TABLE 1
FROM:
Recent clinical studies of the immunomodulatory drug (IMiD®) lenalidomide
J B Bartlett, A Tozer, D Stirling and J B Zeldis
BACK TO ARTICLETable 1. Completed and ongoing clinical studies of Lenalidomide
| Drug | Indication | Country | Phase | Status | Comments and references |
|---|---|---|---|---|---|
| Multiple myeloma, monotherapy | |||||
| Lenalidomide | Multiple myeloma, relapsed (n=27) | USA | I | Completed | First published report in MM (Richardson et al, 2002). A dose-escalating study with 24 evaluable patients. Best responses in terms of reduction in serum M-protein in evaluated patients were >50% in seven out of 24 (30%), >25–50% in 10 out of 24 (42%), <25% in two out of 24 (8%) patients. The maximum tolerated dose was 25 mg day-1. Grade 3 myelosuppression was apparent with patients treated with 50 mg day-1. No somnolence or neuropathy was observed. |
Lenalidomide Dex | Multiple myeloma, relapsed/refractory (n=102) | Multicentre, USA | II | Completed | Preliminary data from American Society of Hematology (ASH 2003) (Richardson et al, 2003) comparing two dose levels (15 mg b.i.d. vs 30 mg qd  3 weeks with 1 week rest) of lenalidomidedexamethasone. Overall response rate was 38%, including 6%CR and 18%PR. In all, 33% of patients who received dex for progressive disease achieved  PR. Significant toxicities were thrombocytopenia (18%) and neutropenia (28%). Lower frequency of myelosuppression with the 30 mg qd cohort. |
| Lenalidomide | Multiple myeloma, relapsed/refractory (n=224) | Multicentre, USA | II | Ongoing | Closed to enrolment. Preliminary data from International Myeloma Workshop (IMW) 2005 (Haematologica/The Hematology Journal; 90 (Suppl 1): 154, Abstract # PO.737) demonstrated 25% paraprotein reduction in 28% of patients with advanced MM and poor prognosis. Most common grade 3 or 4 adverse events were neutropenia and thrombocytopenia. |
| Lenalidomide | Multiple myeloma, relapsed/refractory (n=100) | USA | II | Ongoing | Closed to enrolment. Very early data on the first 38 patients (IMW 2003; Hematology Journal; 4(Suppl 1): S5–S7) reported that lenalidomide at 50 mg qd 10 days repeated q 28 days appeared inferior in terms of response (compared to 25 mg qd 20) prompting dose modification to 50 mg qod-1 10. No significant sedation or neurotoxicity was observed. Myelosuppression was dose limiting. |
| Multiple myeloma, combination therapy | |||||
| Lenalidomide+bortezomib | Multiple myeloma, relapsed/refractory (n=58) | USA | I | Ongoing | Preliminary data from European Haematology Association (EHA) 2005 (Haematologica/The Hematology Journal 2005; 90 (Suppl 1): 26–27, Abstract # PL5.04) on the first nine patients treated: MTD was not reached in the first three cohorts. With a median of six cycles completed, patients have tolerated bortezomib 1.0–1.3 mg m-2 and lenalidomide 5–10 mg day-1 without DLT. All nine patients achieved minor response or stable disease. Grade 4 neutropenia (two patients, <5 days duration) and grade 3 thrombocytpopenia was reported in four patients. |
| Lenalidomide+DVd (DVd-R) Doxil, Vincristine, dexamethasone-Revlimid | Multiple myeloma, advanced relapsed/refractory (n=55) | USA | I/II | Ongoing | Preliminary results from 2004 ASH meeting (Hussein et al, 2004) report that DVd-R is an extremely effective regimen in refractory stage III MM. In 21 evaluable patients, the response rate (SWOG) was >66%, including CR+near CR rate of 33%, with minimal toxicity. Maximum tolerated dose defined as 10 mg qd 21, q 28 days. The DLTs included sepsis/shock (at 15 mg), non-neutropenic sepsis (two patients), PE (one patient) and grade 3 neutropenia (two patients) and neuropathy (one patient). |
| Lenalidomide plus dexamethasone | Multiple myeloma, newly diagnosed (n=34) | USA | II | Completed | Preliminary results presented at 2004 American Society of Hematology (Rajkumar et al, 2004a, 2004b) suggest that lenalidomide /dexamethasone offers clinical benefit and is well tolerated in newly diagnosed MM. Objective responses were reported in 25 out of 30 patients (83%). Daily aspirin was given, no DVTs were reported. No grade4 toxicities were reported. A total of 33% experienced various grade 3 toxicities. |
| Lenalidomide and dexamethasone vs dexamethasone alone | Multiple myeloma, refractory (n=354) | Multicentre, USA/Canada | III | Ongoing | Closed to enrolment. Results presented at the 2005 EHA (Haematologica/The Hematology Journal 2005; 90 (Suppl 2): 160, Abstract # 0402). Planned interim analysis by Independent Data Monitoring Committee showed statistically significant increase in TTP in the lenalidomide/dex arm (not reached at 60 weeks) vs 19.9 weeks in dex only arm. Overall response rate: 51.3% (len/dex) vs 22.9% (dex); CR assessed by investigator: 19.5% (len/dex) vs 3.8% (dex).Well tolerated. |
| Lenalidomide and dexamethasone vs dexamethasone alone | Multiple myeloma, refractory (n=351) | Multicentre, International | III | Ongoing | Closed to enrolment. Planned interim analysis by Independent Data Monitoring Committee showed statistically significant increase in the TTP in lenalidomide/dex arm (not reached at 47 weeks) vs 20.4 weeks in dex only arm (Dimopoulos et al, 2005). Overall response rate: 47.6% (len/dex) vs 18.4% (dex); CR assessed by investigator: 9.1% (len/dex) vs 1.2% (dex). Well tolerated. |
| Lenalidomide and dexamethasone vs dexamethasone alone | Multiple myeloma, newly diagnosed (n= 500) | USA, National Cancer Institute (NCI) and Southwest Oncology group (SWOG), USA | III | Ongoing | No data reported as yet |
| Lenalidomide+dexamethasone vs lenalidomide+low-dose dexamethasone | Multiple myeloma (n=412) | USA, Eastern Cooperative Oncology Group (ECOG) | III | Ongoing | No data reported as yet |
| Lenalidomide+bortezomib vs bortezomib | Multiple myeloma, relapsing/progressing on total therapy III (n=315) | USA | III | Ongoing | No data reported as yet |
| Myelodysplastic syndromes | |||||
| Lenalidomide | Myelodysplastic syndromes with 5q- cytogenetic abnormality (n=151) | Multicentre, USA | II | Ongoing | Closed to enrolment. Preliminary data on 148 patients with del 5q31, reported at ASCO 2005 (List et al, 2005a, 2005b) included transfusion independence in 64% of patients with a median Hb increase of 3.9 g dl-1 and 4-week time to response. Cytogentic response occurred in 76% of patients, with complete cytogenetic remission in 55%. Pathologic complete response in 29%. After a median follow up of 9.3 months, median response duration had not been reached and only 9% of patients had failed therapy. Neutropenia and thrombocytopenia were the most common AEs necessitating treatment interruption/dose reduction. |
| Lenalidomide | MDS (n=215) | Multicentre, USA | II | Ongoing | Closed to enrolment. Data from the 2005 International Symposium on MDS reported transfusion-independence in 21% of 215 patients (ITT) with a median Hb increase of 3.0 g/ dl-1. Of 169 low-int-1 risk patients, 25% became transfusion-indepdendent and 43% achieved at least a minor response. Neutropenia (19%) and thrombocytopenia (15%) were the most common adverse effects. |
| Lenalidomide | MDS (n=45) | USA | II | Ongoing | Closed to enrolment. Data presented at the 2005 International Symposium on MDS (Raza et al, abstract # P-121) from this study indicated substantial activity in low-risk MDS, including an overall haematological response rate in 43 patients of 56%, with 20 out of 32 transfusion-dependent patients achieving transfusion-independence. Response rate was highest in patients with deletion of 5q.31.1 (83%). Eleven out of 20 patients had cytogenetic remission, including complete cytogenetic remission in 10. Neutropenia and thrombocytopenia were the most common adverse events. |
| Chronic lymphocytic leukaemia | |||||
| Lenalidomide+rituximab | Chronic lymphocytic leukaemia, relapsed/refractory (n=29) | USA | II | Ongoing | Preliminary data from EHA 2005 (Haematologica/The Hematology Journal 2005; 90(Suppl 2): 160, Abstract # 97) on eight patients who completed 30 days of therapy: all eight patients responded with decreases either in ALC or lymph node size. Two patients achieved CR/CRu, two PR and four SD. Since no patients had PD, rituximab was not added. AEs included: grade 3/4 thrombocytopenia (six patients); grade 3/4 neutropenia (three patients); flare reaction (three patients) and tumour lysis syndrome (two patients). Antitumour activity was noted as early as 7 days after therapy. |
| Other – listed alphabetically by disease, phase | |||||
| Lenalidomide | Glioma, recurrent high-grade (n=36) | USA, National Cancer Institute | I | Completed | Preliminary results on the first 18 patients, presented at the 2003 American Society of Clinical Oncology meeting (Fine et al, abstract # 418), report that lenalidomide has been well tolerated with only one drug-related toxicity >grade 1 (grade 2 myelosuppression in patient with previous BMT). One patient with rapidly progressive spinal hemangioblastomas, and two patients with rapidly progressive glioblastoma experienced disease stabilisation for 6, 5 and 7 months, respectively. |
| Lenalidomide | Metastatic malignant melanoma and other advanced solid tumours (n= 20) | UK | I | Completed | First published report in solid tumours (Bartlett et al, 2004a, 2004b). A total of 17 evaluable patients. One partial response and two clear objective responses, such as resolution of subcutaneous and cutaneous lesions. Evidence of T-cell activation and increased serum IL-12, GM-CSF and TNF- was found. No serious adverse effects were observed. |
| Lenalidomide | Metastatic malignant melanoma (n=295) | Multicentre, (USA, Canada) | III | Completed | Unblinded interim results determined that the trial would not demonstrate a statistically significant treatment effect, although the safety profile was acceptable. On the recommendation of the Data Monitoring Committee, the trial was halted. |
| Lenalidomide vs placebo | Metastatic malignant melanoma (n=305) | Multicentre, International | III | Completed | Unblinded interim results determined that the trial would not demonstrate a statistically significant treatment effect, although the safety profile was acceptable. On the recommendation of the Data Monitoring Committee, the trial was halted. |
| Lenalidomide | Metastatic cancer, refractory (n=51) | USA, National Cancer Institute | I | Ongoing | Preliminary results from 2003 meeting of ASCO (Liu et al., abstract # 927) on 12 patients (all with metastatic hormone-refractory prostate cancer) report MTD as not yet determined, and administration schedule to be amended. Six out of 12 patients had stable PSA for 8 weeks, no PR or CR. Dose-limiting toxicity at 20 mg day-1 was grade 3 thrombosis and grade 3 hypotension. |
| Lenalidomide | Myelofibrosis with myeloid metaplasia (n=27) | USA | II | Ongoing | Preliminary data on the first 15 patients from the 2004 ASH (Tefferi et al, 2004) meeting reported substantial biological activity of lenalidomide in MMM, with substantial benefit for a subset of patients. Clinically relevant responses were documented in four out of 15 (27%) patients, including improvement in anaemia (two patients), splenomegaly (two patient), +/or constitutional symptoms (three patients). One patient became transfusion independent; another had Hb increase of >5 g dl-1+leucocyte count reduction of >48 109 l-1. Two patients discontinued due to drug toxicity. |
| Lenalidomide | Renal cell cancer (n=40) | USA | II | Completed | Preliminary data presented at ASCO 2004 (Rawat et al, abstract # 4761) reported that lenalidomide was well tolerated with 7.5% PR rate in 36 evaluable patients with progressive, metastatic RCC. |
