Symptoms and General Pathology

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Leukemia

Myeloproliferative Disorders

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Myelodysplastic Syndromes

Leukemia, Myelomonocytic, Chronic

Leukemia, Myelomonocytic, Juvenile

Leukemia, Myelomonocytic, Acute

Myelodysplastic-Myeloproliferative Diseases

Neoplasms by Histologic Type

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Leukemia, Myeloid

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Antineoplastic Agents

All Drugs and Chemicals

Amino Acids

Azacitidine

Quizartinib

Antimetabolites

Enzyme Inhibitors

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Tyrosine

Patients receive azacitidine SC or IV over about 30 minutes on days 1-5 and quizartinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Guillermo M. Bravo

Guillermo M Bravo

This phase I/II trial studies the side effects and best dose of quizartinib when given with azacitidine and to see how well they work in treating patients with myelodysplastic syndrome or myelodysplastic/myeloproliferative neoplasm with FLT3 or CBL mutations. Chemotherapy drugs, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Quizartinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving azacitidine and quizartinib may help to control myelodysplastic syndrome or myelodysplastic/myeloproliferative neoplasm.

PRIMARY OBJECTIVES:

I. To determine the safety, tolerability and maximum tolerable dose (MTD) of quizartinib in combination with azacytidine.

II. To assess overall response (ORR) rate to quizartinib in combination with azacitidine.

SECONDARY OBJECTIVES:

I. To assess overall survival (OS), duration of response, leukemia-free survival (LFS), relapse-free survival (RFS) and safety profile.

II. Correlative studies.

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

Patients receive azacitidine subcutaneously (SC) or intravenously (IV) over about 30 minutes on days 1-5 and quizartinib orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days.

Azacitidine and Quizartinib for the Treatment of Myelodysplastic Syndrome or Myelodysplastic/Myeloproliferative Neoplasm With FLT3 or CBL Mutations

Phase I/II Study of Azacitidine in Combination With Quizartinib for Patients With Myelodysplastic Syndromes and Myelodysplastic/Myeloproliferative Neoplasms With FLT3 or CBL Mutations

Will be defined as complete remission, partial remission, complete remission with incomplete count recovery, marrow compete remission or hematological improvement. Will be estimated for all patients along with the 95% credible interval.

Will be listed and summarized by the Kaplan-Meier estimator.

The severity of the toxicities will be graded according to the latest version of National Cancer Institute Common Terminology Criteria for Adverse Events. The number and percent of subjects with treatment-emergent adverse events will be summarized according to intensity and drug relationship, and categorized by System Organ Class and preferred term by dose level/Part. All reported AEs that occur after signing informed consent will be included in the analysis of all reported AEs. Exposure to study drug and reasons for discontinuation of study drug will be tabulated.

National Cancer Institute (NCI)

M.D. Anderson Cancer Center

Leukemia, Myeloid, Acute

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Anti-Infective Agents

Cytarabine

Fludarabine

Fludarabine phosphate

Lenograstim

Ivosidenib

Vidarabine

Immunosuppressive Agents

Immunologic Factors

Antiviral Agents

Adjuvants, Immunologic

INDUCTION: Patients receive filgrastim SC QD on days 0-6, fludarabine phosphate IV QD over 30 minutes on days 1-5, cytarabine IV QD over 4 hours on days 1-5, and ivosidenib PO QD on days 7-28. Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION: Patients receive filgrastim SC QD on days 0-5, fludarabine phosphate IV QD over 30 minutes on days 1-4, cytarabine IV QD over 4 hours on days 1-4, and ivosidenib PO QD on days 1-28. Treatment continues for 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients receive ivosidenib PO QD on days 1-28. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity.

Filgrastim

Fludarabine Phosphate

Study Coordinator

Shira N. Dinner, M.D.

Shira N Dinner, M.D.

This phase I trial studies the side effects and best dose of ivosidenib when given together with combination chemotherapy for the treatment of 1DH1 mutant acute myeloid leukemia that has come back (relapsed) or does not respond to treatment (refractory). Ivosidenib may stop the growth of cancer cells by blocking the IDH1 mutation and some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fludarabine phosphate, cytarabine, and filgrastim, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ivosidenib with combination chemotherapy may work better in treating patients with acute myeloid leukemia compared to chemotherapy alone.

PRIMARY OBJECTIVE:

I. To determine the maximum tolerated dose (MTD) of ivosidenib in combination with fludarabine, cytarabine, plus granulocyte-colony stimulating factor (G-CSF) (FLAG) chemotherapy.

SECONDARY OBJECTIVES:

I. To evaluate the safety profile of ivosidenib in combination with FLAG chemotherapy.

II. To determine the rate of complete remission (CR + complete remission with incomplete hematological recovery \[CRi\] + complete remission with incomplete platelet recovery \[CRp\]) with ivosidenib in combination with FLAG chemotherapy.

III. To evaluate the 1 year progression free survival. IV. To evaluate the 1 year overall survival. V. To assess the number of patients that receive allogeneic stem cell transplant after ivosidenib in combination with FLAG chemotherapy.

EXPLORATORY OBJECTIVES:

I. To assess for minimal residual disease negativity by polymerase chain reaction (PCR) for IDH1 mutations after treatment with ivosidenib in combination with FLAG chemotherapy.

II. To assess for minimal residual disease negativity by PCR for IDH1 mutations after 3 cycles of maintenance therapy.

OUTLINE:

INDUCTION: Patients receive filgrastim subcutaneously (SC) once daily (QD) on days 0-6, fludarabine phosphate intravenously (IV) QD over 30 minutes on days 1-5, cytarabine IV QD over 4 hours on days 1-5, and ivosidenib orally (PO) QD on days 7-28. Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION: Patients receive filgrastim SC QD on days 0-5, fludarabine phosphate IV QD over 30 minutes on days 1-4, cytarabine IV QD over 4 hours on days 1-4, and ivosidenib PO QD on days 1-28. Treatment continues for 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients receive ivosidenib PO QD on days 1-28. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every month for up to 1 year.

Ivosidenib and Combination Chemotherapy for the Treatment of IDH1 Mutant Relapsed or Refractory Acute Myeloid Leukemia

Phase 1 Trial of Ivosidenib and FLAG Chemotherapy in Relapsed/Refractory IDH1+ Acute Myeloid Leukemia (AML)

Will be assessed for a DLT per the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Will be assessed by the CTCAE version 5.0. Toxicity profiles will be summarized for toxicities of any grade, with rates of \>= grade 3 toxicities also analyzed separately. Adverse events rates will be summarized and accompanied by 95% exact binomial confidence intervals.

Patients that complete the induction cycle will be eligible for assessment

Will be estimated using Kaplan-Meier curves.

Patients that complete the induction cycle will be eligible for assessment.

Northwestern University

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Azacitidine and Quizartinib for the Treatment of Myelodysplastic Syndrome or Myelodysplastic/Myeloproliferative Neoplasm With FLT3 or CBL Mutations	NCT04493138	Chronic Myelomo... Myelodysplastic... Myeloproliferat... Recurrent Chron... Recurrent Myelo... Recurrent Myelo...	Azacitidine Quizartinib	18 Years -	M.D. Anderson Cancer Center
Azacitidine and Quizartinib for the Treatment of Myelodysplastic Syndrome or Myelodysplastic/Myeloproliferative Neoplasm With FLT3 or CBL Mutations	NCT04493138	Chronic Myelomo... Myelodysplastic... Myeloproliferat... Recurrent Chron... Recurrent Myelo... Recurrent Myelo...	Azacitidine Quizartinib	18 Years -	M.D. Anderson Cancer Center
Ivosidenib and Combination Chemotherapy for the Treatment of IDH1 Mutant Relapsed or Refractory Acute Myeloid Leukemia	NCT04250051	Recurrent Acute... Recurrent Myelo... Recurrent Myelo... Refractory Acut... Refractory Myel...	Cytarabine Filgrastim Fludarabine Fludarabine Pho... Ivosidenib	18 Years -	Northwestern University
Azacitidine and Quizartinib for the Treatment of Myelodysplastic Syndrome or Myelodysplastic/Myeloproliferative Neoplasm With FLT3 or CBL Mutations	NCT04493138	Chronic Myelomo... Myelodysplastic... Myeloproliferat... Recurrent Chron... Recurrent Myelo... Recurrent Myelo...	Azacitidine Quizartinib	18 Years -	M.D. Anderson Cancer Center

Spots Global Cancer Trial Database for recurrent myeloproliferative neoplasm