg/sqm/day, 5 days per cycle, up to 26 cycles.

OR carmustine: i.v. administration, up to 200 mg/sqm/day, 1 day per cycle, up to 8 cycles;

OR 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.

Chemotherapy

Total

Age, Continuous

Sex: Female, Male

White

Black

Asian

Hispanic or Latino

American Indian or Native Alaskan

Native Hawaiian or Other Pacific Islander

Race/Ethnicity, Customized

Spain

Austria

Russian Federation

India

Mexico

Canada

Germany

Israel

Poland

Study was discontinued early because of the inability to recruit a sufficient number of suitable participants within the planned recruitment period, therefore not all planned sites recruited participants. Only those regions that recruited at least one participant are listed.

Region of Enrollment

Height is missing for one participant in the Chemotherapy group.

Height (cm) (Descriptive analysis, only)

Weight is missing for one participant in the Chemotherapy group.

Weight (kg) (Descriptive analysis, only)

Refractory

Recurrent

Twenty-six participants were diagnosed with Anaplastic Astrocytoma, and one participant was diagnosed with Secondary Glioblastoma Multiforme.

Diagnosis of Anaplastic Astrocytoma (AA) World Health Organization (WHO) Grade III

Time of first diagnosis (in years before study entry) is available for all 14 participants in the Trabedersen group and 11 participants in the chemotherapy group.

Time of first diagnosis of AA WHO Grade III (years) (Descriptive analysis, only)

AA WHO Grade I

AA WHO Grade II

Not diagnosed with Other Brain Tumor

Other diagnosis

Diagnosis of other brain tumor prior to diagnosis of Anaplastic Astrocytoma WHO Grade III

Diagnosis of Secondary Glioblastoma Multiforme (GBM) (WHO Grade IV)

Time of first diagnosis (in years before study entry) of Secondary Glioblastoma Multiforme. One participant in the Chemotherapy group was diagnosed with Secondary Glioblastoma Multiforme (GBM); all other participants were diagnosed with Anaplastic Astrocytoma (AA).

Time to first diagnosis of Secondary GBM (years) (Descriptive analysis, only)

Previous diagnosis of Astrocytoma

Previous diagnosis of Anaplastic Astrocytoma

Previous diagnosis of Astrocytoma or AA before diagnosis of Secondary Glioblastoma Multiforme

One or more Prior Surgical Treatments

One or more Prior Radiotherapy Regimens

One or more Prior Chemotherapy

One or more Prior Immunotherapy

The Intent-to-treat population includes all participants randomized.

Early termination of the study leading to recruitment of 27 of 180 planned subjects and incomplete collection of data. Survival results are based on post-study collection of additional survival data under a protocol amendment.

Medical Officer

The Intent-to-treat population includes all participants randomized. Early study discontinuation with site closures led to a high proportion of participants being censored or lost to follow-up in the initial analysis. Additional survival data were collected in a post-hoc fashion under a protocol amendment. These data are presented.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study of Combination With TBI-1401(HF10) and Ipilimumab in Japanese Patients With Unresectable or Metastatic Melanoma	NCT03153085	Melanoma Stage ... Melanoma Stage ...	TBI-1401(HF10) Ipilimumab	20 Years -	Takara Bio Inc.
Efficacy and Safety of AP 12009 in Patients With Recurrent or Refractory Anaplastic Astrocytoma or Secondary Glioblastoma	NCT00761280	Anaplastic Astr... Glioblastoma	trabedersen temozolomide Drug delivery s... Placement of Dr... carmustine lomustine	18 Years - 70 Years	Isarna Therapeutics GmbH
Efficacy and Safety of AP 12009 in Patients With Recurrent or Refractory Anaplastic Astrocytoma or Secondary Glioblastoma	NCT00761280	Anaplastic Astr... Glioblastoma	trabedersen temozolomide Drug delivery s... Placement of Dr... carmustine lomustine	18 Years - 70 Years	Isarna Therapeutics GmbH
A Study of TBI-1401(HF10) in Patients With Solid Tumors With Superficial Lesions	NCT02428036	Solid Tumor	TBI-1401(HF10) TBI-1401(HF10)	20 Years -	Takara Bio Inc.
A Study of TBI-1401(HF10) in Patients With Solid Tumors With Superficial Lesions	NCT02428036	Solid Tumor	TBI-1401(HF10) TBI-1401(HF10)	20 Years -	Takara Bio Inc.

Spots Global Cancer Trial Database for intratumoral administration