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Panobinostat, Carfilzomib, and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma

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ClinicalTrials.gov Identifier: NCT03256045
Recruitment Status : Recruiting
First Posted : August 21, 2017
Last Update Posted : March 5, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
University of Washington

Brief Summary:
This phase II trial studies how well panobinostat, carfilzomib, and dexamethasone work in treating patients with multiple myeloma that has come back or does not respond to treatment. Panobinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as carfilzomib and dexamethasone, 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. Using multiple myeloma cells from patients' blood samples, the researchers will do laboratory tests to look at how well each of the drugs, alone and in different combinations, kill multiple myeloma cells. If the laboratory tests work well, they may be used in the future to help plan treatment for future patients.

Condition or disease Intervention/treatment Phase
Recurrent Plasma Cell Myeloma Refractory Plasma Cell Myeloma Drug: Carfilzomib Other: Chemosensitivity Assay Drug: Dexamethasone Other: Laboratory Biomarker Analysis Drug: Panobinostat Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To correlate in vitro drug sensitivity testing with clinical response by determining the rate of in vitro drug sensitivity to panobinostat, carfilzomib, and dexamethasone singly and in combination, doublets and triplets.

SECONDARY OBJECTIVES:

I. To monitor response rates (partial response [PR], very good partial response [VGPR], and complete response) using the International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma.

EXPLORATORY OBJECTIVES:

I. Progression free survival and overall survival will be assessed for up to 3 years after last dose.

OUTLINE:

Patients receive panobinostat orally (PO) on days 1, 3, 5, 15, 17, and 19. Patients also receive carfilzomib intravenously (IV) and dexamethasone PO on days 1, 2, 8, 9, 15, and 16. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood and/or bone marrow samples for testing via in vitro chemosensitivity assay.

After completion of study treatment, patients are followed up every 3 months for up to 3 years.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: CLBH589DUS108T: Panobinostat With Carfilzomib and Dexamethasone for Relapsed/Refractory Multiple Myeloma: Correlation With In Vitro Chemosensitivity Testing
Actual Study Start Date : February 8, 2018
Estimated Primary Completion Date : May 16, 2021
Estimated Study Completion Date : May 16, 2024


Arm Intervention/treatment
Experimental: Treatment (panobinostat, carfilzomib, dexameth, chemo assay)
Patients receive panobinostat PO on days 1, 3, 5, 15, 17, and 19. Patients also receive carfilzomib IV and dexamethasone PO on days 1, 2, 8, 9, 15, and 16. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood and/or bone marrow samples for testing via in vitro chemosensitivity assay.
Drug: Carfilzomib
Given IV
Other Names:
  • Kyprolis
  • PR-171

Other: Chemosensitivity Assay
Undergo in vitro chemosensitivity testing
Other Name: Chemosensitivity Testing

Drug: Dexamethasone
Given PO
Other Names:
  • Aacidexam
  • Adexone
  • Aknichthol Dexa
  • Alba-Dex
  • Alin
  • Alin Depot
  • Alin Oftalmico
  • Amplidermis
  • Anemul mono
  • Auricularum
  • Auxiloson
  • Baycuten
  • Baycuten N
  • Cortidexason
  • Cortisumman
  • Decacort
  • Decadrol
  • Decadron
  • 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
  • Dexamethasonum
  • Dexamonozon
  • Dexapos
  • Dexinoral
  • Dexone
  • Dinormon
  • Fluorodelta
  • Fortecortin
  • Gammacorten
  • Hexadecadrol
  • Hexadrol
  • Lokalison-F
  • Loverine
  • Methylfluorprednisolone
  • Millicorten
  • Mymethasone
  • Orgadrone
  • Spersadex
  • Visumetazone

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Panobinostat
Given PO
Other Names:
  • Faridak
  • Farydak
  • LBH589




Primary Outcome Measures :
  1. Partial response (PR) rate [ Time Frame: Up to 3 years after last study treatment ]
    Assessed using the International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma.

  2. Very good partial response (VGPR) rate [ Time Frame: Up to 3 years after last study treatment ]
    Assessed using the International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma.

  3. Complete Response (CR) rate [ Time Frame: Up to 3 years after last study treatment ]
    Assessed using the International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma.

  4. Rate of multiple myeloma cells in-vitro drug sensitivity to Panobinostat [ Time Frame: At baseline ]
    The half maximal inhibitory concentration (IC50) will be generated in vitro.

  5. Rate of multiple myeloma cells in-vitro drug sensitivity to Carfilzomib [ Time Frame: At baseline ]
    The half maximal inhibitory concentration (IC50) will be generated in vitro.

  6. Rate of multiple myeloma cells in-vitro drug sensitivity to Dexamethasone [ Time Frame: At baseline ]
    The half maximal inhibitory concentration (IC50) will be generated in vitro.

  7. Rate of multiple myeloma cells in-vitro drug sensitivity to Carfilzomib and Panobinostat in combination [ Time Frame: At baseline ]
    The half maximal inhibitory concentration (IC50) will be generated in vitro.

  8. Rate of multiple myeloma cells in-vitro drug sensitivity to Dexamethasone Panobinostat in combination [ Time Frame: At baseline ]
    The half maximal inhibitory concentration (IC50) will be generated in vitro.

  9. Rate of multiple myeloma cells in-vitro drug sensitivity to Carfilzomib and Dexamethasone in combination [ Time Frame: At baseline ]
    The half maximal inhibitory concentration (IC50) will be generated in vitro.

  10. Rate of multiple myeloma cells in-vitro drug sensitivity to Panobinostat, Carfilzomib and Dexamethasone in combination [ Time Frame: At baseline ]
    The half maximal inhibitory concentration (IC50) will be generated in vitro.


Other Outcome Measures:
  1. Progression Free Survival [ Time Frame: Up to 3 years after last study treatment ]
  2. Overall Survival [ Time Frame: Up to 3 years after last study treatment ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of multiple myeloma refractory to or relapsed after >= 1 line of prior therapy (International Myeloma Working Group [IMWG] criteria)
  • Measurable disease, as indicated by one of the following:

    • Serum monoclonal (M)-protein >= 1.0 g/dL
    • Elevated free light chain as per IMWG criteria, and abnormal ratio
    • Urine Bence Jones protein > 200 mg/24 hr
  • Absolute neutrophil count (ANC) of >= 1,000/uL
  • Platelet count of >= 75,000/uL
  • Hemoglobin >= 7 g/dL
  • Creatinine =< 2.0 mg/dL or calculated creatinine clearance >= 30 mL/min
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) unless elevation is thought to be due to Gilbert's syndrome
  • Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamate pyruvate transaminase (SPGT) (alanine aminotransferase [ALT]) =< 2.5 x ULN
  • The following laboratory values must be, or corrected to with supplements, over the lower limit of normal before starting treatment:

    • Serum sodium
    • Potassium
    • Magnesium
    • Phosphorus
  • Patients must avoid consumption of grapefruit, pomegranates, starfruit, Seville oranges or products containing the juice of each during the entire study and preferably 7 days before the first dose of study medications; orange juice is allowed

Exclusion Criteria:

  • Another bone marrow malignancy
  • Another cancer with expected survival of < 2 years
  • Active viral, bacterial, or fungal infection progressing on current treatment
  • Clinically significant uncontrolled heart disease and/or recent cardiac event within 6 months prior to enrollment, such as:

    • History of angina pectoris, symptomatic pericarditis, or myocardial infarction
    • Left ventricular ejection fraction (LVEF) < 45% as determined by echocardiogram (ECHO) or multi gated acquisition (MUGA) scan
    • History or presence of any significant, uncontrolled, or persistent cardiac arrhythmias, e.g. ventricular, supraventricular, nodal arrhythmias or conduction abnormality; stable atrial fibrillation within 6 months prior to enrollment is permitted
    • Presence of unstable atrial fibrillation (ventricular response rate > 100 beats per minute [bpm]); NOTE: patients with stable atrial fibrillation can be enrolled provided they do not meet other cardiac exclusion criteria
    • Resting heart rate < 50 bpm
    • Complete left bundle branch block (LBBB), bifascicular block
    • Congenital long QT syndrome
    • Any clinically significant ST segment and/or T-wave abnormalities
    • Corrected QT (QTcF) > 450 msec for males and females using Fridericia's correction on screening electrocardiogram (ECG) by mean value of triplicate ECGs
    • History of documented congestive heart failure (New York Heart Association functional classification III-IV)
    • Uncontrolled hypertension defined by a systolic blood pressure (SBP) >= 150 mmHg and/or diastolic blood pressure (DBP) >= 100 mmHg with or without antihypertensive medication; NOTE: initiation or adjustment of antihypertensive medication(s) is allowed prior to screening
    • Other clinically significant heart disease or vascular disease
  • Currently taking medications that risk prolonging the QT interval or inducing Torsades de pointes; the medication must be discontinued or switched to a safe alternative medication prior to starting treatment
  • Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of panobinostat or dexamethasone (e.g. ulcerative disease uncontrolled nausea, vomiting, malabsorption syndrome, obstruction, or stomach and/or small bowel resection)
  • Unresolved diarrhea >= Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or a medical condition associated with chronic diarrhea (such as irritable bowel syndrome, inflammatory bowel disease)
  • Major surgery =< 14 days prior to starting study treatment or who have not recovered from side effects to < grade 2 CTCAE
  • Women who are pregnant or breast feeding or women of childbearing potential (WOCBP) not using an effective method of birth control; WOCBP are defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (i.e. who has had menses anytime in the proceeding 12 consecutive months); women of childbearing potential must have a negative serum pregnancy test within 24 hrs of receiving the first dose of study medication
  • Male patients whose sexual partners are WOCBP not using effective birth control

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): NCT03256045


Locations
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United States, Washington
Fred Hutch/University of Washington Cancer Consortium Recruiting
Seattle, Washington, United States, 98109
Contact: Pamela S. Becker    206-606-7273    pbecker@u.washington.edu   
Principal Investigator: Pamela S. Becker         
Sponsors and Collaborators
University of Washington
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Pamela Becker Fred Hutch/University of Washington Cancer Consortium

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Responsible Party: University of Washington
ClinicalTrials.gov Identifier: NCT03256045     History of Changes
Other Study ID Numbers: 9757
NCI-2017-00453 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
9757 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
P30CA015704 ( U.S. NIH Grant/Contract )
RG1016013 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
First Posted: August 21, 2017    Key Record Dates
Last Update Posted: March 5, 2019
Last Verified: March 2019

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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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Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone
Dexamethasone acetate
Panobinostat
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