Study of Oral Ixazomib in Combination With Melphalan and Prednisone in Participants With Newly Diagnosed Multiple Myeloma

Browse trials for

• Multiple Myeloma 3,632
• Neoplasms, Plasma Cell 2,306

Keywords

• Drug Therapy

Multiple Myeloma

3,632 studies on the registry are indexed under Multiple Myeloma; 745 are open to participants now.

This study's enrollment of 61 is above the median of 41 across 2,907 interventional studies indexed under Multiple Myeloma.

Lead sponsor

Millennium Pharmaceuticals, Inc. is the lead sponsor of 173 studies on the registry; none are open to participants now.

Of its 73 completed or terminated interventional studies of FDA-regulated products, 72 (99%) have results posted.

Study arms

• Experimental
  Arm A: Ixazomib 3.0 mg

  Ixazomib 3.0 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m\^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m\^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle for up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 23 maintenance cycles; overall up to 32 cycles \[34 months\]).

  Drug: Ixazomib · Drug: Melphalan · Drug: Prednisone

• Experimental
  Arm A: Ixazomib 3.7 mg

  Ixazomib 3.7 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m\^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m\^2, tablets, orally on Days 1 to 4 in 42-day cycle for up 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 10 maintenance cycles; overall up to 19 cycles \[21 months\]).

  Drug: Ixazomib · Drug: Melphalan · Drug: Prednisone

• Experimental
  Arm B: Ixazomib 3.0 mg

  Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m\^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m\^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 15 maintenance cycles; overall up to 27 cycles \[25 months\]).

  Drug: Ixazomib · Drug: Melphalan · Drug: Prednisone

• Experimental
  Arm B: Ixazomib 4.0 mg

  Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 cycle plus melphalan 6 mg/m\^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m\^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 49 maintenance cycles; overall up to 61 cycles \[58 months\]).

  Drug: Ixazomib · Drug: Melphalan · Drug: Prednisone

• Experimental
  Arm B: Ixazomib 5.5 mg

  Ixazomib 5.5 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m\^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m\^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 24 cycles \[24 months\]).

  Drug: Ixazomib · Drug: Melphalan · Drug: Prednisone

• Experimental
  Arm C: Ixazomib 3.0 mg

  Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m\^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m\^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 30 maintenance cycles; overall up to 39 cycles \[40 months\]).

  Drug: Ixazomib · Drug: Melphalan · Drug: Prednisone

• Experimental
  Arm C: Ixazomib 4.0 mg

  Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m\^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m\^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 21 cycles \[24 months\]).

  Drug: Ixazomib · Drug: Melphalan · Drug: Prednisone

• Experimental
  Arm D: Ixazomib 4.0 mg

  Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 22, and 29 plus melphalan 9 mg/m\^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m\^2, tablets, orally, on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 28 maintenance cycles; overall up to 37 cycles \[38 months\]).

  Drug: Ixazomib · Drug: Melphalan · Drug: Prednisone

Interventions

• DrugIxazomib

  Ixazomib capsules

• DrugMelphalan

  Melphalan tablets

• DrugPrednisone

  Prednisone tablets

Primary outcomes

1. Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Ixazomib (Phase 1)

   The RP2D is the maximum tolerated dose (MTD) or less. The MTD is defined as the dose range at which ≤ 1 of 6 evaluable participants experience dose limiting toxicities (DLT) within the first 28 days of treatment (end of Cycle 1).

   Time frame: Cycle 1, phase 1 (Up to 42 days)

2. Very Good Partial Response (VGPR) or Better Response Rate (Phase 2)

   VGPR or better response rate is defined as percentage of participants with a complete response (CR) and very good partial response (VGPR). Per International Myeloma Working Group Uniform Response Criteria (IMWG), CR: 1) Negative immunofixation on the serum and urine, 2) Disappearance of any soft tissue plasmacytomas and 3) \< 5% plasma cells in bone marrow. VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level \< 100 mg per 24 hour.

   Time frame: Day 1 of every other cycle from Day 1 of Cycle 2 (each cycle of 28 days) until death (Up to 5.5 years)

Secondary outcomes

1. Maximum Inhibition Rate (Emax) (Phase 1)

   Whole blood 20S proteasome inhibition parameters

   Time frame: At multiple time points during Cycles 1-3 of each phase and arm of the study, throughout approximately 84-126 days depending on the arm of the study

2. Time of Occurrence of Emax (TEmax) (Phase 1)

   Whole blood 20S proteasome inhibition parameters

   Time frame: At multiple time points during Cycles 1-3 of each phase and arm of the study, throughout approximately 84-126 days depending on the arm of the study

3. Cmax: Maximum Observed Plasma Concentration for Ixazomib (Phase 1)

   Time frame: Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D

4. Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib (Phase 1)

   Time frame: Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D

5. AUCtau: Area Under the Plasma Concentration-time Curve Over the Dosing Interval for Ixazomib (Phase 1)

   Time frame: Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D

6. Terminal Elimination Rate Constant (λz) for Ixazomib (Phase 1)

   Terminal elimination rate constant, calculated as the negative of the slope of the log-linear regression of the natural logarithm concentration-time curve during the terminal phase.

   Time frame: Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D

7. Terminal Phase Elimination Half-life (T1/2) for Ixazomib (Phase 1)

   Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma.

   Time frame: Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D

8. Observed Accumulation Ratio for AUCtau (Rac) (Phase 1)

   Accumulation ratio for AUCtau (Rac) was calculated as area under the curve from time zero to end of dosing interval (AUCtau) on Day 14 divided by area under the curve from time zero to end of dosing interval (AUCtau) on Day 1.

   Time frame: Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D

9. Overall Response Rate (ORR)

   ORR is defined as percentage of participants with overall response including CR, VGPR, and partial response (PR). Per IMWG criteria, CR:1)Negative immunofixation on serum and urine, 2)Disappearance of any soft tissue plasmacytomas, 3)\< 5% plasma cells in bone marrow. VGPR: Serum+urine M-protein detectable by immunofixation but not on electrophoresis/ 90% or \>reduction in serum M-protein + urine M-protein level \< 100 mg/ 24-hour. PR:1)≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24-hour. If serum+urine M-protein are unmeasurable, ≥50% decrease in difference between involved and uninvolved FLC levels is required. If serum+urine M-protein are unmeasurable and serum free light assay is also unmeasurable, ≥50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was ≥30%. In addition, if present at baseline, a ≥50% reduction in size of soft tissue plasmacytomas is required.

   Time frame: Day 1 of every other cycle from Day 1 of Cycle 2 (each cycle of 28 days) up to 61 cycles, at end of treatment (Up to 5.5 years)

10. Time to First Response (Phase 2)

    Response is defined as CR, VGPR and PR. Per IMWG criteria, CR:1)Negative immunofixation on serum+urine, 2)Disappearance of any soft tissue plasmacytomas, 3)\< 5% plasma cells in bone marrow. VGPR: Serum+urine M-protein detectable by immunofixation but not on electrophoresis/ 90% or \>reduction in serum M-protein + urine M-protein level \< 100 mg/ 24-hour. PR:1)≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24-hour. If serum+urine M-protein are unmeasurable, ≥50% decrease in difference between involved and uninvolved FLC levels is required. Else, ≥50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was ≥30%. In addition, if present at baseline, a ≥50% reduction in size of soft tissue plasmacytomas is required.

    Time frame: From the date of enrollment to the date of the first documented response for up to 5.5 years

11. Duration of Response (DOR) (Phase 2)

    DOR is defined as time of first documentation of a confirmed PR or better response to first documented PD or start of alternative therapy. DOR was presented for those achieving CR+VGPR+PR. Per IMWG criteria, CR:1)Negative immunofixation on serum+urine, 2)Disappearance of any soft tissue plasmacytomas, 3)\< 5% plasma cells in bone marrow. VGPR: Serum+urine M-protein detectable by immunofixation but not on electrophoresis/ 90% or \>reduction in serum M-protein + urine M-protein level \< 100 mg/ 24-hour. PR:1)≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24-hour. If serum+urine M-protein are unmeasurable, ≥50% decrease in difference between involved and uninvolved FLC levels is required. Else, ≥50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was ≥30%. In addition, if present at baseline, a ≥50% reduction in size of soft tissue plasmacytomas is required.

    Time frame: From the time from the date of first documentation of PR or better to the date of first documented disease progression for up to 5.5 years

12. Time to Progression (TTP) (Phase 2)

    TTP is defined as time from date of enrollment to date of first documented disease progression (PD). Per IMWG criteria, progressive disease requires any 1 or more of following: Increase of ≥25% from nadir in serum M-component and/or (absolute increase must be ≥0.5 g/dL), urine M-component and/or (absolute increase must be ≥200 mg/24 hour. Participants without measurable serum+urine M-protein levels: difference between involved and uninvolved FLC levels. The absolute increase must be \>10 mg/dL. Bone marrow plasma cell percentage: absolute % must be ≥10%. Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in size of existing bone lesions or soft tissue plasmacytomas. Development of hypercalcemia (corrected serum calcium \>11.5 mg/dL or 2.85 mmol/L) that can be attributed solely to plasma cell proliferative disorder.

    Time frame: From the date of enrollment to the date of the first documented disease progression for up to 5.5 years

13. Time to Next Therapy (Phase 2)

    Time to Next Therapy is defined as time from the date of enrollment to the date of subsequent antineoplastic therapy.

    Time frame: From the date of enrollment to the date of subsequent antineoplastic therapy for up to 5.5 years

14. Progression Free Survival (Phase 2)

    Progression Free Survival is defined as time in months from start of study treatment to first documentation of objective tumor progression per investigator assessment or up to death due to any cause, whichever occurs first. Per IMWG criteria, progressive disease requires any 1 or more of following: Increase of ≥25% from nadir in serum M-component and/or (absolute increase must be ≥0.5 g/dL), urine M-component and/or (absolute increase must be ≥200 mg/24 hour. Participants without measurable serum+urine M-protein levels: difference between involved and uninvolved FLC levels. The absolute increase must be \>10 mg/dL. Bone marrow plasma cell percentage: absolute % must be ≥10%. Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in size of existing bone lesions or soft tissue plasmacytomas. Development of hypercalcemia (corrected serum calcium \>11.5 mg/dL or 2.85 mmol/L) that can be attributed solely to plasma cell proliferative disorder.

    Time frame: From the date of enrollment to the date of the first documented disease progression or death due to any cause for up to 5.5 years

15. Overall Survival (Phase 2)

    Overall Survival is the time in months from start of study treatment to date of death due to any cause.

    Time frame: From date of enrollment to date of death, approximately 5.5 years (Approximate median follow-up: 43.6 months)

16. Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)

    An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment.

    Time frame: From first dose of study drug through 30 days after last dose of study drug or until the start of subsequent antineoplastic therapy for up to 5.6 years

17. Assessments of Quality of Life (Phase 2)

    Time frame: Baseline, Day 1 of each treatment cycle, and Day 1 of each maintenance cycle, up to 5.5 years

Baseline characteristics

1 further baseline measures are reported on the registry.

Publications

• San-Miguel JF, Echeveste Gutierrez MA, Spicka I, Mateos MV, Song K, Craig MD, Blade J, Hajek R, Chen C, Di Bacco A, Estevam J, Gupta N, Byrne C, Lu V, van de Velde H, Lonial S. A phase I/II dose-escalation study investigating all-oral ixazomib-melphalan-prednisone induction followed by single-agent ixazomib maintenance in transplant-ineligible newly diagnosed multiple myeloma. Haematologica. 2018 Sep;103(9):1518-1526. doi: 10.3324/haematol.2017.185991. Epub 2018 Jun 28. PubMed 29954932 ↗