Symptoms and General Pathology

All Conditions

Neoplasms

Rare Diseases

Recurrence

Glioblastoma

Glioma

Disease Attributes

Astrocytoma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Carboplatin

Talazoparib

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

Single fraction, low dose (2Gy) whole brain radiation therapy, followed by combination talazoparib and carboplatin

low dose whole brain radiation, followed by combination talazoparib and carboplatin

Aya Helali, MD, PhD

ECL Kwan, BSc

Tai-Chung Lam, FRCR

Chi-Leung Chiang, FRCR

Tsz-Him So, MBBS

In view of the strong biological rationale of employing PARP inhibition in high grade glioma, the current study purposes testing of talazoparib in a biomarker-enriched group of glioma. Carboplatin will be added to sensitize the tumor to PARP inhibition, and low dose radiation therapy will be applied to increase talazoparib drug penetration through blood-brain barrier. The goal is to estimate the effect size of such combinational treatment approach in recurrent high-grade glioma with DNA damage repair deficiency (dDDR)

Recurrent high grade glioma with dDDR, defined by genomic aberrations associated including IDH mutation, PTEN mutation and "BRCAness" signature as defined by next-generation-sequencing (NGS) based comprehensive genomic profiling, will be enrolled.

Patients will receive treatment in 7-day cycle. D1-4: Oral talazoparib 0.75mg daily; D1: Carboplatin (AUC 1.5). On cycle 1 day 1 low dose whole radiation radiation therapy will be given to increase drug penetration. Primary outcome is 6-month progression free survival (PFS-6) by RANO criteria. The study intended to recruit 33 subjects

Talazoparib - Carboplatin for Recurrent High-grade Glioma With DDRd

Combination Talazoparib - Carboplatin for Recurrent High-grade Glioma With DNA Damage Repair Deficiency (DDRd)

Free from disease progression based on RANO criteria

from date of study enrollment to the date of death from any cause

The percentage of patients with radiologically complete or partial response as determined by the investigator according to RANO criteria

The time interval between the time patient develops radiologically complete or partial response to disease progression according to RANO criteria

The University of Hong Kong

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Carcinoma

Endocrine Gland Neoplasms

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Genital Neoplasms, Female

Urogenital Neoplasms

Endocrine System Diseases

Gonadal Disorders

Ovarian Cancer

Ovarian Epithelial Cancer

Trabectedin

Antineoplastic Agents, Alkylating

Alkylating Agents

Trabectedin 1.3 mg/m2 q 21 days

Patients will receive trabectedin until disease progression or unacceptable toxicity

Catholic University of Sacred Heart .

Catholic University of Sacred Heart, .

Catholic University of Sacred Heart

Giovanni Scambia, Prof

Domenica Lorusso

This is a multicenter phase II study on trabectedin in advanced or recurrent ovarian cancer patients with BRCA mutation and BRCAness phenotype.

The purpose of this study is to determine the feasibility in terms of objective response rate by RECIST version 1.1 (Complete and Partial Response \[CR + PR\]) with trabectedin in patients with BRCA1 or BRCA2 mutation carrier or BRCAness phenotype advanced ovarian cancer patients.

The main contribution to hereditary ovarian cancer comes from breast cancer (BRCA) genes mutations, which are responsible of 90% of hereditary ovarian cancer. The two susceptibility genes associated with epithelial-type OC are BRCA1 and BRCA2.

The BRCA proteins play an important role in the DNA repair mechanisms and are also involved in the control of the cell cycle checkpoints, in protein ubiquitinization and chromatin remodelling.

Mutations in the BRCA genes have been extensively described in families affected by breast and/or OC; mutated BRCA1 has been found in up to 75% of families with hereditary OC - Recent data suggest that dysfunction of BRCA1andBRCA2, so-called BRCAness, maybe more prevalent than originally assumed. Both genetic and epigenetic mechanisms can create the BRCAness phenotype in at least a third of all epithelial ovarian cancers. The definition of BRCAness ovarian cancer is: high-grade serous cancers, high initial sensitivity to platinum drugs and retention of platinum-sensitivity through multiple relapses, longer history of disease, longer survival, longer TFIs between relapses.

Yondelis® (trabectedin) is proposed to block the transcriptional activation of a subset of inducible genes without affecting their constitutive expression. Trabectedin binds to the minor groove of DNA, bending the helix to the major groove. This binding to DNA triggers a cascade of events affecting several transcription factors, DNA binding proteins, and DNA repair pathways, resulting in perturbation of the cell cycle.

Cell cycle studies of the action of trabectedin on tumor cells in vitro reveal that it decreases the rate of progression of the cells through S phase towards G2 and causes a prolonged blockade in G2/M at biologically relevant concentrations (20-80 nM). These cell cycle blocks are p53-independent and lead to a strong apoptopic response. Cells in G1 are more sensitive to the cytotoxic effects of trabectedin. These effects appear to be related to the unique 3-subunit structure, where two of the subunits or rings are involved in binding to the minor groove of DNA in guanine-cytosine rich sequences and alkylation N2 of guanine forming adducts that distorted the DNA helix structure and they are recognized by the TC-NER mechanism.

DNA repair proficiency is a major determinant for the cytotoxicity of trabectedin: human cell lines deficient for genes essential for TC-NER activity as XPA, XPB, XPD, XPF, XPG, ERCC1, CSA and CSB are resistant to trabectedin, and this resistance is reverted by complementation of the cells with the corresponding gene. Trabectedin induces double strand breaks and that the BRCA1-/- human cell line HCC1937 and BRCA2Δ22/Δ22 mice cells are more sensitive to trabectedin and this hypersensitivity is reverted by complementation by the BRCA1 or BRCA2 gene.

Based in these observations it was hypothesized that the NER machinery trapped in the DNA lesion induced by trabectedin was resolved by the cells producing double strand breaks that were repaired by the HRR machinery, and synergistic action of TC-NER and HRR machinery would be necessary for maximal trabectedin cytotoxicity.

Study With Trabectedin in BRCA1 and BRCA2 Mutation Carrier and BRCAness Phenotype Ovarian Cancer

Phase II Study With Trabectedin (Yondelis®) in BRCA1 and BRCA2 Mutation Carrier and BRCAness Phenotype Advanced Ovarian Cancer Patients

To evaluate the feasibility (in terms of objective response rate by RECIST version 1.1) of Yondelis treatment in recurrent ovarian cancer population selected for BRCA mutation or BRCAness phenotype.

The response rate will be compared with an hystorical control arm of recurrent ovarian cancer patients unselected for BRCA mutation or BRCAness phenotype.

-Progression-free survival \[the diagnosis of progression will be assessed by radiological criteria; CA 125 increases alone (GCIG criteria of progression) will not be considered as progression of disease without a radiological confirmation of progression\].

Safety profile of trabectedin in this patient population

Catholic University of the Sacred Heart

Professor Giovanni Scambia

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Talazoparib - Carboplatin for Recurrent High-grade Glioma With DDRd	NCT04740190	Recurrent Gliom... Recurrent Gliob... Poly ADP Ribose... PTEN Gene Inact... IDH Mutation	Talazoparib	18 Years -	The University of Hong Kong
Study With Trabectedin in BRCA1 and BRCA2 Mutation Carrier and BRCAness Phenotype Ovarian Cancer	NCT01772979	BRCA1 and BRCA2...	Trabectedin	18 Years -	Catholic University of the Sacred Heart

Spots Global Cancer Trial Database for brcaness

Every month we try and update this database with for brcaness cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for brcaness

Every month we try and update this database with for brcaness cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for brcaness cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.