Chemoembolisation of Hepatocellular Carcinomas Not Subject to Interventive Care by Idarubicin-loaded Beads - IDASPHERE II (IDASPHERE II)
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|ClinicalTrials.gov Identifier: NCT02185768|
Recruitment Status : Completed
First Posted : July 10, 2014
Last Update Posted : March 6, 2019
The most frequently used products in CHE are doxorubicin (36%), cisplatin (31%), and epirubicin (12%). But until recently, there were no obvious reasons to use one product over another. In fact, systemic chemotherapy is considered ineffective in HCC [hepatocellular carcinoma], which does not allow any argument in favour of the product. Moreover, 2 randomised trials comparing the molecules (doxorubicin vs. epirubicin) proved to be negative in terms of survival.
Cytotoxicity of different anticancer agents on HCC cell lines have been compared in order to select the best candidate for CHE. Eleven chemotherapy molecules have been tested, including those more frequently used in CHE. Among them, idarubicin (an anthracycline) proved to be the most effective in vitro by far. The superiority of idarubicin (as opposed to doxorubicin) was noted especially on the SNU-449 line, which is known for its resistance to several chemotherapy agents. The best cytotoxicity of idarubicin can be explained by 2 mechanisms: 1) idarubicin has a better intracellular penetration than the other anthracyclines. This is probably due to its more considerable lipophily, facilitating thus its passage through the membrane made up of a double lipid layer, 2) idarubicin is resistant to the multidrug resistance system (MDR). The MDR mechanism, which is often noted in HCC, consists of membrane pumps transporting the molecule outside the cell. These two particularities could explain a more significant accumulation of idarubicin in the HCC cells, and thus better efficacy. It is interesting to note that orally administered idarubicin (5 mg/day for 21 days) has proved to be less toxic and is effective in HCC. Currently, idarubicin is used to treat leukaemia. Its toxicity profile (especially, haematological and cardiac) is known.
On these grounds, A pilot study has been conducted in order to assess the tolerance and efficacy of lipiodol-based CHE using a 10 mg dose of idarubicin in 21 patients with unresectable HCC. These preliminary data reveal that CHE with idarubicin is effective and less toxic.
Idarubicin can be loaded in microbeads. A phase I study (IDASPHERE) has been conducted on DC Beads® microbeads (300-500µm) loaded with idarubicin (dose increased from 5 to 25 mg). The DLT [dose-limiting toxicity] and MTD [maximum tolerated dose] have been determined in 21 patients using a CRM. The MTD of idarubicin was assessed at 10 mg. In our study, the idarubicin-loaded beads did not give rise to any specific toxicity-related problem. The 10 mg dose is compatible with the known toxicity profile of idarubicin: cumulative cardiotoxicity of doxorubicin is noted from 550 mg/m², whereas that of idarubicin is noted from 93 mg/m². There is thus a 5.9:1 ratio between their cumulative toxicities. The most frequently used dose (and also the weakest one) for the doxorubicin-based CHE is 50 mg. The equivalent of the idarubicin dose would thus be: 50 mg (doxorubicin) / 5.9 (doxorubicin/idarubicin ratio) = approx. 10 mg of idarubicin.
It has been already demonstrated that hepatic extraction of idarubicin is better than those of doxorubicin and daunorubicin in an animal sarcoma model. In this study, AUC 0-48h and AUC 0-72h were 1.35 times higher with idarubicin, proving that its intra-hepatic penetration was 35% higher.
The randomised phase II PRECISION V study compared conventional CHE (cCHE) with CHE by doxorubicin beads (DC Bead®) in patients with HCC. It is currently the largest randomised trial on CHE published. The PRECISION V data can be thus used to compare the other studies in terms of efficacy and tolerance.
To continue our preliminary study and the phase I IDASPHERE study, investigators wish to assess thus the efficacy and confirm the tolerance of idarubicin-loaded beads for the CHE of HCC according to a protocol similar to PRECISION V, as part of a single-arm phase II study.
|Condition or disease||Intervention/treatment||Phase|
|Liver Cancer||Drug: idarubicin Device: Dc- Beads 300-500µm||Phase 2|
By using a 2-step Fleming plan (Fleming, 1982) with a unilateral alpha risk of 5% and 90% potency, it is necessary to include 86 assessable patients.
On the 1st step: 43 patients will be included (+/- 2 patients, if non-assessable patient(s)
- If 10 patients or less present an objective response, the trial will be discontinued on grounds of futility (H1 rejected)
- If 18 patients or less present an objective response, the trial will be discontinued on grounds of efficacy (H0 rejected)
If not, we proceed with the 2nd step including 43 additional patients. If 29 patients or more present an objective response, the treatment will be considered as effective (H0 rejected)
Considering a 5% ratio of visual loss or non-assessable patients, 91 patients will be included.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||46 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Chemoembolisation of Hepatocellular Carcinomas Not Subject to Interventive Care by Idarubicin-loaded Beads - IDASPHERE II|
|Actual Study Start Date :||January 2015|
|Actual Primary Completion Date :||May 2018|
|Actual Study Completion Date :||May 2018|
Experimental: DC-BEADS + Idarubicin
Chemoembolization with DC BEAD loaded with idarubicin
Device: Dc- Beads 300-500µm
- Rate of patients in objective response (complete or partial response) [ Time Frame: up to 6 months ]The main judgement criterion is the rate of patients in objective response (complete or partial response) at 6 months according to the mRECIST criteria and based on the central review.
- Rate of patients in objective response (complete or partial response) and assessed according to the investigator. [ Time Frame: up to 6 months ]The rate of patients in objective response (complete or partial response) at 6 months according to the mRECIST criteria, and assessed according to the investigator.
- Treatment failure date [ Time Frame: up to 2 years ]
The time interval until treatment failure This is defined by the time interval between the inclusion date and the protocol Treatment failure date. Death, progression, and any protocol treatment discontinuation (regardless of the cause) are considered as treatment failure.
Surviving patients not subject to treatment failure will be withdrawn on the date of the last 6-month morphological assessment.
- Best response [ Time Frame: up to 6 months ]The best response according to the mRECIST criteria
- Survival without progression [ Time Frame: up to 2 years ]
Survival without progression:
This is defined by the time interval between the inclusion date and the date of the 1st progression according to the mRECIST criteria (assessed in central review) or death (regardless of the cause).
The surviving patients without progression will be withdrawn on the date of the last recorded news
- Overall survival [ Time Frame: up to 2 years ]Overall survival This is defined by the time interval between the inclusion date and the date of death (regardless of the cause) or the date of the last recorded news for the surviving patients.
- Treatment tolerance [ Time Frame: up to 2 years ]Treatment tolerance Toxicities will be assessed using the NCI-CTC criteria v4.0. They will be described according to their degree as number of toxicities and number of patients presenting toxicity.
- Quality of life [ Time Frame: up to 6 months ]Quality of life (QLQ-C30 questionnaires and its HCC18 module specific to HCC)
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02185768
|Angers, France, 49933|
|CHU - Hôpital François Mitterand|
|Dijon, France, 21079|
|Hôpital La Croix Rousse|
|Lyon, France, 69317|
|Hôpital Edouard Herriot|
|Lyon, France, 69437|
|CHU St Eloi|
|Montpellier, France, 34295|
|Hôpital de l'Archet II|
|Nice, France, 06202|
|Principal Investigator:||Boris GUIU, PhD||Fédération Francophone de Cancérologie Digestive|