Trial Title:
Pilot Study Using Changes in Serum BCMA to Determine Disease Progression in Multiple Myeloma
NCT ID:
NCT06209606
Condition:
Multiple Myeloma
Conditions: Official terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Disease Progression
Methylprednisolone
Methylprednisolone Acetate
Methylprednisolone Hemisuccinate
Prednisolone
Prednisolone acetate
Lenalidomide
Prednisolone hemisuccinate
Prednisolone phosphate
Study type:
Interventional
Study phase:
Early Phase 1
Overall status:
Not yet recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Sequential Assignment
Intervention model description:
This is a pilot, multicenter, open-label study evaluating the utility of using increases
in serum BCMA > 25% versus IMWG criteria to determine disease progression among patients
with RRMM treated with ruxolitinib and methylprednisolone to determine when to add
lenalidomide to the regimen. Subjects that were treated with ruxolitinib with
methylprednisolone and showed disease progression will have lenalidomide added to their
regimen. PD is defined by either change in sBCMA (≥ 25% increase from nadir) or by
standard IMWG criteria, whichever occurs first. PD will be confirmed by two consecutive
tests.
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Ruxolitinib Oral Tablet [Jakafi]
Description:
Ruxolitinib will be administered on days 1-28 of the treatment cycle.
Arm group label:
Rux + Steroid
Arm group label:
Rux + Steroid + Len
Other name:
Ruxolitinib, Jakafi
Intervention type:
Drug
Intervention name:
Lenalidomide
Description:
Lenalidomide will be administered on Days 1-21 of the treatment cycle.
Arm group label:
Rux + Steroid + Len
Other name:
Revlimid
Intervention type:
Drug
Intervention name:
Methylprednisolone
Description:
Methyl-prednisolone will be administered on Days 1-28 of the treatment cycle.
Arm group label:
Rux + Steroid
Arm group label:
Rux + Steroid + Len
Other name:
Depo-Medrol, Solu-Medrol, Methyl Prednisolonate
Summary:
This is a phase 1, multicenter, open-label study evaluating the safety and efficacy of
ruxolitinib, steroids and lenalidomide among MM patients who currently show progressive
disease using BCMA to test progression.
Detailed description:
In recent years, new and more effective drugs have become available for the treatment of
multiple myeloma (MM), resulting in a dramatic increase in median overall survival (OS).1
Therapeutic options have expanded to include immune-based approaches such as daratumumab
and elotuzumab.2 The clinical course of MM is highly variable, and relapsing/refractory
(RR)MM more so, with periods of response followed by periods of relapse. Improvements in
predicting and determining individual patient outcome would allow for more effective and
timely treatment interventions.
Over the last several years, we have identified a new serum biomarker, B cell maturation
antigen (BCMA), for monitoring patients with MM. Changes in serum (s)BCMA quickly
identify changes in the clinical status of MM and it is also a promising new prognostic
marker. Specifically, we demonstrated that compared to healthy donors, patients with MM
showed elevated levels of sBCMA.3 These levels were positively correlated with the
proportion of plasma cells in bone marrow biopsies and changes in monoclonal (M)-protein
and serum free light chain (SFLC) levels and indicated a patient's current clinical
status.3 Importantly, sBCMA levels were also independent of renal function and maintained
independent significance when tested against other known prognostic markers for MM
including age, serum β-2-microglobulin, hemoglobin, and presence of bone disease.
Furthermore, we demonstrated that increases in sBCMA by > 25% from start of any new
therapy predicted a markedly shorter progression free survival (PFS) and occurred much
more quickly than those observed with standard biomarkers to monitor the course of MM
including M-protein and SFLC levels.
To further validate sBCMA as a disease status biomarker for MM, we have incorporated
monitoring of sBCMA for all patients participating in several ongoing clinical trials.
Specifically, patients participating in a Phase 1 study of ruxolitinib,
methylprednisolone and lenalidomide for RRMM patients, were monitored weekly for sBCMA
and standard MM markers during their first treatment cycle and monthly thereafter. We
determined the safety and efficacy of this novel, all oral combination consisting of the
Janus kinase 1/2 inhibitor ruxolitinib in combination with lenalidomide and
methylprednisolone.5 Successive cohorts of participants (3 participants per cohort) were
given the following doses of drugs, all oral (PO): Dose Level 0: ruxolitinib 5 mg twice a
day (BID), methylprednisolone 40 mg every other day (QOD) and lenalidomide 5 mg daily
(QD) on days 1-21 of a 28-day cycle; Dose Level 1: ruxolitinib 10 mg BID,
methylprednisolone 40 mg QOD, and lenalidomide 5 mg QD on days 1 21 of a 28-day cycle;
Dose Level 2: ruxolitinib 15 mg BID, methylprednisolone 40 mg QOD, and lenalidomide 5 mg
QD on days 1 21 of a 28-day cycle), and Dose Level 3: ruxolitinib 15 mg BID,
methylprednisolone 40 mg QOD and lenalidomide 10 mg QD on days 1 21 of a 28-day cycle.
Dose Level 3 was the maximum administered dose.
Data analysis on the first 28 patients treated with this triple combination demonstrated
promising safety and efficacy profiles.5 Specifically, the clinical benefit rate (CBR)
and overall response rate (ORR)7 were 46% and 38%, respectively.5 No dose-limiting
toxicities occurred. Grade 3 or grade 4 adverse events (AEs) included anemia (18%),
thrombocytopenia (14%), and lymphopenia (14%). Most common serious AEs (SAE) included
sepsis (11%) and pneumonia (11%). Notably, all 12 responding patients were refractory to
lenalidomide and steroids.
To date, we have enrolled a total of 49 patients. Forty are evaluable for safety and
efficacy.8 The CBR and ORR were 47% and 37%, respectively. Responses included 1 complete
response (CR), 4 very good partial responses (VGPR), 10 partial responses (PR), and 4
minimal responses (MR), and 16 and 5 patient showed stable disease (SD) and progressive
disease (PD), respectively. Notably, all 19 patients achieving > MR were refractory to
lenalidomide (i.e., progressed while on or within 8 weeks of receiving the last dosage of
this drug). PFS for all evaluable patients was 4.0 months with the median follow-up time
of 3.0 months (range, 0.2 13.3). The median follow-up time for the responding patients
was 5.4 months (0.9 13.3) with the duration of response (DOR) of 5.0 months. This all
oral regimen was well tolerated, and reversible Grade 3/4 cytopenias occurred in only a
small minority of patients.
We analyzed sBCMA levels for these patients and demonstrated that its baseline levels
predicted PFS and increases of > 25% occurred more rapidly than those observed with M
protein or SFLC and predicted for a much shorter PFS.9 Specifically, serum BCMA was a
faster predictor than International Myeloma Working Group (IMWG) criteria of disease
progression for 67% of the MM patients showing disease progression, and no patient showed
progression more rapidly using IMWG criteria than sBCMA.
Furthermore, an expansion of the ongoing Phase 1 study is evaluating the combination of
ruxolitinib 15 mg BID and methylprednisolone 40 mg QOD continuously without lenalidomide
in this same patient population. Subjects are enrolled and treated with this two-drug
combination until disease progression. Twenty-nine patients were enrolled in the doublet
combination, and the ORR and CBR were both 45% (2 VGPR, 11 PR, 0 MR). Per study design,
once disease progression occurred as determined using IMWG criteria, lenalidomide at 10
mg PO daily on days 1 21 of a 28-day cycle was added to the regimen. To date, 19 subjects
have been enrolled in this portion of the study and 17 patients have completed at least 2
full cycles of lenalidomide-containing therapy. Ten patients have responded (3 PR and 7
MR) while 4 patients exhibited SD and 5 patients had PD.
These results show that the combination of ruxolitinib and steroids is active for
treating RRMM and that the addition of lenalidomide upon disease progression will
overcome disease progression in many patients. These results provide the basis for the
current trial which will use monitoring of sBCMA levels and IMWG criteria to more quickly
allow addition of lenalidomide to patients failing the two-drug combination.
Therefore, in this pilot study involving patients with RRMM initially treated with
ruxolitinib and methylprednisolone, we specifically propose to use changes in sBCMA
levels (> 25% increase from its nadir level) or conventional indicators of disease
progression per IMWG criteria (changes in M-protein and SFLC levels), whichever occurs
first, to determine when to add lenalidomide to patients failing the doublet combination
of ruxolitinib and methylprednisolone.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Subjects must meet all the following inclusion criteria to be eligible to enroll in
this study.
1. Has a diagnosis of MM based on standard criteria as follows:
Major criteria:
1. Plasmacytomas on tissue biopsy
2. BM plasmacytosis (greater than 30% plasma cells)
3. Monoclonal immunoglobulin spike on serum electrophoresis IgG greater than 3.5
g/dL or IgA greater than 2.0 g/dL or kappa or lambda light chain excretion
greater than 1 g/day on 24-hour urine protein electrophoresis
Minor criteria:
1. BM plasmacytosis (10% to 30% plasma cells)
2. Monoclonal immunoglobulin present but of lesser magnitude than given under
major criteria
3. Lytic bone lesions
4. Normal IgM less than 50 mg/dL, IgA less than 100 mg/dL, or IgG less than 600
mg/dL
Any of the following sets of criteria will confirm the diagnosis of multiple myeloma:
- any 2 of the major criteria
- major criterion 1 plus minor criterion 2, 3, or 4
- major criterion 3 plus minor criterion 1 or 3
- minor criteria 1, 2, and 3, or 1, 2, and 4
2. Currently has MM with measurable disease, defined as:
- a monoclonal immunoglobulin spike on serum electrophoresis of at least 0.5 g/dL
and/or urine monoclonal protein levels of at least 200 mg/24 hours
- for patients without measurable serum and urine M-protein levels, an involved SFLC >
100 mg/L or abnormal SFLC ratio
- for patients with IgD MM, a monoclonal immunoglobulin IgD of at least 5500 mg/L or
meet other measurable disease eligibility criteria
3. Currently has progressive MM and has received at least 2 prior regimens
including lenalidomide, a proteasome inhibitor, and an anti-CD38 antibody:
- Patients are considered relapsed when they progress greater than 8 weeks from their
last dose of treatment
- Patients are refractory when they progress while currently receiving the treatment
or within 8 weeks of its last dose
4. Ruxolitinib naïve
5. Understand and voluntarily sign an informed consent form before receiving any
study-related procedure that is not part of normal medical care, with the
understanding that consent may be withdrawn at any time without prejudice to
their future medical care
6. Able to adhere to the study visit schedule and other protocol requirements
7. ECOG performance status of ≤ 2 at study entry
8. Life-expectancy of greater than 3 months
9. Laboratory test results within these ranges at Screening and confirmed at
enrollment prior to drug dosing on Cycle 1, Day 1:
- Absolute neutrophil count ≥ 1.5 x 109/L
o If the bone marrow is extensively infiltrated (≥ 70% plasma cells) then ≥ 1.0 x
109/L
- Platelet count ≥ 75 x 109/L
o Patients must not have received platelet transfusion for at least 7 days prior to
receiving screening platelet count
- If the bone marrow is extensively infiltrated (≥ 70% plasma cells) then ≥ 50 x
109/L
- If patient have creatinine clearance of less than 60mL/min, patient's platelet
count must be greater than 150 x 109/L
- Hemoglobin ≥ 8.0 g/dL within 21 days prior to enrollment
o Use of erythropoietic stimulating factors and red blood cell (RBC) transfusions
per institutional guidelines is allowed; however, most recent RBC transfusion must
have been at least 7 days prior to obtaining screening hemoglobin.
- Calculated or measured CrCl > 60 mL/minute per Cockcroft-Gault (Appendix 3)
- Total bilirubin levels ≤ 2.0 mg/dL
- AST (SGOT) and ALT (SGPT) ≤ 2 x ULN
- Serum potassium 3.0 - 5.5 mEq/L
10. Patients receiving lenalidomide (Part 2 of the study) must be registered into
the mandatory REVLIMID REMS™ program, and be willing and able to comply with
the requirements of the REVLIMID REMS™ program
11. FCBP† must have a negative serum or urine pregnancy test with a sensitivity of
at least 25 mIU/mL within 10 - 14 days prior to and again within 24 hours of
starting ruxolitinib + methylprednisolone and must either commit to continued
abstinence from heterosexual intercourse or use acceptable methods of birth
control, one highly effective method and one additional effective method AT THE
SAME TIME, and at least 28 days before she starts taking ruxolitinib with or
without lenalidomide. FCBP must also agree to ongoing pregnancy testing. Men
must agree to use a latex condom during sexual contact with a FCBP even if they
have had a vasectomy. All subjects must be counseled at a minimum of every 28
days about pregnancy precautions and risks of fetal exposure.
†A FCBP (female of childbearing potential) is a sexually mature woman who: 1) has
not undergone a hysterectomy or bilateral oophorectomy; and 2) has not been
naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at
any time in the preceding 24 consecutive months)
12. Able to take antiplatelet therapy if platelet count is above 30 x 109/L.
Options include aspirin (acetylsalicylic acid, ASA) at 81 or 325 mg/daily and
warfarin or low molecular weight heparin if ASA-intolerant
Exclusion Criteria:
- Subjects meeting any of the following exclusion criteria are not to be enrolled in
the study:
1. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal
protein, and skin changes)
2. Plasma cell leukemia (> 2.0 × 109/L circulating plasma cells by standard
differential)
3. Primary amyloidosis
4. Non-hematologic malignancy within the past 5 years with the exception of a)
adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid
cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of
Gleason Grade 6 or less with stable prostate-specific antigen levels; or d)
cancer considered cured by surgical resection or unlikely to impact survival
during the duration of the study, such as localized transitional cell carcinoma
of the bladder or benign tumors of the adrenal or pancreas
5. Patients with uncontrolled infections
6. Impaired cardiac function or clinically significant cardiac diseases, including
any one of the following:
- Myocardial infarction within 6 months prior to enrollment
- New York Heart Association (NYHA) Class II or greater heart failure or
uncontrolled angina
- Clinically significant pericardial disease
- Severe uncontrolled ventricular arrhythmias
- Echocardiogram or MUGA evidence of LVEF below institutional normal within
28 days prior to enrollment
- Electrocardiographic evidence of acute ischemia or active conduction
system abnormalities. Prior to study entry, any ECG abnormality at
Screening must be documented by the investigator as not medically
relevant.
- Severe hypercalcemia, i.e., serum calcium ≥ 12 mg/dL (3.0 mmol/L)
corrected for albumin
7. Any serious medical condition, laboratory abnormality, or psychiatric illness
that would prevent the subject from signing the informed consent form
8. Any condition, including the presence of laboratory abnormalities, which places
the subject at unacceptable risk if he/she were to participate in the study or
confounds the ability to interpret data from the study
9. Undergone major surgery within 28 days prior enrollment or has not recovered
from side effects of such therapy (vertebroplasty or kyphoplasty is not
considered to be a major surgery; however, the investigator is to discuss
enrollment of a subject with a recent history of kyphoplasty with the medical
monitor).
10. Pregnant or breastfeeding females (lactating females must agree not to breast
feed while taking lenalidomide)
11. Received the following prior therapy:
- Chemotherapy within 3 weeks of study drugs
- Corticosteroids (>20 mg/daily prednisone or equivalent) within 3 weeks of
study drugs to ensure that steroid dose intensity at the beginning of the
treatment is not altered by administration of steroids prior to the study.
Consumption of steroids within 3 weeks of the treatment may interfere with
efficacy and side effects due to differences of steroid intensity.
- Immunotherapy, antibody therapy, immunomodulatory drugs, or proteasome
inhibitors within 3 weeks of study drugs
- Extensive radiation therapy within 28 days before study drugs. Receipt of
localized radiation therapy does not preclude enrollment.
- Use of any other experimental drug or therapy within 28 days of study
drugs
- JAK inhibitor including ruxolitinib
12. Strong CYP3A4 inhibitors, strong CYP3A4 inducers and fluconazole doses >200 mg
daily within 5 half-lives before study drugs. (For example, clarithromycin has
half-life of 4 hours so washout period for clarithromycin is 20 hours.)
13. Known hypersensitivity to compounds of similar chemical or biological
composition to thalidomide and lenalidomide or steroids.
14. Concurrent use of other anti-cancer agents or treatments
15. The development of erythema nodosum if characterized by a desquamating rash
while taking thalidomide or similar drugs
16. Known positivity for human immunodeficiency virus (HIV), hepatitis B or C, and
/or active tuberculosis (TB) including subjects with latent TB or with the risk
factor for activation of latent TB.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Start date:
January 2024
Completion date:
February 2029
Lead sponsor:
Agency:
Oncotherapeutics
Agency class:
Industry
Collaborator:
Agency:
Incyte Corporation
Agency class:
Industry
Source:
Oncotherapeutics
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06209606
