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

Study Overview
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Brief Summary
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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. 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. The response in patients who received pomalidomide 2 mg per day compared to 4 mg per day was higher, with a longer duration of response. 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, from a patient and societal perspective, the investigators want to explore if an alternative scheme would be possible by performing a PKPD bio-equivalence pilot study.

Detailed Description
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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. 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. The response in patients who received pomalidomide 2 mg per day compared to 4 mg per day was higher, with a longer duration of response. 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, from a patient and societal perspective, the investigators want to explore if an alternative scheme would be possible by performing a PKPD bio-equivalence pilot study.

Official Title
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Alternative Dosing Scheme of Pomalidomide 4 mg Every Other Day Versus Pomalidomide 2 mg and 4 mg Every Day: Reduction in Costs, Same Efficacy? A PKPD Bioequivalence Pilot Study; the POMAlternative Study

Conditions
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Multiple Myeloma in Relapse, Multiple Myeloma, Multiple Myeloma, Refractory

Intervention / Treatment
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* Drug: Pomalidomide 4 mg every day in cycle 1
* Drug: Pomalidomide 4 mg every other day in cycle 2
* Drug: Pomalidomide 2 mg every day in cycle 2
* Drug: Pomalidomide 2 mg every day in cycle 3
* Drug: Pomalidomide 4 mg every other day in cycle 3


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A; Pomalidomide 4 mg every other day in cycle 2<br>Group A (6 patients): Cycle 1: Pomalidomide 4 mg every day on day 1-21; Cycle 2: 4 mg every other day on day 1-21; Cycle 3: 2 mg every day on day 1-28. In Cycles of 28 days. | Drug: Pomalidomide 4 mg every day in cycle 1<br>* Pomalidomide 4 mg every day, on days 1-21 in a cycle of 28 days<br>* Other names: Cycle 1;Drug: Pomalidomide 4 mg every other day in cycle 2<br>* Pomalidomide 4 mg every other day, on days 1-21 in a cycle of 28 days<br>* Other names: Cycle 2 (Group A);Drug: Pomalidomide 2 mg every day in cycle 3<br>* Pomalidomide 2 mg every day, on days 1-28 in a cycle of 28 days<br>* Other names: Cycle 3 (Group A);|
| Experimental: Group B; Pomalidomide 4 mg every other day in cycle 3<br>Group B (6 patients): Cycle 1: Pomalidomide 4 mg every day on day 1-21; Cycle 2: 2 mg every day on day 1-28; Cycle 3: 4 mg every other day on day 1-21. In Cycles of 28 days. | Drug: Pomalidomide 4 mg every day in cycle 1<br>* Pomalidomide 4 mg every day, on days 1-21 in a cycle of 28 days<br>* Other names: Cycle 1;Drug: Pomalidomide 2 mg every day in cycle 2<br>* Pomalidomide 2 mg every day, on days 1-28 in a cycle of 28 days<br>* Other names: Cycle 2 (Group B);Drug: Pomalidomide 4 mg every other day in cycle 3<br>* Pomalidomide 4 mg every other day, on days 1-21 in a cycle of 28 days<br>* Other names: Cycle 3 (Group B);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The AUC/MIC ratio | The AUC/MIC ratio during usage of pomalidomide 4 mg QD on day 1-21, 4 mg EOD on day 1-21, and 2 mg QD on day 1-28 in cycles of 28 days. | During three cycles of 28 days | 
| The level of the Ctrough | The level of the Ctrough during usage of pomalidomide 4 mg QD on day 1-21, 4 mg EOD on day 1-21, and 2 mg QD on day 1-28 in cycles of 28 days. | During three cycles of 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax | The Cmax during usage of pomalidomide 4 mg QD on day 1-21, 4 mg EOD on day 1- 21, and 2 mg QD on day 1-28 in cycles of 28 days. | During three cycles of 28 days | 
| Time above EC50 | The time above the EC50 during usage of pomalidomide 4 mg QD on day 1-21, 4 mg EOD on day 1- 21, and 2 mg QD on day 1-28 in cycles of 28 days. | During three cycles of 28 days | 
| Toxicity and side effects | Toxicity and side effects during usage of pomalidomide 4 mg every day on day 1-21, pomalidomide 4 mg every other day on day 1-21, and pomalidomide 2 mg every day on day 1-28 in cycles of 28 days. | During three cycles of 28 days | 
| Overall response rate (ORR) | Overall response rate (ORR), based on the IMWG criteria | During three cycles of 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple myeloma, Pomalidomide, Pharmacokinetics/dynamics, Cost-effectiveness