Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

CB-839 HCl in Combination With Carfilzomib and Dexamethasone in Treating Patients With Recurrent or Refractory Multiple Myeloma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03798678
Recruitment Status : Recruiting
First Posted : January 10, 2019
Last Update Posted : October 15, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE January 9, 2019
First Posted Date  ICMJE January 10, 2019
Last Update Posted Date October 15, 2019
Actual Study Start Date  ICMJE December 26, 2018
Estimated Primary Completion Date January 30, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 9, 2019)
Maximum tolerated dose (MTD) and recommended phase II dose (RP2D) [ Time Frame: Up to 28 days ]
MTD will be determined by dose limiting toxicity (DLT). MTD is defined as the dose level below the lowest dose that induces DLT in at least 2 patients (out of 6). The highest dose is defined as the RP2D. A standard cohort 3+3 design will be used.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03798678 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 9, 2019)
  • Incidence of adverse events [ Time Frame: Up to 30 days after study treatment ]
    Incidence of adverse events will be graded according to Common Terminology Criteria for Adverse Events version 5.0. The number and severity of all AEs (overall and by dose-level) will be tabulated and summarized in this patient population. These data will be summarized with and without regard to the relationship to the treatment (i.e., ignoring the relationship data and after sub-setting the data to only events that are at least possibly related to study drug).
  • Overall response rate (ORR) [ Time Frame: Up to 1 year ]
    The ORR will be defined as the percentage of patients that achieve at least a partial response (as their best response). Properties of the binomial distribution will be used in order to construct an exact 95% confidence interval around this proportion.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: January 9, 2019)
Pharmacokinetic (PK) profiles and pharmacodynamic effect [ Time Frame: Days 1 and 15 of cycle 1 ]
PK and pharmacodynamic data will be examined in an exploratory manner.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE CB-839 HCl in Combination With Carfilzomib and Dexamethasone in Treating Patients With Recurrent or Refractory Multiple Myeloma
Official Title  ICMJE Phase I Dose-Escalation and Dose-Expansion Trial of a Novel Glutaminase Inhibitor (CB-839 HCl) in Combination With Carfilzomib and Dexamethasone in Relapsed and/or Refractory Multiple Myeloma
Brief Summary This phase I trial studies the best dose of CB-839 HCl when given together with carfilzomib and dexamethasone in treating patients with multiple myeloma that has come back or does not respond to previous treatment. CB-839 HCl and carfilzomib may stop the growth of cancer 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 cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving CB-839 HCl, carfilzomib, and dexamethasone may work better in treating patients with multiple myeloma.
Detailed Description

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of glutaminase inhibitor CB-839 hydrochloride (CB-839 HCl) in combination with carfilzomib and dexamethasone.

SECONDARY OBJECTIVES:

I. Evaluate the safety and tolerability of CB-839 HCl in combination with carfilzomib and dexamethasone.

II. To determine the overall response rate (ORR) associated with the combination of CB-839 HCl with carfilzomib and dexamethasone.

CORRELATIVE RESEARCH OBJECTIVES:

I. Evaluate plasma pharmacokinetic (PK) profiles of CB-839 HCl and carfilzomib when used in combination.

II. To perform molecular profiling assays on malignant and normal tissues, including, but not limited to, whole exome sequencing (WES), messenger ribonucleic acid (RNA) sequencing (RNAseq), circulating cell free (cf) deoxyribonucleic acid (DNA) analysis, flow cytometry assessments, immunohistochemical (IHC) staining, and metabolomics-based assessments in order to identify potential predictive and prognostic biomarkers, and identify resistance mechanisms using genomic DNA, RNA, flow cytometry, IHC, and metabolomics-based assessment platforms.

III. To contribute genetic analysis data from de-identified biospecimens to Genomic Data Commons (GDC), a well annotated cancer molecular and clinical data repository, for current and future research.

IV. To bank CD138+ multiple myeloma (MM) cells from the bone marrow, and blood (for cfDNA analysis) obtained from patients at the Experimental Therapeutics Clinical Trials Network (ETCTN) Biorepository at Nationwide Children's Hospital.

OUTLINE: This is a dose escalation study of glutaminase inhibitor CB-839 hydrochloride.

Patients receive glutaminase inhibitor CB-839 hydrochloride orally (PO) every 12 hours on days 1-28, dexamethasone PO on days 1, 2, 8, 9, 15, 16, and 23, and carfilzomib intravenously (IV) over 10 minutes on days 1, 2, 8, 9, 15, and 16. 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 and then periodically for up to 1 year.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Recurrent Plasma Cell Myeloma
  • Refractory Plasma Cell Myeloma
Intervention  ICMJE
  • Drug: Carfilzomib
    Given IV
    Other Names:
    • Kyprolis
    • PR-171
  • Drug: Dexamethasone
    Given 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: Glutaminase Inhibitor CB-839 Hydrochloride
    Given PO
    Other Name: CB-839 HCl
Study Arms  ICMJE Experimental: Treatment (CB-839 HCI, dexamethasone, carfilzomib)
Patients receive glutaminase inhibitor CB-839 Patients receive glutaminase inhibitor CB-839 hydrochloride PO every 12 hours on days 1-28, dexamethasone PO on days 1, 2, 8, 9, 15, 16, and 23, and carfilzomib IV over 10 minutes on days 1, 2, 8, 9, 15, and 16. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity
Interventions:
  • Drug: Carfilzomib
  • Drug: Dexamethasone
  • Drug: Glutaminase Inhibitor CB-839 Hydrochloride
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 9, 2019)
36
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 30, 2022
Estimated Primary Completion Date January 30, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients must have relapsed and/or refractory myeloma and be experiencing disease relapse
  • Patients must have measurable disease by International Myeloma Working Group (IMWG) criteria (any of the following):

    • Serum M-protein >= 0.5 g/dL or for IgA myeloma, an elevated IgA level by quantitative IgA nephelometry
    • Urine M-protein >= 200 mg in a 24-hour collection
    • Serum free light chain level >= 10 mg/dL with an abnormal free light chain ratio
    • Measurable plasmacytoma by cross sectional imaging (computed tomography [CT], magnetic resonance imaging [MRI] or [18F]-fluorodeoxyglucose positron emission tomography with CT [FDG PET/CT])
    • 20% or more light chain restricted, clonal plasma cells in the bone marrow
  • At least two prior lines of therapy and all patients should have at least been exposed to a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count >= 1,000 cells/mm3 without growth factors (within 14 days of enrollment)
  • Hemoglobin >= 8 g/dL (within 14 days of enrollment)
  • Platelets >= 50,000 cells/mm3 (>= 30,000 cells/mm3 if bone marrow plasma cells >= 50% at enrollment)
  • Total bilirubin =< 1.5 x upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN
  • Creatinine =< institutional ULN OR glomerular filtration rate (GFR) >= 40 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
  • Willingness to undergo interim bone marrow biopsy/aspiration for clinical purposes
  • Negative pregnancy test done =< 7 days prior to registration, for women of childbearing potential only

    • The effects of CB-839 HCl on the developing human fetus are unknown. For this reason and because carfilzomib caused embryo-fetal toxicity in pregnant rabbits at doses lower than the recommended dose, women of child-bearing potential and men must agree to use two effective methods of contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and 4 months after completion of CB-839 HCl, carfilzomib, and dexamethasone administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of CB-839 HCl, carfilzomib, and dexamethasone administration
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Patients who are refractory or intolerant to carfilzomib (prior carfilzomib exposure accepted)
  • Patients who have received recent prior chemotherapy with:

    • Alkylators (e.g., melphalan, cyclophosphamide) and anthracyclines =< 14 days prior to registration,
    • High dose corticosteroids and immunomodulatory drugs (thalidomide or lenalidomide) =< 7 days prior to registration, or
    • Monoclonal antibodies =< 14 days prior to registration
  • Patients who have not recovered from adverse events (AEs) due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1 except peripheral neuropathy)
  • Patients who are receiving any other investigational agents
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to CB-839 HCl, carfilzomib, or dexamethasone
  • Patients with uncontrolled intercurrent illness
  • Any of the following:

    • Pregnant women or women of reproductive ability who are unwilling to use two effective methods of contraception from the time of signing the informed consent form through 4 months after the last dose of study drug
    • Nursing women
    • And men who are unwilling to use birth control while taking the drug and for 4 months after stopping treatment

      • Pregnant women are excluded from this study because carfilzomib is a PI with the potential for abortifacient effects. Because there is an unknown but potential risk for AEs in nursing infants secondary to treatment of the mother with CB-839 HCl, carfilzomib, and dexamethasone, breastfeeding should be discontinued if the mother is treated with this drug combination
  • Adverse cardiac history (unstable angina, myocardial infarction less than 4 months, New York Heart Association [NYHA] class III or IV congestive heart failure [CHF], ejection fraction [EF] < 40%, uncontrolled arrhythmias)
  • Concomitant high dose corticosteroids other than what is part of treatment protocol (concurrent use of corticosteroids). EXCEPTION: Patients may be on chronic steroids (maximum dose 10 mg/day prednisone equivalent) if they are being given for disorders other than myeloma, e.g., adrenal insufficiency, rheumatoid arthritis, etc
  • Central nervous system (CNS) involvement

    • Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other AEs
  • Concurrent amyloid light-chain (AL) amyloidosis
  • Diagnosed or treated for another malignancy within 2 years before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection
  • Patient has >= grade 3 peripheral neuropathy or grade 2 with pain on clinical examination during the screening period
  • Major surgery within 14 days before study registration
  • On concurrent treatment with an HIV protease inhibitor

    • Human immunodeficiency virus (HIV) protease inhibitors can affect the unfolded protein response in myeloma cells as well as the activity of PIs
  • Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol
  • Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of CB-839 HCl including difficulty swallowing, refractory vomiting, gastric resection or bypass, or duodenal/jejunal resection
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03798678
Other Study ID Numbers  ICMJE NCI-2019-00111
NCI-2019-00111 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
10219 ( Other Identifier: Mayo Clinic Cancer Center LAO )
10219 ( Other Identifier: CTEP )
UM1CA186686 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Wilson I Gonsalves Mayo Clinic Cancer Center LAO
PRS Account National Cancer Institute (NCI)
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP