Alternative Dosing Scheme of Pomalidomide 4 mg Every Other Day Versus Pomalidomide 2 mg and 4 mg Every Day; the POMAlternative Study

• Status: Not yet recruiting
• Trial end date: 2023-08-01
• Target enrollment: 0
• Participant gender: All

Summary

Pomalidomide either as single therapy or in combination with cyclophosphamide, elotuzumab, bortezomib, or daratumumab are effective treatment regimens in relapsed refractory multiple myeloma (RRMM). Standard dosing is 4 mg/day during 21 days of a 28-day cycle (21/28). However, a clear dose-response association for pomalidomide in patients with multiple myeloma (MM) is lacking. Firstly, pharmacokinetic-pharmacodynamic (PKPD) research showed no association between area under the time curve (AUC) and response in dosages of pomalidomide of 1 to 4 mg. Secondly, there is data supporting that a dose of 2 mg/day continuously (28/28) induces fewer side effects while efficacy is preserved, compared to 4 mg/day continuously. In addition, a randomized phase II study showed no difference in efficacy between 4 mg (21/28) and 4 mg continuously. These clinical studies support that a dosage of pomalidomide of 2 mg (28/28) is at least comparable with a dosage of 4 mg (21/28).

It is not known if 4 mg every other day (EOD) is comparable to a dosage of pomalidomide 2 mg (28/28) or 4 mg every day (QD, 21/28). For cost reasons, this is interesting as the costs of pomalidomide 4 mg and 2 mg are comparable.

Therefore, the investigators performed Monte Carlo simulations, based on published clinical population PK data and in vitro half effective concentration (EC50) and half inhibitory concentration (IC50) data. In simulations of 1000 studies of 12 patients each the investigators calculated in how many of the proposed dosing regimens, patients reached the target concentration. The target levels were considered to be a minimal trough concentration of pomalidomide in plasma at steady state (Ctrough) that showed T-cell immunomodulatory activity, cereblon-dependent ubiquitination and proteasome degradation of substrate proteins Ikaros and Aiolos; and an average concentration at steady state (Cavg) that showed sufficient tumor cell inhibition.

On the basis of PK-simulations, the investigators predict that 43.5% (CI 95%: 41.1 - 45.9%) of the patients will reach the target AUC/MIC ratio and have their lowest Ctrough above the EC50 with a dosage of 4 mg EOD. In this cross-over pilot study, the investigators aim to validate these simulations in 12 patients who will receive three dosing schemes (4 mg QD 21/28, 4 mg EOD 21/28, and 2 mg QD 28/28).

• Phase: Phase 4
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Maarten Seefat
• Treatments: Pomalidomide; Thalidomide

Criteria

Inclusion Criteria:

• Patients with relapsed/refractory multiple myeloma, who are eligible for a treatment regimen which contains pomalidomide. Either monotherapy or in combination with bortezomib, daratumumab, cyclophosphamide, or elotuzumab

• Patients who received a minimum of two cycles of pomalidomide 4mg every day on day 1-21/28

• Age > 18 years

• WHO performance status 0-3

• Written informed consent

Exclusion Criteria:

• Usage of CYP1A2 inhibitors (e.g. ciprofloxacin, enoxacin, ketoconazole, carbamazepine, fluvoxamine, and grapefruit juice)

• Renal insufficiency requiring dialysis

• Significant hepatic dysfunction (total bilirubin > 330 μmol/l or transaminases > 3 times normal level)

• Current smoker

• Hemoglobin <6.5 mmol/L

• Thrombocytes <100 *10^9/L

• Neutrophiles <1.5 *10^9/L

• Pregnant patients

• Female patients who are able to get pregnant and who do not agree to adequate birth control or complete abstinence

• Male patients who do not agree to adequate birth control or complete abstinence

• Hypersensitivity to pomalidomide or constituents