Symptoms and General Pathology

All Conditions

Neoplasms

Rare Diseases

Recurrence

Glioma

Glioblastoma

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

Niraparib

Temozolomide

Antineoplastic Agents, Alkylating

Alkylating Agents

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

Niraparib 100 mg/die + TMZ 75 mg/m2 both given for 7 consecutive days, followed by 7 days OFF, in a cycle of 28 days (starting dose).

Niraparib 100 mg/die + TMZ 100 mg/m2 both given for 7 consecutive days, followed by 7 days OFF, in a cycle of 28 days.

Niraparib 200 mg/die + TMZ 75 mg/m2 both given for 7 consecutive days, followed by 7 days OFF, in a cycle of 28 days

Level 3: Niraparib 200 mg/die + TMZ 100 mg/m2 both given for 7 consecutive days, followed by 7 days OFF, in a cycle of 28 days.

Niraparib 100 mg given on alternate days for 7 days, followed by 7 days of OFF + TMZ given 75 mg/m2 for 7 consecutive days, followed by 7 days OFF, in a cycle of 28 days.

Niraparib RP2D dose given on alternate days for 7 days, followed by 7 days of OFF + TMZ given RP2D for 7 consecutive days, followed by 7 days OFF, in a cycle of 28 days.

given orally for 7 consecutive days, followed by 7 days OFF, in a cycle of 28 days

Temodal

Matteo Simonelli, MD

Angelo Dipasquale, MD

The study evaluates safety, tolerability, pharmacokinetics at recommended phase II dose (RP2D) and preliminary antitumor activity of Niraparib + dd-TMZ "one week on, one week off" in patients affected by recurrent GBM IDH wild-type and recurrent IDH mutant (WHO grade 2-4) gliomas.

The treatment will be administered until progressive disease, unacceptable toxicity, consent withdrawal, lost to follow-up or death.

The entire study is expected to last approximately 40 months.

Diffuse malignant gliomas are the most common central nervous system (CNS) primary tumours in adults, characterized by poor prognosis and few treatment options. In the last 15 years, standard treatment consisting of surgery, adjuvant radiotherapy and temozolomide (TMZ)-based chemotherapy has remained unchanged. New therapeutic approaches are urgently needed.

TMZ is a DNA-methylating chemotherapeutic agent with good CNS penetration. Its mechanism of action is increased by either gene promoter methylation or consumption of the methylguanine-DNA methyltransferase (MGMT), an enzyme repairing chemotherapy-induced genome damages.

Alternative, intensified schedules of TMZ (dose-dense TMZ, dd-TMZ) can give patients an increased total dose of drugs per each cycle, progressively consuming MGMT and overcoming resistance of cancer cells to standard first-line schedule. They are usually used at disease recurrence, with a tolerable safety profile. For example, a clinical study testing the 7 day on / 7 day off schedule showed that MGMT activity in blood mononuclear cells decreased at day 8 and progressively recovered during the week-off. This may limit haematological toxicity.

The inhibition of Poly (ADP-ribose) polymerase (PARP) proteins, normally involved in genomic stability, may rationally improve TMZ efficacy. Switching off PARP molecules can block both base-excision repair (BER) system and Poly-ADP ribose-ylation of MGMT (a key process for its function), leading to an amplification in DNA damages. In the subset of Isocitrate dehydrogenase (IDH) 1/2 mutant gliomas, the enzyme leads to 2-hydroxy-glutarate (2HG) accumulation in cancer cells. This onco-metabolite increases sensitivity to DNA damages by alkylating agents and induces a Breast Cncer gene(BRCA)-ness phenotype indeed. Considering all this, the use of PARP inhibitors seems promising even for these patients.

When compared to other PARP inhibitors, Niraparib has peculiar pharmacokinetics proprieties, such as higher volume of distribution (Vd) and blood-brain barrier (BBB) penetration. These characteristics lead to a progressive drug accumulation in brain and other body tissues with standard daily administration, reaching concentration well over that necessary for PARP inhibition. Overall, Niraparib can represent an ideal candidate to explore for treatment of malignant gliomas and a non-continuous administration may lead to a reduced bone marrow exposure, decreasing haematological toxicity without compromising anticancer activity.

Previous clinical experiences have already explored PARP inhibitors combined to TMZ in solid malignancies, with scarce tolerability mainly due to bone marrow exhaustion. In one small trial, a continuous administration of Niraparib in combination with standard schedule TMZ across several cohorts confirmed high rate of hematologic toxicities and interestingly showed signals of activity in glioblastoma (GBM).

Considering the peculiar pharmacokinetics proprieties of Niraparib and the recovery in MGMT activity described for dd-TMZ, investigator speculate that different schedules and doses of the two drugs (compared to the ones approved in clinical practice) may be explored to improve tolerability preserving the synergistic activity.

The "3+3 method" will be followed in the safety run-in.

Niraparib and Temozolomide in Patients Glioblastoma

A Phase I-II Study of Niraparib Plus Temozolomide "One Week on, One Week Off" in Patients With Recurrent Isocitrate Dehydrogenase (IDH) Wild Type Glioblastoma and IDH Mutant Gliomas.

To determine the MTD of the combination of dd-TMZ and Niraparib, established in the first cycle of therapy, in order to determine the recommended phase II dose (RP2D).

To assess the proportion of patients progression-free at 6 months for recurrent IDH wild-type glioblastoma (Cohort 1) and at 8 months for recurrent IDH-mutant lower-grade gliomas (Cohort 2)

To evaluate the pharmacokinetics proprieties of the combination of dd-TMZ and Niraparib given on a 7d ON/7d OFF schedule at specific time-points during experimental treatment.Niraparib given on a 7d ON/7d OFF schedule

To evaluate cerebrospinal fluid (CSF) drug concentration of the combination of dd-TMZ and Niraparib given on a 7d ON/7d OFF schedule in those cases where it is safely feasible collecting liquor samples through lumbar puncture and only after patient's appropriate consent.

To assess the safety and tolerability of the combination of dd-TMZ and Niraparib given at the RP2D on a 7d ON/7d OFF schedule

To evaluate tissue drug concentration schedule and visualized intra-tumor distribution by mass spectrometry imaging in surgical specimen of the combination of dd-TMZ and Niraparib given on a 7d ON/7d OFF from patients who need second surgery after patient's consent.

To assess objective response rate (ORR) defined as the proportion of patients who achieved partial response or complete response according to RANO criteria and LGGs RANO criteria on a 7d ON/7d OFF schedule

To assess disease control rate (DCR) defined as the proportion of patients who achieved objective partial response, complete response or stable disease according to RANO criteria and LGGs RANO criteria

To assess progression-free survival (PFS) defined as the time from the start of experimental treatment to disease progression according to RANO criteria and LGGs RANO criteria or death from any cause

To assess overall survival (OS) defined as the time from start of experimental treatment to death from any cause in patients with recurrent/progressive IDH wild-type glioblastoma (Cohort 1) and IDH mutant lower-grade gliomas (Cohort 2).

To explore the magnitude of PFS in cohort 2 according to brain MRI features (enhancing vs non-enhancing lesions)

To explore the magnitude of ORR in cohort 2 according to brain MRI features (enhancing vs non-enhancing lesions)

To explore the magnitude of OS in cohort 2 according to brain MRI features (enhancing vs non-enhancing lesions)

Istituto Clinico Humanitas

GlaxoSmithKline

Armando Santoro, MD

Professor

Skin and Connective Tissue Diseases

Breast Neoplasms

Breast Diseases

Skin Diseases

Paclitaxel

Albumin-Bound Paclitaxel

Carboplatin

Veliparib

Tubulin Modulators

Antimitotic Agents

Veliparib 40 mg twice daily (BID) Days 1 through 7 plus TMZ 150 to 200 mg/m\^2 QD Days 1 through 5 in each 28-day cycle.

Placebo BID Days 1 through 7 plus carboplatin target area under the curve (mg•min/mL) (AUC) 6 administered on Day 3 of each 21-day cycle and paclitaxel 175 mg/m\^2 administered on Day 3 of each 21-day cycle.

Veliparib 80 mg BID Days 1 through 7 plus carboplatin target AUC 6 administered on Day 3 of each 21-day cycle and paclitaxel 175 mg/m\^2 administered on Day 3 of each 21-day cycle.

Placebo

AbbVie Inc.

The primary objective of the study is to assess the progression-free survival (PFS) of oral veliparib in combination with TMZ or in combination with carboplatin and paclitaxel compared to placebo plus carboplatin and paclitaxel in subjects with BRCA1 or BRCA2 mutation and locally recurrent or metastatic breast cancer.

Study Evaluating Efficacy And Tolerability Of Veliparib in Combination With Temozolomide (TMZ) or In Combination With Carboplatin and Paclitaxel Versus Placebo in Participants With Breast Cancer Gene (BRCA)1 and BRCA2 Mutation and Metastatic Breast Cancer

A Randomized, Phase 2 Study of the Efficacy and Tolerability of Veliparib in Combination With Temozolomide or Veliparib in Combination With Carboplatin and Paclitaxel Versus Placebo Plus Carboplatin and Paclitaxel in Subjects With BRCA1 or BRCA2 Mutation and Metastatic Breast Cancer

AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual and trial-level data (analysis data sets), as well as other information (e.g., protocols and clinical study reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications.

PFS is defined as the number of months from the date the participant was randomized to the date of radiographic progression as determined by the central imaging center, or to the date of all cause deaths within 63 days of last tumor assessment if disease progression was not reached.

Time to death for a given participant was defined as the number of months from the day the participant is randomized to the date of the participant's death. All events of death were included, regardless of whether the event occurs while the participant was still taking study drug, or after the participant discontinued study drug. If a participant had not died, then the data will be censored at the date when the participant was last known to be alive.

CBR: percentage of participants who were progression-free at 18 weeks, defined as complete response (CR), partial response (PR), stable disease (SD) or non-CR/non-disease progression (PD) per Response Evaluation Criteria in Solid Tumors \[RECIST\] 1.1.

CR: The disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 0 mm. PR: \>= 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters (SOD). PD: \>= 20% increase in the SOD of target lesions, taking as reference the smallest SOD recorded since the treatment started (baseline or after) or the appearance of \>=1 new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD since the treatment started (baseline or after).

The objective response rate, defined as percentage of participants with a confirmed CR or PR based on RECIST 1.1 criteria. CR: The disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 0 mm. PR: \>= 30% decrease in the sum of diameters of target lesions, taking as reference the baseline SODs.

EORTC QLQ-CIPN20 sensory subscale score was calculated following the standard scoring algorithm, transformed to a 0 (low quality of life) to 100 (best quality of life) scale. A positive change from baseline indicates improvement.

AbbVie

All-Cause Mortality: All randomized participants. AEs/SAEs: As Treated population: all randomized participants who took at least 1 dose of study drug (veliparib/placebo), analyzed by the actual treatment that participant received.

Placebo BID Days 1 through 7 plus carboplatin carboplatin target AUC 6 administered on Day 3 of each 21-day cycle and paclitaxel 175 mg/m\^2 administered on Day 3 of each 21-day cycle.

Group 1 Placebo + Carboplatin/Paclitaxel

Group 1 Veliparib + Carboplatin/Paclitaxel

Veliparib 40 mg BID Days 1 through 7 plus TMZ 150 to 200 mg/m\^2 QD Days 1 through 5 in each 28-day cycle.

Group 1 Veliparib + TMZ

Placebo BID Days 1 through 7 plus carboplatin target AUC 6 administered on Day 3 of each 21-day cycle and paclitaxel 175 mg/m\^2 administered on Day 3 of each 21-day cycle.

Group 2 Placebo + Carboplatin/Paclitaxel

Veliparib 120 mg BID Days 1 through 7 plus carboplatin target AUC 6 administered on Day 3 of each 21-day cycle and paclitaxel 175 mg/m\^2 administered on Day 3 of each 21-day cycle.

Group 2 Veliparib + Carboplatin/Paclitaxel

Group 2 Veliparib + TMZ

Total

Age, Customized

Sex: Female, Male

Race/Ethnicity, Customized

Global Medical Services

Group 2: All randomized participants with suspected deleterious or deleterious breast cancer gene (BRCA)1 or BRCA2 mutation determined by sponsor core lab.

Progression-Free Survival (PFS)

Group 2: All randomized participants with suspected deleterious or deleterious BRCA1 or BRCA2 mutation determined by sponsor core lab.

Overall Survival (OS)

Clinical Benefit Rate (CBR) at Week 18

Group 2: All randomized participants with suspected deleterious or deleterious BRCA1 or BRCA2 mutation determined by sponsor core lab. Participants with at least 1 measurable lesion at baseline.

Objective Response Rate (ORR)

Group 2: All randomized participants with suspected deleterious or deleterious BRCA1 or BRCA2 mutation determined by sponsor core lab. Participants with a baseline and post baseline value. Per protocol, this outcome measure was not planned for the Veliparib + TMZ arm.

Change From Baseline at Week 18 in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy Module (EORTC QLQ-CIPN20) Sensory Subscale Score

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Niraparib and Temozolomide in Patients Glioblastoma	NCT06258018	Glioma, Maligna...	Temodal Niraparib	18 Years -	Istituto Clinico Humanitas
Study Evaluating Efficacy And Tolerability Of Veliparib in Combination With Temozolomide (TMZ) or In Combination With Carboplatin and Paclitaxel Versus Placebo in Participants With Breast Cancer Gene (BRCA)1 and BRCA2 Mutation and Metastatic Breast Cancer	NCT01506609	Metastatic Brea...	Placebo Veliparib Carboplatin Temozolomide Paclitaxel	18 Years -	AbbVie

Spots Global Cancer Trial Database for temodal

Every month we try and update this database with for temodal 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 temodal

Every month we try and update this database with for temodal 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 temodal 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.