Study on the Effect of Ibrutinib on High Risk Smoldering Multiple Myeloma Patients

• Sponsor: Icahn School of Medicine at Mount Sinai (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02943473
• Collaborator: Pharmacyclics LLC. (Industry)
• Enrollment: 9
• Location: 1
• Arm: 1
• Actual Duration (Months): 27.8
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this research study is to test whether the drug ibrutinib (trademark name:

IMBRUVICA®) is effective at preventing the development of multiple myeloma in people who currently have smoldering myeloma. The researchers conducting this trial) have reason to believe that ibrutinib can delay the development of multiple myeloma, thus giving people who currently have smoldering myeloma a longer period of time when they feel healthy and well.

Smoldering myeloma is an abnormal condition that is considered to be an early phase of the disease multiple myeloma. In this disorder, there is an abnormal growth of plasma cells, which is a type of blood cell found in the bone marrow. This growth is not as severe in people with smoldering myeloma as it is in multiple myeloma, so people with smoldering myeloma do not have any symptoms and tend to feel well. However, they have a higher risk of developing multiple myeloma than people in the general population.

Some people with smoldering myeloma are at an especially high risk of developing myeloma - 50% of these people will develop multiple myeloma 2 years after they are diagnosed with smoldering myeloma. The investigators identify these people by looking at the amount of myeloma in the bone marrow (called "bone marrow plasma cell percentage") and the amount of myeloma protein (called "serum protein electrophoresis" and "serum free light chain assay") in the blood. To be considered high risk, individuals must have highly abnormal levels for these tests.

Based upon current guidelines, people with smoldering myeloma do not require any treatment. However, known is that many of these people will develop multiple myeloma in the near future. Currently there have been no proven and effective way of preventing these people from developing multiple myeloma, which remains an incurable disease.

Condition or Disease	Intervention/Treatment	Phase
High Risk Smoldering Multiple Myeloma	Drug: Ibrutinib	Phase 2

Detailed Description

This is a phase 2, open-label, single center, prospective pilot study designed to assess the efficacy of ibrutinib in subjects with high risk smoldering multiple myeloma.

All enrolled subjects will be treated with ibrutinib 560 mg (4 capsules, each containing 140 mg) taken PO daily for 12 cycles (28 days each). If a subject demonstrates benefit from ibrutinib, therapy may be extended beyond 12 cycles to a maximum of 2 years. Subjects who progress and meet criteria for symptomatic multiple myeloma will be withdrawn from study.

An initial cohort of 15 subjects will be accrued. If 4 or more patients progress to symptomatic myeloma in one year, then the study will be reviewed with the FDA to determine whether to employ a higher dose of ibrutinib, or to stop for futility. Otherwise, 21 additional patients will be accrued for a total sample size of 36.

Study Design

• Study Type: Interventional
• Actual Enrollment: 9 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Study of the Effect of the Bruton's Tyrosine Kinase Inhibitor Ibrutinib on Disease Response in Patients With High Risk Smoldering Multiple Myeloma
• Actual Study Start Date: May 18, 2017
• Actual Primary Completion Date: Sep 10, 2019
• Actual Study Completion Date: Sep 10, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ibrutinib Ibrutinib (trademark name is IMBRUVICA®). 560 mg dose administered on a continuous basis	Drug: Ibrutinib; Ibrutinib is a type of drug called a "kinase inhibitor." Kinases are proteins inside cells that help cells live and grow. Ibrutinib blocks a specific kinase protein in our bodies. This protein is thought to be very important in helping blood cancer cells live and grow. By blocking this kinase protein, ibrutinib stops cancer cells from growing.; Other Names: IMBRUVICA

Outcome Measures

Primary Outcome Measures

1. Number of Patients Without Symptomatic Myeloma [up to 1 year]

   Disease response - the proportion of patients with high risk smoldering multiple myeloma who do not progress to symptomatic myeloma as defined by the IMWG.

Secondary Outcome Measures

1. Overall Response Rate [up to 1 year]

   Overall response rate, defined as partial response or better per IMWG criteria. (IMWG response criteria are - Complete Response, Very good partial response, partial response, Minimal response, stable disease, and progressive disease)

2. Bone Density Changes [baseline and one year]

   Changes in bone density, particularly in patients with osteopenia (defined as T-score on bone densitometry testing (DEXA) of -1 to -2.5).

3. PET-MRI Changes [baseline and one year]

   Changes in PET-MRI, particularly in patients with osteopenia

4. Change in Serum Interleukin-6 (IL-6) [baseline and up to one year]

   Bone Related Biomarker Changes

5. Change in Serum Stromal Cell-derived Factor-1 (SDF-1) [baseline and up to one year]

   Bone Related Biomarker Changes

6. Change in Serum Receptor Activator of Nuclear-factor Kappa B Ligand (RANKL) [baseline and up to one year]

   Bone Related Biomarker Changes

7. Change in Serum Macrophage Inflammatory Protein-1α (MIP-1α) [baseline and up to one year]

   Bone Related Biomarker Changes

8. Change in Serum Dickkopf-1 (DKK-1) [baseline and up to one year]

   Bone Related Biomarker Changes

9. Change in Serum C-terminal Telopeptide (CTX) [baseline and up to one year]

   Bone Related Biomarker Changes

10. Change in Urine N-terminal Telopeptide (NTx) [baseline and up to one year]

    Bone Related Biomarker Changes

Eligibility Criteria

Criteria

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

Inclusion Criteria Disease Related

1. High risk SMM, defined as follows by Mayo Clinic criteria:

2. Bone marrow plasma cells between 10% and 60%

3. Serum M-protein ≥ 3 g/dL [except IgA ≥ 2 g/dL] or urine M-protein > 500 mg per 24 hours

4. Serum free light chain ratio < 0.126 or > 8; an involved to uninvolved ratio of ≥ 100 is permitted

5. Measurable disease, defined as: M-protein ≥ 1 g/dL OR Bence-Jones protein (BJP) > 200 mg/24 hr OR involved free light chain > 100 mg/dL

6. Diagnosed with SMM within the last 4 years

Laboratory

1. Adequate hematologic function independent of transfusion and growth factor support for at least 7 days prior to screening, with the exception of pegylated G-CSF (pegfilgrastim) and darbopoetin which require at least 14 days prior to screening defined as:

• Absolute neutrophil count > 750 cells/mm3 (1.0 x 109/L).

• Platelet count > 75,000 cells/mm3 (75 x 109/L).

1. Adequate hepatic and renal function defined as:

• Serum aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 x upper limit of normal (ULN).

• Estimated creatinine clearance ≥ 30 ml/min (Cockcroft-Gault)

• Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin, in which case the total bilirubin should be < 3 x ULN)

1. PT/INR < 1.5 x ULN and PTT (aPTT) < 1.5 x ULN

Demographic

1. Men and women ≥ 18 years of age

2. Eastern Cooperative Oncology Group (ECOG) performance status of < 2

Exclusion Criteria Disease-Related

1. No end organ damage attributable to a plasma cell disorder, defined as having ANY of the following:

2. Hypercalcemia: Serum calcium > 1 mg/dL above the upper limit of normal or > 11 mg/dL

3. Renal insufficiency: Serum creatinine > 2 mg/dL or creatinine clearance < 30 mL per min

4. Anemia: Hemoglobin value > 2 g/dL below the upper limit of normal or a hemoglobin value < 10 g/dL

5. Bone lesions: One or more lytic lesions on skeletal radiography, CT, MRI, PET-CT, or PET-MRI

6. Bone marrow plasma cells < 10% or > 60%

7. Has received prior anti-myeloma therapy of any type

8. Has received prior bisphosphonate therapy

9. Has received an investigational drug, investigational vaccine, or has used an investigational medical device within 4 weeks or 4 half-lives, whichever is longer, before Cycle 1, Day 1 of study therapy

10. Osteoporosis, defined as having a T-score on DEXA of ≤ -2.5

Concurrent Conditions

1. History of other malignancies, except:

• Malignancy treated with curative intent and with no known active disease present for ≥ 3 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician

• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease

• Adequately treated carcinoma in situ without evidence of disease

1. Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, tacrolimus, etc). Any use of corticosteroids EITHER for > 14 days OR at dosages > 20 mg/day of prednisone or equivalent is prohibited.

2. Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug

3. Recent infection requiring systemic treatment that was completed ≤ 14 days before the first dose of study drug

4. Known bleeding disorders (eg, von Willebrand's disease) or hemophilia

5. History of stroke or intracranial hemorrhage within 6 months prior to enrollment

6. Known HIV, HCV or HBV infection. Subjects who are positive for hepatitis B core antibody or hepatitis B surface antigen must have a negative polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive will be excluded.

7. Any uncontrolled active systemic infection

8. Major surgery within 4 weeks of first dose of study drug

9. Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigators' opinion, could compromise the subject's safety or put the study outcomes at undue risk

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Icahn School of Medicine at Mount Sinai	New York	New York	United States	10029

Sponsors and Collaborators

• Icahn School of Medicine at Mount Sinai
• Pharmacyclics LLC.

Investigators

• Principal Investigator: Ajai Chari, MD, Icahn School of Medicine at Mount Sinai

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 17, 2017

More Information

Publications

None provided.

• Responsible Party: Ajai Chari, Associate Professor, Icahn School of Medicine at Mount Sinai
• ClinicalTrials.gov Identifier: NCT02943473
• Other Study ID Numbers: GCO 16-1867
• First Posted: Oct 24, 2016
• Last Update Posted: Dec 16, 2020
• Last Verified: Nov 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Ajai Chari, Associate Professor, Icahn School of Medicine at Mount Sinai: Smoldering multiple myeloma; myeloma; smoldering; ibrutinib
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Smoldering Multiple Myeloma

Study Results

Participant Flow

Recruitment Details	Participants enrolled from May 2017 through June 2019

Arm/Group Title	Ibrutinib
Arm/Group Description	Ibrutinib (trademark name is IMBRUVICA®). 560 mg dose taken PO daily for 12 cycles (28 days each). Ibrutinib: Ibrutinib is a type of drug called a "kinase inhibitor." Kinases are proteins inside cells that help cells live and grow. Ibrutinib blocks a specific kinase protein in our bodies. This protein is thought to be very important in helping blood cancer cells live and grow. By blocking this kinase protein, ibrutinib stops cancer cells from growing.
Period Title: Overall Study
STARTED	9
COMPLETED	3
NOT COMPLETED	6

Baseline Characteristics

Arm/Group Title	Ibrutinib
Arm/Group Description	Ibrutinib (trademark name is IMBRUVICA®). 560 mg dose administered on a continuous basis Ibrutinib: Ibrutinib is a type of drug called a "kinase inhibitor." Kinases are proteins inside cells that help cells live and grow. Ibrutinib blocks a specific kinase protein in our bodies. This protein is thought to be very important in helping blood cancer cells live and grow. By blocking this kinase protein, ibrutinib stops cancer cells from growing.
Overall Participants	9
Age, Customized (Count of Participants)
50-59 years old	3 33.3%
60 years and older	6 66.7%
Sex: Female, Male (Count of Participants)
Female	3 33.3%
Male	6 66.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 22.2%
Not Hispanic or Latino	7 77.8%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	8 88.9%
More than one race	0 0%
Unknown or Not Reported	1 11.1%

Outcome Measures

1. Primary Outcome

Title	Number of Patients Without Symptomatic Myeloma
Description	Disease response - the proportion of patients with high risk smoldering multiple myeloma who do not progress to symptomatic myeloma as defined by the IMWG.
Time Frame	up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ibrutinib
Arm/Group Description	Ibrutinib (trademark name is IMBRUVICA®). 560 mg dose administered on a continuous basis Ibrutinib: Ibrutinib is a type of drug called a "kinase inhibitor." Kinases are proteins inside cells that help cells live and grow. Ibrutinib blocks a specific kinase protein in our bodies. This protein is thought to be very important in helping blood cancer cells live and grow. By blocking this kinase protein, ibrutinib stops cancer cells from growing.
Measure Participants	7
Count of Participants [Participants]	5 55.6%

2. Secondary Outcome

Title	Overall Response Rate
Description	Overall response rate, defined as partial response or better per IMWG criteria. (IMWG response criteria are - Complete Response, Very good partial response, partial response, Minimal response, stable disease, and progressive disease)
Time Frame	up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Bone Density Changes
Description	Changes in bone density, particularly in patients with osteopenia (defined as T-score on bone densitometry testing (DEXA) of -1 to -2.5).
Time Frame	baseline and one year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	PET-MRI Changes
Description	Changes in PET-MRI, particularly in patients with osteopenia
Time Frame	baseline and one year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Change in Serum Interleukin-6 (IL-6)
Description	Bone Related Biomarker Changes
Time Frame	baseline and up to one year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Change in Serum Stromal Cell-derived Factor-1 (SDF-1)
Description	Bone Related Biomarker Changes
Time Frame	baseline and up to one year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Change in Serum Receptor Activator of Nuclear-factor Kappa B Ligand (RANKL)
Description	Bone Related Biomarker Changes
Time Frame	baseline and up to one year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Secondary Outcome

Title	Change in Serum Macrophage Inflammatory Protein-1α (MIP-1α)
Description	Bone Related Biomarker Changes
Time Frame	baseline and up to one year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Secondary Outcome

Title	Change in Serum Dickkopf-1 (DKK-1)
Description	Bone Related Biomarker Changes
Time Frame	baseline and up to one year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Secondary Outcome

Title	Change in Serum C-terminal Telopeptide (CTX)
Description	Bone Related Biomarker Changes
Time Frame	baseline and up to one year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Secondary Outcome

Title	Change in Urine N-terminal Telopeptide (NTx)
Description	Bone Related Biomarker Changes
Time Frame	baseline and up to one year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	1 year
Arm/Group Title	Ibrutinib
Arm/Group Description	Ibrutinib (trademark name is IMBRUVICA®). 560 mg dose administered on a continuous basis Ibrutinib: Ibrutinib is a type of drug called a "kinase inhibitor." Kinases are proteins inside cells that help cells live and grow. Ibrutinib blocks a specific kinase protein in our bodies. This protein is thought to be very important in helping blood cancer cells live and grow. By blocking this kinase protein, ibrutinib stops cancer cells from growing.
All Cause Mortality
	Ibrutinib
	Affected / at Risk (%)	# Events
Total	0/3 (0%)
Serious Adverse Events
	Ibrutinib
	Affected / at Risk (%)	# Events
Total	0/3 (0%)
Other (Not Including Serious) Adverse Events
	Ibrutinib
	Affected / at Risk (%)	# Events
Total	3/3 (100%)
Blood and lymphatic system disorders
Leukopenia	2/3 (66.7%)	3
Neutropenia	2/3 (66.7%)	2
Anemia	2/3 (66.7%)	2
Thrombocytopenia	1/3 (33.3%)	3
Gastrointestinal disorders
Nausea	2/3 (66.7%)	2
Vomiting	1/3 (33.3%)	1
Diarrhea	2/3 (66.7%)	2
Loose stools	1/3 (33.3%)	1
Gastroesophageal reflux	1/3 (33.3%)	1
Abdominal Pain	1/3 (33.3%)	1
General disorders
Headache	1/3 (33.3%)	1
Tingling in Tongue	1/3 (33.3%)	1
Fatigue	1/3 (33.3%)	1
Hepatobiliary disorders
Elevated AST	1/3 (33.3%)	1
Infections and infestations
Urinary tract infection	1/3 (33.3%)	1
Upper respiratory infection	1/3 (33.3%)	1
Investigations
Elevated ALT	1/3 (33.3%)	2
Metabolism and nutrition disorders
Hyponatremia	1/3 (33.3%)	1
Hypertension	1/3 (33.3%)	1
Musculoskeletal and connective tissue disorders
Leg cramps	1/3 (33.3%)	1
Left musculoskeletal chest pain	1/3 (33.3%)	2
Blateral ankle pain	1/3 (33.3%)	1
Knee discomfort right	1/3 (33.3%)	1
Right shoulder pain	1/3 (33.3%)	1
Groin pain right	1/3 (33.3%)	1
Psychiatric disorders
Insomnia	1/3 (33.3%)	1
Anxiety	1/3 (33.3%)	1
Renal and urinary disorders
Hematuria	1/3 (33.3%)	1
Reproductive system and breast disorders
Irregular menses	1/3 (33.3%)	1
Skin and subcutaneous tissue disorders
Rash	1/3 (33.3%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.