The CLARIDHY study: Overview
Study design1,5
Multicentre, randomized, double-blind, placebo-controlled phase 3 study in patients with locally advanced or metastatic CCA with an IDH1-R132 mutation, who progressed on prior therapy
185 patients with CCA and confirmed IDH1 mutation
ECOG PS 0 or 1
1 TO 2 prior treatment regimens, including at least one gemcitabine- or 5-FU-containing regimen
An expected survival of ≥3 months
2:1 randomization (n=185)*
TIBSOVO® (500 mg/day)†
(n=124)
Placebo
(n=61)†
70.5% of patients in the placebo arm crossed over to receive TIBSOVO® following radiographic disease progression, as assessed by the investigator
Primary endpoint:
Progression-free survival (PFS) by the central IRC based on RECIST assessment
- Secondary endpoints:
- OS
- Objective response rate by RECIST
- Duration of response and time to response
- PFS by investigator assessment
- Pharmacokinetics and pharmacodynamics
- QoL by EORTC
- Safety profile
*At the data cut-off for the primary analysis (Jan 31, 2019). As of May 31, 2020 (data cut-off date for the final OS analysis), 187 patients had been randomized to receive TIBSOVO® (n=126) or placebo (n=61).
†Given orally, once daily, in 28-day cycles.
Adapted from the TIBSOVO® Product Monograph and Abou-Alfa et al. 2020.
- Patients were randomized to receive either TIBSOVO® 500 mg orally once daily or matched placebo until disease progression or development of unacceptable toxicity.1
- Randomization was stratified by number of prior therapies (1 or 2).1
- Eligible patients who were randomized to placebo were allowed to cross over to receive TIBSOVO® after documented radiographic disease progression as assessed by the investigator.1
Key inclusion criteria1
- Locally advanced or metastatic cholangiocarcinoma with an IDH1 R132 mutation
- Disease had progressed following at least 1 but not more than 2 prior treatment regimens including at least one gemcitabine- or 5-FU-containing regimen
- Expected survival of ≥ 3 months.
Study population demographics
Demographic and clinical characteristics at baseline were similar between the two arms
TIBSOVO® (N=124) | ||
|---|---|---|
Demographic | ||
Age (years) Median (min, max) | 61 (33, 80) | |
Age category (years), n (%) | ||
<45 | 11 (9) | |
45-<65 | 67 (54) | |
65+ | 46 (37) | |
Sex, n (%) | ||
Male | 44 (36) | |
Female | 80 (65) | |
Race, n (%) | ||
Asian | 15 (12) | |
White | 70 (57) | |
Other | 4 (3) | |
Missing | 35 (28) | |
Disease characteristics | ||
ECOG at baseline, n (%) | ||
0 | 49 (40) | |
1-3 | 75 (60) | |
IDH1 mutation*, n (%) | ||
R132C | 84 (68) | |
R132G | 17 (14) | |
R132H | 0 | |
R132L | 21 (17) | |
R132S | 2 (2) | |
CCA type at diagnosis, n (%) | ||
Intrahepatic | 111 (90) | |
Extrahepatic and perihilar | 5 (4) | |
Unknown | 8 (7) | |
Randomization strata, n (%) | ||
1 prior line of therapy | 66 (53) | |
2 prior lines of therapy | 58 (47) | |
Extent of disease at screening, n (%) | ||
Local/regional | 9 (7) | |
Metastatic† | 115 (93) | |
Biliary stent at screening, n (%) | ||
Yes | 14 (11) | |
No | 110 (89) | |
Ascites at screening, n (%) | ||
Yes | 34 (27) | |
No | 90 (73) | |
ECOG: Eastern Cooperative Oncology Group; IDH: isocitrate dehydrogenase; max: maximum; min: minimum.
*From IDH1 central testing.
†Subject with both local/regional and metastatic disease is considered as metastatic.
Adapted from the TIBSOVO® Product Monograph.
Consult the TIBSOVO® Product Monograph
2-HG: 2-hydroxyglutarate; α-KG: alpha-ketoglutarate; AML: acute myeloid leukemia; AZA: azacitidine; PBO: placebo; CCA: cholangiocarcinoma; CI: confidence interval; CR: complete response; CRh: complete response with partial hematologic recovery; CTCAE: Common Terminology Criteria for Adverse Events; DLCO: diffusing capacity for carbon monoxide; ECG: electrocardiogram; ECOG PS: Eastern Cooperative Oncology Group Performance Status; EFS: event-free survival; eGFR: estimated glomerular filtration rate; FEV1: forced expiratory volume in 1 second; HR: hazard ratio; IDH1: isocitrate dehydrogenase-1; IRC: Independent Radiology Centre; IV: intravenous; mIDH1: mutated isocitrate dehydrogenase-1; MOA: mechanism of action; NCCN: National Comprehensive Cancer Network; OR: odds ratio; OS: overall survival; PBO: placebo; PCR: polymerase chain reaction; PD: pharmacodynamics; PK: pharmacokinetics; QD: daily; RECIST: Response Evaluation Criteria In Solid Tumors; SC: subcutaneous.
References:
- TIBSOVO® Product Monograph. Servier Canada. July 19, 2024.
- Montesinos P, et al. N Engl J Med. 2022 Apr 21;386(16):1519–1531.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Acute Myeloid Leukemia Version 2.2025 — January 27, 2025.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Biliary Duct Cancers Version 6.2024 — January 10, 2025.
- Abou-Alfa GK, et al. Lancet Oncol. 2020 Jun;21(6):796-807.
- Zhu AX, et al. JAMA Oncol. 2021 Nov 1;7(11):1669-1677.
- Dammacco F, Silvestris F, eds. Oncogenomics: From Basic Research to Precision Medicine. Academic Press; 2019.
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