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

NCT03256045 | Terminated Phase 2 Results DMC FDA Drug

• 4 other identifiers: 9757NCI-2017-00453P30CA015704RG1016013
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

Brief Summary

This phase II trial studies how well panobinostat, carfilzomib, and dexamethasone work in treating patients with multiple myeloma that has come back (relapsed) or does not respond to treatment (refractory). Panobinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, 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.

Conditions

Recurrent Plasma Cell Myeloma; Refractory Plasma Cell Myeloma

Outcome Measures

Primary Outcomes (6)

• Best Overall Response, by Subject

  Assessed using the International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma. Key: 1 = very good partial response (VGPR); 2 = partial response (PR); 3 = minimal response (MR); 4 = stable disease (SD); 5 = progressive disease (PD). Please see IC50 and CI results in the other primary outcome measures.

  14 months

• Multiple Myeloma Cells In-vitro Drug Sensitivity to Panobinostat, by Subject

  Multiple myeloma cells are added to assay with panobinostat. Cell viability and IC50 is determined. IC50 is the inhibitory concentration that kills 50% of cells. Results are reported in concentrations E-9.

  At baseline

• Multiple Myeloma Cells In-vitro Drug Sensitivity to Carfilzomib, by Subject

  Multiple myeloma cells are added to assay with carfilzomib. Cell viability and IC50 is determined. IC50 is the inhibitory concentration that kills 50% of cells.

  At baseline

• Multiple Myeloma Cells In-vitro Drug Sensitivity to Dexamethasone, by Subject

  Multiple myeloma cells are added to assay with dexamethasone. Cell viability and IC50 is determined. IC50 is the inhibitory concentration that kills 50% of cells. Results are reported in concentrations E-6.

  At baseline

• Synergy of Panobinostat and Carfilzomib in Combination, Per Subject.

  Concentration of carfilzomib and panobinostat in combination leading to 90% growth inhibition of multiple myeloma cells in-vitro. The combination index (CI) is calculated using formula: CI = (\[D1\] in the combination / \[D1\] alone) + (\[D2\] in the combination / \[D2\] alone). Key: CI = 1 no synergy; CI\<1 synergy; CI\>1 antagonism.

  At baseline

• Synergy of Panobinostat and Dexamethasone in Combination, Per Subject

  Concentration of panobinostat and dexamethasone in combination leading to 90% growth inhibition of multiple myeloma cells in-vitro. The combination index (CI) is calculated using formula: CI = (\[D1\] in the combination / \[D1\] alone) + (\[D2\] in the combination / \[D2\] alone). Key: CI = 1 no synergy; CI\<1 synergy; CI\>1 antagonism.

  At baseline

Study Arms (1)

Treatment-panobinostat, carfilzomib, dexamethasone,chemo assay

EXPERIMENTAL

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 cycles 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; Other: Chemosensitivity Assay; Drug: Dexamethasone; Other: Laboratory Biomarker Analysis; Drug: Panobinostat

Interventions

Carfilzomib DRUG

Given IV

Also known as: Kyprolis, PR-171

Treatment-panobinostat, carfilzomib, dexamethasone,chemo assay

Chemosensitivity Assay OTHER

Undergo in vitro chemosensitivity testing

Also known as: Chemosensitivity Testing

Treatment-panobinostat, carfilzomib, dexamethasone,chemo assay

Dexamethasone DRUG

Given PO

Also known as: 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

Treatment-panobinostat, carfilzomib, dexamethasone,chemo assay

Laboratory Biomarker Analysis OTHER

Correlative studies

Treatment-panobinostat, carfilzomib, dexamethasone,chemo assay

Panobinostat DRUG

Given PO

Also known as: Faridak, Farydak, LBH589

Treatment-panobinostat, carfilzomib, dexamethasone,chemo assay

Eligibility Criteria

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

You may qualify if:

• 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 involved free light chain \>= 10 mg/dL as per IMWG criteria, and abnormal ratio
• Urine Bence Jones protein \> 200 mg/24 hour (hr)
• Absolute neutrophil count (ANC) \>= 750/uL
• Platelet count \>= 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
• 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
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, should have a pregnancy test prior to the initiation of treatment and use highly effective methods of contraception during and for 3 months post study treatment; highly effective contraception methods include total abstinence, female sterilization, male sterilization, use of oral, injected, or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal contraception that have comparable efficacy; women using hormonal contraceptives should additionally use a barrier method of contraception; women are considered post-menopausal and not of child-bearing potential if they have had 12 months of natural amenorrhea or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks ago
• Sexually active males must use a condom during intercourse while taking study drug and for 6 months after stopping treatment; males should not father a child in this period; a condom is required to be used also by vasectomized men as well as during intercourse with a male partner; female partners of sexually active men should also use an effective contraception during treatment and for 6 months after their male partner has stopped taking the drug

You may not qualify if:

• 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 randomization is permitted
• 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 \> 470 msec for females using Fridericia's correction on screening electrocardiogram (ECG)
• 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

Sponsors & Collaborators

• University of Washington: lead
• National Cancer Institute (NCI): collaborator
• SecuraBio: collaborator

Study Sites (1)

Fred Hutch/University of Washington Cancer Consortium

Seattle, Washington, 98109, United States

Location

MeSH Terms

Conditions

Multiple Myeloma

Interventions

carfilzomib; Dexamethasone; Calcium Dobesilate; auricularum; dexamethasone acetate; dexamethasone 21-phosphate; Panobinostat

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Hydroxamic Acids; Hydroxylamines; Amines; Hydroxy Acids; Carboxylic Acids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Limitations and Caveats

Study was limited by lower accrual than expected due to: competing studies, other investigators' treatment preferences, and ultimately, the departure of the initial PI from the institution. Because of PI's departure and lab closure, the study closed to accrual after the 9th patient enrolled. Because only 9 subjects were enrolled and some in-vitro assay results are unavailable, it is difficult to analyze the in-vitro assay results and determine the parameters that predict disease response.

Results Point of Contact

• Title: Dr. Andrew Cowan
• Organization: University of Washington

ajcowan@seattlecca.org

206-606-7348

Study Officials

• Andrew Cowan

  Fred Hutch/University of Washington Cancer Consortium

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor, Division of Medical Oncology

Study Record Dates

• First Submitted: August 16, 2017
• First Posted: August 21, 2017
• Study Start: February 8, 2018
• Primary Completion: February 5, 2021
• Study Completion: February 5, 2021
• Last Updated: May 9, 2022
• Results First Posted: May 9, 2022

Record last verified: 2022-05

Locations

US (1)