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Palbociclib and Sorafenib, Decitabine, or Dexamethasone in Treating Patients With Recurrent or Refractory Leukemia

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ClinicalTrials.gov Identifier: NCT03132454
Recruitment Status : Recruiting
First Posted : April 27, 2017
Last Update Posted : December 21, 2020
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:
This phase I trial studies the side effects and best dose of palbociclib when given alone and in combination with sorafenib, decitabine, or dexamethasone in treating patients with leukemia that has come back (recurrent) or that does not respond to previous treatment (refractory). Palbociclib, sorafenib, and decitabine may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as dexamethasone, 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 palbociclib alone and in combination with sorafenib, decitabine, or dexamethasone may work better in treating patients with recurrent or refractory leukemia.

Condition or disease Intervention/treatment Phase
Recurrent Acute Lymphoblastic Leukemia Recurrent Acute Myeloid Leukemia Refractory Acute Lymphoblastic Leukemia Refractory Acute Myeloid Leukemia Drug: Decitabine Drug: Dexamethasone Drug: Palbociclib Drug: Sorafenib Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of various combinations with palbociclib in patients with relapsed and refractory leukemias.

SECONDARY OBJECTIVES:

I. To assess pharmacodynamic effects of palbociclib on the Cyclin-CDK-Rb axis in leukemic blasts of patients with relapsed/refractory (R/R) leukemias.

II. To explore the efficacy (complete response [CR], complete remission without platelet recovery [CRp], complete remission without blood count recovery [CRi], partial response [PR], or clinical benefit [CB]) of palbociclib as a single-agent and in combinations in patients with R/R leukemias.

III. To explore biomarkers of response and resistance in patients with R/R leukemias treated with palbociclib.

IV. To assess the safety and tolerability of one cycle of single-agent palbociclib in patients with R/R leukemias.

OUTLINE: This is a dose-escalation study of sorafenib, decitabine, and dexamethasone. Patients are assigned to 1 of 3 arms.

ARM I: Patients receive palbociclib orally (PO) once daily (QD) on days 1-28. Patients also receive sorafenib PO QD on days 1-28 beginning on cycle 2. Treatment repeats every 28 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive palbociclib as in Arm I. Beginning cycle 2, patients receive palbociclib PO QC on days 1-7 and decitabine intravenously (IV) QD over 1 hour on days 8-17 of cycle 2 and days 8-12 of cycles 3-8. Treatment repeats every 28 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.

ARM III: Patients receive palbociclib as in Arm I. Patients also receive dexamethasone PO QD or IV over 15-30 minutes on days 1-4 and 15-18 beginning on cycle 2. Treatment repeats every 28 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 54 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Study of Palbociclib Alone and in Combination in Patients With Relapsed and Refractory Leukemias
Actual Study Start Date : July 25, 2017
Estimated Primary Completion Date : June 1, 2021
Estimated Study Completion Date : June 1, 2021


Arm Intervention/treatment
Experimental: Arm I (palbociclib, sorafenib)
Patients receive palbociclib PO QD on days 1-28. Patients also receive sorafenib PO QD on days 1-28 beginning on cycle 2. Treatment repeats every 28 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.
Drug: Palbociclib
Given PO
Other Names:
  • 6-Acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-8h-pyrido(2,3-d)pyrimidin-7-one
  • Ibrance
  • PD 0332991
  • PD 332991
  • PD 991
  • PD-0332991

Drug: Sorafenib
Given PO
Other Names:
  • BA4 43 9006
  • BAY 43-9006
  • Bay-439006

Experimental: Arm II (palbociclib, decitabine)
Patients receive palbociclib as in Arm I. Beginning cycle 2, patients receive palbociclib PO QC on days 1-7 and decitabine IV QD over 1 hour on days 8-17 of cycle 2 and days 8-12 of cycles 3-8. Treatment repeats every 28 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.
Drug: Decitabine
Given IV
Other Names:
  • 5-Aza-2''-deoxycytidine
  • Dacogen
  • Decitabine for Injection
  • Deoxyazacytidine
  • Dezocitidine

Drug: Palbociclib
Given PO
Other Names:
  • 6-Acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-8h-pyrido(2,3-d)pyrimidin-7-one
  • Ibrance
  • PD 0332991
  • PD 332991
  • PD 991
  • PD-0332991

Experimental: Arm III (palbociclib, dexamethasone)
Patients receive palbociclib as in Arm I. Patients also receive dexamethasone PO QD or IV over 15-30 minutes on days 1-4 and 15-18 beginning on cycle 2. Treatment repeats every 28 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.
Drug: Dexamethasone
Given IV or PO
Other Names:
  • Aacidexam
  • Adexone
  • Aknichthol Dexa
  • Alba-Dex
  • Alin
  • Alin Depot
  • Alin Oftalmico
  • Amplidermis
  • Anemul mono
  • Auricularum
  • Auxiloson
  • Baycadron
  • Baycuten
  • Baycuten N
  • Cortidexason
  • Cortisumman
  • Decacort
  • Decadrol
  • Decadron
  • Decadron DP
  • Decalix
  • Decameth
  • Decasone R.p.
  • Dectancyl
  • Dekacort
  • Deltafluorene
  • Deronil
  • Desamethasone
  • Desameton
  • Dexa-Mamallet
  • Dexa-Rhinosan
  • Dexa-Scheroson
  • Dexa-sine
  • Dexacortal
  • Dexacortin
  • Dexafarma
  • Dexafluorene
  • Dexalocal
  • Dexamecortin
  • Dexameth
  • Dexamethasone Intensol
  • Dexamethasonum
  • Dexamonozon
  • Dexapos
  • Dexinoral
  • Dexone
  • Dinormon
  • Fluorodelta
  • Fortecortin
  • Gammacorten
  • Hexadecadrol
  • Hexadrol
  • Lokalison-F
  • Loverine
  • Methylfluorprednisolone
  • Millicorten
  • Mymethasone
  • Orgadrone
  • Spersadex
  • TaperDex
  • Visumetazone
  • ZoDex

Drug: Palbociclib
Given PO
Other Names:
  • 6-Acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-8h-pyrido(2,3-d)pyrimidin-7-one
  • Ibrance
  • PD 0332991
  • PD 332991
  • PD 991
  • PD-0332991




Primary Outcome Measures :
  1. Maximum tolerated dose (MTD) as determined by dose limiting toxicity (DLT) [ Time Frame: Up to cycle 2 (each cycle is 28 days) ]
    MTD is defined as the highest dose level in which 6 patients have been treated with at most 1 instance of dose limiting toxicity using a classic '3+3' dose-escalation design. DLT is defined as drug-related adverse events during cycle two (i.e., the first cycle of palbociclib in combination). The number and proportion of DLTs will be summarized by treatment arm and dose level.


Secondary Outcome Measures :
  1. Pharmacodynamic (PD) effects of palbociclib [ Time Frame: Up to 3 years ]
    PD biomarker concentration will be summarized by time points. The relationship between drug concentrations and PD effects will be explored graphically. Based on review of these graphs, analyses to describe the relationship may also be performed.

  2. Efficacy as determined by complete response (CR]), complete remission without platelet recovery (CRp), complete remission without blood count recovery (CRi), partial response (PR), or clinical benefit (CB) [ Time Frame: Up to 3 years ]
    For the preliminary efficacy analysis, the study will summarize the number and rate of CR, CRp, CRi and PR by treatment arm and dose level.

  3. Assessment of biomarkers of response and resistance [ Time Frame: Up to 3 years ]
    The study will also explore the biomarkers associated with response or resistance to treatment using descriptive statistics and exploratory graphics.

  4. Incidence of adverse events graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to 3 years ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   15 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with a diagnosis of histologically confirmed relapsed or refractory (R/R) acute myeloid leukemia or R/R acute lymphoblastic leukemia for which no available standard therapies are indicated or anticipated to result in a durable response
  • Only patients with R/R ALL will be eligible for cohort C
  • Patients must not have had leukemia therapy for 14 days prior to starting palbociclib. However, patients with rapidly proliferative disease may receive hydroxyurea as needed until 24 hours prior to starting therapy on this protocol and during the first cycle of study
  • Bilirubin =< 2 mg/dL
  • Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) =< 3 x upper limit of normal (ULN) or =< 5 x ULN if related to leukemic involvement
  • Creatinine =< 1.5 x ULN
  • Known cardiac ejection fraction of > or = 45% within the past 3 months
  • Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
  • A negative urine pregnancy test is required within 1 week for all women of childbearing potential prior to enrolling on this trial
  • Patient must have the ability to understand the requirements of the study and signed informed consent. A signed informed consent by the patient or his legally authorized representative is required prior to their enrollment on the protocol

Exclusion Criteria:

  • Pregnant women are excluded from this study because the agent used in this study has the potential for teratogenic or abortifacient effects. Because there is a potential risk for adverse events in nursing infants secondary to treatment of the mother with the chemotherapy agents, breastfeeding should also be avoided
  • Uncontrolled intercurrent illness including, but not limited to active uncontrolled infection, symptomatic congestive heart failure (New York Heart Association [NYHA] class III or IV), unstable angina pectoris, clinically significant cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Patient with documented hypersensitivity to any of the components of the therapy program
  • Patients with active, uncontrolled central nervous system (CNS) leukemia will not be eligible
  • Men and women of childbearing potential who do not practice contraception. Women of childbearing potential and men must agree to use contraception prior to study entry and for the duration of study participation
  • Patients with known history of serous retinopathy will not be eligible
  • Prior treatment with palbociclib

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03132454


Contacts
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Contact: Tapan Kadia 713-563-3534 tkadia@mdanderson.org

Locations
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United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Tapan M. Kadia    713-563-3534      
Principal Investigator: Tapan M. Kadia         
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Tapan M Kadia M.D. Anderson Cancer Center
Additional Information:
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT03132454    
Other Study ID Numbers: 2016-0772
NCI-2018-01194 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2016-0772 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
First Posted: April 27, 2017    Key Record Dates
Last Update Posted: December 21, 2020
Last Verified: December 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone
Dexamethasone acetate
Sorafenib
Decitabine
Palbociclib
Ichthammol
BB 1101
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Protease Inhibitors