Clinical Trials /

Adaptive Strategy in Treatment for Newly Diagnosed Multiple Myeloma With Upfront Daratumumab-based Therapy

NCT04140162

Description:

This phase 2 trial will test whether the combination of DaraRd (daratumumab + lenalidomide + dexamethasone) as induction therapy, followed by DRVd (daratumumab + lenalidomide + bortezomib + dexamethasone) consolidation therapy, if needed, will result in more patients achieving minimal residual disease (MRD)-negative status, relative to the standard of care. Consolidation therapy will be administered only to those patients with MRD-positive status after induction therapy. This is a study based on adaptive design for decision making of treatment options. Duration of therapy (daratumumab cycles) will depend on individual approach, response, evidence of disease progression and tolerance.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Adaptive Strategy in Treatment for Newly Diagnosed Multiple Myeloma With Upfront Daratumumab-based Therapy
  • Official Title: Phase 2 Study With Minimal Residual Disease (MRD) Driven Adaptive Strategy in Treatment for Newly Diagnosed Multiple Myeloma (MM) With Upfront Daratumumab-based Therapy

Clinical Trial IDs

  • ORG STUDY ID: UMCC 2018.056
  • SECONDARY ID: HUM00147751
  • NCT ID: NCT04140162

Conditions

  • Multiple Myeloma

Interventions

DrugSynonymsArms
DaratumumabDara-Rd followed by Dara-RVd
LenalidomideDara-Rd followed by Dara-RVd
BortezomibDara-Rd followed by Dara-RVd
DexamethasoneDara-Rd followed by Dara-RVd

Purpose

This phase 2 trial will test whether the combination of DaraRd (daratumumab + lenalidomide + dexamethasone) as induction therapy, followed by DRVd (daratumumab + lenalidomide + bortezomib + dexamethasone) consolidation therapy, if needed, will result in more patients achieving minimal residual disease (MRD)-negative status, relative to the standard of care. Consolidation therapy will be administered only to those patients with MRD-positive status after induction therapy. This is a study based on adaptive design for decision making of treatment options. Duration of therapy (daratumumab cycles) will depend on individual approach, response, evidence of disease progression and tolerance.

Trial Arms

NameTypeDescriptionInterventions
Dara-Rd followed by Dara-RVdExperimentalInduction regimen with Daratumumab, Lenalidomide and Dexamethasone (Dara-Rd) in all study subjects, weeks 1-24 Consolidation regimen with Daratumumab, Lenalidomide, Bortezomib and Dexamethasone (Dara-RVd) in post-induction MRD+ population, weeks 25-36 Maintenance regimen with Daratumumab and Lenalidomide (Dara-R) in all study subjects, weeks 37-88 Maintenance regimen with lenalidomide (R) until progression or intolerance
  • Daratumumab
  • Lenalidomide
  • Bortezomib
  • Dexamethasone

Eligibility Criteria

        INCLUSION

          1. Participants ≥18 years of age or legal age of consent per local regulations (whichever
             is greater).

          2. Voluntary written consent must be given before performance of any study-related
             procedure not part of standard medical care, with the understanding that consent may
             be withdrawn by the participant at any time without prejudice to future medical care.

          3. ECOG status (Appendix A) of ≤2 and able to tolerate all applicable treatments per
             investigator's evaluation and standard institutional criteria.

          4. Both transplant eligible and ineligible myeloma patients can be included in this
             study. If applicable, participant should be able to tolerate all treatments per
             investigator's evaluation, including high-dose chemotherapy and autologous stem cell
             transplant (ASCT) based on standard criteria at the institution where this treatment
             will be administered.

          5. Participant must have a diagnosis of active MM according to International Myeloma
             Working Group (IMWG) diagnostic criteria.

          6. Participant must also have measurable disease per protocol.

          7. Participant agrees to refrain from blood donations during therapy on study and for 12
             weeks after therapy is completed.

          8. Participant must be registered in and must comply with all requirements of REMSTM
             program for lenalidomide.

          9. Female participant who:

               -  Is post-menopausal for at least one year prior to study enrollment, OR

               -  Is surgically sterile, OR

               -  If of childbearing potential, must have a negative urine or serum pregnancy test
                  within 10-14 days prior to and again within 24 hours of starting lenalidomide.
                  They must also be willing to use TWO effective forms of contraception
                  simultaneously from the time of signing the study consent until 90 days following
                  the administration of the last dose of study medication, OR

               -  Agree to practice true abstinence if that is aligned with their lifestyle, which
                  does not include periodic abstinence or withdrawal.

         10. Male participant, even if surgically sterilized, must agree to one of the following:

               -  Agree to practice effective barrier contraception during the entire study
                  treatment period and through 90 days after the last dose of study drug, OR

               -  Agree to practice true abstinence if that is aligned with their lifestyle, which
                  does not include periodic abstinence or withdrawal.

        EXCLUSION:

          1. Diagnoses of smoldering MM (SMM), monoclonal gammopathy of undetermined significance
             (MGUS), non-secretory MM, plasma cell leukemia, AL amyloidosis, Waldenstrom's.
             macroglobulinemia, POEMS syndrome. History of SMM and/or MGUS is not excluded.

          2. Known disease involvement of the CNS.

          3. History of prior hematopoietic stem cell transplant of any type.

          4. Received more than one cycle of anti-myeloma therapy prior to enrollment. Up to one
             cycle of myeloma therapy is allowed. Concomitant treatment is allowed with low-dose
             corticosteroids and bisphosphonates. The dose of corticosteroids for myeloma treatment
             should not exceed the equivalent of 160 mg of dexamethasone over a two-week period
             before initiation of protocol. Prednisone up to but no more than 10 mg po daily or its
             equivalent is allowed, for symptom management and comorbid conditions.

          5. Significant renal insufficiency, defined as creatinine clearance <30ml/min per
             Cockcroft-Gault formula.

          6. Hepatic impairment, defined as bilirubin >1.5 x institutional upper limit of normal
             (ULN) or AST (SGOT), ALT (SGPT), or alkaline phosphatase > 3x institutional ULN.

          7. Absolute neutrophil count (ANC) < 1000 cells/mm3 within 14 days of enrollment. Growth
             factor may not be used to meet ANC eligibility criteria.

          8. Hemoglobin (Hgb) < 8g/dL within 14 days of enrollment. Transfusion may not be used to
             meet Hgb eligibility criteria.

          9. Platelet count < 75,000 cells/mm3 within 14 days of enrollment. Transfusion may not be
             used to meet platelet eligibility criteria.

         10. Any condition, including laboratory abnormalities, that in the opinion of the
             investigator places the subject at unacceptable risk if subject were to participate in
             the study.

         11. Major surgery ≤ 4 weeks prior to starting study drug or who have not recovered from
             complications of the surgery.

         12. Clinically significant peripheral neuropathy not well controlled with treatment,
             defined as ≥grade 2 on clinical examination.

         13. Symptomatic uncontrolled cardiac disease including congestive heart failure with New
             York Heart Association class III-IV symptoms, arrhythmia, unstable angina or
             myocardial infarction within the past six months, or any other uncontrolled or severe
             cardiovascular condition.

         14. Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in
             1 second (FEV1) <50% of predicted normal.

         15. Clinically uncontrolled asthma of any classification or known moderate or severe
             persistent asthma within the past two years (see asthma guidelines.
             https://www.nhlbi.nih.gov/files/docs/guidelines/asthma_qrg.pdf).

         16. Serious intercurrent illness including but not limited to clinically relevant
             cerebrovascular disease, uncontrolled diabetes mellitus, cirrhosis, pulmonary disease.

         17. Active autoimmune process or other disease requiring systemic immunosuppressive,
             monoclonal antibody, small molecule, or radiation therapy.

         18. Participant is:

               -  Seropositive for 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) DNA
                  levels. Those who are PCR positive will be excluded.

               -  Participants 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).

         19. History of additional active malignancy in the past five years (not including squamous
             cell or basal cell carcinoma of the skin or in situ cervical cancer). However,
             malignancy treated with curative intent with <5% chance of disease relapse /
             recurrence in the next two years is allowed.

         20. Known drug allergy or intolerance to study medications (including steroids) or
             appropriate prophylactic medications (e.g. acyclovir, aspirin, warfarin or
             low-molecular weight heparin).

         21. Women with a positive pregnancy test during the screening period prior to study
             initiation or who are lactating.

         22. Participation in other clinical trials, including those with other investigational
             agents not included in this trial, within 30 days of the start of this trial and
             throughout the duration of this trial.

         23. Any significant history of non-compliance to medical regimens or unwilling or unable
             to comply with the instructions given.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Proportion of participants who achieve MRD negativity either after induction or, if still MRD-positive after induction, after consolidation.
Time Frame:At the end of week 36 (post-consolidation therapy)
Safety Issue:
Description:Of participants who complete at least one cycle of induction therapy, proportion that achieve MRD-negativity after completion of induction + those who achieve MRD-negativity after completion of consolidation (if still MRD-positive after induction). MRD status determined by International Myeloma Working Group (IMWG) Response Criteria.

Secondary Outcome Measures

Measure:Overall Survival (OS)
Time Frame:Up to 3 years after start of study treatment
Safety Issue:
Description:Time from initiation of daratumumab-based combination regimen until death or last follow-up date (whichever occurs first).
Measure:Progression-free Survival (PFS)
Time Frame:Up to 3 years after start of study treatment
Safety Issue:
Description:Time from initiation of daratumumab-based combination regimen to disease progression, where disease progression is according to the IMWG criteria, death, or last disease evaluation before the start of any subsequent anti-myeloma therapy (whichever occurs first).
Measure:Proportion of participants who were MRD-positive after induction and subsequently achieve MRD-negative after consolidation.
Time Frame:At the end of week 36 (post-consolidation therapy)
Safety Issue:
Description:Of participants who are still MRD-positive after induction, proportion that achieve MRD-negative after consolidation. Per IMWG Response Criteria
Measure:Proportion of participants who maintain post-induction MRD-negativity to post-consolidation
Time Frame:At the end of week 36 (post-consolidation therapy)
Safety Issue:
Description:Of participants who achieve post-induction MRD-negativity, proportion that maintain MRD-negativity through completion of consolidation therapy.
Measure:Proportion of participants who maintain post-induction MRD-negativity to post-consolidation.
Time Frame:At the end of week 88 (post 1 year of maintenance therapy)
Safety Issue:
Description:Of participants who achieve post-induction MRD-negativity, proportion that maintain MRD-negativity through completion of 1 year of maintenance therapy.
Measure:Proportion of participants who maintain post-induction MRD-negativity to last follow-up visit.
Time Frame:After week 88, up to 3 years after start of study treatment
Safety Issue:
Description:Of participants who achieve post-induction MRD-negativity, proportion that maintain MRD-negativity until last follow-up visit (if after week 88).
Measure:Health-related quality of life assessment changes from baseline using EuroQol survey "EQ-5D."
Time Frame:Baseline to 16 weeks post-last-dose of study treatment (Dara, R, V or d)
Safety Issue:
Description:EQ-5D is a standardized participant-reported outcome measure developed by the EuroQol Group and used in this trial to assess health-related quality of life.
Measure:Neurotoxicity assessment changes from baseline using Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) questionnaire.
Time Frame:Baseline to 16 weeks post-last-dose of study treatment (Dara, R, V or d)
Safety Issue:
Description:The FACT/GOG-Ntx is a patient-reported outcome measure used to assess health-related quality of life in patients undergoing cancer therapy, plus an eleven-item subscale (Ntx subscale) that evaluates symptoms and concerns associated specifically with chemotherapy-induced neuropathy.
Measure:Incidence of treatment-emergent adverse events
Time Frame:From start of study treatment (Dara-Rd) up to 30 days post last dose of study treatment (Dara, R, V or d)
Safety Issue:
Description:Toxicity will be assessed according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.
Measure:Proportion of participants with a successful stem cell mobilization after receiving Dara-based induction therapy.
Time Frame:At the end of week 24 (post-induction therapy)
Safety Issue:
Description:Of participants who have stem cells collected, proportion who have enough CD34+ cells after mobilization to be able to proceed with an autologous stem cell transplant (ASCT) if needed. Successful mobilization for each participant will be based on standard criteria at the institution where the transplant will be administered.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of Michigan Rogel Cancer Center

Trial Keywords

  • Dara-R
  • DaraRd
  • Dara-RVd
  • MRD

Last Updated

January 6, 2020