Phase 2 Study to Evaluate the Oral Combination of Ixazomib (MLN9708) With Cyclophosphamide and Dexamethasone in Patients With Newly Diagnosed or Relapsed and/or Refractory Multiple Myeloma

Multiple Myeloma Clinical Trial

Official title:

An Open-Label, Phase 2 Study to Evaluate the Oral Combination of Ixazomib (MLN9708) With Cyclophosphamide and Dexamethasone in Patients With Newly Diagnosed or Relapsed and/or Refractory Multiple Myeloma Requiring Systemic Treatment

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02046070
• Other study ID #: C16020
• Secondary ID: 2013-003113-17U1
• Status: Completed
• Phase: Phase 2
• Start date: March 5, 2014
• Est. completion date: June 29, 2018

Study information

• Verified date: June 2019
• Source: Takeda
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a phase 2, multicenter, open-label study in patients with Newly Diagnosed Multiple Myeloma (NDMM) who have not received prior systemic treatment for multiple myeloma (MM) and who are ineligible for high-dose therapy (HDT)-stem cell transplantation (SCT) due to age (ie, ≥ 65 years) or comorbid disease(s) or with Relapsed and/or Refractory Multiple Myeloma (RRMM).

Description:

The investigational drug being tested in this study is called MLN9708 also known as Ixazomib. This study will look at disease response rates and safety in people who take ixazomib in addition to cyclophosphamide and dexamethasone. NDMM participants will be randomly assigned (by chance, like flipping a coin) to one of two treatment groups and RRMM participants will be assigned to a third group:

• NDMM - ixazomib (MLN9708) 4.0 mg + cyclophosphamide 300 mg/m^2 + dexamethasone 40 mg

• NDMM - ixazomib (MLN9708) 4.0 mg + cyclophosphamide 400 mg/m^2 + dexamethasone 40 mg

• RRMM - ixazomib (MLN9708) 4.0 mg + cyclophosphamide 300 mg/m^2 + dexamethasone 40 mg

The study enrolled 148 participants. This multi-centre trial will be conducted in the United States, European Union, and Australia.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 148
• Est. completion date: June 29, 2018
• Est. primary completion date: June 29, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

Each participant with newly diagnosed multiple myeloma (NDMM) must meet all of the following inclusion criteria to be enrolled in the study:

1. Adult male or female participants 18 years of age or older with a confirmed diagnosis of symptomatic multiple myeloma (MM) according to standard criteria.

2. Participants for whom cyclophosphamide and dexamethasone treatment is appropriate and who are considered not eligible for high-dose therapy (HDT)-stem cell transplantation (SCT) for 1 or more of the following reasons:

• The participant is 65 years of age or older.

• The participant is less than 65 years of age but has significant comorbid condition(s) that are, in the opinion of the investigator, likely to have a negative impact on tolerability of HDT-SCT.

Each participant with relapsed and/or refractory multiple myeloma (RRMM) must meet all of the following inclusion criteria to be enrolled in the study:

1. Adult male or female participants 18 years or older with a confirmed diagnosis of symptomatic MM either currently or at the time of initial diagnosis, according to standard criteria, and relapsed and/or refractory disease after 1 to 3 lines of prior therapy. A participant is considered to have refractory disease if disease progression occurred during the treatment period or within 60 days of receiving the last dose of a given therapy. A line of therapy is defined as 1 or more cycles of a single-agent or combination therapy or a sequence of planned treatments such as induction therapy followed by autologous stem cell transplantation (ASCT) and then maintenance therapy.

2. No evidence of graft-versus-host disease for participants who have undergone prior allogeneic stem cell transplantation.

In addition, all participants (NDMM and RRMM) must meet all of the remaining criteria:

1. Participants must have measurable disease defined by at least 1 of the following 3 measurements:

• Serum M-protein = 1 g/dL (= 10 g/L).

• Urine M-protein = 200 mg/24 hours.

• Serum free light chain assay: involved free light chain level = 10 mg/dL (= 100 mg/L), provided that the serum free light chain ratio is abnormal.

2. Participants must meet all of the following clinical laboratory criteria:

• Absolute neutrophil count (ANC) = 1000/mm^3 and platelet count = 75,000/mm^3. Platelet transfusions to help participants meet eligibility criteria are not allowed within 3 days prior to administration of the study drug.

• Total bilirubin = 1.5 x the upper limit of the normal range (ULN).

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) = 3 x ULN.

• Calculated creatinine clearance (CrCL) = 30 mL/min.

3. Eastern Cooperative Oncology Group performance status of 0, 1, or 2.

4. Female participants who:

• are postmenopausal for at least 1 year before the screening visit, or

• are surgically sterile, or

• If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 90 days after the last dose of study drug, or

• agree to practice true abstinence over the period previously described, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence [ie, calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable methods of contraception.), and

• adhere to any treatment-specific pregnancy prevention guidelines for cyclophosphamide and dexamethasone.

5. Male participants, even if surgically sterilized (ie, status post-vasectomy), who:

• 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 over the period previously described, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods for the female partner] and withdrawal are not acceptable methods of contraception.), and

• adhere to any treatment-specific pregnancy prevention guidelines for cyclophosphamide and dexamethasone.

6. 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.

7. Suitable venous access for the study-required blood sampling.

8. Is willing and able to adhere to the study visit schedule and other protocol requirements.

Exclusion Criteria:

1. Prior treatment for multiple myeloma with either standard of care treatment or investigational regimen (for participants with NDMM only).

NOTE: Prior treatment with corticosteroids (maximum dose of corticosteroids should not exceed the equivalent of 160 mg of dexamethasone over 14 days. Localized radiation is permitted as long as it is below a therapeutic level and administered at least 14 days prior to the first dose of study treatment.

2. Diagnosis of smoldering MM, Waldenström's macroglobulinemia, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome.

3. Central nervous system involvement.

4. Diagnosed or treated for another malignancy within 2 years before the first dose or previously diagnosed with another malignancy and have any evidence of residual disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.

5. Peripheral neuropathy Grade 1 with pain or Grade 2 or higher peripheral neuropathy of any cause on clinical examination during the Screening period.

6. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of study drug, including difficulty swallowing.

7. Infection requiring intravenous (IV) antibiotic therapy or other serious infection within 14 days before the first dose of study drug.

8. Ongoing or active infection, known human immunodeficiency virus (HIV) positive, active hepatitis B or C infection.

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

10. Known allergy to any of the study medications, their analogues, or excipients in the various formulations.

11. Major surgery within 14 days before the first dose of study drug. (Note: kyphoplasty or vertebroplasty is not considered major surgery.)

12. Female participants who are lactating and breastfeeding or have a positive serum pregnancy test during the Screening period.

13. Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.

14. Comorbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the participant inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.

15. Treatment with any investigational products for reasons other than MM within 30 days before the first dose of study drug.

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

Drug:
• Cyclophosphamide
Cyclophosphamide tablets
• Ixazomib
Ixazomib capsules
• Dexamethasone
Dexamethasone tablets

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Millennium Pharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Australia,  Greece,  Poland,  Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Combined Response Rate During the Induction Phase in Newly Diagnosed Multiple Myeloma (NDMM) Participants	Combined Response Rate is the percentage of participants with Complete Response (CR), including stringent Complete Response (sCR), and Very Good Partial Response (VGPR) according to the International Myeloma Working Group (IMWG) criteria during the Induction Phase (Cycles 1-13, 28-day cycles). CR=negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow. VGPR=serum and urine M-component detectable by immunofixation but not on electrophoresis or 90% reduction in serum M-component plus urine M-component <100 mg/24 hour.	Day 1 of Cycles 1-13, 28-day cycles (Up to 1 year)
Primary	Overall Response Rate (ORR) in Relapsed and/or Refractory Multiple Myeloma (RRMM) Participants	ORR is the percentage of participants with CR, VGPR or PR according to IMWG criteria. CR=negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas and <5% plasma cells (PC) in bone marrow. VGPR=serum and urine M-component detectable by immunofixation but not on electrophoresis or 90% reduction in serum M-component plus urine M-component <100 mg/24 hour. PR=50% reduction of serum M-protein and reduction in 24 hour urine M-protein by 90% or <200 mg/24 hour or decrease 50% difference between involved free light chain (FLC) levels or 50% reduction in bone marrow plasma cells if baseline percentage was 30%; and if present at Baseline, 50% reduction in the size of soft tissue plasmacytomas.	Day 1 of each 28 day cycle (Up to 45 months)
Secondary	Number of Participants With Adverse Events (AEs), Grade 3 or Higher AEs, AEs Resulting in Treatment Discontinuation, AEs Resulting in Dose Reduction and Serious Adverse Events (SAEs) in NDMM Participants	An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not it is related to the medicinal product. This includes any newly occurring event, or a previous condition that has increased in severity or frequency since the administration of study drug.; A SAE is any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event. Relationship of each AE to study drug was determined by the Investigator.	First dose of study drug through 30 days after last dose of drug (Up to 45 months)
Secondary	Percentage of Participants With CR + VGPR + PR (ORR), CR, VGPR, PR and Stable Disease (SD), Progressive Disease (PD) During the Induction Phase	Percentage of participants with CR + VGPR + PR (ORR), CR, VGPR, PR, SD, PD according to IMWG criteria. CR=negative immunofixation of serum and urine; disappearance of soft tissue plasmacytomas;<5% PC in bone marrow. VGPR=serum and urine M-component detectable by immunofixation but not on electrophoresis or 90% reduction in serum M-component plus urine M-component <100 mg/24 hour. PR=50% reduction of serum M-protein and reduction in 24 hour urine M-protein by 90% or <200 mg/24 hour or decrease 50% difference between involved FLC levels or 50% reduction in bone marrow plasma cells if baseline percentage was 30%; and if present at Baseline, 50% reduction in the size of soft tissue plasmacytomas. SD=not meeting criteria for VGPR, PR or PD. PD=25% increase in lowest value any of the following: serum M-component, urine M-component, difference between involved and uninvolved FLC levels, bone marrow PC percentage; new or increase in size of existing bone lesions or soft tissue plasmacytomas.	Day 1 of Cycles 1-13, 28-day cycles (Up to 1 year)
Secondary	Percentage of Participants With CR + VGPR + PR (ORR), CR + VGPR, CR, VGPR, PR, SD and PD Throughout the Entire Treatment Period in NDMM Participants	Percentage of participants with CR + VGPR + PR (ORR), CR, VGPR, PR, SD, PD according to IMWG criteria. CR=negative immunofixation of serum and urine; disappearance of soft tissue plasmacytomas;<5% PC in bone marrow. VGPR=serum and urine M-component detectable by immunofixation but not on electrophoresis or 90% reduction in serum M-component plus urine M-component <100 mg/24 hour. PR=50% reduction of serum M-protein and reduction in 24 hour urine M-protein by 90% or <200 mg/24 hour or decrease 50% difference between involved FLC levels or 50% reduction in bone marrow plasma cells if baseline percentage was 30%; and if present at Baseline, 50% reduction in the size of soft tissue plasmacytomas. SD=not meeting criteria for VGPR, PR or PD. PD=25% increase in lowest value any of the following: serum M-component, urine M-component, difference between involved and uninvolved FLC levels, bone marrow PC percentage; new or increase in size of existing bone lesions or soft tissue plasmacytomas.	Day 1 of each 28-day Cycle (Up to 45 months)
Secondary	Time to Response (TTR) in NDMM Participants During the Induction Phase	TTR is defined as the time interval from the date of the first dose of study treatment to the date of the first documented confirmed response of PR or better up to the initiation of alternative therapy in a participant who responded.	Up to 1 year
Secondary	Duration of Response (DOR) in NDMM Participants	DOR is defined as the time from the date of first documentation of a confirmed PR or better to the date of first documented PD up to the initiation of alternative therapy.	Up to 45 Months
Secondary	Time to Progression (TTP) in NDMM Participants	TTP is defined as the time from the date of first dose of study treatment to the date of first documentation of disease progression.	Up to 45 months
Secondary	Progression Free Survival (PFS) in NDMM Participants	PFS is defined as the time from the date of first dose of study treatment to the date of the first documented disease progression or death.	Up to 45 months
Secondary	Number of Participants With AEs, SAEs, AEs Resulting in Discontinuation and AEs Resulting in Dose Reduction in NDMM Participants Remaining on Treatment After 13 Cycles	An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not it is related to the medicinal product. This includes any newly occurring event, or a previous condition that has increased in severity or frequency since the administration of study drug.; A SAE is any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event. Relationship of each AE to study drug was determined by the Investigator.	First dose of study drug through 30 days after the last dose of drug (Up to 45 months)
Secondary	Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) During the Induction Phase in NDMM Participants	EORTC QLQ-C30 is a patient completed 30 item questionnaire that consists of 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 1 global health status scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The patient evaluates their health status over the previous week. There are 28 questions answered on a 4-point scale where1=Not at all (best) to 4=Very Much (worst) and 2 questions answered on a 7-point scale where 1=Very poor (worst) to 7= Excellent (best). All of the scales and single-item measures are transformed to a score:0 to 100. For functioning scales and global QOL higher scores indicate better functioning (a positive change from Baseline indicates improvement); for symptom scales higher scores indicate more severe symptoms (a negative change from Baseline indicates improvement).	Baseline (BL) (Day 1 of Cycle 1), Day 1 of Cycle 13 (Up to 1 year)
Secondary	Percentage of Participants With CR + VGR + PR (ORR), CR, VGPR, and PR in NDMM Participants Remaining on Treatment After 13 Cycles	Percentage of participants with Overall Response (CR + VGPR + PR), CR, VGPR and PR according to IMWG criteria. CR=negative immunofixation of serum and urine; disappearance of soft tissue plasmacytomas;<5% PC in bone marrow. VGPR=serum and urine M-component detectable by immunofixation but not on electrophoresis or 90% reduction in serum M-component plus urine M-component <100 mg/24 hour. PR=50% reduction of serum M-protein and reduction in 24 hour urine M-protein by 90% or <200 mg/24 hour or decrease 50% difference between involved FLC levels or 50% reduction in bone marrow plasma cells if baseline percentage was 30%; and if present at Baseline, 50% reduction in the size of soft tissue plasmacytomas.	Day 1 of each 28-day Cycle (Up to 45 months)
Secondary	Cmax: Maximum Observed Plasma Concentration for Ixazomib in NDMM Participants		Cycle 1 Days 1 and 15 predose and at multiple timepoints (up to 168 hours) postdose
Secondary	Tmax: Time to First Occurrence of Cmax for Ixazomib in NDMM Participants		Cycle 1 Days 1 and 15 predose and at multiple timepoints (up to 168 hours) postdose
Secondary	AUCtau: Area Under the Concentration-time Curve During a Dosing Interval for Ixazomib in NDMM Participants		Cycle 1 Days 1 and 15 predose and at multiple timepoints (up to 168 hours) postdose
Secondary	Number of Participants With AEs, Grade 3 or Higher AEs, AEs Resulting in Treatment Discontinuation, AEs Resulting in Dose Reduction, SAEs in RRMM Participants	An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment.; A SAE is any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event. Relationship of each AE to study drug was determined by the Investigator.	First dose of study drug through 30 days after last dose of drug (Up to 45 months)
Secondary	Cmax: Maximum Observed Plasma Concentration for Ixazomib in RRMM Participants		Cycle 1 Days 1 and 15 predose and at multiple timepoints (up to 168 hours) postdose
Secondary	Tmax: Time to First Occurrence of Cmax for Ixazomib in RRMM Participants		Cycle 1 Days 1 and 15 predose and at multiple timepoints (up to 168) hours postdose
Secondary	AUCtau: Area Under the Concentration-time Curve During a Dosing Interval for Ixazomib in RRMM Participants		Cycle 1 Days 1 and 15 predose and at multiple timepoints (up to 168 hours) postdose
Secondary	Percentage of Participants With (CR + VGPR), CR, VGPR, PR, SD and PD in RRMM Participants	Percentage of participants with CR + VGPR + PR (ORR), CR, VGPR, PR, SD, PD according to IMWG criteria. CR=negative immunofixation of serum and urine; disappearance of soft tissue plasmacytomas;<5% PC in bone marrow. VGPR=serum and urine M-component detectable by immunofixation but not on electrophoresis or 90% reduction in serum M-component plus urine M-component <100 mg/24 hour. PR=50% reduction of serum M-protein and reduction in 24 hour urine M-protein by 90% or <200 mg/24 hour or decrease 50% difference between involved FLC levels or 50% reduction in bone marrow plasma cells if baseline percentage was 30%; and if present at Baseline, 50% reduction in the size of soft tissue plasmacytomas. SD=not meeting criteria for VGPR, PR or PD. PD=25% increase in lowest value any of the following: serum M-component, urine M-component, difference between involved and uninvolved FLC levels, bone marrow PC percentage; new or increase in size of existing bone lesions or soft tissue plasmacytomas.	Day 1 of each 28-day Cycle (Up to 45 months)
Secondary	Time to Response (TTR) in RRMM Participants	TTR is defined as the time interval from the date of the first dose of study treatment to the date of the first documented confirmed response of PR or better up to the alternative therapy in a participant who responded.	Up to 45 months
Secondary	Duration of Response (DOR) in RRMM Participants	DOR is defined as the time from the date of first documentation of a confirmed PR or better to the date of first documented PD up to the alternative therapy.	Up to 45 months
Secondary	Time to Progression (TTP) in RRMM Participants	TTP is defined as the time from the date of first dose of study treatment to the date of first documentation of disease progression.	Up to 45 months
Secondary	Progression Free Survival (PFS) in RRMM Participants	PFS is defined as the time from the date of first dose of study treatment to the date of the first documented disease progression or death.	Up to 45 months
Secondary	Change From Baseline in EORTC Quality of Life Questionnaire (QLQ-C30) in RRMM Participants	EORTC QLQ-C30 is a patient completed 30 item questionnaire that consists of 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 1 global health status scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The patient evaluates their health status over the previous week. There are 28 questions answered on a 4-point scale where1=Not at all (best) to 4=Very Much (worst) and 2 questions answered on a 7-point scale where 1=Very poor (worst) to 7= Excellent (best). All of the scales and single-item measures are transformed to a score:0 to 100. For functioning scales and global QOL higher scores indicate better functioning (a positive change from Baseline indicates improvement); for symptom scales higher scores indicate more severe symptoms (a negative change from Baseline indicates improvement).	Baseline (Day 1 of Cycle 1), Day 1 of End of Treatment (EOT) (Up to 45 months)