Cladribine Based Induction Therapy With All-Trans Retinoic Acid and Midostaurin in Relapsed/Refractory AML

NCT01161550 | Completed Phase 1

• 1 other identifier: 10-1181 / 201108160
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 1

Brief Summary

This study will evaluate the investigational drug Midostaurin in various doses given with ATRA and CLAG chemotherapy. Midostaurin is a FLT3 inhibitor that is activated or overexpressed in a significant proportion of AML patients. Research has shown that midostaurin and drugs like midostaurin may work better in combination with chemotherapy, like CLAG. CLAG is a combination of cladribine, cytarabine, and G-CSF which is approved by the FDA and used to treat AML.

Conditions

Leukemia, Myeloid, Acute

Outcome Measures

Primary Outcomes (2)

• Tolerability of midostaurin + ATRA given with CLAG chemotherapy

  28 days following completion of therapy

• Dose limiting toxicity (DLT) of midostaurin + ATRA with CLAG chemotherapy

  28 days following completion of therapy

Secondary Outcomes (4)

• Response

  1 year

• Survival

  1 year

• Toxicity profile of midostaurin + ATRA

  28 days following completion of treatment

• Pharmacokinetics of midostaurin

  Cycle 1 Day 7, Cycle 1 Day 14, and Cycle 1 Day 20

Study Arms (2)

Arm 1

EXPERIMENTAL

GCSF 300 mcg SC Days 1-6 Cladribine 5 mg/m2 IV Days 2-6 Cytarabine 2 mg/m2 IV Days 2-6 ATRA 15 mg/m2 PO QD Days 7-20 Midostaurin 25 mg PO BID Days 7-20

Drug: Granulocyte colony-stimulating factor (G-CSF); Drug: Cladribine; Drug: Cytarabine; Drug: All-Trans Retinoic Acid (ATRA); Drug: Midostaurin

Arm 2

EXPERIMENTAL

GCSF 300 mcg SC Days 1-6 Cladribine 5 mg/m2 IV Days 2-6 Cytarabine 2 mg/m2 IV Days 2-6 ATRA 15 mg/m2 PO QD Days 7-20 Midostaurin 50 mg PO BID Days 7-20

Drug: Granulocyte colony-stimulating factor (G-CSF); Drug: Cladribine; Drug: Cytarabine; Drug: All-Trans Retinoic Acid (ATRA); Drug: Midostaurin

Interventions

Granulocyte colony-stimulating factor (G-CSF) DRUG

Also known as: Filgrastim

Arm 1; Arm 2

Cladribine DRUG

Also known as: Litak, Movectro

Arm 1; Arm 2

Cytarabine DRUG

Also known as: Cytosar-U, Depocyt

Arm 1; Arm 2

All-Trans Retinoic Acid (ATRA) DRUG

Also known as: Tretinoin

Arm 1; Arm 2

Midostaurin DRUG

Also known as: PKC412

Arm 1; Arm 2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient must be ≥18 of age. Because no dosing or adverse event data are currently available on the use of midostaurin in combination with ATRA and CLAG in patients \<18 years of age, children are excluded from this study but will be eligible for future pediatric phase 2 combination trials.
• Patient must be diagnosed with refractory or relapsed AML. For the purpose of the study, refractory AML is defined as failure to achieve CR after 2 cycles of induction chemotherapy or persistent \> 40% bone marrow blasts after one cycle of chemotherapy induction. Relapsed AML is defined as any evidence of disease recurrence after achieving CR. Early relapse is defined as relapse occurring earlier than 12 months and late relapse is defined as relapse occurring later than 12 months.
• Patient must have a Karnofsky Performance Status of ≥ 70% (unless poor performance status is related to the disease).
• Patient must have the following laboratory values:
• AST and ALT ≤ 1.5 x Upper Limit of Normal (ULN),
• Serum Bilirubin ≤ 1.5 x ULN,
• Serum Creatinine ≤ 1.5 x ULN. Laboratory values can be outside this range if secondary to AML disease.
• Patient must able to understand and willing to sign a written informed consent document prior to registration on study.

You may not qualify if:

• Patient must not have newly diagnosed AML.
• Patient must not have acute promyelocytic leukemia
• Patient must not have known CNS leukemia
• Patient must not have a history of allergic reactions to compounds of similar chemical or biologic composition to midostaurin or other agents used in the study.
• Patient must not have any uncontrolled or intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, myocardial infarction within 6 months, poorly controlled hypertension, uncontrolled diabetes, chronic renal disease, or psychiatric illness/social situation that would limit compliance with study requirements.
• Patient must not have any condition, including the presence of laboratory abnormalities, which places him/her at unacceptable risk if s/he were to participate in the study or confounds the ability to interpret data from the study.
• Patient may not concurrently use other anti-cancer agents or treatments (with the exceptions of hydroxyurea, steroids, and leukopheresis).
• Female patients must not be pregnant or breastfeeding.
• Adults of reproductive potential must employ an effective method of birth control. Barrier contraceptives must be used throughout the study in both sexes. Women of childbearing potential must have a negative serum pregnancy test 48 hours prior to administration of midostaurin. Women considered not of childbearing potential include any of the following: no menses for at least 5 years; menses within 5 years but amenorrheic for at least 2 months and luteinizing hormone (LH) and follicular stimulating hormone (FSH) values within normal range (according to definition of postmenopausal for laboratory used); bilateral oophorectomy amenorrheic for at least 3 months.
• Patient must not have impaired cardiac function including any of the following:
• Screening ECG with a QTc \> 450 msec
• Patients with congenital long QT syndrome
• History or presence of sustained ventricular tachycardia
• Any history of ventricular fibrillation or torsades de pointes
• Bradycardia defined as HR \< 50 bpm

Sponsors & Collaborators

• Washington University School of Medicine: lead

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Related Publications (1)

• Ramsingh G, Westervelt P, McBride A, Stockerl-Goldstein K, Vij R, Fiala M, Uy G, Cashen A, Dipersio JF, Abboud CN. Phase I study of cladribine, cytarabine, granulocyte colony stimulating factor (CLAG regimen) and midostaurin and all-trans retinoic acid in relapsed/refractory AML. Int J Hematol. 2014 Mar;99(3):272-8. doi: 10.1007/s12185-014-1503-4. Epub 2014 Feb 2.

  PMID: 24488798 DERIVED

Related Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

Granulocyte Colony-Stimulating Factor; Filgrastim; Cladribine; Cytarabine; Tretinoin; midostaurin

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; 2-Chloroadenosine; Adenosine; Purine Nucleosides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Deoxyadenosines; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Arabinonucleosides; Vitamin A; Retinoids; Carotenoids; Polyenes; Alkenes; Hydrocarbons, Acyclic; Hydrocarbons; Organic Chemicals; Cyclohexenes; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Diterpenes; Pigments, Biological

Study Officials

• Camille Abboud, M.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 9, 2010
• First Posted: July 13, 2010
• Study Start: November 1, 2010
• Primary Completion: August 1, 2011
• Study Completion: August 1, 2012
• Last Updated: July 23, 2013

Record last verified: 2013-07

Locations

US (1)