Ixazomib, Cyclophosphamide and Dexamethasone for Multiple Myeloma

• Sponsor: John L. Reagan (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02412228
• Collaborator: Rhode Island Hospital (Other), The Miriam Hospital (Other), Memorial Hospital of Rhode Island (Other)
• Enrollment: 12
• Locations: 3
• Arm: 1
• Duration (Months): 109
• Patients Per Site: 4
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The goal of this proposal is to develop a more effective and better tolerated regimen. Ixazomib appears to have greater activity than bortezomib with less peripheral neuropathy.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: Ixazomib; Drug: Cyclophosphamide; Drug: Dexamethasone	Phase 2

Detailed Description

1.1 PRIMARY OBJECTIVE: 1.1.1 To evaluate the response rate of Ixazomib with metronomic cyclophosphamide and dexamethasone for first-line treatment of multiple myeloma 1.2 SECONDARY OBJECTIVES: 1.2.1To evaluate the toxicities associated with Ixazomib with metronomic cyclophosphamide and dexamethasone.

1.2.2 Estimate the progression-free survival and overall survival of Ixazomib with metronomic cyclophosphamide and dexamethasone for first-line treatment of multiple myeloma

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: BrUOG 299: Ixazomib, Oral Metronomic Cyclophosphamide and Dexamethasone for First-Line Treatment of Multiple Myeloma: A Phase II Brown University Oncology Group Study.
• Study Start Date: Aug 1, 2015
• Actual Primary Completion Date: Mar 29, 2019
• Anticipated Study Completion Date: Sep 1, 2024

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Ixazomib Regimen Cycle 1: Ixazomib: 4mg/day 1, 8, 15, Cyclophosphamide: 50 mg/day continuous daily, Dexamethasone: 20 mg/day 1, 8, 15 Cycles 2-6: Ixazomib: 4mg/day 1, 4, 8, 11, 15, 18, Cyclophosphamide: 50 mg/day continuous, daily, Dexamethasone: 20 mg/day 1, 4, 8, 11, 15, 18 Maintenance: Ixazomib at 4 mg days 1, 8 and 15 of a 28 day cycle for 1 ½ years

Drug: Ixazomib; Cycle 1: Ixazomib: 4mg/day 1, 8, 15 Cycles 2-6: Ixazomib: 4mg/day 1, 4, 8, 11, 15, 18, Maintenance: Ixazomib at 4 mg days 1, 8 and 15 of a 28 day cycle for 1 ½ years; Other Names: MLN978 ; Drug: Cyclophosphamide; Cycle 1: Cyclophosphamide: 50 mg/day continuous daily Cycles 2-6: Cyclophosphamide: 50 mg/day continuous daily; Other Names: cytophosphane ; Drug: Dexamethasone; Cycle 1: Dexamethasone: 20 mg/day 1, 8, 15 Cycles 2-6: Dexamethasone: 20 mg/day 1, 4, 8, 11, 15, 18; Other Names: Ozurdex

Outcome Measures

Primary Outcome Measures

1. Evaluation of the Response Rate of Ixazomib With Metronomic Cyclophosphamide and Dexamethasone for First-line Treatment of Multiple Myeloma. [Through study treatment completion, an average of 2 years]

Secondary Outcome Measures

1. Evaluation of the Toxicities Associated With Ixazomib With Metronomic Cyclophosphamide and Dexamethasone. [Assessed at baseline and end of study, up to 2 years, end of study reported]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age ≥ 18 years of age

• Histologically confirmed multiple myeloma according to WHO classification. Pathology report to be sent to BrUOG for confirmation

• Diagnosis of Multiple Myeloma that has not been previously treated (although patients that received emergent steroid and/or local radiation therapy will be permitted to enter the study). , Details need to be submitted to BrUOG with dates and doses.

• Measureable disease defined as either an elevated serum M-protein, urine M-protein, bone marrow involvement >30% or serum free light chains per the IMWG criteria. Confirmation to be sent to BrUOG, see section 7 for criteria

• Life expectancy of ≥ 6 months, confirmation per treating investigator required

• Absolute neutrophil count (ANC) ≥ 1,000/mm3 and platelet count ≥ 75,000/mm3. Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days before study enrollment. If transfusional support provided, please document for submission to BrUOG

• Calculated creatinine clearance ≥30 mL/min (based on the Cockcroft-Gault Equation below)

For males:

Creatinine Clearance = (140-age[years] x weight [kg]) 72 x (serum creatinine[mg/dL])

For females:

Creatinine Clearance = 0.85 (140-age[years] x weight [kg]) 72 x (serum creatinine[mg/dL])

• ECOG performance status of 0-1.

• Adequate Liver function; AST or ALT < 3.0 x upper limit of normal (ULN); Total bilirubin <1.5x ULN

• 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 patient at any time without prejudice to future medical care.

• Female patients 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 form through 90 days after the last dose of study drug and obtain a pregnancy test, which must come back negative prior to drug, OR

• Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject and obtain a serum pregnancy test, which must come back negative prior to drug. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.) Documentation and confirmation of conversations and patient commitment to contraception is required to be noted and sent to BrUOG. Female's menopausal status to be documented and submitted to BrUOG if applicable. Pregnancy test, if applicable, required to be sent to BrUOG.

• Male patients, even if surgically sterilized (ie, status post-vasectomy), 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 when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.) Documentation and confirmation of conversations and patient commitment to contraception is required to be noted and sent to BrUOG.

Exclusion Criteria:

• Female patients who are lactating or have a positive serum pregnancy test during the screening period.

• Any surgery within 14 days before enrollment.

• Radiotherapy within 14 days before enrollment.

• Central nervous system involvement (myeloma-related).

• Active infection requiring systemic antibiotic therapy or other serious active infection within 7 days before study enrollment.

• Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months.

• Systemic treatment, within 14 days before the first dose of ixazomib, 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.

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

• Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol. If not applicable, then investigator to document not applicable

• Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent. If not applicable, then investigator to document not applicable

• Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib including difficulty swallowing. If not applicable, then investigator to document not applicable

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

• Patient has ≥ Grade 2 peripheral neuropathy or Grade 1 with pain.

• Participation in other therapeutic 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Memorial Hospital of Rhode Island	Pawtucket	Rhode Island	United States	02860
2	Rhode Island Hospital	Providence	Rhode Island	United States	02903
3	The Miriam Hospital	Providence	Rhode Island	United States	02906

Sponsors and Collaborators

• John L. Reagan
• Rhode Island Hospital
• The Miriam Hospital
• Memorial Hospital of Rhode Island

Investigators

• Study Chair: Howard Safran, MD, BrUOG

Study Documents (Full-Text)

• Study Protocol, Statistical Analysis Plan, and Informed Consent Form - Dec 10, 2018

More Information

Publications

None provided.

• Responsible Party: John L. Reagan, Principal Investigator: Sponsor-Investigator, Brown University
• ClinicalTrials.gov Identifier: NCT02412228
• Other Study ID Numbers: 299
• First Posted: Apr 9, 2015
• Last Update Posted: Jul 25, 2022
• Last Verified: Jul 1, 2022

• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Dexamethasone; Cyclophosphamide; Ixazomib

Study Results

Participant Flow

Arm/Group Title	Ixazomib Regimen
Arm/Group Description	Cycle 1: Ixazomib: 4mg/day 1, 8, 15, Cyclophosphamide: 50 mg/day continuous daily, Dexamethasone: 20 mg/day 1, 8, 15 Cycles 2-6: Ixazomib: 4mg/day 1, 4, 8, 11, 15, 18, Cyclophosphamide: 50 mg/day continuous, daily, Dexamethasone: 20 mg/day 1, 4, 8, 11, 15, 18 Maintenance: Ixazomib at 4 mg days 1, 8 and 15 of a 28 day cycle for 1 ½ years Ixazomib: Cycle 1: Ixazomib: 4mg/day 1, 8, 15 Cycles 2-6: Ixazomib: 4mg/day 1, 4, 8, 11, 15, 18, Maintenance: Ixazomib at 4 mg days 1, 8 and 15 of a 28 day cycle for 1 ½ years Cyclophosphamide: Cycle 1: Cyclophosphamide: 50 mg/day continuous daily Cycles 2-6: Cyclophosphamide: 50 mg/day continuous daily Dexamethasone: Cycle 1: Dexamethasone: 20 mg/day 1, 8, 15 Cycles 2-6: Dexamethasone: 20 mg/day 1, 4, 8, 11, 15, 18
Period Title: Overall Study
STARTED	12
COMPLETED	12
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Ixazomib Regimen
Arm/Group Description	Cycle 1: Ixazomib: 4mg/day 1, 8, 15, Cyclophosphamide: 50 mg/day continuous daily, Dexamethasone: 20 mg/day 1, 8, 15 Cycles 2-6: Ixazomib: 4mg/day 1, 4, 8, 11, 15, 18, Cyclophosphamide: 50 mg/day continuous, daily, Dexamethasone: 20 mg/day 1, 4, 8, 11, 15, 18 Maintenance: Ixazomib at 4 mg days 1, 8 and 15 of a 28 day cycle for 1 ½ years Ixazomib: Cycle 1: Ixazomib: 4mg/day 1, 8, 15 Cycles 2-6: Ixazomib: 4mg/day 1, 4, 8, 11, 15, 18, Maintenance: Ixazomib at 4 mg days 1, 8 and 15 of a 28 day cycle for 1 ½ years Cyclophosphamide: Cycle 1: Cyclophosphamide: 50 mg/day continuous daily Cycles 2-6: Cyclophosphamide: 50 mg/day continuous daily Dexamethasone: Cycle 1: Dexamethasone: 20 mg/day 1, 8, 15 Cycles 2-6: Dexamethasone: 20 mg/day 1, 4, 8, 11, 15, 18
Overall Participants	12
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	8 66.7%
>=65 years	4 33.3%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	61
Sex: Female, Male (Count of Participants)
Female	2 16.7%
Male	10 83.3%
Race and Ethnicity Not Collected (Count of Participants)
Region of Enrollment (Count of Participants)
United States	12 100%

Outcome Measures

1. Primary Outcome

Title	Evaluation of the Response Rate of Ixazomib With Metronomic Cyclophosphamide and Dexamethasone for First-line Treatment of Multiple Myeloma.
Time Frame	Through study treatment completion, an average of 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ixazomib Regimen
Arm/Group Description	Cycle 1: Ixazomib: 4mg/day 1, 8, 15, Cyclophosphamide: 50 mg/day continuous daily, Dexamethasone: 20 mg/day 1, 8, 15 Cycles 2-6: Ixazomib: 4mg/day 1, 4, 8, 11, 15, 18, Cyclophosphamide: 50 mg/day continuous, daily, Dexamethasone: 20 mg/day 1, 4, 8, 11, 15, 18 Maintenance: Ixazomib at 4 mg days 1, 8 and 15 of a 28 day cycle for 1 ½ years Ixazomib: Cycle 1: Ixazomib: 4mg/day 1, 8, 15 Cycles 2-6: Ixazomib: 4mg/day 1, 4, 8, 11, 15, 18, Maintenance: Ixazomib at 4 mg days 1, 8 and 15 of a 28 day cycle for 1 ½ years Cyclophosphamide: Cycle 1: Cyclophosphamide: 50 mg/day continuous daily Cycles 2-6: Cyclophosphamide: 50 mg/day continuous daily Dexamethasone: Cycle 1: Dexamethasone: 20 mg/day 1, 8, 15 Cycles 2-6: Dexamethasone: 20 mg/day 1, 4, 8, 11, 15, 18
Measure Participants	12
Count of Participants [Participants]	12 100%

2. Secondary Outcome

Title	Evaluation of the Toxicities Associated With Ixazomib With Metronomic Cyclophosphamide and Dexamethasone.
Time Frame	Assessed at baseline and end of study, up to 2 years, end of study reported

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ixazomib Regimen
Arm/Group Description	Cycle 1: Ixazomib: 4mg/day 1, 8, 15, Cyclophosphamide: 50 mg/day continuous daily, Dexamethasone: 20 mg/day 1, 8, 15 Cycles 2-6: Ixazomib: 4mg/day 1, 4, 8, 11, 15, 18, Cyclophosphamide: 50 mg/day continuous, daily, Dexamethasone: 20 mg/day 1, 4, 8, 11, 15, 18 Maintenance: Ixazomib at 4 mg days 1, 8 and 15 of a 28 day cycle for 1 ½ years Ixazomib: Cycle 1: Ixazomib: 4mg/day 1, 8, 15 Cycles 2-6: Ixazomib: 4mg/day 1, 4, 8, 11, 15, 18, Maintenance: Ixazomib at 4 mg days 1, 8 and 15 of a 28 day cycle for 1 ½ years Cyclophosphamide: Cycle 1: Cyclophosphamide: 50 mg/day continuous daily Cycles 2-6: Cyclophosphamide: 50 mg/day continuous daily Dexamethasone: Cycle 1: Dexamethasone: 20 mg/day 1, 8, 15 Cycles 2-6: Dexamethasone: 20 mg/day 1, 4, 8, 11, 15, 18
Measure Participants	12
Count of Participants [Participants]	12 100%

Adverse Events

Time Frame	All adverse events and special reporting situations were reported from the time a signed and dated ICF is obtained until 30 days after the last dose of drug, up to 25 months, or until the subject withdraws consent from study participation (declines participation) or at the time patient becomes a screen failure, whichever occurs first, an average of 2 years.
Arm/Group Title	Ixazomib Regimen
Arm/Group Description	Cycle 1: Ixazomib: 4mg/day 1, 8, 15, Cyclophosphamide: 50 mg/day continuous daily, Dexamethasone: 20 mg/day 1, 8, 15 Cycles 2-6: Ixazomib: 4mg/day 1, 4, 8, 11, 15, 18, Cyclophosphamide: 50 mg/day continuous, daily, Dexamethasone: 20 mg/day 1, 4, 8, 11, 15, 18 Maintenance: Ixazomib at 4 mg days 1, 8 and 15 of a 28 day cycle for 1 ½ years Ixazomib: Cycle 1: Ixazomib: 4mg/day 1, 8, 15 Cycles 2-6: Ixazomib: 4mg/day 1, 4, 8, 11, 15, 18, Maintenance: Ixazomib at 4 mg days 1, 8 and 15 of a 28 day cycle for 1 ½ years Cyclophosphamide: Cycle 1: Cyclophosphamide: 50 mg/day continuous daily Cycles 2-6: Cyclophosphamide: 50 mg/day continuous daily Dexamethasone: Cycle 1: Dexamethasone: 20 mg/day 1, 8, 15 Cycles 2-6: Dexamethasone: 20 mg/day 1, 4, 8, 11, 15, 18
All Cause Mortality
	Ixazomib Regimen
	Affected / at Risk (%)	# Events
Total	0/12 (0%)
Serious Adverse Events
	Ixazomib Regimen
	Affected / at Risk (%)	# Events
Total	1/12 (8.3%)
Gastrointestinal disorders
Enterocolitis	1/12 (8.3%)
Other (Not Including Serious) Adverse Events
	Ixazomib Regimen
	Affected / at Risk (%)	# Events
Total	12/12 (100%)
Blood and lymphatic system disorders
Anemia	9/12 (75%)
Cardiac disorders
Palpitations	1/12 (8.3%)
Eye disorders
Eye disorders, other	4/12 (33.3%)
Gastrointestinal disorders
Abdominal distension	1/12 (8.3%)
Bloating	2/12 (16.7%)
Constipation	3/12 (25%)
Dental caries	1/12 (8.3%)
Diarrhea	4/12 (33.3%)
Dyspepsia	2/12 (16.7%)
Mucositis	3/12 (25%)
Nausea	5/12 (41.7%)
Oral pain	1/12 (8.3%)
Vomit	1/12 (8.3%)
General disorders
Chills	2/12 (16.7%)
Edema	4/12 (33.3%)
Fatigue	3/12 (25%)
Fever	1/12 (8.3%)
Flu-like symptoms	2/12 (16.7%)
Non-cardiac chest pain	1/12 (8.3%)
Pain	7/12 (58.3%)
Immune system disorders
Allergic reaction	1/12 (8.3%)
Infections and infestations
Infection and infestations, other	6/12 (50%)
Rhinitis	1/12 (8.3%)
Sinusitis	1/12 (8.3%)
Thrush	1/12 (8.3%)
Injury, poisoning and procedural complications
Bruising	1/12 (8.3%)
Investigations
Alanine aminotransferase increased	1/12 (8.3%)
Alkaline phosphatase increased	2/12 (16.7%)
Blood bicarbonate decreased	1/12 (8.3%)
Creatinine increased	6/12 (50%)
Ejection fraction decreased	1/12 (8.3%)
Lymphocyte count decreased	10/12 (83.3%)
Neutrophil count decreased	4/12 (33.3%)
Platelet count decreased	11/12 (91.7%)
Weight gain	6/12 (50%)
Weight loss	4/12 (33.3%)
White blood cell decreased	8/12 (66.7%)
Metabolism and nutrition disorders
Hyperglycemia	5/12 (41.7%)
Hypoalbuminemia	1/12 (8.3%)
Obesity	2/12 (16.7%)
Hypercalcemia	1/12 (8.3%)
Hyperkalemia	1/12 (8.3%)
Hypermagnesemia	4/12 (33.3%)
Hypokalemia	1/12 (8.3%)
Hypomagnesemia	1/12 (8.3%)
Hyponatremia	2/12 (16.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	3/12 (25%)
Back pain	4/12 (33.3%)
Bone pain	3/12 (25%)
Muscle weakness	1/12 (8.3%)
Myalgia	2/12 (16.7%)
Neck pain	2/12 (16.7%)
Pain in extremity	1/12 (8.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasm benign, other	1/12 (8.3%)
Nervous system disorders
Dizziness	4/12 (33.3%)
Dysgeusia	2/12 (16.7%)
Headache	2/12 (16.7%)
Paresthesia	1/12 (8.3%)
Peripheral sensory neuropathy	7/12 (58.3%)
Presyncope	1/12 (8.3%)
Psychiatric disorders
Anxiety	2/12 (16.7%)
Insomnia	6/12 (50%)
Renal and urinary disorders
Bladder pressure	1/12 (8.3%)
Hematuria	1/12 (8.3%)
Proteinuria	1/12 (8.3%)
Urinary retention	1/12 (8.3%)
Reproductive system and breast disorders
Testicular pain	2/12 (16.7%)
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	1/12 (8.3%)
Cough	3/12 (25%)
Dyspnea	3/12 (25%)
Epistaxis	1/12 (8.3%)
Nasal congestion	3/12 (25%)
Sore throat	4/12 (33.3%)
Skin and subcutaneous tissue disorders
Alopecia	1/12 (8.3%)
Dry skin	1/12 (8.3%)
Photosensitivity	2/12 (16.7%)
Pruritus	2/12 (16.7%)
Rash	10/12 (83.3%)
Urticaria	1/12 (8.3%)
Vascular disorders
Flushing	2/12 (16.7%)
Hypertension	2/12 (16.7%)
Hypotension	3/12 (25%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.