Phase II study assessing the effect of carfilzomib treatment on early free light chain kinetics in myeloma patients with renal impairment
Australiasian Leukemia and Lymphoma Group
40 participants
Apr 2, 2015
Interventional
Conditions
Summary
The efficacy of proteasome inhibitors (bortezomib, carfilzomib) in reversing or ameliorating renal impairment in myeloma patients has been demonstrated. The response to myeloma therapy can often be better gauged by the reduction in serum free light chains which have a shorter half-life of 3 to 5 hours, as compared with the full immunoglobulin paraprotein. The initial, very early impact on the level of free light chains is therefore likely to be critical in the effectiveness of carfilzomib in reversing renal failure. We aim to assess the effect of carfilzomib therapy on serum free light chains at very early time-points (24 and 48 hours after the day 2 dose and 24 hours after day 9 dose) following dose administration, with the aim of assessing the value of these measurements as a marker of efficacy and, in future trials, the basis on which to modify treatment regime to maximise the improvement in renal function.
Eligibility
Inclusion Criteria18
- All of the following criteria must be satisfied for enrolment in the study.
- Male and Female patients, >=18 years of age
- Patients with newly diagnosed MM (diagnosis of MM as per IMWG –21)
- Or
- Multiple myeloma with relapsing or progressing disease at study entry,
- With either
- Measurable M-component in serum or urine,
- In patients with no detectable M-component, an abnormal FLC ratio on the Serum FLC assay
- For IgA patients whose disease can only be reliably measured by serum quantitative immunoglobulin (qIgA) >= 750 mg^dL (0.75 g^dL).
- Patients with acute renal injury as the cause of reduced renal function, with creatinine clearance 15-40 ml^min at screening (calculated by the CKD-EPI and MDRD formulae)
- Difference between involved and uninvolved free light chain >=300 mg^L
- Adequate liver function (total bilirubin < 1.5 ULN, ALT < 2.5x ULN)
- Absolute neutrophil count >= 1.0 x 109^L within one week of starting therapy.
- Platelet count >= 50 x 109^L (>= 30 x 109^L if myeloma involvement in the marrow is greater than 50%) within one week of starting therapy, patients should not have received platelet transfusions within one week of the screening platelet count
- Hb >= 80g^L, red cell transfusions as per institutional protocol are allowed
- Subject must have LVEF >= 40%, determined by 2-D transthoracic echocardiogram (ECHO) is the preferred method of evaluation. Multigated Acquisition Scan (MUGA) is acceptable if ECHO is not available.
- Has provided written informed consent
- Males capable of parenting a child and females of childbearing potential must be using a medically acceptable and adequate method of contraception while undergoing protocol treatment and for 12 weeks after the last treatment
Exclusion Criteria17
- Presence of any of the following criteria will exclude the subject from enrolment in the study.
- Patients who have had myocardial infarction within 6 months prior to enrolment, or NYHA (New York Hospital Association) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, electrocardiographic evidence of acute ischemia or active conduction system abnormalities at any time.
- Other uncontrolled intercurrent illness including, but not limited to, severe active infection, or psychiatric illness/social situations that would limit compliance with study requirements
- Evidence of infection, dehydration or hypercalcaemia as the cause of acute kidney injury that has not been corrected.
- Patients on dialysis at Screening.
- Patients with known amyloidosis.
- Patients with myelodysplastic syndrome.
- Known history of allergy to Captisol (a cyclodextrin derivative used to solubilise carfilzomib)
- Patients with contraindication to dexamethasone.
- Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to antiviral drugs, or intolerance to hydration due to pre-existing pulmonary or cardiac impairment.
- Women who are pregnant or lactating. Females of child-bearing potential must have a negative urine pregnancy test at Screening.
- Known Hepatitis B, Hepatitis C, HIV infection, other immunosuppressive therapy including dexamethasone or autoimmune disease
- Prior diagnosis of cancer that was:
- more than 5 years prior to current diagnosis with subsequent evidence of disease recurrence or clinical expectation of recurrence is greater than 10%.
- within 5 years of current diagnosis with the exception of successfully treated basal cell or squamous cell skin carcinoma or carcinoma in situ of the cervix.
- Participation in other therapeutic studies in the last 60 days except for studies with a non-medical intervention. Documented evidence of receiving placebo will be required.
- Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule. This condition must be discussed with the patient prior to signing consent and registration in the trial.
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Interventions
Carfilzomib is a proteasome inhibitor and protease inibitors have been shown to be particularly effective in patients with renal failure, with an increased incidence of reversal or amelioration of renal impairment, and have been considered treatment-of-choice in MM patients presenting with renal failure. Carfilzomib (IV) will be given on Days 1, 2, 8, 9, 15, 16 of a 4-week cycle for Cycles 1 to 9, followed by days 1, 2, 15, 16 in a 4-week cycle from Cycle 10. For the first 10 patients enrolled, the dose of carfilzomib will be 20 mg/m^2 on Cycle 1 Day 1, escalated to 27 mg/m^2 from Cycle 1 Day 8. Safety data will be analysed in these 10 patients, and if well tolerated the next 26-30 patients will be treated with a higher dose escalation, with 20 mg/m^2 on Cycle 1 Day 1, escalated to 56 mg/m^2 from Cycle 1 Day 8. In all patients carfilzomib will be administered in combination with dexamethasone 20 mg PO on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each cycle. For newly diagnosed patients who become transplant-eligible according to the assessment of the investigator, stem cell mobilisation may be performed after 4 cycles followed by autologous transplantation using the institutional protocol. For newly diagnosed patients who are not eligible for transplant, after 10 cycles of carfilzomib, treatment is ceased when response assessment has indicated CR for 2 consecutive monthly assessments, or if CR is not achieved carfilzomib is continued until progression or toxicity. For relapsed patients carfilzomib is continued until progression or toxicity.
Locations(5)
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ACTRN12614000301662