Clinical Trials /

Daratumumab After Stem Cell Transplant in Treating Patients With Multiple Myeloma

NCT03346135

Description:

This phase II trial studies how well daratumumab after a stem cell transplant works in treating patients with multiple myeloma. Monoclonal antibodies, such as daratumumab, may kill cancer cells that are left after chemotherapy.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Daratumumab After Stem Cell Transplant in Treating Patients With Multiple Myeloma
  • Official Title: A Multicenter, Open-Label, Single Arm, Phase II Study of Daratumumab as Consolidation/Maintenance Therapy After Autologous Stem Cell Transplantation in Patients With Multiple Myeloma

Clinical Trial IDs

  • ORG STUDY ID: 18560
  • SECONDARY ID: NCI-2017-02087
  • SECONDARY ID: 18560
  • NCT ID: NCT03346135

Conditions

  • Plasma Cell Myeloma
  • Secondary Amyloidosis

Interventions

DrugSynonymsArms
DaratumumabAnti-CD38 Monoclonal Antibody, Darzalex, HuMax-CD38, JNJ-54767414Treatment (ASCT, melphalan, daratumumab)
MelphalanAlanine Nitrogen Mustard, CB-3025, L-PAM, L-Phenylalanine mustard, L-sarcolysin, L-Sarcolysin Phenylalanine mustard, L-Sarcolysine, Melphalanum, Phenylalanine Mustard, Phenylalanine Nitrogen Mustard, Sarcoclorin, Sarkolysin, WR-19813Treatment (ASCT, melphalan, daratumumab)

Purpose

This phase II trial studies how well daratumumab after a stem cell transplant works in treating patients with multiple myeloma. Monoclonal antibodies, such as daratumumab, may kill cancer cells that are left after chemotherapy.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To determine the anti-myeloma activity of single-agent daratumumab post-autologous stem
      cell transplantation (ASCT) as assessed by progression-free survival at 1 year post ASCT.

      SECONDARY OBJECTIVES:

      I. To characterize the extent of minimal residual disease (MRD) pre-/post-consolidation
      treatment segment and at one year during the maintenance treatment segment.

      II. To characterize and evaluate toxicities, including type, frequency severity, attribution,
      and duration (e.g., infections, secondary primary malignancies, peripheral neuropathy).

      III. To obtain estimates of overall response rate (stringent complete response [sCR],
      complete response [CR], very good partial response [VGPR], and partial response [PR]),
      response duration, depth of response, clinical benefit response, and overall survival.

      EXPLORATORY OBJECTIVES:

      I. Quantify CD38+ cells from the peripheral blood mononuclear cells (PBMC) fraction,
      including T, natural killer (NK), and monocytic subsets using pre- and on-daratumumab
      treatment samples by flow cytometry.

      II. Assess possible changes in CD38+ expression, as well as the co-receptor marker CD31, and
      possible correlation with response using pre- and on-daratumumab treatment samples by flow
      cytometry.

      III. Assess cytokine levels in peripheral blood plasma. IV. Quantify CD38+ cells from the
      bone marrow CD-138 negative fractions and acellular fractions, including T, NK, and monocyte
      subsets using pre- and on-daratumumab treatment samples by flow cytometry.

      V. Assess possible changes in CD38+ expression, as well as the co-receptor marker CD31, and
      possible correlation with response using pre- and on-daratumumab treatment samples by flow
      cytometry.

      VI. Assess cytokine levels in the bone marrow acellular fraction. VII. Investigate CD38
      cellular localization in multiple myeloma cells and extracellular vesicles from blood plasma.

      VIII. Assess messenger ribonucleic acid (mRNA) expression in the PBMC, the bone marrow
      CD130-negative fraction, the T cell fraction, and multiple myeloma cells.

      IX. If differences in CD38 expression are found, investigate epigenetic changes in CD38 mRNA
      expression.

      OUTLINE:

      Patients undergo standard of care ASCT with a conditioning regimen of melphalan. Beginning
      60-120 days after ASCT, patients receive daratumumab intravenously (IV) every week for 8
      weeks, every 2 weeks for 16 weeks, and then every 4 weeks for up to 24 months in the absence
      of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months for 18 months.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (ASCT, melphalan, daratumumab)ExperimentalPatients undergo standard of care ASCT with a conditioning regimen of melphalan. Beginning 60-120 days after ASCT, patients receive daratumumab IV every week for 8 weeks, every 2 weeks for 16 weeks, and then every 4 weeks for up to 24 months in the absence of disease progression or unacceptable toxicity.
  • Daratumumab
  • Melphalan

Eligibility Criteria

        Inclusion Criteria:

          -  All subjects must have the ability to understand and the willingness to sign a written
             informed consent

          -  Histologically confirmed diagnosis of multiple myeloma; (patients with multiple
             myeloma with secondary amyloidosis are eligible)

          -  Received at least two cycles of any regimen as initial systemic therapy for multiple
             myeloma and are within 2-13 months of the first dose of initial therapy

          -  Eastern Cooperative Oncology Group (ECOG) =< 2

          -  Patients with planned standard of care ASCT using melphalan 200 mg/m^2; dose
             modifications in accordance with creatinine clearance levels are allowed per physician
             judgment

          -  Adequate organ function for high dose chemotherapy and autologous stem cell transplant
             (as per institution standard operating procedure [SOP])

          -  Adequate cell dose > 2.5 x 10^6 CD34+ cells/kg

          -  Absolute neutrophil count (ANC) >= 1000/mm^3

          -  Platelet count >= 75,000/mm^3; platelet transfusions to help patients meet eligibility
             criteria are not allowed within 7 days before study enrollment

          -  Total bilirubin =< 1.5 x the upper limit of normal (ULN)

          -  Aspartate aminotransferase (AST) =< 3 x ULN

          -  Alanine aminotransferase (ALT) =< 3 x ULN

          -  Calculated creatinine clearance >= 30 mL/min

          -  Woman of childbearing potential must be practicing a highly effective method of birth
             control consistent with local regulations regarding the use of birth control methods
             for subjects participating in clinical studies: e.g., established use of oral,
             injected, or implanted hormonal methods of contraception; placement of an intrauterine
             device or intrauterine system; barrier methods; condom with spermicidal
             foam/gel/film/cream/suppository or occlusive cap (diaphragm or cervical/vault caps)
             with spermicidal foam/gel/film/cream/suppository; male partner sterilization; true
             abstinence (when this is in line with the preferred and usual lifestyle of the
             subject) during and after the study (6 months after the last dose of daratumumab for
             women)

               -  A man who is sexually active with a woman of childbearing potential and has not
                  had a vasectomy must agree to use a barrier method of birth control, e.g., either
                  condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive
                  cap (diaphragm or cervical/vault caps) with spermicidal
                  foam/gel/film/cream/suppository, and all men must also not donate sperm during
                  the study and for 6 months after receiving the last dose of study drug

        Exclusion Criteria:

          -  Prior disease progression with daratumumab or other anti-CD38 antibody

          -  History of organ or previous autologous/allogeneic stem cell transplantation

          -  Any condition medical or psychosocial that in the opinion of the investigator would
             hinder compliance

          -  Female patients who are lactating or have a positive pregnancy test during the
             screening period

          -  Evidence of multiple myeloma (MM) disease progression any time prior to enrollment;
             progression from smoldering to active myeloma is not exclusionary

          -  History of plasma cell leukemia or central nervous system (CNS) involvement

          -  Major surgery within 14 days prior to start of study treatment

          -  Infection requiring systemic antibiotic therapy within 14 days prior to the start of
             study treatment

          -  Subject is receiving concurrent chemotherapy or biologic or hormonal therapy for
             cancer treatment; Note: Concurrent use of hormones for noncancer-related conditions
             (e.g., insulin for diabetes) is acceptable

          -  Vaccination with live attenuated vaccines within 4 weeks of first study agent
             administration

          -  Subject is currently using or has used immunosuppressive medication within 14 days
             prior to the first dose of study treatment; the following are exceptions:

               -  Intranasal, topical, inhaled, or local steroid injections (e.g., intra-articular
                  injection)

               -  Chronic systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
                  prednisone or equivalent

               -  Steroids as premedication for hypersensitivity reaction (e.g., infusion-related
                  reactions, computed tomography [CT] scan premedication)

          -  Subject has plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS syndrome
             (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes),
             or primary amyloidosis

          -  Subjects with uncontrolled, systematic infection should be excluded

          -  Subject has known chronic obstructive pulmonary disease (COPD) with a forced
             expiratory volume in 1 second (FEV1) < 50% predicted normal; Note that FEV1 testing is
             required for patients suspected of having COPD and subjects must be excluded if FEV1 <
             50%

          -  Subject has known moderate or severe persistent asthma within 2 years, or currently
             has uncontrolled asthma of any classification; (Note that subjects who currently have
             controlled intermittent asthma or controlled mild persistent asthma are allowed in the
             study)

          -  Subject has active or prior documented autoimmune or inflammatory disorders (including
             inflammatory bowel disease [e.g., Crohn's disease], diverticulitis, celiac disease,
             irritable bowel disease, or other serious gastrointestinal chronic conditions
             associated with diarrhea; systemic lupus erythematosus; Wegener syndrome; myasthenia
             gravis; Graves' disease; rheumatoid arthritis; hypophysitis, uveitis, etc) within the
             past 3 years prior to the start of treatment; the following are exceptions:

               -  Subjects with vitiligo or alopecia

               -  Subjects with hypothyroidism (e.g., following Hashimoto's disease) stable on
                  hormone replacement

               -  Psoriasis not requiring systemic treatment

          -  Subject has known allergies, hypersensitivity, or intolerance to monoclonal antibodies
             or human proteins, or their excipients

          -  Subject has history of primary immunodeficiency

          -  Subject is seropositive for human immunodeficiency virus (HIV-1)

          -  Active hepatitis A

          -  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 finding 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)

          -  Subject has any one of the following:

               -  Clinically significant abnormal electrocardiogram (ECG) finding at screening

               -  Congestive heart failure (New York Heart Association class III or IV)

               -  Myocardial infarction within 12 months prior to starting study treatment

               -  Unstable or poorly controlled angina pectoris, including Prinzmetal variant
                  angina pectoris

          -  Subject has prior history of malignancies, other than MM, unless the subject has been
             free of the disease for >= 5 years with the exception of the following malignancies:

               -  Basal cell carcinoma of the skin

               -  Squamous cell carcinoma of the skin

               -  Carcinoma in situ of the cervix

               -  Carcinoma in situ of the breast

               -  Incidental histologic finding of prostate cancer (T1a or T1b using the tumor,
                  node, metastasis [TNM] clinical staging system) or prostate cancer that is
                  curative

          -  Any other condition that would, in the opinion of the investigator's judgement,
             contraindicate the patient's participation in the clinical study due to safety
             concerns with clinical study procedures

          -  Prospective participants who, in the opinion of the investigator, may not be able to
             comply with all study procedures (including compliance issues related to
             feasibility/logistics)
      
Maximum Eligible Age:70 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival
Time Frame:From date of first dose of study drug to first documented date of disease relapse, progression, or death (from any cause), whichever occurs first, assessed for up to 18 months after last dose of study drug
Safety Issue:
Description:Will be estimated using the product-limit method of Kaplan-Meier.

Secondary Outcome Measures

Measure:Minimal residual disease (MRD) defined as if a positive result is obtained using the Adaptive MRD testing
Time Frame:Up to 30 days after last dose of study drug
Safety Issue:
Description:
Measure:Incidence of adverse events graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 5.0
Time Frame:Up to 30 days after last dose of study drug
Safety Issue:
Description:
Measure:Overall response rate (stringent complete response [sCR]/complete response [CR], very good partial response [VGPR]) based on the International Myeloma Working Group (IMWG) Uniform Response Criteria
Time Frame:At 1 year
Safety Issue:
Description:Will be calculated as the percent of evaluable patients that have confirmed sCR/CR/VGPR (overall) or sCR/CR/VGPR/partial response (PR)/minimal response (MR) or stable disease (SD) (clinical benefit). Exact 95% confidence intervals will be calculated for these estimates. Will also be evaluated based on the number and type of prior therapy(ies).
Measure:Response duration
Time Frame:From the date of first documented response (sCR/CR/VGPR) to documented disease relapse, progression, or death, whichever occurs first, assessed up to 18 months after last dose of study drug
Safety Issue:
Description:
Measure:Depth of response
Time Frame:Up to 18 months after last dose of study drug
Safety Issue:
Description:Will be calculated as the percent of evaluable patients that have confirmed sCR/CR/VGPR (overall) or sCR/CR/VGPR/PR/MR or SD (clinical benefit). Exact 95% confidence intervals will be calculated for these estimates.
Measure:Clinical benefit response based on the IMWG criteria
Time Frame:Up to 18 months after last dose of study drug
Safety Issue:
Description:Will be calculated as the number of responders plus those with a PR, MR, or SD, divided by the number of evaluable patients. Exact 95% confidence intervals will be calculated for these estimates.
Measure:Overall survival
Time Frame:From date of first dose of study drug to date of death from any cause, assessed for up to 18 months after last dose of study drug
Safety Issue:
Description:Will be estimated using the product-limit method of Kaplan-Meier.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:City of Hope Medical Center

Last Updated

November 29, 2019