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Efficacy & Safety of INQOVI
ASCERTAIN trial design1,2
The phase 3 crossover trial was designed to assess systemic decitabine exposure, demethylation activity, and safety between IV decitabine and INQOVI tablets. The trial allowed for intrapatient comparison in the first 2 randomized treatment cycles, then assessment of the long-term efficacy and safety of INQOVI as a single arm.1,2
The phase 3 crossover trial had a median follow-up of approximately 2.6 years.1,2
| Phase 3 (N=133)1 |
Phase 3 Long-term Follow-up (N=133)2 |
|
|---|---|---|
| Primary endpoint | 5-day area under the curve (AUC) between oral decitabine-cedazuridine and IV decitabine for Cycles 1 and 2 |
5-day area under the curve (AUC) between oral decitabine-cedazuridine and IV decitabine for Cycles 1 and 2 |
| Key secondary endpoints |
Complete response Rate of conversion from transfusion dependence to transfusion independence |
Clinical response, transfusion independence, median overall and leukemia-free survival (LFS), safety, and pharmaco-dynamics |
| Other endpoints |
Median duration of complete response and best response Median time to complete response |
Median duration of complete response and best response. Median time to first response |
Phase 3 crossover design1
Open-label, randomized, 2-cycle, 2-sequence, crossover clinical trial in treatment-experienced or -naive patients with MDS, including CMML (IPSS intermediate-1, -2, or high-risk). Patients were allowed to have 1 prior cycle of decitabine or azacitidine, and there was no limit for body weight or surface area.
- Patients were randomized 1:1 to INQOVI (decitabine 35 mg/cedazuridine 100 mg) or IV decitabine 20 mg/m2 daily from day 1 through day 5 of each 28-day cycle
- In Cycle 1, patients received one agent and then crossed over to receive the other agent in Cycle 2
- After Cycle 2, all patients received INQOVI and treatment continued until disease progression or unacceptable toxicity
Baseline patient characteristics1
| Characteristic | Phase 3 (N=133) |
|---|---|
| Age (years) | |
| Median (min, max) | 71 (44, 88) |
| Sex | |
| Male | 65% |
| Female | 35% |
| Race | |
| White | 91% |
| Black or African-American | 3% |
| Asian | 2% |
| Other or not reported | 4% |
| ECOG performance score | |
| 0 | 41% |
| 1 | 59% |
| 2 | 0 |
| Disease category/IPSS | |
| MDS intermediate-1 risk | 44% |
| MDS intermediate-2 risk | 20% |
| MDS high risk | 16% |
| MDS low risk | 8% |
| CMML | 12% |
| Prior HMA therapya | |
| Prior azacitidine | 5% |
| Prior decitabine | 3% |
| Transfusion dependenceb | |
| RBC transfusion dependence | 39% |
| Platelet transfusion dependence | 8% |
aOne cycle only, per the exclusion criteria.
bDefined as documentation of ≥2 units of transfusion within 56 days of the first day of study treatment.
CMML=chronic myelomonocytic leukemia; ECOG=Eastern Cooperative Oncology Group; MDS=myelodysplastic syndromes; RBC=red blood cell.
The only oral HMA with equivalent systemic exposure to IV decitabine1-3
Primary endpoint results1,2
ratio of oral to IV 5-day decitabine AUC
(indicating equivalent pharmacokinetic exposure)
(90% Cl: 93, 106)
- This ratio is the geometric mean of the 5-day cumulative decitabine AUC between INQOVI® (decitabine and cedazuridine) tablets and IV‑administered decitabine when administered once daily for 5 consecutive days1
Efficacy results in patients with MDS or CMML1-3
| Phase 3 (N=133)1 |
Phase 3 Long-term Follow-up (N=133)2 |
|
|---|---|---|
| Median follow-up time | 12.6 months |
~32 months |
| Patients who achieved CR (CI)a | 21% (95% CI: 15, 29) | 25% (95% CI: 17, 34)b |
| Median duration of CRc | 7.5 months (range: 1.6-17.5) | 14.1 months (range: 11.7-18.7) |
| Median time to CRa | 4.3 months (range: 2.1-15.2) | 4.5 months (range: 2.1-18.7)3 |
| Patients who went on to receive stem cell transplant (n/N)d |
20% (27/133) | 20% (27/133) |
| Median duration of best responsea |
NE | 12.2 months (95% CI: 9.5, 14.4) |
| Median time to fi rst response | NE | 58 days (IQR: 35-116) |
aComplete or partial response may take longer than 4 cycles.1
bOf the evaluable 117 participants, 25% (29/117) achieved a CR.2
cFrom start of CR until relapse or death.1
dNo apparent difference between survival of those transplanted vs those who continued oral decitabine/cedazuridine treatment.3
CI=confidence interval; CR=complete response; IQR=interquartile range; NE=not evaluated.
Transfusion independence
Phase 3 Results (N=133)1
of patients who were initially transfusion dependent achieved post-treatment RBC and platelet transfusion independence (30/57)
of patients who initially were RBC and platelet transfusion independent remained transfusion independent post‑treatment (48/76)
Phase 3 Long-term Follow-up Results (N=133)2
of patients who were initially transfusion dependent achieved post-treatment RBC transfusion independence (28/54)
of patients who were initially transfusion dependent achieved post-treatment platelet transfusion independence (6/12)
of participants in each transfusion category were transfusion independent for at least 112 consecutive days
Secondary endpoint: overall survival (N=133)2
Median overall survival (95% CI. 28.0, NE)
- Median follow-up was ~32 months
- Clinical response rate was a secondary endpoint that included complete response, marrow complete response, partial response, and hematologic improvement
- Of the evaluable participants with MDS, 70% ([95% CI: 50, 69] 82 of 117 participants) displayed a clinical response
- Overall survival and clinical response were secondary endpoints that are not reflected in the full Prescribing Information
- Due to potential variability in the natural history of the disease, a single-arm study may not adequately characterize this time-to-event endpoint, and the results may not be interpretable
- This data presentation is not intended to draw conclusions regarding the efficacy of INQOVI
AUC=area under the curve; CI=confidence interval; CMML=chronic myelomonocytic leukemia; CR=complete response; HMA=hypomethylating agent; IV=intravenous; MDS=myelodysplastic syndromes; NE=not evaluated; RBC=red blood cell.
Safety profile similar to IV decitabine1
Adverse reactions reported in ≥10% of patients in the pooled phase 2 and phase 3 safety population1
| Adverse reactionsa | INQOVI Cycle 1 n=107 |
IV decitabine Cycle 1 n=106 |
INQOVI all cycles n=208c |
|||
|---|---|---|---|---|---|---|
| All grades (%) |
Grades 3‑4 (%) |
All grades (%) |
Grades 3‑4 (%) |
All grades (%) |
Grades 3‑4 (%) |
|
| General disorders and administration site conditions | ||||||
| Fatigueb | 29 | 2 | 25 | 0 | 55 | 5 |
| Hemorrhageb | 24 | 2 | 17 | 0 | 43 | 3 |
| Edemab | 10 | 0 | 11 | 0 | 30 | 0.5 |
| Pyrexia | 7 | 0 | 7 | 0 | 19 | 1 |
| Gastrointestinal disorders | ||||||
| Constipationb | 20 | 0 | 23 | 0 | 44 | 0 |
| Mucositisb | 18 | 1 | 24 | 2 | 41 | 4 |
| Nausea | 25 | 0 | 16 | 0 | 40 | 0.5 |
| Diarrheab | 16 | 0 | 11 | 0 | 37 | 1 |
| Transaminase increasedb | 12 | 1 | 3 | 0 | 21 | 3 |
| Abdominal painb | 9 | 0 | 7 | 0 | 19 | 1 |
| Vomiting | 5 | 0 | 5 | 0 | 15 | 0 |
| Musculoskeletal and connective tissue disorders | ||||||
| Myalgiab | 9 | 2 | 16 | 1 | 42 | 3 |
| Arthralgiab | 9 | 1 | 13 | 1 | 40 | 3 |
| Respiratory, thoracic, and mediastinal disorders | ||||||
| Dyspneab | 17 | 3 | 9 | 3 | 38 | 6 |
| Coughb | 7 | 0 | 8 | 0 | 28 | 0 |
| Blood and lymphatic system disorders | ||||||
| Febrile neutropenia | 10 | 10 | 13 | 13 | 33 | 32 |
| Skin and subcutaneous tissue disorders | ||||||
| Rashb | 12 | 1 | 11 | 1 | 33 | 0.5 |
| Nervous system disorders | ||||||
| Dizzinessb | 16 | 1 | 11 | 0 | 33 | 2 |
| Headacheb | 22 | 0 | 13 | 0 | 30 | 0 |
| Neuropathyb | 4 | 0 | 8 | 0 | 13 | 0 |
| Metabolism and nutritional disorders | ||||||
| Decreased appetite | 10 | 1 | 6 | 0 | 24 | 2 |
| Infections and infestations | ||||||
| Upper respiratory tract infectionb | 6 | 0 | 3 | 0 | 23 | 1 |
| Pneumoniab | 7 | 7 | 7 | 5 | 21 | 15 |
| Sepsisb | 6 | 6 | 2 | 1 | 14 | 11 |
| Cellulitisb | 4 | 1 | 3 | 2 | 12 | 5 |
| Investigations | ||||||
| Renal impairmentb | 9 | 0 | 8 | 1 | 18 | 0 |
| Weight decreased | 5 | 0 | 3 | 0 | 10 | 1 |
| Injury, poisoning, and procedural complications | ||||||
| Fall | 4 | 0 | 1 | 0 | 12 | 1 |
| Psychiatric disorders | ||||||
| Insomnia | 6 | 0 | 2 | 0 | 12 | 0.5 |
| Vascular disorders | ||||||
| Hypotensionb | 4 | 0 | 6 | 1 | 11 | 2 |
| Cardiac disorders | ||||||
| Arrhythmiab | 3 | 0 | 2 | 0 | 11 | 1 |
aPlease see full Prescribing Information for complete list of adverse event occurring during all cycles.
bIncludes multiple adverse reaction terms.
cIncludes adverse reactions that occurred during all cycles, including during treatment with 1 cycle of intravenous decitabine.
- Safety results were similar to IV decitabine with no unexpected adverse reactions reported in the first 2 cycles1
- Incidence of cytopenias was slightly higher in INQOVI tablets during Cycle 1 compared to IV decitabineKim,1
- In the pooled safety population of phases 2 and 3, 61% of patients receiving INQOVI were exposed for ≥6 months and 24% were exposed for >1 year1
- Long-term follow-up study: Adverse event profile was similar to what was observed in the pooled safety population2
- The incidence of serious adverse reactions in Cycles 1 and 2 was 31% (40 of 130 participants) with oral decitabine-cedazuridine and 18% (24 of 132 participants) with IV decitabine
Additional safety profile information
- Clinically relevant adverse reactions in <10% of patients who received INQOVI tablets included: acute febrile neutrophilic dermatosis (Sweet's syndrome) (1%) and tumor lysis syndrome (0.5%)1
- Serious adverse reactions occurred in 68% of patients who received INQOVI. Serious adverse reactions in >5% of patients included febrile neutropenia (30%), pneumonia (14%), and sepsis (13%)1
- In the long-term follow-up study, there were 5 treatment-related deaths; 2 deemed related to oral therapy (sepsis and pneumonia) and 3 to IV treatment (septic shock [n=2] and pneumonia [n=1])2
- Fatal adverse reactions occurred in 6% of patients and included sepsis (1%), pneumonia (1%), respiratory failure (1%), septic shock (1%), and 1 case each of cerebral hemorrhage and sudden death1
- In the long-term follow-up study, 11 (8%) of 133 participants had fatal treatment-emergent serious adverse reactions during the study2
- Dose interruptions due to an adverse reaction occurred in 41% of patients who received INQOVI. Adverse reactions requiring dosage interruptions in >5% of patients who received INQOVI included neutropenia (18%), febrile neutropenia (8%), thrombocytopenia (6%), and anemia (5%)1
- Dose reductions due to an adverse reaction occurred in 19% of patients who received INQOVI. Adverse reactions requiring dosage reductions in >2% of patients included neutropenia (12%), anemia (3%), and thrombocytopenia (3%)1
Select hematologic lab abnormalities1
>20% in the pooled safety population
| Lab parametera | INQOVI Cycle 1b | IV decitabine Cycle 1b | INQOVI all cyclesb | |||
|---|---|---|---|---|---|---|
| All grades (%) |
Grades 3‑4 (%) |
All grades (%) |
Grades 3‑4 (%) |
All grades (%) |
Grades 3‑4 (%) |
|
| Hematology | ||||||
| Leukocytes decreased | 79 | 65 | 77 | 59 | 87 | 81 |
| Platelet count decreased | 79 | 65 | 77 | 67 | 82 | 76 |
| Neutrophil count decreased | 70 | 65 | 62 | 59 | 73 | 71 |
| Hemoglobin decreased | 58 | 41 | 59 | 36 | 71 | 55 |
aIncludes any lab abnormalities that worsened by ≥1 grades. Grades 3 to 4 include any lab abnormalities that worsened to grade 3 or grade 4.
bThe denominator used to calculate the rate varied from 103 to 107 for INQOVI Cycle 1, from 102 to 106 for the IV decitabine cycle, and from 203 to 208 for INQOVI (all cycles) based on the number of patients with a baseline value and ≥1 post‐treatment value.
Please see full Prescribing Information for chemistry lab safety parameters.
Discontinuation rate
- 5% of patients discontinued treatment with INQOVI due to an adverse reaction1
- Treatment discontinuations due to an adverse reaction during the first 2 treatment cycles were low (1 participant in each group)2
- Overall treatment discontinuations due to an adverse reaction were also low (1 of 132 with IV decitabine and 2 of 130 with oral decitabine-cedazuridine)2
- The most frequent adverse reactions resulting in permanent discontinuation were febrile neutropenia (1%) and pneumonia (1%)1
- The most common reason for treatment discontinuation was undergoing allogeneic hematopoietic stem-cell transplantation (HSCT) (27 [20%])2
References: 1. INQOVI [package insert]. Princeton, NJ: Taiho Oncology, Inc.; 2022. 2. Garcia‑Manero G, Griffiths EA, Steensma DP, et al. Oral cedazuridine/decitabine: a phase 2, pharmacokinetic/pharmacodynamic, randomized, crossover study in MDS and CMML. Blood. doi:10.1182/blood.2019004143 3. Data on file. Taiho Oncology Inc., Princeton, NJ.