Clinical trial NCT03520985: Alternate Day Dosing of Pomalidomide in Patients With Refractory Multiple Myeloma
Official title: Alternate Day Dosing of Pomalidomide in Patients With Refractory Multiple Myeloma. A Multi-center, Single Arm Phase II Trial
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Refractory Multiple Myeloma
Keywords: refractory Multiple Myeloma
Phase II
Pomalidomide
OptiPOM
Lead sponsor: Swiss Group for Clinical Cancer Research
Sponsor class: OTHER
First posted: 2018-05-11
Enrollment: 34
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Pomalidomide is an approved treatment for refractory multiple myeloma. Toxicity of pomalidomide in the pivotal MM-003 trial, was considerable, with 60% of patients experiencing drug-related G3/4 toxicity. Neutropenia (48% vs 16%) and pneumonia (13% vs 8%) were significantly more common in the pomalidomide arm. This resulted in frequent dose interruptions (67%) and dose reductions (27%). This suggests that for the majority of patients the 4 mg daily dosing schedule is too toxic, and that strategies to deliver reduced dosing of pomalidomide are of high practical relevance. The aim of this trial therefore is to establish that alternate day dosing of pomalidomide (4 mg q2d, d1-28) is non-inferior to daily dosing (4 mg d1-21 q28) in terms of efficacy of the drug with potentially less side effects.

Detailed description: Multiple myeloma (MM) accounts for 1% of all cancers and ∼10% of all hematological malignancies. Despite recent advances in myeloma treatment, including the introduction of proteasome inhibitors, immunomodulatory drugs (IMiDs) and stem cell transplantation, myeloma remains an incurable disease. The treatment of bortezomib and lenalidomide refractory myeloma is still an unmet medical need. Once patients have relapsed after IMiD-containing therapies and have become bortezomib-resistant, their prognosis is extremely poor.

Pomalidomide is a third-generation, Swissmedic approved, oral immunomodulatory drug with activity in such patients. However the toxicity of pomalidomide in the pivotal MM-003 trial was considerable, with 60% of patients experiencing drug-related G3/4 toxicity. Neutropenia (48% vs 16%) and pneumonia (13% vs 8%) were significantly more common in the pomalidomide arm. This resulted in frequent dose interruptions (67%) and dose reductions (27%). This suggests that for the majority of patients the 4 mg daily dosing schedule (4 mg daily on 21 of 28 days) is toxic, and that strategies to deliver reduced dosing of pomalidomide are of high practical relevance.

Alternative dosing schedules:

There is robust data available indicating that lower pomalidomide doses (e.g. 2 mg daily) lead to similar responses and progression free survival with fewer side effects. Due to its unique pharmacological characteristics, pomalidomide is well suited for alternate day dosing. The decline of the plasma concentration at the terminal phase is slow. These data make pomalidomide an ideal candidate for alternate day dosing. Therefore, a phase I study has already been conducted in 2008 to test the alternating administration of the drug showing excellent responses with a marked reduction of thrombotic events and less severe myelosuppression.

The drug costs of pomalidomide are quite high. Interestingly, the manufacturer determined a pricing model that is independent from the capsule strength (costs for one capsule 1 mg=2 mg=3 mg=4 mg). In patients requiring dose reductions due to hematologic toxicity, daily dosing of reduced strength pomalidomide (e.g. 2 mg daily) is approved and suggested by the manufacturer. This delivers 50% less pomalidomide to the patient, albeit at 100% of the price of full dosing.

In summary, the establishment of the modified pomalidomide schedule would be an interesting option for our patients to achieve similar efficacy with fewer side effects. In addition, it would optimize the cost-effectiveness of the drug.

Eligibility criteria: Key inclusion criteria:

* Patient was diagnosed with multiple myeloma based on standard IMWG criteria
* Prior treatment with ≥ 2 treatment lines of anti-myeloma therapy
* Patients must have been exposed to both lenalidomide and bortezomib
* Measurable disease for myeloma defined as one of the following: serum M-protein ≥ 5 g/L; urine M-protein ≥ 0.2 g/24 hours
* Refractory or relapsed and refractory disease defined as documented disease progression during or within 60 days of completing their last myeloma therapy.
* Adequate hematological and hepatic function
* A negative pregnancy test before inclusion into the trial is required for all women with child-bearing potential

Key exclusion criteria:

* History of hematologic or primary solid tumor malignancy, unless in remission for at least 3 years from registration, with the exception of pT1-2 prostate cancer Gleason score ≤6, adequately treated, cervical carcinoma in situ or localized non-melanoma skin cancer.
* Polyneuropathy grade \> 2
* Patients who received any of the following within the last 14 days of initiation of trial treatment:

  * Plasmapheresis
  * Major surgery (kyphoplasty is not considered major surgery)
  * Radiation therapy
  * Use of any anti-myeloma drug therapy
* Known or clinically suspected myeloma manifestations in the central nervous system
* Severe or uncontrolled cardiovascular disease

Primary outcomes:
measure: Overall Response Rate (ORR)
timeFrame: From date of registration until 28 days after last dose of trial medication with longest treatment time of approximately 36 months
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: From date of registration until 28 days after last dose of trial medication with longest treatment time of approximately 36 months
measure: Overall Survival (OS) at 12 months
timeFrame: at 12 months
measure: Progression-free survival (PFS)
timeFrame: From date of registration until 28 days after last dose of trial medication with longest treatment time of approximately 36 months
Other outcomes:
Locations:
city: Aarau
country: Switzerland
facility: Kantonspital Aarau
city: Baden
country: Switzerland
facility: Kantonsspital Baden (Baden/Brugg)
city: Basel
country: Switzerland
facility: Universitätsspital Basel
city: Bellinzona
country: Switzerland
facility: Istituto Oncologico Svizzera Italiana IOSI
city: Bern
country: Switzerland
facility: Inselspital Bern
city: Chur
country: Switzerland
facility: Kantonsspital Graubünden
city: Fribourg
country: Switzerland
facility: Hopital Fribourgeois HFR
city: Liestal
country: Switzerland
facility: Kantonsspital Liestal
city: Luzerne
country: Switzerland
facility: Kantonsspital Luzern
city: Münsterlingen
country: Switzerland
facility: Spital Thurgau AG
city: St. Gallen
country: Switzerland
facility: Kantonsspital St. Gallen
city: Thun
country: Switzerland
facility: Regionalspital Thun
city: Winterthur
country: Switzerland
facility: Kantonsspital Winterthur
city: Zurich
country: Switzerland
facility: Onkozentrum Hirslanden Zürich
city: Zürich
country: Switzerland
facility: OnkoZentrum Zürich AG - Klinik im Park
city: Zürich
country: Switzerland
facility: Universitätsspital Zürich
Study officials:
affiliation: Luzerner Kantonsspital
name: Thilo Zander, MD
role: STUDY_CHAIR
affiliation: Cantonal Hospital of St. Gallen
name: Christoph Driessen, Prof
role: STUDY_CHAIR
affiliation: Onkozentrum Zürich
name: Christoph Renner, Prof
role: STUDY_CHAIR
References: