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An Intensive Program With Quadruplet Induction and Consolidation Plus Tandem Autologous Stem Cell Transplantation in Newly Diagnosed High Risk Multiple Myeloma Patients

NCT03606577

Description:

According to international guidelines, upfront therapy for transplant eligible myeloma patients should include triplet induction containing proteasome inhibitor and immunomodulatory agent, autologous stem cell transplant, PI+Imid based triplet consolidation and lenalidomide maintenance. Despite this approach, virtually all MM patients experience disease relapse, especially those with High Risk disease defined by adverse cytogenetic abnormalities (i.e. del(17p), or t(14;16) or t(4;14)) detected by FISH and/or SNP arrays. Indeed, HR myeloma is associated with poorer progression free survival and overall survival and frontline therapy should therefore be improved for this subset of HR patients. The primary objective of this prospective multicenter, open label, interventional phase 2 trial is to evaluate the feasibility of an intensive program including quadruplet induction and consolidation, tandem autologous stem cell transplantation and maintenance in newly diagnosed multiple myeloma patients presenting with HR cytogenetic. Quadruplet induction and consolidation include carfilzomib, lenalidomide, dexamethasone and daratumumab. Maintenance will include lenalidomide and daratumumab. Secondary objectives will include efficacy parameters (i.e. response rate, minimal residual disease, safety, progression free survival, overall survival).

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: An Intensive Program With Quadruplet Induction and Consolidation Plus Tandem Autologous Stem Cell Transplantation in Newly Diagnosed High Risk Multiple Myeloma Patients
  • Official Title: An Intensive Program With Quadruplet Induction and Consolidation Plus Tandem Autologous Stem Cell Transplantation in Newly Diagnosed High Risk Multiple Myeloma Patients: a Phase II Study of the Intergroupe Francophone du Myélome "IFM 2018-04"

Clinical Trial IDs

  • ORG STUDY ID: RC18_0206
  • NCT ID: NCT03606577

Conditions

  • Multiple Myeloma

Interventions

DrugSynonymsArms
CarfilzomibCarfilzomib, Daratumumab, Lenalidomide and Dexaméthasone
DaratumumabCarfilzomib, Daratumumab, Lenalidomide and Dexaméthasone
LenalidomideCarfilzomib, Daratumumab, Lenalidomide and Dexaméthasone
DexamethasoneCarfilzomib, Daratumumab, Lenalidomide and Dexaméthasone

Purpose

According to international guidelines, upfront therapy for transplant eligible myeloma patients should include triplet induction containing proteasome inhibitor and immunomodulatory agent, autologous stem cell transplant, PI+Imid based triplet consolidation and lenalidomide maintenance. Despite this approach, virtually all MM patients experience disease relapse, especially those with High Risk disease defined by adverse cytogenetic abnormalities (i.e. del(17p), or t(14;16) or t(4;14)) detected by FISH and/or SNP arrays. Indeed, HR myeloma is associated with poorer progression free survival and overall survival and frontline therapy should therefore be improved for this subset of HR patients. The primary objective of this prospective multicenter, open label, interventional phase 2 trial is to evaluate the feasibility of an intensive program including quadruplet induction and consolidation, tandem autologous stem cell transplantation and maintenance in newly diagnosed multiple myeloma patients presenting with HR cytogenetic. Quadruplet induction and consolidation include carfilzomib, lenalidomide, dexamethasone and daratumumab. Maintenance will include lenalidomide and daratumumab. Secondary objectives will include efficacy parameters (i.e. response rate, minimal residual disease, safety, progression free survival, overall survival).

Trial Arms

NameTypeDescriptionInterventions
Carfilzomib, Daratumumab, Lenalidomide and DexaméthasoneExperimental
  • Carfilzomib
  • Daratumumab
  • Lenalidomide
  • Dexamethasone

Eligibility Criteria

        Inclusion Criteria:

          1. Male or female subjects, 18 years of age or older, younger than 66 years (< 66 years)

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

          3. Subject must have documented multiple myeloma satisfying the Diagnostic criteria for
             symptomatic Myelome Multiple and measurable disease as defined by:

               -  Monoclonal plasma cells in the bone marrow ≥ 10% or presence of a biopsy proven
                  plasmacytoma AND any one or more of the following myeloma defining events:

                    -  Hypercalcemia: serum calcium > 0.25 mmol/L higher than ULN or > 2.75 mmol/L

                    -  Renal insufficiency: creatinine clearance < 40mL/min or serum creatinine >
                       177 μmol/L

                    -  Anemia: hemoglobin > 2 g/dL below the lower limit of normal or hemoglobin <
                       10 g/dL

                    -  Bone lesions: one or more osteolytic lesions on skeletal radiography, CT or
                       PET-CT

                    -  Clonal bone marrow plasma cell percentage ≥ 60%

                    -  Involved: uninvolved serum free light chain ratio ≥ 100

                    -  Superior 1 focal lesion on MRI studies

               -  Measurable disease as defined by the following:

             M-component ≥ 5g/l, and/or urine M-component ≥ 200 mg/24h and/or serum Free Light
             Chain ≥ 100 mg/l.

          4. Newly diagnosed subjects eligible for high dose therapy and autologous stem cell
             transplantation

          5. Subject must have high risk disease according to FISH analysis: del(17p), or t(14;16)
             or t(4;14). The FISH-positivity cut-off value for defining the presence of del(17p) in
             this study is 50%

          6. Karnofsky performance status score ≥ 50%

          7. Women of childbearing potential must have a negative serum or urine pregnancy test
             within 10 to 14 days prior to therapy and repeated within 24 hours before starting
             study drug. They must commit to continued abstinence from heterosexual intercourse or
             begin 2 acceptable methods of birth control used at the same time, beginning at least
             4 weeks before initiation of lenalidomide treatment and continuing for at least 30
             days after the last dose of Lenalidomide. Women must also agree to notify pregnancy or
             doubt upon pregnancy during the study.

          8. Men must agree to not father a child and agree to use a latex condom during therapy
             and for 4 weeks after the last dose of study drug, even if they have had a successful
             vasectomy, if their partner is of childbearing potential.

          9. Subject must have pretreatment clinical laboratory values meeting the following
             criteria during the Screening Phase (Lab tests should be repeated if done more than 15
             days before C1D1):

               1. Hemoglobin ≥ 7.5 g/dL. Prior red blood cell transfusion or recombinant human
                  erythropoietin use is permitted;

               2. Absolute neutrophil count ≥ 1.0 Giga/l (GCSF use is permitted);

               3. ASAT ≤ 3 x ULN;

               4. ALAT ≤ 3 x ULN;

               5. Total bilirubin ≤ 3 x ULN (except in subjects with congenital bilirubinemia, such
                  as Gilbert syndrome, direct bilirubin ≤ 1.5 x ULN);

               6. Calculated creatinine clearance ≥ 40 mL/min/1.73 m² ;

               7. Corrected serum calcium ≤ 14 mg/dL; or free ionized calcium ≤6.5 mg/dL;

               8. Platelet count ≥ 50 Giga/l for subjects in whom < 50% of bone marrow nucleated
                  cells are plasma cells; otherwise platelet count > 50 Giga/l (transfusions are
                  not permitted to achieve this minimum platelet count).

         10. Affiliation with French social security system or beneficiary from such system

        Exclusion Criteria:

          1. Subjects must not have been treated previously with any systemic therapy for multiple
             myeloma. Prior treatment with corticosteroids or radiation therapy does not disqualify
             the subject (the maximum dose of corticosteroids should not exceed the equivalent of
             160 mg of dexamethasone in a 2-week period). Two weeks must have elapsed since the
             date of the last radiotherapy treatment. Enrolment of subjects who require concurrent
             radiotherapy (which must be localized in its field size) should be deferred until the
             radiotherapy is completed and 2 weeks have elapsed since the last date of therapy

          2. Subject has received daratumumab or other anti-CD38 therapies previously

          3. Subject has a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined
             significance, smoldering multiple myeloma, or solitary plasmacytoma.

          4. Subject has a diagnosis of Waldenström's macroglobulinemia, or other conditions in
             which IgM M-protein is present in the absence of a clonal plasma cell infiltration
             with lytic bone lesions.

          5. Subject has had plasmapheresis within 28 days of C1D1.

          6. Subject is exhibiting clinical signs of meningeal involvement of multiple myeloma.

          7. Myocardial infarction within 6 months prior to enrolment according to NYHA Class III
             or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias,
             or electrocardiographic evidence of acute ischemia or active conduction system
             abnormalities

          8. Uncontrolled hypertension

          9. Subjects with known chronic obstructive pulmonary disease (COPD) with a Forced
             Expiratory Volume (FEV1) in 1 second < 50% of predicted normal. Note that FEV1 testing
             is required for patients suspected of having COPD and subjects must be excluded if
             FEV1 < 50% of predicted normal.

         10. Subjects with a history of moderate or severe persistent asthma within the past 2
             years, or with uncontrolled asthma of any classification at the time of screening
             (Note that subjects who currently have controlled intermittent asthma or controlled
             mild persistent asthma are allowed in the study).

         11. Subject has plasma cell leukemia (according to WHO criterion: ≥ 20% of cells in the
             peripheral blood with an absolute plasma cell count of more than 2 × 10^9/L) or
             polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes
             syndrome.

         12. Systemic treatment with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin), strong
             inhibitors of CYP3A (as clarithromycin, telithromycin, itraconazole, voriconazole,
             ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (as rifampin,
             rifapentine, rifabutin, carbamazepine, phenytoin, fosphenytoin phenobarbital), or use
             of Ginkgo biloba or St. John's wort within 14 days before the first dose of study
             treatment.

         13. Known intolerance to steroid therapy

         14. History of hypersensitivity to any of the study medications, their analogues, or
             excipients in the various formulations, or to study-required co medication

         15. Subject has had major surgery within 2 weeks before the first dose of study treatment
             or will not have fully recovered from surgery, or has surgery planned during the time
             the subject is expected to participate in the study. Kyphoplasty or Vertebroplasty are
             not considered major surgery.

         16. Clinically relevant active infection or serious co-morbid medical conditions

         17. Prior malignancy except adequately treated basal cell or squamous cell skin cancer, in
             situ cervical, breast or prostate cancer free of disease since 5 years.

         18. Female subject who is pregnant or breast-feeding + male and female refusing birth
             control conditions

         19. Serious medical or psychiatric illness likely to interfere with participation in study

         20. Uncontrolled diabetes mellitus

         21. Known HIV infection; Known active hepatitis B or C viral infection; or other ongoing
             uncontrolled infection

         22. Incidence of gastrointestinal disease that may significantly after the absorption of
             oral drugs

         23. Subjects unable or unwilling to undergo antithrombotic prophylactic treatment

         24. Person under guardianship, trusteeship or deprived of freedom by a judicial or
             administrative decision
      
Maximum Eligible Age:65 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage of patients receiving the second Autologous Stem Cell Transplant
Time Frame:15 months
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Number of adverse events
Time Frame:48 months
Safety Issue:
Description:
Measure:Number of responses
Time Frame:48 months
Safety Issue:
Description:
Measure:Number of MRD
Time Frame:48 months
Safety Issue:
Description:
Measure:Number of death
Time Frame:84 months
Safety Issue:
Description:
Measure:Percentage of time to progression
Time Frame:84 months
Safety Issue:
Description:
Measure:Number of patients having survival without progress
Time Frame:84 months
Safety Issue:
Description:
Measure:Percentage duration of response
Time Frame:84 months
Safety Issue:
Description:
Measure:Number of cells collected
Time Frame:168 days
Safety Issue:
Description:
Measure:percentage of value of biological prognostic factors
Time Frame:48 months
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Nantes University Hospital

Trial Keywords

  • Multiple Myeloma
  • Newly Diagnosed
  • High Risk
  • Revlimid
  • Carfilzomib
  • Daratumumab
  • Dexaméthasone

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