Table 5.
Clinical trials of bortezomib, alone and in combination, in indolent non-Hodgkin’s lymphomas.
| Ref. | Prior therapy | Bortezomib combination studied | Bortezomib dosing/frequency | Phase | No. of patients | Results |
|---|---|---|---|---|---|---|
| [103] | Variable (11 previously untreated) | Monotherapy | 1.5 mg/m2 on days 1, 4, 8, 11, every 21 days | II | 16 (all MALT lymphoma) | 80% ORR, 43% CRs; unexpectedly high toxicity |
| [102] | Median 2 prior therapies | Monotherapy | 1.3 mg/m2 on days 1, 4, 8, 11, every 21 days × up to 6 cycles | II | 32 enrolled, 31 treated, 29 assessable (all MALT lymphoma) | 48% ORR, 31% CRs, median DOR not reached after median f/u of 24 months |
| [105] | 0 to ≥ 3 (only 1 treatment-naïve patient) | Bortezomib + rituximab, 375 mg/m2 weekly × 4 weeks | 1.3 mg/m2 on days 1, 4, 8, 11 every 21 days × 5 cycles versus 1.6 mg/m2 on days 1, 8, 15, 22, every 35 days × 3 cycles | II | 41 in twice-weekly arm, 40 in weekly arm, FL or MZL | 49% ORR, 14% CR/CRu rate, median TTP 7 months and DOR not reached in twice-weekly arm; 43% ORR, 10% CR/CRu rate, median TTP 10 and DOR 9.3 months in weekly arm |
| [108] | Median 2 prior therapies | Bortezomib + rituximab, 375 mg/m2 on days 1 and 8 | 1.3 – 1.5 mg/m2 on days 1, 4, 8, 11, every 21 days × 1 – 5 cycles (median 3) | II | 25 (11 FL + 14 MCL) | ORR 40% (55% in FL patients, 29% in MCL patients); 2-year PFS 24% overall, 60% in responders |
| [104] | 1 to ≥ 3 (prior rituximab required) | Monotherapy | 1.3 mg/m2 on days 1, 4, 8, 11, every 21 days × up to 8 cycles | II | 60 enrolled (40 FL + 12 SLL + 7 MZL), 53 evaluable | ORR 13%, 1 CR, 3 CRu, median time to response 2.2, DOR 7.9, OS 27.7, PFS 5.1, TTP 5.1 and EFS 1.8 months |
| [109] | Median 4 prior therapies | Bortezomib + bendamustine 90 mg/m2 on days 1 and 4 + rituximab 375 mg/m2 on day 1 × 6 cycles | 1.3 mg/m2 on days 1, 4, 8, 11, every 28 days | II | 31 (16 FL + 3 MZL + 3 SLL + 7 MCL + 2 lymphoplasmacytic lymphoma), 29 evaluable | 83% ORR, 15 CRs, 2-year PFS 47% at a median f/u of 24 months, ORR 93% in FL patients and 71% in MCL patients |
| [74] | Median 3 prior therapies | Monotherapy | 1.5 mg/m2 on days 1,4,8,11, every 21 days | II | 26 registered (10 FL + 11 MCL + 3 SLL/CLL + 2 MZL), 24 assessable | 58% ORR, 1 CR (FL), 2 CRu (1 MCL, 1 FL) |
| [131] | Median 4 prior therapies in weekly group, 2 in twice weekly group | Rituximab, cyclophosphamide, bortezomib, prednisone every 21 days × 4; rituximab 375 mg/m2 on day 1 and prednisone 100 mg PO on days 2 – 6 | 1.3 – 1.8 mg/m2 on days 2 and 8 in weekly group; 1 – 1.5 mg/m2 on days 2, 5, 9, 12 in twice weekly group; bortezomib and cyclophosphamide (750 – 1000 mg/m2) alternately escalated | I | 57 (46 evaluable, 24 FL + 10 MCL + 6 MZL + 2 SLL + 4 transformed) | ORR 46% (23% CR/CRu) and 64% (36% CR/CRu) in weekly and twice weekly groups, respectively |
| [107] | Median 2 prior therapies | Bortezomib + rituximab 375 mg/m2 on day 1 every 21 days (twice-weekly bortezomib group) or on days 1, 8, 15 and 22 every 35 days (weekly bortezomib group) | 1.3 mg/m2 on days 1, 4, 8, 11, every 21 days versus 1.6 mg/m2 on days 1, 8, 15, 22, every 35 days | I/II | 49 (7 in Phase I and 42 in randomized Phase II portion; 21 MCL + 17 FL + 11 WM) | ORR 67% (MCL 11/19, FL 8/15, WM 9/10) |
| [106] | None | Bortezomib + rituximab 375 mg/m2 for 4 weekly doses in cycle 1 and on day 1 only in cycles 2 and 3 | 1.6 mg/m2 on days 1, 8, 15, 22, every 35 days × 3 | II | 42 (33 FL + 5 MZL + 3 SLL + 1 WM) | ITT ORR 70% (FL 76%), 40% CRs (FL 44%), 4-year PFS 44% (FL 44%) and OS 87% (FL 97%) |
| [112] | Median 2.5 prior therapies | Bortezomib + alvocidib (hybrid schedule of administration on days 1 and 8, MTD 30 mg/m2) | MTD 1.3 mg/m2 on days 1, 4, 8, 11, every 21 days | I | 16 (9 NHL + 7 MM) | 44% ORR, 12% CR |
| [119] | ≤ 3 prior therapies | Monotherapy | 1.8 mg/m2 weekly × 4 every 5 weeks × 3 cycles (median; range 1 – 10) | II | 26 (16 FL + 10 MCL), 22 assessable (14 FL + 8 MCL) | 18% ORR (14% in FL patients, 25% in MCL patients), 0% CRs |
| [96] | Median 3 prior therapies | Monotherapy | 1.5 mg/m2 on days 1, 4, 8, 11, every 21 days | II | 77 registered (22 FL + 40 MCL + 6 SLL/CLL + 8 MZL + 1 WM), 69 assessable | 45% ORR (40% on ITT analysis), 10 CRs; 9 of 18 (50%) evaluable FL patients responded with 4 CRs, 18 of 36 (50%) evaluable MCL patients responded with 6 CRs |
CLL: Chronic lymphocytic leukemia; CR: Complete response; CRu: Unconfirmed complete response; DOR: Duration of response; EFS: Event-free survival; FL: Follicular lymphoma; f/u: Follow up; ITT: Intention to treat; MALT: Mucosa-associated lymphoid tissue; MCL: Mantle cell lymphoma; MM: Multiple myeloma; MTD: Maximum tolerated dose; MZL: Marginal zone lymphoma; NHL: Non-Hodgkin’s lymphoma; ORR: Overall response rate; SLL: Small lymphocytic lymphoma; TTP: Time to progression; WM: Waldenström’s macroglobulinemia.