Alternate Day Actimid™ (CC-4047) Is Well Tolerated and Is Active When Used to Treat Relapsed/Refractory Myeloma.
Authors: Streetly Matthew , Gyertson Kylie , Kazmi Majid , Zeldis Jerome , Schey Steve A. 
Published: October 2019

Abstract
Actimid™ (CC-4047[Celgene]) is a thalidomide derivative that induces apoptosis, disrupts myeloma-stromal cell adhesion, reduces cytokine secretion, is anti-angiogenic and stimulates anti-myeloma NK cell proliferation. In vivo T-cell and NK cell stimulatory cytokines are enhanced. We have reported a phase I study of daily Actimid with a MTD of 2 mg daily and have carried out a further phase I study using alternate day dosing.
Methods: Patients (pts) with relapsed/refractory myeloma who had received at least one prior line of therapy were eligible.This was a dose escalation study designed to define the maximum tolerated alternate day (a/d) dose (1mg, 2mg, 5mg, 10mg). Pts discontinued therapy after 4 weeks if grade 3/4 non-haematological toxicity developed, grade 4 haematological toxicity had not resolved or there was progressive disease. Pts who relapsed following response were eligible to receive dexamethasone (20 mg od for 4 days alternate weeks).
Results: 20 pts were treated with median age 58 years (range 34 – 75) and a median of 4 (range 1 – 7) prior lines of chemotherapy (including HDT(65%) and/or thalidomide (85%)). 3/20 pts developed grade 4 neutropaenia within 4 weeks of treatment. All were receiving 10mg a/d. This resolved in all pts within 5 weeks without recourse to growth factors and therapy was restarted at a lower dose. There were no dose limiting grade 3/4 non-haematological toxicities. The maximum tolerated dose was identified as 5 mg a/d. One patient was withdrawn from treatment following the development of relapsing /remitting fevers of unknown origin. He had previously had similar symptoms following treatment with bortezomib. One patient was withdrawn following the development of transverse myelitis and one patient withdrew consent within two weeks of commencing treatment. No pts withdrew due to recurrent neutropaenia. The median duration of exposure to single agent actimid is 5 months (1 – 14) and the overall median duration of therapy is 10 months (1 – 21). All 20 pts are evaluable for response. With a median follow-up of 12 months 12(60%) achieved at least a 25% paraprotein reduction. 19 achieved a best response of stable disease(SD) or better. 1/20 pts progressed within 4 weeks of starting therapy. 2/20 pts attained a complete response, 8/20 pts achieved at least 75% paraprotein reduction (VGPR+CR), 10/20 pts achieved a > 50% paraprotein reduction and a further 2/20 pts achieved a 25 – 50% paraprotein reduction. 6/20 pts had dexamethasone added. Two pts achieved a best response after the addition of dexamethasone (both had relapsed following PR and SD respectively and both achieved VGPR). Additionally 1/6 pts achieved MR and 3/6 pts achieved SD. In the group overall the median time to achieve maximum response was 4 months (1 – 17). 8/20 progressed on treatment with a median time to progression of 10 months (1 – 21). 5/20 pts have subsequently died due to progressive disease. There have been no treatment related deaths.
Conclusions: Actimid is a well tolerated oral agent with activity in myeloma. The maximum tolerated dose was 5mg a/d. No grade 3/4 non-haematological toxicity was observed and the neutropaenia resolved rapidly. Responses were excellent with 50% patients achieving at least a 50% reduction in paraprotein. Dexamethasone improved response in 2/6 patients. This study indicates that Actimid has good anti-myeloma activity either as a single agent or in combination with dexamethasone and further clinical studies are justified.