Symptoms and General Pathology

All Conditions

Neoplasms

Nervous System Diseases

Rare Diseases

Recurrence

Glioma

Brain Neoplasms

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Neuroepithelioma

All Drugs and Chemicals

Antineoplastic Agents

Antibodies

Antibodies, Monoclonal

Immune Checkpoint Inhibitors

Nivolumab

Immunoglobulins

Antineoplastic Agents, Immunological

Nivolumab is administered by a 30 minutes intravenous infusion at dose of 240 mg every 2 weeks for 8 doses (4 months), followed by a 60 minutes intravenous infusion at dose of 480 mg every 4 weeks for 8 doses (8 months) or until progression, death , unacceptable toxicity or end of the research.

Nivolumab (Opdivo) is a potent human monoclonal antibody (mAb) of the IgG4 isotype designed to directly block the interaction between Programmed Cell Death 1 (PD-1) and its ligands, Programmed Death Ligand 1 (PD-L1) and PD-L2.

Nivolumab is administered by a 30 minutes intravenous infusion at dose of 240 mg every 2 (+/- 2 days) weeks for 8 cycles (4 months), followed by a dose of 480 mg administered by a 60 minutes intravenous infusion every 4 weeks (+/-3 days) (beginning at cycle 9) for a total therapy duration of 1 year (maximum 16 cycles of treatment) or until progression, death, unacceptable toxicity.

DEHAIS Caroline, MD

Immune checkpoint blockade therapies targeting the immunomodulatory effect of cytotoxic T-lymphocyte antigen (CTLA-4) and programmed cell death-1/ Programmed death-ligand 1 (PD-1/PD-L1) have recently demonstrated survival benefit and durable response in phase III trials in several human cancers, especially in tumors that bear high mutation load and/or tumor-associated neoantigen signatures. The aim of these treatments is to restore effector T-cell function and antitumor activity, which could be enhanced in the context of high mutational/neoantigen load. In Isocitrate DeHydrogenase mutated High Grade Gliomas (IDHm HGGs), acquired resistance to alkylating chemotherapy frequently results from the inactivation of mismatch-repair (MMR) proteins which in turn leads to the acquisition of a hypermutator phenotype. These findings suggest that at least in a subset of recurrent IDHm HGGs immune checkpoint blockade therapies may be particularly effective. IDHm HGGs most frequently occur in young adults. The first line treatment consists of maximal safe surgical resection followed by radiotherapy and adjuvant alkylating chemotherapy (Temozolomide or Procarbazine-CCNU-Vincristine regimen (PCV)). Despite these treatments, most IDHm HGGs recurred in few years. There is no standard of care at recurrence and the median overall survival after it is less than 3 years.

The investigators make the hypothesis that treatment with the anti-PD-1 monoclonal antibody Nivolumab will improve 24 weeks progression-free survival in IDHm HGGs that have recurred after initial treatment with radiotherapy and alkylating chemotherapy.

IDHm HGGs (High-Grade (grade III or IV) Gliomas that harbor mutations in Isocitrate Dehydrogenase 1 (IDH1) or Isocitrate Dehydrogenase 2 (IDH2)) most frequently occur in young adults. Favorable prognostic factors include high Karnofsky performance score, young age, 1p/19q codeletion and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. Despite primary management, which consists of maximal safe surgical resection followed by radiotherapy and adjuvant alkylating chemotherapy with temozolomide (TMZ) or Procarbazine, CCNU, Vincristine (PCV), most IDHm HGGs recur, resulting in death with a median overall survival of 5 years. At recurrence, there is currently no standard of care. Because of the lack of clinical trials specifically designed for patients with relapsed IDHm HGGs, most patients receive alkylating chemotherapy (nitrosourea- or TMZ-containing regimens). However, these treatments have modest efficacy, as shown in several phase II trials that have reported response rates of 17-44% and 6-month progression-free survival (PFS6) of 29-51%. The efficacy of alkylating agents as DNA damaging agents is dependent on a functional MMR pathway. In IDHm HGGs, acquired resistance to alkylating chemotherapy can arise after the inactivation of MMR proteins, which in turn leads to the acquisition of a hypermutator phenotype. Paired analyses of newly diagnosed and recurrent tumors (after treatment with alkylating agents), have demonstrated that IDHm HGGs that recur after treatment with alkylating chemotherapy often harbor hypermutator phenotype associated with defects in the MMR pathway. While such MMR defects are extremely rare in newly diagnosed IDHm HGGs, MMR mutations were reported in 20-50% of patients with recurrent IDHm HGGs giving support that there is selective pressure to decreased MMR in glial tumors treated with alkylating chemotherapy. These findings suggest that, at least in a subset of recurrent IDHm HGGs, Nivolumab may be effective. Nivolumab has demonstrated overall survival (OS) benefit in multiple tumor types and has demonstrated a manageable safety profile in \> 12300 subjects across all clinical trials. For monotherapy, the safety profile is similar across tumor types. Preliminary data from phase I and phase III trials in patient with gliomas have indicated that Nivolumab is well tolerated in patients with primary brain tumors. Yet, these tumors may represent particularly good candidates for immune checkpoint blockade therapies since they frequently develop a hypermutated phenotype after alkylating chemotherapy.

This is a phase II, open label, non-randomized multicentric trial evaluating the efficacy of Nivolumab in adults' patients with recurrent IDHm HGGs. The main objective is to evaluate the efficacy of Nivolumab, based on 24 weeks progression-free survival (PFS24w) rate as assessed by RANO criteria.

Nivolumab is administered by a 30 minutes intravenous infusion at dose of 240 mg every 2 (+/- 2 days) weeks for 8 cycles (4 months), followed by a dose of 480 mg administered by a 60 minutes intravenous infusion every 4 weeks (+/-3 days) (beginning at cycle 9) for a total therapy duration of 1 year (maximum 16 cycles of treatment) or until progression, death, unacceptable toxicity.

Patients will undergo efficacy assessments using magnetic resonance imaging (MRI) every 8 weeks (every 4 cycles during 8 first cycles, then every 2 cycles). Patient outcomes measures will be completed at the time of each imaging study. Toxicity assessments will occur before the initiation of each cycle. Health related Quality of life (EORTC QLQ-C30 and QLQ-BN20) will be assessed before day 1, every 4 cycles during 8 first cycles, then every 2 cycles.

* In case of discontinuation from study treatment for toxicity or severe adverse events, subject request or investigator decision :

  * PFS-24w assessment should be done at W24 +/- 2weeks if applicable
  * date of tumor progression according to RANO and iRANO criteria and date of death if applicable
* In case of end of treatment duration :

  * A brain MRI will be performed 4 weeks after the C16
  * After the end of the research, patient will be followed every 3 months as usual care, by phone, to record date of tumor progression according to RANO criteria and date of death, if applicable.
* Adverse events must be notified and documented by investigator for a minimum of 100 days after last dose of treatment. Drug-related toxicities should continue be followed until they resolve, return to baseline or are deemed irreversible.

Efficacy of Nivolumab for Recurrent IDH Mutated High-Grade Gliomas

A Phase II Study From the POLA National Network of Nivolumab for Recurrent IDH Mutated High-Grade Gliomas

Data are available upon reasonable request. The procedures carried out with the French data privacy authority (CNIL, Commission nationale de l'informatique et des libertés) do not provide for the transmission of the database, nor do the information and consent documents signed by the patients.

Consultation by the editorial board or interested researchers of individual participant data that underlie the results reported in the article after deidentification may nevertheless be considered, subject to prior determination of the terms and conditions of such consultation and in respect for compliance with the applicable regulations.

Efficacy of Nivolumab will be based on PFS24w. PFS24w was defined by the percentage of patients alive without progression according to RANO criteria at 24 weeks +/- 2 weeks after treatment initiation.

PFS24w was defined by the percentage of patients alive without progression according to iRANO criteria at 24 weeks +/- 2 weeks after treatment initiation.

Median-PFS is defined by the time in which fifty percent (50%) of patients have experienced tumor progression or death due to any cause. It will be documented using RANO criteria

Median-PFS is defined by the time in which fifty percent (50%) of patients have experienced tumor progression or death due to any cause. It will be documented using iRANO criteria

Overall survival is defined as the time from treatment initiation to death due to any cause

Overall response rate is defined by the percentage of patients with at least a complete response and partial response using RANO criteria documented during treatment

Overall response rate is defined by the percentage of patients with at least a complete response and partial response using iRANO criteria documented during treatment

Duration of response is defined by the time from confirmation of stable, partial and complete response using RANO criteria until the tumor progression has been shown

Duration of response is defined by the time from confirmation of stable, partial and complete response using iRANO criteria until the tumor progression has been shown

Data at each time point will be compared to t0 (before first infusion of Nivolumab)

The adverse events will be described and graded according to the revised NCI Common Terminology Criteria V4.03 for Adverse Events (CTCAE V4.03)

Bristol-Myers Squibb

Assistance Publique - Hôpitaux de Paris

Blood and Lymph Conditions

Leukemia

Hematologic Neoplasms

Myeloproliferative Disorders

Bone Marrow Diseases

Hematologic Diseases

Chronic Myeloproliferative Disorders

Tin Fluorides

Ivosidenib

Enzyme Inhibitors

After genetic testing, if participants are found to have IDH1 Mutations (a genetic mutation) then they will be assigned to this group and will receive the following study drugs:

Single agent Phase (Cycles 1-3):

The initial phase of treatment will consist of 3 cycles (lasting 28 days) of ivosidenib 500mg daily x 28 days

Combination Phase (Cycle 4 onwards):

If a participant shows clinical benefit (including their disease stabilizing) following the first 3- cycle phase, he or she may go onto the combination phase. Combination treatment will consist of ivosidenib daily x 28 days along with fedratinib daily x 28 days.

After genetic testing, if participants are found to have IDH2 Mutations (a genetic mutation) then they will be assigned to this group and will receive the following study drugs:

Single agent Phase (Cycles 1-3):

The initial phase of treatment will consist of 3 cycles (lasting 28 days) of enasidenib 100mg daily x 28 days

Combination Phase (Cycle 4 onwards):

If a participant shows clinical benefit (including their disease stabilizing) following the first 3- cycle phase, he or she may go onto the combination phase.Combination treatment will consist of enasidenib 100mg daily x 28 days along with fedratinib daily x 28 days.

A drug used to treat acute myeloid leukemia that has a mutated (changed) form of a gene called isocitrate dehydrogenase-1 (IDH1).

A drug used to treat acute myeloid leukemia (AML) that has recurred (come back) or has not gotten better after treatment with other anticancer therapy.

Enasidenib

This medication is used to treat a certain type of cancer (myelofibrosis). Fedratinib belongs to a class of drugs known as JAK (janus kinase) inhibitors. It works by slowing or stopping the growth of cancer cells.

Fedratinib

Olatoyosi Odenike, MD

Anand Patel, MD

The purpose of this research is to gather information on the safety and effectiveness of fedratinib (a drug called a "jak inhibitor" ) in combination with ivosidenib or enasidenib (two anti-cancer drugs). While all three drugs are FDA-approved for various conditions, the US Food and Drug Administration (FDA) has not approved the combination of these drugs for the treatment of rare blood cancers that present Isocitrate dehydrogenase (IDH) mutations, and therefore these drugs can only be given in a research study.

Doctors leading this study hope to learn about the safety of combining fedratinib (a type of drug called a "JAK inhibitor" whichblocks the activity of janus kinase enzymes in your body) with anti-cancer drugs ivosidenib and enasidenib in participants who have rare blood cancers that show Isocitrate dehydrogenase (IDH) mutations (a type of genetic mutation). Your participation in this research will last about 24 months.

The purpose of this research is to gather information on the safety and effectiveness of fedratinib in combination with ivosidenib or enasidenib. While all three drugs are FDA-approved for various conditions, the US Food and Drug Administration (FDA) has not approved the combination of these drugs for the treatment of IDH-mutated blood cancers (known as myeloproliferative neoplasms), and therefore these drugs can only be given in a research study.

A Study of Fedratinib With IDH Inhibition in Advanced-Phase, IDH-Mutated Ph-Negative Myeloproliferative Neoplasms

A Phase Ib Study of Fedratinib With IDH Inhibition in Advanced-Phase, IDH-Mutated Ph-Negative Myeloproliferative Neoplasms

The maximum tolerated dose of fedratinib in combination with ivosidenib in participants who have IDH1-mutated blood cancer. This will be assessed by the number of reported dose-limiting toxicities and adverse events among participants according to the Common Terminology Criteria for Adverse Events version 5.

The number of patients who are living 1 year after the beginning of treatment on study as assessed by data from clinical records.

Overall response rate as assessed by the number of participants who achieve a complete molecular response (CMR), cytogenetic complete response (CCR), acute leukemia response-complete (ALR-C), or acute leukemia response-partial (ALR-P).

Time to response will be defined as time from treatment administration to first documented complete molecular response (CMR), cytogenetic complete response (CCR), acute leukemia response-complete (ALR-C), or acute leukemia response-partial (ALR-P). DCR will be defined as the portion of subjects achieving a complete molecular response,cytogenetic complete response (CCR), acute leukemia response-complete (ALR-C), or acute leukemia response-partial (ALR-P) or stabilized disease for ≥ 3 months.

University of Chicago

Astrocytoma

Oligodendroglioma

Oligoastrocytoma

Temozolomide

Antineoplastic Agents, Alkylating

Alkylating Agents

Patients with IDH wild type, according to the result of genetic sequencing of their surgical resected specimens. Intervention: oral temozolomide, 75 mg/m2/day for 21 days repeated every 4 weeks, 6 cycles.

Patients with IDH mutations, according to the result of genetic sequencing of their surgical resected specimens. Intervention: oral temozolomide, 75 mg/m2/day for 21 days repeated every 4 weeks, 6 cycles.

75 mg/m2/day for 21 days repeated every 4 weeks, 6 cycles.

Jinsong Wu, Professor

Low grade gliomas (LGGs) are the most common primary central nervous system malignancies. Brain surgeries with the most possible extent of resection are endeavored to achieve longer survivals in LGG patients. For patients with tumor located in eloquent areas so that gross total resection is not applicable, National Comprehensive Cancer Network (NCCN) 2013 guidelines assigned both radiotherapy or chemotherapy as adjuvant treatments of low grade glioma following surgeries. Retrospective studies have suggested that temozolomide (an oral chemotherapeutics) chemotherapy have good effects on the control of tumor progression or recurrence in LGG patients after surgeries, especially in those with isocitrate dehydrogenase (IDH) gene mutations.

Therefore, our prospective cohort study is to provide a higher level(IIb) of evidence for the correlation between IDH mutation and the responsiveness to up-front adjuvant metronomic temozolomide chemotherapy in young patients with LGG located in eloquent brain areas. And hopefully justify future RCTs with comparison between effects of adjuvant radiotherapy and chemotherapy in these patients.

Low grade gliomas, according to the 2007 WHO classification of tumors of the central nervous system, include astrocytomas, oligodendrogliomas, and oligoastrocytomas. It contributes to 25% of diffuse gliomas and 15% of all gliomas in adults. The majority of age group that is the most vulnerable to this neoplasm is from 30-45 years old. Median survival is usually 5-12 years, but can be prolonged up to 20 years under optimal treatment strategies. National Comprehensive Cancer Network (NCCN) and Chinese Guideline for Gliomas 2012 both point out that for LGG patients in low-risk group (oligodendrogliomas or oligoastrocytomas; no more than 40 years old; KPS 80 and higher; tumor size less than 6cm; no or minor neurological deficits), "wait and see" strategy could be considered after gross total resection; but when the tumors are in eloquent areas so that gross total resections are not applicable, the standard strategies for this specific group of patients are maximum safely resection with adjuvant treatments (radiotherapy and/or chemotherapy). Conventionally, radiotherapy is used as adjuvant treatment after surgeries. However, a recent phase III randomized trial comparing early versus later irradiation has demonstrated that early adjuvant radiotherapy had no significant impact on overall survival. Moreover, radiotherapy brings as much side effects as its control of tumor recurrence. It inevitably jeopardizes patients, especially young ones, with post-radiation cognitive deficits, which impair their social functions. On the other hand, chemotherapy could be a safer adjuvant treatment for LGG. Several phase II and III studies demonstrated that single chemotherapy is effective for treating LGG, with 50-75% response rate (including minor response), and 24-48 months of median duration of response.PCV regimen (procarbazine-CCNU-vincristine), which is administrated intravenously, used to be considered standard for LGG (oligodendrogliomas and oligoastrocytomas) chemotherapy, but now temozolomide (TMZ), an oral alkylating agent, with relatively less side effects than PCV regimen, is gaining gradual acceptance. Now we propose up-front adjuvant chemotherapy to achieve the effect of early tumor control as well as avoidance or postponement of adverse effects caused by premature adjuvant radiotherapy.

As for different schedules of temozolomide, a systematic review suggested an indication that metronomic regimens of TMZ (75 mg/m2/day for 21 days repeated every 4 weeks) result in better PFS and response rate when compared to the conventional standard 5 day regimen (200 mg/m2/day for 5 days, repeated every 4 weeks), despite of insufficient available data and study heterogeneity, thus justifying future well designed trials to verify the efficacy of the metronomic regimen. More frequent administration of TMZ will lead to MGMT (O6-methylguanine DNA methyl transferase) depletion and render higher levels of O6-methylated DNA adducts, thus reducing the chemotherapeutic resistance.

The spontaneous behavior of LGGs, as well as their response to therapy, is difficult to predict, and their outcome is highly variable. These clinical features are closely relevant to their genetic characteristics, including IDH (isocitrate dehydrogenase) gene, with 2 subtypes, IDH1 and IDH2 (less common). These genetic mutations occur in more than 70% primary LGGs. And its prognostic significance of gliomas has been reported in the New England Journal of Medicine, Journal of Clinical Oncology, and Neuro-oncology. A retrospective study suggested its predictive value of high LGGs sensitivity to TMZ. Basic research provided us the rationale that overexpression of wild IDH1 gene resulted in chemotherapy resistance to a high dose of TMZ in vivo and in vitro, while IDH1 mutation caused cell cycle arrest in G1 stage, with a compromised ability of proliferation and invasion, raising sensitivity to chemotherapy.

During our previous clinical practice, it is interesting to reveal the consistence of IDH mutation, MGMT methylation and 1p19q co-deletion in WHO Grade II and Grade III gliomas. It theoretically acknowledged potential higher sensitivity of TMZ chemotherapy in LGGs.

In order to verify the predictive significance of IDH mutation for a higher sensitivity of LGGs in eloquent areas which entail gross total resection inapplicable, higher level of evidence should be provided. And recent RANO (response assessment in neuro-oncology) revised guidelines for evaluations of objective response rate, cognitive functions, and quality of life have better facilitated standard trials.

A Prospective Cohort to Study the Effect of Temozolomide on IDH Mutational Low Grade Gliomas

A Prospective Cohort to Study the Effect of Postoperative Upfront Temozolomide Chemotherapy on IDH Mutational Low Grade Gliomas in Eloquent Areas

According to the revised RANO criteria (M J van den Bent, et al. 2011), compared to residual tumor volume calculated with iMRI T2/Flair right after surgery and before up-front adjuvant chemotherapy (Baseline tumor volume):

Complete response (CR): disappearance of abnormality Partial response (PR): no less than 50% reduction Minimal response (MR): no less than 25% but less than 50% reduction Stable disease (SD): less than 25% reduction also less than 25% increase Progressive disease (PD): no less than 25% increase

Enhanced T1-weighted imaging, magnetic resonance spectroscopy (MRS), Diffusion tensor imaging (DTI) and perfusion-weighted imaging (PWI) will also be utilized to detect progressions.

According to the Definition of New Endpoints by E. Mandonnet et al, 2013, VDE is calculated with formula D = (2 × V)\^1/3, (V= tumor volume).

Uncontrolled: unchanged or increased VDE compared to baseline VDE. Slowed down: decreased VDE compared to baseline VDE, but still positive. Stabilized: VDE is close to 0 mm/year. Reversed: negative VDE. Treatment escape and relapse: re-growth of the tumor greater than 2 mm, during the course of chemotherapy and after the end of chemotherapy, respectively.

Intensity of response (IOR): how much the diameter has been reduced by the therapy.

Duration of response (DOR): the time period between treatment onset and treatment escape or relapse. If Replapse (25% increase/VDE\>2mm/Maligmant enhancement), start 2° treatment: Second surgery or radiotherapy or salvage chemotherapy

The survival rate of followed patients without progressive disease (PD) 6, 12, and 24 months after the 1st cycle of chemotherapy

Test battery:

Measured with Minimal Mental State Examination (MMSE); Hopkins verbal learning test-revised; Trail making test, part A and B; Multilingual aphasia examination controlled oral word association

Measured with EORTC QLQ-C30 and EORTC-BN20. Duration of response with good quality of life is defined as Time with good quality of life (TQL).

The survival rate of followed patients without any MRI T1 enhancing signals in 6, 12, and 24 months after the 1st cycle of chemotherapy

Measured with M.D. Anderson Symptom Inventory Brain Tumor Module, MDASI-BT.

Measured by one neurologist, number and type of seizure and medication in the past month before each follow-up visit are recorded.

Huashan Hospital

Professor

Escalation/de-escalation dose levels of zotiraciclib given in 28 day cycles

Estimated RP2D of zotiraciclib given in 28 day cycles

One RP2D dose of zotiraciclib given on the day prior to brain tumor biopsy or resection, a continuation of treatment with estimated RP2D of zotiraciclib given in 28 days cycles following the recovery of the surgery

Zotiraciclib will be given orally at the DL1, DL-1, or DL 2 once a day on days 1, 4, 8, 11, 15, 18 of every 28-days cycle (18 cycles total).

Zotiraciclib

NCI NOB Referral Group

Jing Wu, M.D.

National Cancer Institute Referral Office

Background:

Diffuse gliomas are tumors that affect the brain and spinal cord. Gliomas that develop in people with certain gene mutations (IDH1 or IDH2) are especially aggressive. Better treatments are needed.

Objective:

To see if a study drug (zotiraciclib) is effective in people with recurrent diffuse gliomas who have IDH1 or IDH2 mutations.

Eligibility:

People aged 18 years and older with diffuse gliomas that returned after treatment. They must also have mutations in the IDH1 or IDH2 genes.

Design:

Participants will be screened. They will have a physical exam with blood and urine tests. They will have tests of their heart function. They will have an MRI of their brain. A new biopsy may be needed if previous results are not available.

Zotiraciclib is a capsule taken by mouth with a glass of water. Participants will take the drug at home on days 1, 4, 8, 11, 15, and 18 of a 28-day cycle. They may also be given medications to prevent side effects of the study drug. The schedule for taking the study drug may vary for participants who will undergo surgery.

Participants will be given a medication diary for each cycle. They will write down the date and time of each dose of the study drug.

Participants will visit the clinic about once a month. They will have a physical exam, blood tests, and tests to evaluate their heart function. An MRI of the brain will be repeated every 8 weeks.

Participants may remain in the study for up to 18 cycles (1.5 years).

...

Background:

* Zotiraciclib is a multi-kinase inhibitor that has been shown to have anti-glioma effects through transcriptional suppression, mitochondrial dysfunction, and adenosine 5'-triphosphate (ATP) reduction in glioblastoma in our preclinical studies
* Zotiraciclib is orally administered and likely penetrates the blood brain barrier (BBB). There has been a clinical experience in using zotiraciclib as a single agent and in combination with other chemotherapy agents in cancers, including malignant gliomas
* Our phase I study of zotiraciclib and temozolomide (TMZ) in recurrent high-grade astrocytomas determined the maximum tolerated dose (MTD) of zotiraciclib in combination with TMZ and demonstrated the safety of the treatment in recurrent high-grade glioma patients
* Preliminary efficacy analysis of Phase I demonstrated an improved response to zotiraciclib in combination with TMZ in IDH-mutant gliomas compared to the IDH-wildtype counterpart
* A selective vulnerability to zotiraciclib as a single agent was demonstrated in the preclinical models of IDH-mutant gliomas

Objectives:

* Phase I: To estimate recommended phase II dose (RP2D) of zotiraciclib
* Phase II: To determine 12-months progression free survival (PFS) in participants with recurrent glioma, IDH1/2-mutant, World Health Organization (WHO) grade 3 treated with zotiraciclib in comparison with the established brain tumor database matched for tumor molecular characteristics and clinical prognostic factors

Eligibility:

* Age \>=18; Karnofsky performance status (KPS) \>=70%
* Histological confirmation of diffuse glioma, WHO grades 2-4 with IDH1/2 mutation status confirmed by DNA sequence
* Have recurrent disease
* Have prior treatment of radiation and/or conventional chemotherapies
* No prior use of bevacizumab as a treatment for a brain tumor

Design:

* This is a phase I/II study to evaluate the safety and efficacy of zotiraciclib as a single agent in recurrent IDH-mutant gliomas.
* Initially, 9-24 participants (Cohort 1) will be assigned to Phase I to estimate recommended phase 2 dose (RP2D) of zotiraciclib.
* Once RP2D is estimated, we will start enrollment into cohorts for Phase II, non-surgical participants (Cohorts 2-4), and surgical (Cohort 5). Considering non-evaluable participants and screen failures, this trial plans to enroll 96 participants total.
* Drug will be administered on days 1, 4, 8, 11, 15, 18 in cycles of 28 days for a maximum of 18 cycles. Starting dose is 200 mg. In the case that 200 mg is not tolerable, a lower dose 150mg, will be evaluated. If 200 mg is tolerated well, a higher dose level will be evaluated at 250mg.
* Participants in the surgical cohort will get an additional single pre-treatment with one dose of study drug at the RP2D on Day 1 of Cycle 0, followed by brain tumor biopsy or surgical resection within 24 hours on Day 2 of Cycle 0. Approximately 2-4 weeks after surgery or biopsy participants in this Cohort will continue treatment with the study drug and start Day 1 of Cycle 1.

Study of Zotiraciclib for Recurrent High-Grade Gliomas With Isocitrate Dehydrogenase 1 or 2 (IDH1 or IDH2) Mutations

A Phase I/II Study of Zotiraciclib for Recurrent High-Grade Gliomas With Isocitrate Dehydrogenase 1 or 2 (IDH1 or IDH2) Mutations

.All IPD recorded in the medical record will be shared with intramural investigators upon request. In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP.

Proportion of patients that have progressive disease after 12 months

Amount of time until disease progression from initiation of study therapy as compared with data of the brain tumor database

Type, grade and frequency of adverse events

Amount of time subject survives after initiation of study therapy as compared with data of the brain tumor database

National Cancer Institute (NCI)

Glioblastoma

Disease Attributes

Carboplatin

Talazoparib

Poly(ADP-ribose) Polymerase 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

Amino Acids

Imidacloprid

Glutamine

Glutamic Acid

The MEGA-based editing sequences as well as the SLOW-EPSI sequence will be applied to this group using a 3T Prisma and a 7T Terra scanner. Data will be used for optimization of the pulse sequences.

Aim: find those sequence parameters to obtain best spectral quality data (SNR, spatial resolution versus measurement time).

The best performing sequence which will be applied to this group using a 7T Terra scanner. Data will be used normative data for glutamate/glutamine and GABA levels in healthy controls.

Aim: normal reference data for future studies.

Two editing pulse sequence types will be applied to this group at a 3T Prisma and a 7T Terra scanner. The sequences being compared are MEGA-semiLASER-SVS, MEGA-semiLASER based MRSI (on both 3T and 7T) and SLOW-EPSI (on 7T only).

Two different CEST sequence types will be applied to this group at a 3T Prisma and a 7T Terra scanner. The CEST performance will be compared between 3T and 7T, as well which of the two types in the best on each scanner.

Aim: which of the four sequence predicts the IDH-mutation status best.

The MR-scans performed at 3T and 7T are performed to evaluate whether high field MR-examinations bring an advantage to the patient in determining the IDH-status of the glioma. Two MRSI/CEST sequences will be tested against each other.

MR-scans using a 3T Prisma and a 7T Terra scanner (Siemens, Erlangen Germany)

Johannes Slotboom, PhD

Marwan El-Koussy, MD

High field MR-technologies are expected to boost metabolic spectroscopic imaging (MRSI), but also CEST-MRI. This is due to the fact that increased SNR is available which can be used to increase the spatial resolution of all sequences, or reduction of measurement times. Recent findings has shown that MRSI can be used to evaluate the isocitrate dehydrogenase (IDH) status of gliomas, a brain tumor type which is most often diagnosed in humans. Patients with IDH-mutated gliomas have a much longer survival time that IDH-wildtype. In IDH-mutated gliomas the substance 2-hydroxy-glutarate (2HG) is found, whereas in IDH-wildtype gliomas it is not.

The underlying trial aims to measure 2HG directly with different MRSI sequences at 3 Tesla (3T) and 7 Tesla (7T) magnetic field strength. Apart from MRSI-techniques for IDH-typing it has been shown that CEST-imaging can also be performed to determine the IDH-status of gliomas.

A total of 75 patients and 50 healthy controls will be examined in this study to evaluate the most accurate method for pre-operative IDH-status determination.

Introduction - Recently the first commercially available 7T MR-scanner which is approved for clinical use came on to the market. The main motivation to go to higher field strengths is the fact that better SNR can be achieved in shorter acquisition time, or higher spatial resolution can be obtained in the same measurement time. High field MRI also has drawbacks, e.g. substantially higher specific absorption rate (SAR), higher susceptibility related image distortion problems, and longer longitudinal relaxation times. Nevertheless, moving to higher fields is especially beneficial for MR-spectroscopy. This is due to the fact that better signal to noise ration (SNR) is combined with higher spectral resolution. The two most commonly used techniques for spectroscopic imaging (MRSI) are: (i.) relative slow 2D/3D techniques like PRESS and semiLASER based techniques, and (ii.) fast 3D echo planar based (EPI) techniques. Although echo planar spectroscopic imaging (EPSI) is a technique that has been introduced by Sir Peter Mansfield in the first half of 80es, the method is still continuously being improved, and recently very promising applications related to brain tumor diagnostics were published. To be mentioned in this context is the fact that the method can be combined with spectral editing for the detection of 2-hydroxy-glutarate (2HG) in glioma patients. 2HG is only present if the glioma that has mutations in the IDH-gene. It is shown that gliomas having the IDH-mutation have a much better overall survival prognosis. Apart from brain tumor typing, high resolution EPSI imaging also enables investigation the investigation of tumor infiltration using metabolic criteria. In surgery the patients' preoperative intake of the 5-aminolevulinic acid (5-ALA) before surgery selectively makes malignant glioma tissues fluorescent under blue light irradiation and tumor itself becomes clearly visible during the neurosurgical intervention. The fact that 5-ALA-guided completely-resected glioma patients have a significant longer survival time, underlines the necessity to know the exact tumor boundaries.

Aims - The major aims of the study proposed are manifold:

(i.) The development of a novel EPSI-pulse sequence utilizing 3D-radial k-space sampling schemes, that focuses on robustness w.r.t. patient motion, is robust with respect to chemical shift displacement artifacts, includes the possibility of 2HG-spectral editing, uses SAR-reduced radiofrequency (RF) pulses, and operate with total acquisition times that are acceptable for clinical routine use; (ii.) Comparison of the novel sequence with available conventional EPSI-techniques and semiLASER-based techniques for clinical routine use comparing its performance at 3T and 7T; (iii.) The development of a graphic processor unit (GPU) based fitting algorithm for quantification of 3D-radial EPSI-data based on the existing tdfdfit-algorithm; (iv.) Extension of a locally developed machine learning based automatic quality-filtering algorithm to be applied on the researchers' novel EPSI-data; (v.) Quantitative investigation on the effect spatial non-uniform transmit and receive properties for all relevant metabolites and spatial dependent signal amplitude correction schemes (extension of a locally developed method); (vi.) Investigation of the exact effects of selective excitation on J-coupled spin systems, and comparison of these effects between 3T and 7T; (vii.) Reproducibility study on 20 healthy volunteers measured twice with the same protocol (10 recorded twice at 7T and 10 recorded twice at 3T); (viii.) Pre-operative application of the best suited EPSI-pulse sequence in a total of 75 patients. All patients will be recorded at 3T as well as at 7T using the equivalent protocols; (ix.) Co-registration of pre-operative, spatially resolved 3D-EPSI-MRSI data with post-operative 3D-FLAIR and T1c-imaging in IDH-wildtype patients with had complete resection during 5-ALA guided neurosurgical interventions will provide information on whether MRSI-techniques are helpful to predict the tumor affected volume; (x.) Documentation of the location of a biopsy, histology to enable a better correlation between MR-spectroscopic patterns and histology.

(xi) Comparison of the performance of CEST versus the CMRR-semiLASER MRSI sequence w.r.t. to the prediction accuracy of the IDH-type of the glioma by the two technologies.

Methodology - The implementation of a robust EPSI sequence that uses 3D-radial k-space sampling schemes and reconstruction will be performed on Siemens IDEA developer platforms for VE- and XA-software versions. The sequence will be compared to the performance obtained with another EPSI implementation, available via Siemens, as well as the CMRR-implementation of the MEGA (MEscher-GArwood) semi-LASER (Localization by Adiabatic SElective Refocusing) for 2HG-editing (CMRR Spectroscopy Package, 2012). The quantification of the EPSI-data of the reference sequence will be performed with the MIDAS package. The EPSI-data of the novel sequence as well as MEGA-semi-LASER sequence will be quantified using a parallelized GPU-re-implementation of the tdfdfit-algorithm made available as separate plugin within jMRUI-spectroscopy package (jMRUI: java magnetic resonance user interface). Co-registration of pre-surgery EPSI-data with post-operative structural MRI-data will be performed with the SPM (Statistical Parameter Mapping) program. Further statistical analysis and machine learning algorithms will be based on statistical programming language "R". The CEST pulse sequences will be obtained via Siemens-Healthineers.

Potential significance - (a.) Pre-surgical knowledge of the IDH-status will enable better individual neurosurgical treatment of the patient; (b.) Coregistration of metabolic EPSI-data, with post-operative structural MR-data will give information on the fundamental usefulness of MRSI-techniques to detect glioma infiltration zones; (c.) Improved follow-up of IDH-mutated glioma patients, who typically have a long period of minimal progression, followed rapidly by aggressive growth and transformation to higher grade; (d.) The availability of an imaging biomarker to monitor tumor recurrence would be a major advance for all glioma patients.

Metabolic Characterization of Space Occupying Lesions of the Brain

Metabolic Characterization of Space Occupying Lesions of the Brain Using in Vivo MR- (Spectroscopic) Imaging at 3 Tesla and 7 Tesla

Finding the most optimal (2HG-edited, radial kspace-sampled) EPSI MRSI/CEST technique for the initial diagnosis of gliomas with respect to IDH-typing. Pre-operative knowledge of the IDH-type is important information for further neurosurgical treatment.

The retrospective analysis of tumor affected tissue volumes identified by 3D-MRSI/CEST image data with the factual resected volumes during 5-ALA guided complete tumor resection interventions enable to find the relationship between the spectral or CEST pattern and the location of the glioma.

Swiss National Science Foundation

Insel Gruppe AG, University Hospital Bern

Dermatologic Agents

Tretinoin

Keratolytic Agents

Subjects in Arm A are alkylator-refractory and at high risk for progression of disease, have failed temozolmide and another alkylating agent. Subjects in Arm A will receive 28-day cycles of treatment, with ATRA 45mg/m2/day given orally in two equally divided doses on days 1 through 14 and retifanlimab 500mg IV on day 1.

Subject in Arm B are patients who have failed only one prior alkylating chemotherapy regimen and have gone at least 12 months since the last treatment. Subjects in Arm B will receive 28-day cycles of treatment, with ATRA 45mg/m2/day given orally in two equally divided doses on days 1 through 14 and retifanlimab 500mg IV on day 1.

Subject in Arm C will receive ATRA 45mg/m2/day orally in two equally divided doses for 14 days pre-surgery, then undergo surgery. Following surgery all patients will receive 28-day cycles of treatment, with ATRA 45mg/m2/day given orally in two equally divided doses on days 1-14 and retifanlimab 500mg IV on day 1.

Subject in Arm D will receive the combination of ATRA 45mg/m2/day orally in two equally divided doses for 14 days pre-surgery plus a 500mg IV dose of retifanlimab 14 days prior to the date of surgery. Following surgery all patients will receive 28-day cycles of treatment, with ATRA 45mg/m2/day given orally in two equally divided doses on days 1-14 and retifanlimab 500mg IV on day 1.

Administered 500mg IV on day 1 of every 28-day cycle, continued until disease progression, unacceptable toxicity, or 2 years from the first dose of study medication, whichever occurs first.

Retifanlimab

All-trans retinoic acid (ATRA) 45mg/m2 orally in two equally divided doses on days 1-14 of each 28-day cycle, continued until disease progression, unacceptable toxicity, or 2 years from the first dose of study medication, whichever occurs first.

All-trans retinoic acid

Abramson Cancer Center Clinical Trials Service

Timothy Prior

Stephen Bagley, MD, MSCE

Stephen Bagley, MD MSCE

This is a Phase II study of the combination of All-Trans Retinonic Acid (ATRA) and PD-1 inhibition (Retifanlimab) in patient with recurrent IDH-mutant glioma. The Sponsor-Investigator hypothesizes that the proposed regimen will be safe and stimulate a robust anti-tumor immune response.

The study has a Safety Run-In, a Phase 2 Portion, and a Surgical Portion. The Phase 2 portion and Surgical portion will open to enrollment simultaneously following successful completion of the Safety Run-In.

Safety Run-In subjects receive 28-day cycles of treatment, with ATRA 45mg/m2/day given orally in two equally divided doses on days 1-14 and retifanlimab 500mg IV on day 1. Once Safety Run-In is complete, the Phase 2 and Surgical cohorts will commence uninterrupted.

Phase 2: All Phase 2 patients will receive 28-day cycles of treatment, with ATRA 45mg/m2/day given orally in two equally divided doses on days 1 through 14 and retifanlimab 500mg IV on day 1.

Arm A includes alkylator-refractory patients at high risk for progression of disease, having failed temozolomide and another alkylating agent. At the first stage, 12 subjects will be enrolled onto the study. This arm of the trial will be stopped if no response was obtained among the first 12 subjects (0/12). Otherwise, this arm of the study will continue to stage Four additional subjects will be enrolled on the second stage of this arm of the trial.

Arm B includes patients who have failed only one prior alkylating chemotherapy regimen and have gone at least 12 months since the last treatment (chemotherapy or radiation therapy), i.e., favorable risk patients. At the first stage, 14 subjects will be enrolled onto the study. This arm of the trial will be stopped if 5 or fewer responses were obtained among the first 14 subjects greater than or equal to 5 out of 14 subjects. Otherwise, this arm of the study will continue to stage 2. Three additional subjects will be enrolled on the second stage of this arm of the trial.

Surgical Portion: This portion of the study will enroll patients who are eligible for re-resection at the time of recurrence. Prior to surgical resection, patients are randomized 1:1 to receive either 1) single-agent ATRA 45mg/m2/day orally in two equally divided doses for 14 days pre-surgery (Arm C), or 2) the combination of ATRA 45mg/m2/day orally in two equally divided doses for 14 days pre-surgery plus a 500mg IV dose of retifanlimab 14 (+/-3) days prior to the date of surgery (Arm D). At surgery fresh tumor tissue will be collected for correlative studies. Following surgery all patients will receive 28-day cycles of treatment, with ATRA 45mg/m2/day given orally in two equally divided doses on days 1-14 and retifanlimab 500mg IV on day 1.

The study has a Safety Run-In, a Phase 2 Portion with Arm A and Arm B and a Surgical Portion with Arm C and Arm D. .

All-Trans Retinoic Acid (ATRA) Plus PD-1 Inhibition in Recurrent IDH-Mutant Glioma

A Phase 2 Trial of All-Trans Retinoic Acid (ATRA) Plus PD-1 Inhibition in Recurrent IDH-Mutant Glioma

Objective radiographic response (ORR), as measured by modified Response Assessment in Neuro-Oncology (RANO) criteria. ). The response is classified as Complete Response (CR), Partial Response (PR), Stable Disease (SD), and Progressive Disease (PD).

Adverse events will be evaluated by monitoring frequency, duration, and severity of adverse events (AEs) per NCI CTCAE v 5.0

PFS, defined as the time from date of enrollment until the earliest date of disease progression (as determined by modified RANO criteria) or death due to any cause

OS, defined as the time from date of enrollment until death from any cause

Incyte Corporation

University of Pennsylvania

Assistant Professor of Medicine

Patients will receive 1 dose (5mg) orally, per day of BAY 2402234 for the 2 days prior to standard-of-care craniotomy for tumor resection and 1 dose on the morning of surgery, for a total of 3 administered doses.

Patients will receive 3 doses of 5mg each of BAY 2402234. Drug will be given Day 1 and Day 2 prior to standard-of-care craniotomy for tumor resection and 1 dose on the morning of surgery.

BAY 2402234

Kalil g Abdullah, MD, MSc

This study aims to look at how BAY 2402234 responds in body in patients with recurrent glioma.

To characterize the biological activity of BAY 2402234 in recurrent glioma, IDH-mutant, Grade 3/4 using liquid chromatography-mass spectrometry (LC-MS). The tissue orotate:carbamoyl aspartate ratio will serve as the primary pharmacodynamic biomarker and will be characterized via LC-MS.

Surgical Window of Opportunity Study of Orally Administered BAY 2402234 in Recurrent Glioma

An Open-Label Surgical Window of Opportunity Study Evaluating Pharmacodynamic Response of Orally Administered BAY 2402234 in Subjects With Recurrent Glioma, IDH Mutant, Grade 3 or 4

The primary endpoint is to characterize the biological activity of BAY 2402234 using liquid chromatography-mass spectrometry (LC-MS). The tissue orotate:carbamoyl aspartate ratio will serve as the primary pharmacodynamic biomarker and will be characterized via LC-MS.

To monitor adverse events during treatment with BAY 2402234 and document them in accordance with the Common Technology Criteria for Adverse Events (CTCAE) Version 5.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Efficacy of Nivolumab for Recurrent IDH Mutated High-Grade Gliomas	NCT03925246	High Grade Glio... Brain Cancer	Nivolumab	18 Years - 85 Years	Assistance Publique - Hôpitaux de Paris
A Study of Fedratinib With IDH Inhibition in Advanced-Phase, IDH-Mutated Ph-Negative Myeloproliferative Neoplasms	NCT04955938	IDH Mutation IDH1 Mutation IDH2 Gene Mutat... Blood Cancer Myeloproliferat...	Ivosidenib Enasidenib Fedratinib	18 Years -	University of Chicago
A Prospective Cohort to Study the Effect of Temozolomide on IDH Mutational Low Grade Gliomas	NCT02209428	Astrocytoma Oligodendroglio... Oligoastrocytom...	Temozolomide	18 Years - 40 Years	Huashan Hospital
Study of Zotiraciclib for Recurrent High-Grade Gliomas With Isocitrate Dehydrogenase 1 or 2 (IDH1 or IDH2) Mutations	NCT05588141	Brain Tumor Cancer	Zotiraciclib	18 Years -	National Institutes of Health Clinical Center (CC)
A Study of Fedratinib With IDH Inhibition in Advanced-Phase, IDH-Mutated Ph-Negative Myeloproliferative Neoplasms	NCT04955938	IDH Mutation IDH1 Mutation IDH2 Gene Mutat... Blood Cancer Myeloproliferat...	Ivosidenib Enasidenib Fedratinib	18 Years -	University of Chicago
Study of Zotiraciclib for Recurrent High-Grade Gliomas With Isocitrate Dehydrogenase 1 or 2 (IDH1 or IDH2) Mutations	NCT05588141	Brain Tumor Cancer	Zotiraciclib	18 Years -	National Institutes of Health Clinical Center (CC)
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
Metabolic Characterization of Space Occupying Lesions of the Brain	NCT04233788	Brain Tumor Glioma IDH Mutation	MR-scans using ...	18 Years -	Insel Gruppe AG, University Hospital Bern
All-Trans Retinoic Acid (ATRA) Plus PD-1 Inhibition in Recurrent IDH-Mutant Glioma	NCT05345002	Glioma IDH Mutation Astrocytoma Oligodendroglio...	Retifanlimab All-trans retin...	18 Years -	University of Pennsylvania
A Study of Fedratinib With IDH Inhibition in Advanced-Phase, IDH-Mutated Ph-Negative Myeloproliferative Neoplasms	NCT04955938	IDH Mutation IDH1 Mutation IDH2 Gene Mutat... Blood Cancer Myeloproliferat...	Ivosidenib Enasidenib Fedratinib	18 Years -	University of Chicago
Surgical Window of Opportunity Study of Orally Administered BAY 2402234 in Recurrent Glioma	NCT05061251	Glioma IDH Mutation	BAY 2402234	18 Years -	University of Texas Southwestern Medical Center

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