AEs in idelalisib and duvelisib clinical trials for CLL/SLL and indolent lymphomas
| . | Phase 1, R/R CLL, single-agent idelalisib7 . | Phase 1, R/R MCL44 . | Phase 1, R/R MCL and follicular lymphoma, idelalisib, lenalidomide, rituximab16 . | Phase 1, R/R indolent lymphoma, single-agent idelalisib45 . | Phase 2, R/R classical Hodgkin lymphoma, single-agent idelalisib46 . | Phase 2, treatment-naïve older patients with CLL, idelalisib + rituximab11 . |
|---|---|---|---|---|---|---|
| Number of patients | 54 | 40 | 11 | 64 | 25 | 64 |
| AEs | ||||||
| Colitis/diarrhea | 29.6% Grade ≥3, 5.6% | 40% Grade ≥3, 17.5% | 38% | 36% Grade ≥3, 9.4% | 4% | 64% Grade 3, ≥42% |
| Hepatotoxicity | 33-18% Grade ≥3, ∼2% | 60% Grade ≥3, 20% | 63% Grade ≥3, 18% | 53% Grade ≥3, 23% | Grade ≥3, 16% | 67% Grade ≥3, 23% |
| Infections | 44% Grade ≥3, 20% | 32.5% Grade ≥3, 10% | 25%, All grade ≥3 | 36% Grade ≥3, 17.2% | 16% | 44% Grade ≥3, 25% |
| Cutaneous reactions | 22% | 22.5% Grade ≥3, 2.5% | 63% Grade ≥3, 54% | 25% Grade ≥3, 3.1% | 8% | 58% Grade ≥3, 13% |
| Pneumonitis | 4% | 3%, All grade ≥3 | ||||
| Dose reductions | 36% | 45% | ||||
| Drug discontinuation due to AEs | 13% | 18% | 73% | 21% | 8% | 29.7% |
| Phase 2, double-refractory indolent lymphoma, single-agent idelalisib47 | Phase 2, idelalisib + entospletinib in R/R CLL and NHL17 | Phase 2, treatment-naïve CLL with idelalisib + ofatumumab12 | Phase 3, idelalisib + rituximab vs rituximab in R/R CLL8 | Phase 3, idelalisib vs placebo + BR in R/R CLL14 | Phase 3: idelalisib + ofatumumab in previously treated CLL13 | |
| Number of patients | 125 | 66 | 24 | 220 | 416 | 261 |
| AEs | ||||||
| Colitis/diarrhea | 43% Grade ≥3, 16% | 29% Grade ≥3, 2% | 46% Grade ≥3, 17% | 19% Grade ≥3, 4%* | 38% Grade ≥3, 9% | 54% Grade ≥3, 23% |
| Hepatotoxicity | 47% Grade ≥3, 13% | 23% | 79% Grade ≥3, 54% | 35% Grade ≥3, 5%* | 61% Grade ≥3, 21% | 20% Grade ≥3, 13% |
| Infections | 25% Grade ≥3, 7% | ∼18% | Grade ≥3, 13%* | 32% Grade ≥3, 12.5%-16% | 78% Grade ≥3, 22% | |
| Cutaneous reactions | 13% Grade ≥3, 2% | 30% Grade ≥3, ∼17% | 10% Grade ≥3, 3%* | 16% Grade ≥3, 3% | 18% Grade ≥3, 1% | |
| Pneumonitis | 17%; study terminated early | 13% | 4%* | 1.4% | 6% Grade ≥3, 5% | |
| Dose reductions | 34% | 13% | 58% | |||
| Drug discontinuation due to AEs | 20% | Study terminated early due to AEs | 5% | 27% | 39% | |
| Phase 1, duvelisib monotherapy, R/R CLL48 | Phase 1, duvelisib monotherapy, treatment-naïve CLL48 | Phase 1, duvelisib monotherapy, R/R CLL, iNHL, TCL49 | Phase 1, duvelisib monotherapy, R/R TCL50 | Phase 1, duvelisib monotherapy, R/R iNHL51 | Phase 1, duvelisib + rituximab vs BR, CLL or iNHL52 | |
| Number of patients | 55 | 18 | 210 | 35 | 31 | 46 |
| AEs | ||||||
| Colitis/diarrhea | 47.3% Grade ≥3, 9.1% | 77.8% Grade ≥3, 22.2% | 41.9% Grade ≥3, 11.4% | 31% | 54.8% Grade ≥3, 25.8% | 37% Grade ≥3, 13% |
| Hepatotoxicity | 30.9% Grade ≥3, 10.9% | 33.3% Grade ≥3, 16.7% | 38.6% Grade ≥3, 19.5% | 57% Grade ≥3, 40% | 58.1% Grade ≥3, 38.7% | 21.7% Grade ≥3, 6.5% |
| Infections | >62% Grade ≥3, >23.6% | 22% | 29.5% Grade ≥3, 105 | 23% Grade ≥3, 17% | 19.4% | 34.7% Grade ≥3, 6.5% |
| Cutaneous reactions | 18.2% | 38.9% Grade ≥3, 5.6% | 16.2% Grade ≥3, 5.2% | 23% Grade ≥3, 17% | 42% Grade ≥3, 6.5% | 41.3% Grade ≥3, 19.6% |
| Pneumonitis | 7% | 11% | 4% | 6.5% | ||
| Dose reductions | ||||||
| Drug discontinuation due to AEs | 36% | 33% | ∼30% | 37% | 19% | 23.9% |
| Phase 2, DYNAMO trial, double-refractory FL, SLL, MZL22 | Phase 3 DUO trial, duvelisib vs ofatumumab, R/R CLL/SLL21 | |||||
| Number of patients | 129 | 319 | ||||
| AEs | ||||||
| Colitis/diarrhea | 56.6% Grade ≥3, 20.1 | 64% Grade ≥3, 27% | ||||
| Hepatotoxicity | 14% Grade ≥3, 5.4% | Grade ≥3, 3% | ||||
| Infections | 7.8% Grade ≥3, 5.4% | 48% Grade ≥3 | ||||
| Cutaneous reactions | 18.6% Grade ≥3, 4.7% | 10% Grade ≥3, 2% | ||||
| Pneumonitis | 4.7% | 3% | ||||
| Dose reductions | 66% | |||||
| Drug discontinuation due to AEs | 24% | 35% |
| . | Phase 1, R/R CLL, single-agent idelalisib7 . | Phase 1, R/R MCL44 . | Phase 1, R/R MCL and follicular lymphoma, idelalisib, lenalidomide, rituximab16 . | Phase 1, R/R indolent lymphoma, single-agent idelalisib45 . | Phase 2, R/R classical Hodgkin lymphoma, single-agent idelalisib46 . | Phase 2, treatment-naïve older patients with CLL, idelalisib + rituximab11 . |
|---|---|---|---|---|---|---|
| Number of patients | 54 | 40 | 11 | 64 | 25 | 64 |
| AEs | ||||||
| Colitis/diarrhea | 29.6% Grade ≥3, 5.6% | 40% Grade ≥3, 17.5% | 38% | 36% Grade ≥3, 9.4% | 4% | 64% Grade 3, ≥42% |
| Hepatotoxicity | 33-18% Grade ≥3, ∼2% | 60% Grade ≥3, 20% | 63% Grade ≥3, 18% | 53% Grade ≥3, 23% | Grade ≥3, 16% | 67% Grade ≥3, 23% |
| Infections | 44% Grade ≥3, 20% | 32.5% Grade ≥3, 10% | 25%, All grade ≥3 | 36% Grade ≥3, 17.2% | 16% | 44% Grade ≥3, 25% |
| Cutaneous reactions | 22% | 22.5% Grade ≥3, 2.5% | 63% Grade ≥3, 54% | 25% Grade ≥3, 3.1% | 8% | 58% Grade ≥3, 13% |
| Pneumonitis | 4% | 3%, All grade ≥3 | ||||
| Dose reductions | 36% | 45% | ||||
| Drug discontinuation due to AEs | 13% | 18% | 73% | 21% | 8% | 29.7% |
| Phase 2, double-refractory indolent lymphoma, single-agent idelalisib47 | Phase 2, idelalisib + entospletinib in R/R CLL and NHL17 | Phase 2, treatment-naïve CLL with idelalisib + ofatumumab12 | Phase 3, idelalisib + rituximab vs rituximab in R/R CLL8 | Phase 3, idelalisib vs placebo + BR in R/R CLL14 | Phase 3: idelalisib + ofatumumab in previously treated CLL13 | |
| Number of patients | 125 | 66 | 24 | 220 | 416 | 261 |
| AEs | ||||||
| Colitis/diarrhea | 43% Grade ≥3, 16% | 29% Grade ≥3, 2% | 46% Grade ≥3, 17% | 19% Grade ≥3, 4%* | 38% Grade ≥3, 9% | 54% Grade ≥3, 23% |
| Hepatotoxicity | 47% Grade ≥3, 13% | 23% | 79% Grade ≥3, 54% | 35% Grade ≥3, 5%* | 61% Grade ≥3, 21% | 20% Grade ≥3, 13% |
| Infections | 25% Grade ≥3, 7% | ∼18% | Grade ≥3, 13%* | 32% Grade ≥3, 12.5%-16% | 78% Grade ≥3, 22% | |
| Cutaneous reactions | 13% Grade ≥3, 2% | 30% Grade ≥3, ∼17% | 10% Grade ≥3, 3%* | 16% Grade ≥3, 3% | 18% Grade ≥3, 1% | |
| Pneumonitis | 17%; study terminated early | 13% | 4%* | 1.4% | 6% Grade ≥3, 5% | |
| Dose reductions | 34% | 13% | 58% | |||
| Drug discontinuation due to AEs | 20% | Study terminated early due to AEs | 5% | 27% | 39% | |
| Phase 1, duvelisib monotherapy, R/R CLL48 | Phase 1, duvelisib monotherapy, treatment-naïve CLL48 | Phase 1, duvelisib monotherapy, R/R CLL, iNHL, TCL49 | Phase 1, duvelisib monotherapy, R/R TCL50 | Phase 1, duvelisib monotherapy, R/R iNHL51 | Phase 1, duvelisib + rituximab vs BR, CLL or iNHL52 | |
| Number of patients | 55 | 18 | 210 | 35 | 31 | 46 |
| AEs | ||||||
| Colitis/diarrhea | 47.3% Grade ≥3, 9.1% | 77.8% Grade ≥3, 22.2% | 41.9% Grade ≥3, 11.4% | 31% | 54.8% Grade ≥3, 25.8% | 37% Grade ≥3, 13% |
| Hepatotoxicity | 30.9% Grade ≥3, 10.9% | 33.3% Grade ≥3, 16.7% | 38.6% Grade ≥3, 19.5% | 57% Grade ≥3, 40% | 58.1% Grade ≥3, 38.7% | 21.7% Grade ≥3, 6.5% |
| Infections | >62% Grade ≥3, >23.6% | 22% | 29.5% Grade ≥3, 105 | 23% Grade ≥3, 17% | 19.4% | 34.7% Grade ≥3, 6.5% |
| Cutaneous reactions | 18.2% | 38.9% Grade ≥3, 5.6% | 16.2% Grade ≥3, 5.2% | 23% Grade ≥3, 17% | 42% Grade ≥3, 6.5% | 41.3% Grade ≥3, 19.6% |
| Pneumonitis | 7% | 11% | 4% | 6.5% | ||
| Dose reductions | ||||||
| Drug discontinuation due to AEs | 36% | 33% | ∼30% | 37% | 19% | 23.9% |
| Phase 2, DYNAMO trial, double-refractory FL, SLL, MZL22 | Phase 3 DUO trial, duvelisib vs ofatumumab, R/R CLL/SLL21 | |||||
| Number of patients | 129 | 319 | ||||
| AEs | ||||||
| Colitis/diarrhea | 56.6% Grade ≥3, 20.1 | 64% Grade ≥3, 27% | ||||
| Hepatotoxicity | 14% Grade ≥3, 5.4% | Grade ≥3, 3% | ||||
| Infections | 7.8% Grade ≥3, 5.4% | 48% Grade ≥3 | ||||
| Cutaneous reactions | 18.6% Grade ≥3, 4.7% | 10% Grade ≥3, 2% | ||||
| Pneumonitis | 4.7% | 3% | ||||
| Dose reductions | 66% | |||||
| Drug discontinuation due to AEs | 24% | 35% |
MCL, mantle cell lymphoma; TCL, T-cell lymphoma.
In longer follow-up (median, 18 mo),9 prolonged exposure saw increases in any grade, grade 2, and grade ≥3 diarrhea (46.4%, 17.3%, and 16.4%, respectively); any grade and grade ≥3 colitis (10.9% and 8.2%, respectively); and any grade and grade ≥ 3 pneumonitis, respectively (10.0% and 6.4%). The incidence of elevated hepatic aminotransferases did not increase with time.