Abstract
Abstract 1037
Poster Board I-59
Voreloxin is a first-in-class anticancer quinolone derivative (AQD) that intercalates DNA and inhibits topoisomerase II, inducing apoptosis. Interim results of REVEAL-1, a Phase 2 (Ph 2) dose regimen optimization study of 3 schedules (sch) of single agent voreloxin in newly diagnosed elderly acute myeloid leukemia (AML) patients (pts), are reported. The initial dose regimen, voreloxin 72 mg/m2 qw x 3, was established in a Ph 1 dose-escalation study in relapsed/refractory leukemia pts (Lancet J et al., Proc ASH 2007). Overall remission rate (ORR = CR+CRp) was high (41%), but this regimen was less well tolerated in the frontline elderly population. The protocol explored 2 alternative voreloxin sch: 72 mg/m2 voreloxin qw x 2 and days 1 and 4 (d 1,4). A final cohort of pts is enrolling to the d 1,4 sch at 90 mg/m2. Dose escalation was based on safety data from the 72 mg/m2 cohort and from an ongoing Ph 1b/2 study of 90 mg/m2 voreloxin d 1,4 in combination with 1g/m2/d cytarabine x 5d (Lancet J, et al, ASCO 2009).
Ph 2 study of 3 voreloxin sch (30 pts/sch): A 72 mg/m2 qw x 3 or B 72 mg/m2 qw x 2 or C 72 mg/m2 on d 1,4. C at 90 mg/m2 voreloxin is now enrolling to 20 pts. Eligibility: newly diagnosed AML (de novo or secondary AML), pts age ≥ 60 with ≥ 1 additional adverse risk factor (age ≥ 70, secondary AML, intermediate or unfavorable cytogenetics, or PS 2). PK were evaluated in a pt subset in cycle 1. Patient bone marrow aspirates (BMA) taken prior to dosing were tested ex vivo for extreme drug resistance (EDR®) to voreloxin.
To date, 105 pts have been treated. Preliminary safety and ORR are available for A, B and C at 72 mg/m2 voreloxin. Twelve pts in C at 90 mg/m2 are too early to evaluate (TETE).
| Demographics . | ||||
|---|---|---|---|---|
| Schedule (72 mg/m2) . | A d 1, 8, 15 . | B d 1, 8 . | C d 1, 4 . | All . |
| N | 29 | 35 | 29 | 93 |
| Median Age (range) | 74(60,89) | 74(63,86) | 70(60,83) | 73(60,89) |
| ECOG 0-1 | 86% | 89% | 72% | 83% |
| ECOG 2 | 14% | 11% | 28% | 17% |
| AHD | 38% | 29% | 28% | 31% |
| ≥ 70 | 76% | 77% | 52% | 69% |
| Cytogenetics SWOG | ||||
| Favorable | 0% | 6% | 7% | 4% |
| Unfavorable | 41% | 46% | 48% | 45% |
| Intermediate | 48% | 31% | 31% | 37% |
| Unknown/not available | 10% | 17% | 13% | 14% |
| Demographics . | ||||
|---|---|---|---|---|
| Schedule (72 mg/m2) . | A d 1, 8, 15 . | B d 1, 8 . | C d 1, 4 . | All . |
| N | 29 | 35 | 29 | 93 |
| Median Age (range) | 74(60,89) | 74(63,86) | 70(60,83) | 73(60,89) |
| ECOG 0-1 | 86% | 89% | 72% | 83% |
| ECOG 2 | 14% | 11% | 28% | 17% |
| AHD | 38% | 29% | 28% | 31% |
| ≥ 70 | 76% | 77% | 52% | 69% |
| Cytogenetics SWOG | ||||
| Favorable | 0% | 6% | 7% | 4% |
| Unfavorable | 41% | 46% | 48% | 45% |
| Intermediate | 48% | 31% | 31% | 37% |
| Unknown/not available | 10% | 17% | 13% | 14% |
| Grade 3 or Higher Infections and Mucositis . | |||
|---|---|---|---|
| Schedule (72 mg/m2) . | A d 1, 8, 15 . | B d 1, 8 . | C d 1, 4 . |
| N | 29 | 35 | 29 |
| Febrile Neutropenia | 38% | 63% | 48% |
| Pneumonia | 31% | 34% | 24% |
| Sepsis/bacteremia | 55% | 26% | 10% |
| Infections | 59% | 26% | 28% |
| Upper GI mucositis | 31% | 14% | 21% |
| Lower GI mucositis | 10% | 6% | 0% |
| Grade 3 or Higher Infections and Mucositis . | |||
|---|---|---|---|
| Schedule (72 mg/m2) . | A d 1, 8, 15 . | B d 1, 8 . | C d 1, 4 . |
| N | 29 | 35 | 29 |
| Febrile Neutropenia | 38% | 63% | 48% |
| Pneumonia | 31% | 34% | 24% |
| Sepsis/bacteremia | 55% | 26% | 10% |
| Infections | 59% | 26% | 28% |
| Upper GI mucositis | 31% | 14% | 21% |
| Lower GI mucositis | 10% | 6% | 0% |
| Outcome . | |||
|---|---|---|---|
| Schedule (72 mg/m2) . | A d 1, 8, 15 . | B d 1, 8 . | C d 1, 4 . |
| N | 29 | 35 | 29 |
| CR + CRp % | 41% | 29% | 38% |
| Reinduction (CR) No. | 4(2) | 8(3) | 10(5) |
| Consolidation 1 No. | 9 | 9 | 7 |
| Consolidation 2 No. | 1 | 8 | 4 |
| 30-day all-cause mortality | 17% | 9% | 7% |
| 60-day all-cause mortality | 38%) | 37% | 14% |
| Median OS days (95% CI) | 261d (44, NR) | 147d (55, NR) | TETE |
| Median OS months | 8.7 | 4.9 | TETE |
| NR not yet reached | |||
| Outcome . | |||
|---|---|---|---|
| Schedule (72 mg/m2) . | A d 1, 8, 15 . | B d 1, 8 . | C d 1, 4 . |
| N | 29 | 35 | 29 |
| CR + CRp % | 41% | 29% | 38% |
| Reinduction (CR) No. | 4(2) | 8(3) | 10(5) |
| Consolidation 1 No. | 9 | 9 | 7 |
| Consolidation 2 No. | 1 | 8 | 4 |
| 30-day all-cause mortality | 17% | 9% | 7% |
| 60-day all-cause mortality | 38%) | 37% | 14% |
| Median OS days (95% CI) | 261d (44, NR) | 147d (55, NR) | TETE |
| Median OS months | 8.7 | 4.9 | TETE |
| NR not yet reached | |||
| Characteristics of Responders . | ||||
|---|---|---|---|---|
| Schedule (72 mg/m2) . | A d 1, 8, 15 . | B d 1, 8 . | C d 1, 4 . | All . |
| CR/CRp | CR/CRp | CR/CRp | CR/CRp | |
| N(%) | 12(41%) | 10(29%) | 11(38%) | 33(35%) |
| Age % Response in Category | ||||
| ≥ 70 | 36% | 33% | 33% | 33% |
| <70 | 57% | 13% | 43% | 38% |
| PS % Response in Category | ||||
| ECOG 2 | 50% | 25% | 38% | 38% |
| ECOG 0-1 | 40% | 29% | 38% | 35% |
| Presence of AHD % Response in Category | ||||
| AHD yes | 45% | 20% | 9% | 28% |
| AHD no | 38% | 32% | 48% | 39% |
| Cytogenetics % Response in Category | ||||
| Intermediate/Unfavorable | 35% | 33% | 26% | 32% |
| Intermediate | 43% | 45% | 33% | 41% |
| Unfavorable | 25% | 25% | 21% | 24% |
| Favorable | NA | 0% | 100% | 50% |
| Risk Factors % Response in Category | ||||
| 1 | 66% | 29% | 80% | 55% |
| 2 | 44% | 29% | 14% | 30% |
| 3 | 25% | 25% | 20% | 33% |
| 4 | NA | 50% | NA | 50% |
| NA not applicable | ||||
| Characteristics of Responders . | ||||
|---|---|---|---|---|
| Schedule (72 mg/m2) . | A d 1, 8, 15 . | B d 1, 8 . | C d 1, 4 . | All . |
| CR/CRp | CR/CRp | CR/CRp | CR/CRp | |
| N(%) | 12(41%) | 10(29%) | 11(38%) | 33(35%) |
| Age % Response in Category | ||||
| ≥ 70 | 36% | 33% | 33% | 33% |
| <70 | 57% | 13% | 43% | 38% |
| PS % Response in Category | ||||
| ECOG 2 | 50% | 25% | 38% | 38% |
| ECOG 0-1 | 40% | 29% | 38% | 35% |
| Presence of AHD % Response in Category | ||||
| AHD yes | 45% | 20% | 9% | 28% |
| AHD no | 38% | 32% | 48% | 39% |
| Cytogenetics % Response in Category | ||||
| Intermediate/Unfavorable | 35% | 33% | 26% | 32% |
| Intermediate | 43% | 45% | 33% | 41% |
| Unfavorable | 25% | 25% | 21% | 24% |
| Favorable | NA | 0% | 100% | 50% |
| Risk Factors % Response in Category | ||||
| 1 | 66% | 29% | 80% | 55% |
| 2 | 44% | 29% | 14% | 30% |
| 3 | 25% | 25% | 20% | 33% |
| 4 | NA | 50% | NA | 50% |
| NA not applicable | ||||
Overall incidence of infections and mucositis were reduced in B and C, sch with 2 voreloxin doses, relative to A which had 3 voreloxin doses. Voreloxin PK were similar to those in an earlier Ph 1 study in relapsed/refractory AML (Lancet J, et al., Proc ASH 2007). Pts whose BMA were inhibited < 48% by 1 μM voreloxin had a greater chance of treatment failure (p = 0.043) than those whose BMA were inhibited by ≥ 48%.
In REVEAL-1, voreloxin demonstrates clinical activity with 3 dosing sch in previously untreated elderly (age ≥ 60) AML pts who are unlikely to benefit from standard chemotherapy. ORR across 3 sch was 35%; the majority (76%) were CR. Responses were seen in each risk factor category and with multiple risk factors. Of reinduced pts, 45% achieved CR(p). Durable remissions exceeding 6 months were observed in 50% (A) and 63% (B) thus far. C d 1,4 was selected for further development based on ORR (38%), 30 and 60 day all-cause mortality (7% and 14%, respectively) and an improved safety profile with lower rates of infection compared to previous schedules. Further accrual to C 90 mg/m2voreloxin d 1,4 is ongoing.
Ravandi:Sunesis: sunesis study steering committee. Cripe:Sunesis: Research Funding. Chen:sunesis: Employment. Mahadocon:sunesis: Employment. Fox:Sunesis: Employment. Berman:Sunesis: Employment. Michelson:sunesis: Employment. Stuart:sunesis: sunesis study steering committee.
Author notes
Asterisk with author names denotes non-ASH members.
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