OptiPOM: Alternate Day Dosing of Pomalidomide in Patients With Refractory Multiple Myeloma

Sponsor

Swiss Group for Clinical Cancer Research (Other)

Overall Status

Terminated

CT.gov ID

NCT03520985

Collaborator

(none)

Enrollment

Locations

Arm

28.1

Actual Duration (Months)

2.1

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Refractory Multiple Myeloma	Drug: Pomalidomide Drug: Dexamethasone	Phase 2

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

34 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Alternate Day Dosing of Pomalidomide in Patients With Refractory Multiple Myeloma. A Multi-center, Single Arm Phase II Trial

Actual Study Start Date :

Oct 1, 2018

Actual Primary Completion Date :

Feb 3, 2021

Actual Study Completion Date :

Feb 3, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pomalidomide The treatment in this trial consists of oral pomalidomide on alternate days (ad) plus Low-Dose Dexamethasone (adPOM + LD-DEX)	Drug: Pomalidomide Pomalidomide (4 mg p.o.) will be administered on every other day of each 28-day treatment cycle. Treatment duration: Treatment cycles are repeated until confirmed disease progression. Other Names: Imnovid® Drug: Dexamethasone For patients ≤ 75 years of age: Low-Dose Dexamethasone (40 mg p.o.) will be administered once per day on days 1, 7, 15, and 21 of a 28-day cycle. For patients > 75 years of age: Low-Dose Dexamethasone (20 mg p.o.) will be administered once per day on days 1, 7, 15, and 21 of a 28-day cycle. Treatment duration: Treatment cycles are repeated until confirmed disease progression.

Arm

Intervention/Treatment

Experimental: Pomalidomide

The treatment in this trial consists of oral pomalidomide on alternate days (ad) plus Low-Dose Dexamethasone (adPOM + LD-DEX)

Drug: Pomalidomide

Pomalidomide (4 mg p.o.) will be administered on every other day of each 28-day treatment cycle. Treatment duration: Treatment cycles are repeated until confirmed disease progression.

Other Names:

Imnovid®

Drug: Dexamethasone

For patients ≤ 75 years of age: Low-Dose Dexamethasone (40 mg p.o.) will be administered once per day on days 1, 7, 15, and 21 of a 28-day cycle. For patients > 75 years of age: Low-Dose Dexamethasone (20 mg p.o.) will be administered once per day on days 1, 7, 15, and 21 of a 28-day cycle. Treatment duration: Treatment cycles are repeated until confirmed disease progression.

Outcome Measures

Primary Outcome Measures

Overall Response Rate (ORR) [From date of registration until 28 days after last dose of trial medication with longest treatment time of approximately 36 months]
OR is defined as minimal response or better, assessed according to the IMWG criteria.

Secondary Outcome Measures

Overall Survival (OS) [From date of registration until 28 days after last dose of trial medication with longest treatment time of approximately 36 months]
OS is defined as the time from registration until death from any cause. Patients not having an event at the time of analysis will be censored at the date they were last known to be alive.
Overall Survival (OS) at 12 months [at 12 months]
OS, as defined above, will be evaluated at 12 months.
Progression-free survival (PFS) [From date of registration until 28 days after last dose of trial medication with longest treatment time of approximately 36 months]
PFS is defined as the time from registration until progression according the IMWG criteria or death from any cause, whichever occurs first. Patients not having an event at the time of analysis as well as patients starting a new anticancer therapy in the absence of an event will be censored at the date of their last tumor assessment showing non-progression before starting a new treatment, if any.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Kantonspital Aarau	Aarau	Switzerland	CH-5001
2	Kantonsspital Baden (Baden/Brugg)	Baden	Switzerland	5404
3	Universitätsspital Basel	Basel	Switzerland	4031
4	Istituto Oncologico Svizzera Italiana IOSI	Bellinzona	Switzerland	6500
5	Inselspital Bern	Bern	Switzerland	3010
6	Kantonsspital Graubünden	Chur	Switzerland	CH-7000
7	Hopital Fribourgeois HFR	Fribourg	Switzerland	1708
8	Kantonsspital Liestal	Liestal	Switzerland	CH-4410
9	Kantonsspital Luzern	Luzerne	Switzerland	CH-6000
10	Spital Thurgau AG	Münsterlingen	Switzerland	8596
11	Kantonsspital St. Gallen	St. Gallen	Switzerland	9007
12	Regionalspital Thun	Thun	Switzerland	3600
13	Kantonsspital Winterthur	Winterthur	Switzerland	8401
14	Onkozentrum Hirslanden Zürich	Zurich	Switzerland	8032
15	OnkoZentrum Zürich AG - Klinik im Park	Zürich	Switzerland	8038
16	Universitätsspital Zürich	Zürich	Switzerland	8091