Clinical Trials /

Daratumumab, Azacitidine, and Dexamethasone for Treatment of Patients With Recurrent or Refractory Multiple Myeloma Previously Treated With Daratumumab

NCT04407442

Description:

This phase II trial studies how well daratumumab, azacitidine, and dexamethasone work in treating patients with multiple myeloma that has come back (recurrent) or has not responded to treatment (refractory) and was previously treated with daratumumab. Daratumumab is an antibody made up of immune cells that attaches to a protein on myeloma cells, called CD38. CD38 is found in higher levels on tumor cells than on normal cells. Daratumumab prevents the growth of tumors who have high levels of CD38 by causing those cells to die. Chemotherapy drugs, such as azacitidine, 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. Dexamethasone is a steroid that helps decrease inflammation and lowers the body's normal immune response to help reduce the effect of any infusion-related reactions. Giving azacitidine may help increase the levels of CD38 on the tumor cells to increase the function of daratumumab to attach to those tumor cells to help destroy them.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Daratumumab, Azacitidine, and Dexamethasone for Treatment of Patients With Recurrent or Refractory Multiple Myeloma Previously Treated With Daratumumab
  • Official Title: Phase II Study of Daratumumab in Combination With Azacitidine and Dexamethasone in Relapsed/Refractory Multiple Myeloma Patients Previously Treated With Daratumumab

Clinical Trial IDs

  • ORG STUDY ID: 20251
  • SECONDARY ID: NCI-2020-02985
  • NCT ID: NCT04407442

Conditions

  • Recurrent Plasma Cell Myeloma
  • Refractory Plasma Cell Myeloma

Interventions

DrugSynonymsArms
Azacitidine5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496, VidazaTreatment (azacitidine, dexamethasone, daratumumab)
DaratumumabAnti-CD38 Monoclonal Antibody, Darzalex, HuMax-CD38, JNJ-54767414Treatment (azacitidine, dexamethasone, daratumumab)
DexamethasoneAacidexam, 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, ZoDexTreatment (azacitidine, dexamethasone, daratumumab)

Purpose

This phase II trial studies how well daratumumab, azacitidine, and dexamethasone work in treating patients with multiple myeloma that has come back (recurrent) or has not responded to treatment (refractory) and was previously treated with daratumumab. Daratumumab is an antibody made up of immune cells that attaches to a protein on myeloma cells, called CD38. CD38 is found in higher levels on tumor cells than on normal cells. Daratumumab prevents the growth of tumors who have high levels of CD38 by causing those cells to die. Chemotherapy drugs, such as azacitidine, 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. Dexamethasone is a steroid that helps decrease inflammation and lowers the body's normal immune response to help reduce the effect of any infusion-related reactions. Giving azacitidine may help increase the levels of CD38 on the tumor cells to increase the function of daratumumab to attach to those tumor cells to help destroy them.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To evaluate the efficacy of adding azacitidine to daratumumab and dexamethasone, as
      measured by the overall response rate in patients with relapsed refractory multiple myeloma
      (RRMM) previously treated with daratumumab.

      SECONDARY OBJECTIVES:

      I. To evaluate the duration of response per International Myeloma Working Group (IMWG)
      criteria.

      II. To evaluate the safety and tolerability of azacitidine in combination with daratumumab
      and dexamethasone.

      III. To evaluate progression free and overall survival in patients treated with azacitidine
      in combination with daratumumab and dexamethasone.

      IV. To assess the changes in CD38 expression on plasma cells after treatment with azacitidine
      and correlate this change with the depth and duration of response of azacitidine in
      combination with daratumumab and dexamethasone.

      OUTLINE:

      PRE-INDUCTION (CYCLE 0): Patients receive azacitidine intravenously (IV) on days -6 to -2 in
      the absence of disease progression or unacceptable toxicity.

      INDUCTION PHASE (CYCLES 1-2): Patients receive azacitidine IV on days 22-26 and dexamethasone
      IV or orally (PO) and daratumumab IV over 30-60 minutes on days 1, 8, 15, and 22. Treatment
      repeats every 28 days for up to 2 cycles in the absence of disease progression or
      unacceptable toxicity.

      CONSOLIDATION PHASE (CYCLES 3-6): Patients receive azacitidine IV on days 22-26 of cycle 3
      and on days 1-5 of cycles 4-6 and dexamethasone IV or PO and daratumumab IV over 30-60
      minutes on days 1 and 15. Treatment repeats every 28 days for up to 4 cycles in the absence
      of disease progression or unacceptable toxicity.

      MAINTENANCE PHASE (CYCLES 7+): Patients receive azacitidine IV on days 1-5 and dexamethasone
      IV or PO and daratumumab IV over 30-60 minutes on day 1. Cycles repeat every 28 days in the
      absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 4 weeks for up to 1 year.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (azacitidine, dexamethasone, daratumumab)ExperimentalPRE-INDUCTION (CYCLE 0): Patients receive azacitidine IV on days -6 to -2 in the absence of disease progression or unacceptable toxicity. INDUCTION PHASE (CYCLES 1-2): Patients receive azacitidine IV on days 22-26 and dexamethasone IV or PO and daratumumab IV over 30-60 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. CONSOLIDATION PHASE (CYCLES 3-6): Patients receive azacitidine IV on days 22-26 of cycle 3 and on days 1-5 of cycles 4-6 and dexamethasone IV or PO and daratumumab IV over 30-60 minutes on days 1 and 15. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE PHASE (CYCLES 7+): Patients receive azacitidine IV on days 1-5 and dexamethasone IV or PO and daratumumab IV over 30-60 minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Azacitidine
  • Daratumumab
  • Dexamethasone

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have a known diagnosis of multiple myeloma with evidence of measurable
             disease, AND have evidence of disease progression based on IMWG criteria:

               -  Serum M-protein >= 0.5 g/dL, or urine M-protein >= 200 mg/24 hours. OR

               -  In the absence of measurable M-protein, serum immunoglobulin free light chain >=
                  10 mg/dL, and abnormal serum immunoglobulin kappa lambda free light chain ratio

          -  Relapsed from or refractory to 2 or more different prior therapies, including
             immunomodulatory drugs (IMiDs; e.g., thalidomide, lenalidomide) and proteasome
             inhibitors, chemotherapy-based regimens, monoclonal antibodies, or autologous stem
             cell transplantation (ASCT)

               -  Relapse is defined as progression of disease after an initial response (minimal
                  response (MR) or better) to previous treatment, more than 60 days after cessation
                  of treatment

               -  Refractory disease is defined as < 25% reduction in M-protein or progression of
                  disease during treatment or within 60 days after cessation of treatment

          -  Prior exposure to daratumumab, with most recent dose being at least 6 months prior to
             trial enrollment

          -  Eastern Cooperative Oncology Group (ECOG) performance status < 2 (Karnofsky > 60%)

          -  Absolute neutrophil count >= 1,500/microliter (mcL) (within 7 days of first dose of
             drug)

          -  Platelets >= 75,000/mcL (within 7 days of first dose of drug)

          -  Total bilirubin within normal institutional limits, unless elevated due to Gilbert's
             syndrome and direct bilirubin is within normal limits (within 7 days of first dose of
             drug)

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase (SGOT)) =< 3
             x institutional upper limit of normal (within 7 days of first dose of drug)

          -  Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase (SGPT)) =< 3 x
             institutional upper limit of normal (within 7 days of first dose of drug)

          -  Creatinine =< 1.5 x within institutional upper limit or normal OR creatinine clearance
             glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2, calculated using the
             Cockcroft-Gault equation, unless data exists supporting safe use at lower kidney
             function values, no lower than 30 mL/min/1.73 m^2 (within 7 days of first dose of
             drug)

          -  Life expectancy of at least 3 months

          -  Women of childbearing potential must have at least one negative highly sensitive serum
             (beta-human chorionic gonadotropin (beta-hCG)) during screening, within one week prior
             to the first dose of any component of study treatment

          -  Before enrollment, a woman must be either:

               -  Not of childbearing potential defined as:

                    -  Postmenopausal:

                         -  A postmenopausal state is defined as no menses for 12 months without an
                            alternative medical cause. A high follicle stimulating hormone level (>
                            40 IU/L or milli-international units per milliliter (mIU/mL) in the
                            postmenopausal range may be used to confirm a postmenopausal state in
                            women not using hormonal contraception or hormonal replacement therapy,
                            however in the absence of 12 months of amenorrhea, a single follicle
                            stimulating hormone measurement is insufficient

                    -  Permanently sterile

                         -  Permanent sterilization methods include hysterectomy, bilateral
                            salpingectomy, bilateral tubal occlusion/ligation procedures, and
                            bilateral oophorectomy OR

               -  Of childbearing potential and

                    -  Practicing 2 highly effective user-independent methods of contraception
                       (failure rate of < 1% per year when used consistently and correctly

                         -  Examples of highly effective user-independent methods of contraception
                            include:

                              -  Implantable progesterone-only hormone contraception associated
                                 with inhibition of ovulation; intrauterine device (IUD);
                                 intrauterine hormone-releasing system (IUS); vasectomized partner;
                                 sexual abstinence (sexual abstinence is considered a highly
                                 effective method only if defined as refraining from heterosexual
                                 intercourse during the entire period of risk associated with the
                                 study drug. The reliability of sexual abstinence needs to be
                                 evaluated in relation to the duration of the study and the
                                 preferred and usual lifestyle of the subject.)

                         -  Typical use failure rates may differ from those when used consistently
                            and correctly. Use should be consistent with local regulations
                            regarding the use of contraceptive methods for subjects participating
                            in clinical studies

                         -  Hormonal contraception may be susceptible to interaction with the study
                            drug, which may reduce the efficacy of the contraceptive method

                         -  Agrees to remain on a highly effective method for 4 weeks before the
                            first dose of any component of study treatment, throughout the study
                            (including during dose interruptions), and for 4 weeks following
                            discontinuation of azacitidine, and for 3 months after last daratumumab
                            dose

                              -  Note: If the risk of pregnancy changes (e.g., a woman who is not
                                 heterosexually active becomes active), a woman must begin a highly
                                 effective method of contraception, as described throughout the
                                 inclusion criteria

                                   -  If reproductive status is questionable, additional evaluation
                                      should be considered

                         -  Agrees to not breast feed for the duration of the study (including
                            during dose interruptions), and for 4 weeks following discontinuation
                            of azacitidine, and for 3 months after last daratumumab dose

          -  Women must agree not to donate eggs (ova, oocytes) for the purposes of assisted
             reproduction during the study (including during dose interruptions), and for 4 weeks
             following discontinuation of azacitidine, and if receiving daratumumab, for 3 months
             after the last dose

          -  Due to the teratogenicity of azacitidine and the lack of adequate reproductive
             toxicity data for daratumumab, in addition to the user independent highly effective
             method of contraception, a male or female condom with or without spermicide,
             diaphragm, or cervical cap is required. Male condom and female condom should not be
             used together (due to risk of failure with friction)

          -  During the study (including during dose interruptions), and for 4 weeks following
             discontinuation of azacitidine, and for 3 months after the last daratumumab dose, in
             addition to the user independent highly effective method of contraception (even if he
             has undergone a successful vasectomy), a man

               -  Who is sexually active with a woman of childbearing potential must agree to use a
                  barrier method of contraception (i.e., latex or synthetic condom with spermicidal
                  foam/gel/film/cream/suppository)

               -  Who is sexually active with a woman who is pregnant must use a latex or synthetic
                  condom

               -  Must agree not to donate sperm

          -  Willing and able to adhere to the prohibitions and restrictions specified in this
             protocol and referenced in the informed consent form (ICF)

          -  Must sign an ICF (or their legally acceptable representative must sign) indicating
             that he or she understands the purpose of, and procedures required for, the study and
             is willing to participate in the study

        Exclusion Criteria:

          -  Diagnosed or treated for malignancy (either solid tumor or hematologic) other than
             multiple myeloma, except:

               -  Malignancy treated with curative intent and with no known active disease before
                  enrollment

                    -  Adequately treated non-melanoma skin cancer, lentigo maligna or in situ
                       malignancies (including but not limited to, cervical, breast) with no
                       evidence of disease

          -  Received daratumumab therapy less than 6 months prior to trial enrollment

          -  Primary refractory to prior daratumumab

          -  Subject is:

               -  Seropositive for human immunodeficiency virus (HIV)

               -  Seropositive for hepatitis B (defined by a positive test for hepatitis B surface
                  antigen [HBsAg]). Subjects with resolved infection (i.e., subjects who are HBsAg
                  negative but positive for antibodies to hepatitis B core antigen (anti-HBc)
                  and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened
                  using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus
                  (HBV) deoxyribonucleic acid (DNA) levels. Those who are PCR positive will be
                  excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV
                  vaccination (anti-HBs positivity as the only serologic marker) AND a known
                  history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR

               -  Seropositive for hepatitis C (except in the setting of a sustained virologic
                  response (SVR), defined as aviremia at least 12 weeks after completion of
                  antiviral therapy)

          -  Known chronic obstructive pulmonary disease with a forced expiratory volume in 1
             second (FEV1) < 50% of predicted normal to minimize daratumumab-related pulmonary
             toxicities

               -  Note: FEV1 testing is required for subjects suspected of having chronic
                  obstructive pulmonary disease and asthma. Subjects must be excluded if FEV1 < 50%
                  of predicted normal

          -  Known moderate or severe persistent asthma within the past 2 year or currently has
             uncontrolled asthma of any classification

               -  Note: Subjects who currently have controlled intermittent asthma or controlled
                  mild persistent asthma are allowed in the study. FEV1 testing is required for
                  subjects suspected of having asthma

          -  Concurrent medical condition or disease (e.g., active systemic infection) that is
             likely to interfere with study procedures or results, or that in the opinion of the
             investigator would constitute a hazard for participating in this study

          -  Clinically significant cardiac disease, including:

               -  Myocardial infarction within 6 months before cycle 1, day -6, or unstable or
                  uncontrolled disease/condition related to or affecting cardiac function (e.g.,
                  unstable angina, congestive heart failure, New York Heart Association class
                  III-IV)

               -  Uncontrolled cardiac arrhythmia (National Cancer Institute Common Terminology
                  Criteria for Adverse Events [NCI-CTCAE] version 5.0 grade 2 or higher) or
                  clinically significant electrocardiogram (ECG) abnormalities

               -  Screening 12-lead electrocardiogram (ECG) showing a baseline corrected QT
                  interval (QTc) > 470 msec.

          -  Known allergies, hypersensitivity, or intolerance to monoclonal antibodies or human
             proteins, daratumumab or its excipients (refer to investigator's brochure), or known
             sensitivity to mammalian-derived products

          -  Concurrent plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS syndrome
             (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and/or skin
             changes), or light chain amyloidosis

          -  Known or suspected of not being able to comply with the study protocol (e.g., because
             of alcoholism, drug dependency, or psychological disorder) or the subject has any
             condition for which, in the opinion of the investigator, participation would not be in
             the best interest of the subject (e.g., compromise their well-being) or that could
             prevent, limit, or confound the protocol-specified assessments

          -  Contraindications to the use of daratumumab, azacitidine or dexamethasone per local
             prescribing information

          -  Taken any disallowed therapies before the planned first dose of study drug

          -  Participated in an interventional clinical trial(s) and received an investigational
             drug (including investigational vaccines) or used an invasive investigational medical
             device within 4 weeks before cycle 1, day -6

          -  Had major surgery within 2 weeks before cycle 1, day -6, or will not have fully
             recovered from surgery, or has surgery planned during the time the subject is expected
             to participate in the study or within 2 weeks after the last dose of study drug
             administration

               -  Note: Subjects with planned surgical procedures to be conducted under local
                  anesthesia may participate. Kyphoplasty is not considered a major surgery
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response Rate (ORR)
Time Frame:Up to 18 months
Safety Issue:
Description:ORR is defined as stringent complete response (sCR) + complete response (CR) + very good partial response + partial response (PR) as best response using International Myeloma Working Group (IMWG) Uniform Response Criteria for all subjects who have measurable disease and received at least 2 cycles of study treatment, and have at least 2 efficacy evaluation assessments. The uniformly minimum-variance unbiased estimator, p-value and 95% confidence intervals for the response rates to account for the adaptive nature of Simon's two-stage design will be calculated.

Secondary Outcome Measures

Measure:Incidence of treatment-related adverse events (AE)
Time Frame:Up to 18 months
Safety Issue:
Description:All safety analyses for AEs will be based on all subjects who receive at least 1 cycle of study treatment. AEs will be graded by National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 from the initiation of study treatment until discontinuation of treatment. For each adverse event, the percentage of subjects who experience at least 1 occurrence of the given event will be summarized.
Measure:Duration of Response (DOR)
Time Frame:Up to 18 months
Safety Issue:
Description:DOR is defined as the date of initial documentation of a response (PR or better) to the date of first documented evidence of progressive disease according to the IMWG criteria or death due to progressive disease whichever occurred first all subjects who have measurable disease and received at least 2 cycles of study treatment, and have at least 2 efficacy evaluation assessments. DOR will be summarized using the Kaplan-Meier estimator. Median even-free survival will be reported and the corresponding 95% confidence interval will be calculated using Brookmeyer and Crowley method.
Measure:Overall Survival (OS)
Time Frame:Up to 18 months
Safety Issue:
Description:OS is defined as the date of first dose of study treatment to the date of death due to any cause or censored based on the date of last encounter if patient is alive or lost to follow-up. OS will be summarized using the Kaplan-Meier estimator. Median even-free survival will be reported and the corresponding 95% confidence interval will be calculated using Brookmeyer and Crowley method.
Measure:Progression-free survival (PFS)
Time Frame:Up to 18 months
Safety Issue:
Description:PFS is defined as the date of first dose of study treatment to the date of first documented evidence of progressive disease or death, whichever occurs first. PFS will be summarized using the Kaplan-Meier estimator. Median even-free survival will be reported and the corresponding 95% confidence interval will be calculated using Brookmeyer and Crowley method.
Measure:Change in CD38 surface expression of plasma cells
Time Frame:Starting 6 days before treatment up until the end of cycle 1 (each cycle is 28 days); up to 34 days total
Safety Issue:
Description:Change in CD38 surface expression will be summarized using descriptive statistics and tested using the one-sample t-test. Two-sided p-value less than 0.05 will be considered statistically significant.
Measure:Number of patients who achieve at least 1.5 fold increase in their CD38 expression
Time Frame:At the end of cycle 1 (each cycle is 28 days)
Safety Issue:
Description:Will be assessed by flow cytometry and based on a one-sample t-test at a two-sided type I error rate of 0.05.
Measure:Correlation of change in CD38 expression after azacitidine with overall response
Time Frame:Up to 18 months
Safety Issue:
Description:Will be correlated to overall response using logistic regression, linear regression methods, and Spearman's correlation coefficient, as appropriate.
Measure:Correlation of change in CD38 expression after azacitidine treatment with depth of response
Time Frame:Up to 18 months
Safety Issue:
Description:Correlation will be calculated using logistic regression, linear regression methods, and Spearman's correlation coefficient, as appropriate.
Measure:Correlation of change in CD38 expression after azacitidine with duration of response
Time Frame:Up to 18 months
Safety Issue:
Description:Will be correlated to duration of response using logistic regression, linear regression methods, and Spearman's correlation coefficient, as appropriate.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of California, San Francisco

Last Updated

May 27, 2020