Neoplasms

Blood and Lymph Conditions

All Conditions

Rare Diseases

Leukemia

Hematologic Neoplasms

Myeloproliferative Disorders

Bone Marrow Diseases

Hematologic Diseases

Chronic Myeloproliferative Disorders

All Drugs and Chemicals

Antineoplastic Agents

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

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

DS-1001b

Global Clinical Leader

This is a study to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and anti-tumor activity of DS-1001b in patients with gliomas that harbor IDH1-R132 mutations.

Study of DS-1001b in Patients With Gene IDH1-Mutated Gliomas

A Phase 1 Study of DS-1001b in Patients With IDH1 Mutated Gliomas

De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/

AEs temporally associated with DS-1001b treatment

Daiichi Sankyo

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

Dose escalation:

Various doses of study drug will be tested on a small number of patients/dose with the goal of identifying the most appropriate dose(s) for further evaluation in dose expansion. The MTD of the study drug may or may not be identified. It is anticipated that 3-4 patients will be treated at each dose of study drug to be tested and that 15-20 total patients will be treated in this part of the trial.

Dose expansion:

Up to 2 different doses of study drug will be tested on up to 30 patients/dose with the goal of identifying the most appropriate RP2D for further clinical development. The doses to be evaluated in this part of the trial will be selected based on information obtained during dose escalation.

BAY1436032 administered continuously as a single agent dosed twice a day orally on Days 1 to 28 of a 28-day cycle.

Patients may continue treatment with BAY1436032 until disease progression, development of other unacceptable toxicity or Investigator discretion.

BAY1436032

To determine the maximum tolerated and / or recommended Phase II dose of oral mutant IDH1 (mIDH1) inhibitor BAY1436032 and to characterize its safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical efficacy in patients with mIDH1-R132X advanced acute myeloid leukemia (AML)

BAY1436032 in Patients With Mutant IDH1(mIDH1) Advanced Acute Myeloid Leukemia (AML)

An Open-label, Non-randomized, Multicenter Phase I Study to Determine the Maximum Tolerated and / or Recommended Phase II Dose of Oral Mutant IDH1 (mIDH1) Inhibitor BAY1436032 and to Characterize Its Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Clinical Efficacy in Patients With mIDH1-R132X Advanced Acute Myeloid Leukemia (AML)

If the MTD is not reached during dose escalation, the primary variable will be the recommended phase 2 dose (RP2D) of BAY1436032

Response assessment for AML in this study will be based on the modified Cheson criteria. The following categories are used to capture the investigator's AML response evaluation:

* Complete remission (CR)
* Morphologic CR with CRh (morphologic CR with incomplete hematological recovery) and the response category CRp (morphologic CR with incomplete platelet recovery)
* Partial remission (PR)
* Response categories for morphologic leukemia-free state (MLFS), stable disease and progressive disease
* Progressive disease

EFS defined as time from start of treatment to treatment failure, relapse, or death due to any cause.

Assess pharmacodynamic (PD) effects and evidence of clinical efficacy associated with BAY 1436032 administration in patients. Change from baseline and percent change from baseline will be calculated.

As a secondary objective of this study evaluate the pharmacokinetics (PK) of BAY 1436032 in patients.

PK parameters normalized for dose and / or dose and body weight will be calculated.

Bayer

Symptoms and General Pathology

Recurrence

Glioblastoma

Disease Attributes

Astrocytoma

Temozolomide

Poly(ADP-ribose) Polymerase Inhibitors

Alkylating Agents

Pamiparib

Antineoplastic Agents, Alkylating

Recurrent IDH1/2-mutant grade II-III glioma: BGB290: Days 1-28, 60 mg PO BID TMZ: Days 1-28, 20 QD starting dose

TMZ de-escalated treatment schedule if necessary (days 1-21; days 1-14; days 1-7) BGG held constant at 60mg PO BID

Grade II-III: Recurrent IDH1/2-mutant glioma (WHO grades II/III) who have failed TMZ AND another alkylator

BGB290 + TMZ at dose combination established in Phase 1

Grade II-III:Recurrent IDH1/2-mutant glioma (WHO grades II/III) Failed TMZ OR another alkylator;

\>/=12 months since last treatment

BGB290 + TMZ at dose combination established in Phase 1

Exploratory grade IV patients only BGB290 at Ph II dose for 7 days pre-surgery Progressed following RT + Chemo

Recurrent IDH1/2-mutant glioma (WHO grade II-IV) eligible for re-resection BGB-290: 60mg PO BID for 6 days AND day once day of surgery (day 7)

PARP Inhibitor BGB-290

Therapeutic Conventional Surgery

Ranjit Bindra, MD

David Schiff, MD

This phase I/II trial studies the side effects and how well BGB-290 and temozolomide work in treating patients with gliomas (brain tumors) with IDH1/2 mutations that have come back. BGB-290 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving BGB-290 and temozolomide may work better in treating patients with recurrent gliomas.

PRIMARY OBJECTIVES:

(Phase I) I. Determine the safety and tolerability of the combination of PARP inhibitor BGB-290 (BGB-290) and temozolomide (TMZ) in patients with recurrent IDH1/2 mutant glioma, including the maximum tolerated dose (MTD) and characterization of dose-limiting toxicities (DLTs) in the Phase I portion.

(Phase II) II. Determine the overall response rate of BGB-290 with TMZ in patients with recurrent IDH1/2-mutant gliomas that have progressed on TMZ and another alkylator (Arm A) in the Phase II portion.

III. Determine the overall response rate of BGB-290 with TMZ in patients with recurrent IDH1/2-mutant glioma that have failed one alkylator with \>= 12 months since last treatment (Arm B) in the Phase II portion.

PRIMARY OBJECTIVES:

I. Determine the safety and tolerability of the combination of PARP inhibitor BGB-290 (BGB-290) and temozolomide (TMZ) in patients with recurrent IDH1/2 mutant glioma, including the maximum tolerated dose (MTD) and characterization of dose-limiting toxicities (DLTs) in the Phase I portion. (Phase I) II. Determine the overall response rate of BGB-290 with TMZ in patients with recurrent IDH1/2-mutant gliomas that have progressed on TMZ and another alkylator (Arm A) in the Phase II portion. (Phase II) III. Determine the overall response rate of BGB-290 with TMZ in patients with recurrent IDH1/2-mutant glioma that have failed one alkylator with \>= 12 months since last treatment (Arm B) in the Phase II portion. (Phase II)

SECONDARY OBJECTIVES:

I. Determine the progression-free survival (PFS) and overall survival (OS) after treatment with BGB-290 and TMZ in recurrent IDH1/2-mutant gliomas in Arms A and B.

II. Determine the duration of response to therapy in recurrent IDH1/2-mutant glioma.

III. Confirm the safety and tolerability of BGB-290 in combination with TMZ.

EXPLORATORY OBJECTIVES:

I. Assess tumor response rates, PFS, and OS in patients with World Health Organization (WHO) grade IV glioblastoma (GBM) treated with BGB-290 and TMZ.

II. Assess the mutational landscape via whole-exome sequencing (WES). III. Assess gene expression patterns using ribonucleic acid (RNA) sequencing (RNAseq).

IV. Assess the methylation profiling with Infinium methylation assays. V. Quantify 2-hydroxyglutarate (2HG) in archival formalin-fixed paraffin-embedded (FFPE) specimens via liquid chromatography mass spectrometry (LC-MS) detection and correlate with treatment response.

VI. Correlate response with 2HG levels, somatic alterations, gene expression/methylation patterns in FFPE tumor tissue.

VII. Assess tumor tissue BGB-290 levels, 2HG, and PolyADP-ribosylation (PARylation) in a patient subset treated with drug prior to re-resection.

VIII. Evaluate changes in tumor growth rate in subjects with non-enhancing glioma based on fluid attenuated inverse recovery (FLAIR) tumor volume measurements of serial MRI exams.

IX. Assess if change in tumor growth rate (based on FLAIR tumor volume) in subjects with non-enhancing glioma before and after treatment is associated with progression by Response Assessment in Neuro-Oncology for Low Grade Gliomas (RANO LGG; phase II patients only) or survival.

OUTLINE: This is a phase I, dose de-escalation study of temozolomide followed by a phase II study.

PHASE I: Patients receive PARP inhibitor BGB-290 orally (PO) twice daily (BID) on days 1-28 and temozolomide PO once daily (QD) on days 1-28, 1-21, 1-14, or 1-7. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

SURGICAL PORTION: 10 patients eligible for re-resection at the time of recurrence receive PARP inhibitor BGB-290 PO BID on days 1-6 and QD on day 7 (the morning of surgery). Within 45 days after surgery, patients receive PARP inhibitor BGB-290 PO BID on days 1-28 and temozolomide on the schedule established in Phase I. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients receive PARP inhibitor BGB-290 PO BID on days 1-28 and temozolomide PO QD on the schedule established in Phase I. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days, every 2 months for 2 years, then every 6 months thereafter.

Phase 1: BGB-290 in combination with TMZ in patients w/ IDH1/2-mutant WHO grade II-IV recurrent glioma: Phase 2: Grade II-III patients in will be stratified into 2 arms based on the timing of prior alkylator chemotherapy exposure; a third arm will include the subset of glioblastoma (grade IV) patients

BGB-290 and Temozolomide in Treating Patients With Recurrent Gliomas With IDH1/2 Mutations

Phase I/II Study of BGB-290 With Temozolomide in Recurrent Gliomas With IDH1/2 Mutations

defined as the combination regimen that yields a dose limiting toxicity (DLT) rate less than, or equal to 33%

Percentage of participants who experience grade 3 or higher toxicities as defined by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0

Number of participants with response as defined by Response Assessment in Neuro-oncology (RANO) criteria: Complete Response (CR)= no change in size of T1-gadolinium-enhancing (T1-Gd+) disease, stable or reduced T2/FLAIR signal, no new lesion, no corticosteroid use, and stable or improved clinical status; Partial Response (PR)= ≥50% change in size of T1-Gd+ disease, stable or reduced T2/FLAIR signal, no new lesion, stable or reduced corticosteroid use, and stable or improved clinical status; Stable Disease (SD)= \<50% reduction to \<25% increase size of T1-Gd+ disease, stable or reduced T2/FLAIR signal, no new lesion, stable or reduced corticosteroid use, and stable or improved clinical status; Progressive Disease (PD)= ≥25% increase size of T1-Gd+ disease, or increased T2/FLAIR signal, or presence of new lesion, or worsening clinical status.

Time from date of treatment start to date of initial scan indicating progression

Median time from start date of treatment to date of death

Time from date of initial scan indicating complete or partial response to a date of the initial scan deemed tumor progression. Response is defined by RANO criteria as follows: Complete Response (CR)= no change in size of T1-gadolinium-enhancing (T1-Gd+) disease, stable or reduced T2/FLAIR signal, no new lesion, no corticosteroid use, and stable or improved clinical status; Partial Response (PR)= ≥50% change in size of T1-Gd+ disease, stable or reduced T2/FLAIR signal, no new lesion, stable or reduced corticosteroid use, and stable or improved clinical status; Progressive Disease (PD)= ≥25% increase size of T1-Gd+ disease, or increased T2/FLAIR signal, or presence of new lesion, or worsening clinical status.

Percentage of participants with serious or life-threatening toxicities as defined by CTCAE version 5.0

National Cancer Institute (NCI)

BeiGene

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Nivolumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Ivosidenib will be administered concurrently with nivolumab on a Q28 day schedule.

Ivosidenib will be administered orally at a dose of 500 mg (provided as 250 mg strength tablets) daily. The dose may be reduced to 250 mg for patients experiencing more than one event of Grade 2 nausea or vomiting (related or unrelated), or Grade 3 or Grade 4 adverse events.

Nivolumab will be administered at 480 mg IV every 28 days.

ivosidenib and nivolumab

Jason J Luke, MD, PhD

In this study, response to treatment and (progression free and overall) survival will be described and safety events of ivosidenib in combination with nivolumab will be summarized in patients with advanced solid tumors (nonresectable or metastatic) or enhancing gliomas.

This study will describe the safety, response rate, progression free and overall survival, and summarize safety events of ivosidenib in combination with nivolumab in participants with advanced solid tumors (nonresectable or metastatic) or enhancing gliomas. Participants are required to have a histologically consistent diagnosis of IDH1 gene mutated tumor that is not eligible for curative therapy. Enrolled subjects will receive orally administered ivosidenib dosed daily on 28-day cycles and nivolumab will be infused every 28 days. Participants will be assessed at every visit for adverse events starting from the first dose of study treatment. Assessment (CT or MRI) for evaluation of disease response will be conducted every 8 weeks (±7 days) from the first day of treatment cycle 1 and/or at any time when progression of disease is suspected. A Post-Treatment Follow-Up Visit for safety will occur 28 (+/- 5) days after the last dose of study drug.

Concurrent dosing of ivosidenib and nivolumab.

Ivosidenib (AG-120) With Nivolumab in IDH1 Mutant Tumors

Phase II Study of IDH1 Inhibitor Ivosidenib and Nivolumab in IDH1 Mutant Gliomas and Advanced Solid Tumors

RECIST v1.1 Criteria:Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (target or non-target) with reduction in short axis to \<10 mm. Partial Response (PR): ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

RANO Criteria:Complete Response (CR):Observed in consecutive assessments ≥4 weeks apart per RANO. Partial Response (PR): Observed in consecutive assessments ≥4 weeks apart per RANO.

Proportion of participants surviving without objective tumor progression at six months after the initiation of treatment.

RECIST v1.1 Criteria: Progressive Disease (PD):≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression.

RANO Criteria: Progressive Disease: No CR, PR, SD prior to PD.RANO Criteria: Progressive Disease: No CR, PR, SD prior to PD. Progression: 25% or more increase in enhancing lesions despite stable or increasing steroid dose, increase (significant) in non-enhancing FLAIR/T2W lesions, not attributable to other non-tumor causes, any new lesions; clinical deterioration (not attributable to other non-tumor causes and not due to steroid decrease)

The occurrence (number) of dose limiting toxicity (DLT) in patients receiving ivosidenib plus nivolumab. DLT describes side effects of the treatment that are serious enough to prevent an increase in dose or level of that treatment.

Adverse events per NCI Common Terminology Criteria for Adverse Events (CTCAE v5.0), experienced by patients related to their receiving the treatment combination of ivosidenib and nivolumab.

The time from first dose of either drug until disease progression or death from any cause, whichever occurs first.

RECIST v1.1 Criteria: Progressive Disease (PD):≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression.

RANO Criteria: Progressive Disease: No CR, PR, SD prior to PD.RANO Criteria: Progressive Disease: No CR, PR, SD prior to PD. Progression: 25% or more increase in enhancing lesions despite stable or increasing steroid dose, increase (significant) in non-enhancing FLAIR/T2W lesions, not attributable to other non-tumor causes, any new lesions; clinical deterioration (not attributable to other non-tumor causes and not due to steroid decrease)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
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 DS-1001b in Patients With Gene IDH1-Mutated Gliomas	NCT03030066	Glioma	DS-1001b	20 Years -	Daiichi Sankyo
BAY1436032 in Patients With Mutant IDH1(mIDH1) Advanced Acute Myeloid Leukemia (AML)	NCT03127735	Leukemia, Myelo...	BAY1436032	18 Years -	Bayer
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
BGB-290 and Temozolomide in Treating Patients With Recurrent Gliomas With IDH1/2 Mutations	NCT03914742	IDH1 Mutation IDH2 Mutation Recurrent Gliob... Recurrent WHO G... Recurrent WHO G...	PARP Inhibitor ... Temozolomide Therapeutic Con...	18 Years -	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
BAY1436032 in Patients With Mutant IDH1(mIDH1) Advanced Acute Myeloid Leukemia (AML)	NCT03127735	Leukemia, Myelo...	BAY1436032	18 Years -	Bayer
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
BAY1436032 in Patients With Mutant IDH1(mIDH1) Advanced Acute Myeloid Leukemia (AML)	NCT03127735	Leukemia, Myelo...	BAY1436032	18 Years -	Bayer
Ivosidenib (AG-120) With Nivolumab in IDH1 Mutant Tumors	NCT04056910	Advanced Solid ... IDH1 Mutation Glioma	ivosidenib and ...	18 Years -	University of Pittsburgh

Spots Global Cancer Trial Database for idh1 mutation