randomised phase iii trial of trabectedin versus doxorubicin

8/15/2019 Randomised Phase III Trial of Trabectedin Versus Doxorubicin

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Randomised phase III trial of trabectedin versus doxorubicin-based chemotherapy

as rst-line therapy in translocation-related sarcomas

Translocation TrabectedinAbstract Aim: This randomised phase III trial evaluated rst-line trabectedin versus doxorubicin-based

chemotherapy (DXT! in patients "ith advanced#metastatic translocation-related sarcomas (TR$!%&ethods: 'atients "ere randomly assined ():)! to receive trabectedin )%* m#m+ +,-h intravenous(i%v%! infusion every "ee.s (/".! (Arm A!0 or doxorubicin 1* m#m+ i%v% /".0 or doxorubicin 23m#m+ i%v% plus ifosfamide (rane0 245 #m+! i%v% /". (Arm 6!% 'roression- free survival ('7$! byindependent revie" "as the primary e8cacy end-point%Results: 9ne hundred and t"enty-one patients "ere randomised ;; of them had TR$ conrmed bycentral patholoy revie" (e8cacy population!% T"enty nine '7$ events "ere assessed by independentrevie" ()2 "ith trabectedin ) "ith DXT!% '7$ sho"ed non-sinicant died that trabectedin could induce inother translocation-related sarcomas (TR$! e


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accordin to the Declaration of Felsin.i0 Hood linical 'ractice uidelines andlocal reulations onclinical trials0 and "as approved by respective independent ethics committees%$ined informed consent "as obtained from all patients% An Independent Data&onitorin ommittee (ID&! revie"ed the study conduct%

Trial codes "ere @udra T: +33;-33++2-)) linical- Trials%ov Identier:

T33152)+3%

+%)% $election of patients@liibility criteria included patients '); year-olds "ith initial patholoicaldianosis of TR$ of follo"in subtypes: alveolar soft part sarcoma0 aniomatoidbrous histiocytoma0 clear cell sarcoma0 desmoplastic small round cell tumour0lo" rade endometrial stromal sarcoma0 lo" rade bromyxoid sarcoma0 myxoidchondrosarcoma0 &R and synovial sarcoma% @"ins sarcomaand dermatobrosarcoma protuberans "ere excluded% @vidence of translocationby Juorescencein situ hybridisation "as not re/uired for patient enrolment into the trial0 butonly patients "ith conrmed translocation "ere included in the primary studyanalysis% 'atients had to have unresectable locally advanced or metastaticproressive disease measurable disease accordin to the Response @valuationriteria in $olid Tumours (R@I$T v%)%3! @astern ooperative 9ncoloyHroup (@9H! 'erformance $tatus ('$! score 34+ ade/uate cardiac function Bleftventricular eKection function (L@7! "ithin normal limitsC0 and ade/uatehaematoloical (haemolobin '5 #dl absolute neutrophil count ')%* )35#lplatelets ')33 )35#l!0 renal (serum creatinine 2)%* m#dl! and hepatic functionBbilirubin 2 upper limit of normal (E! aspartate aminotransferase(A$T!#alanine aminotransferase (AT! 2 +%* E al.aline phosphatase (A'!2+%*E (if total A' M+%* E0 A' liver fraction and#or amma lutamyltransferase

and#or *3-nucleotidase had to be 2E! and albumin M+* #lC%'atients "ere excluded if they had received prior chemotherapy prior lesionirradiation (if administered to a sinle taret lesion! if they had any malinancy"ithin the previous * years (except for basal cell carcinoma or treated cervicalcarcinoma in situ!0 or other relevant clinicalconditions (active infection0 active viral hepatitis or chronic liver disease0 brainand#or leptomenineal metastasis0 conestive heart failure or anina pectoris0myocardial infarction "ithin the previous year0 uncontrolled arterialhypertension0 arrhythmias or abnormal L@7!% 'renant or breast-feedin "omenor patients not usin appropriate contraceptive measures "ere excluded%

+%+% Randomisation and treatments

@liible patients "ere randomly assined on a ):) basis to receive trabectedin orDXT% $ince sinle-aent doxorubicin is the standard treatment for advanced$T$0 but some oncoloists prefer combination treatment "ith ifosfamide0especially for certain tumour types0 the choice of doxorubicin sinle aent or incombination "as left to the investiators%

Trabectedin "as administered at a dose of )%* m#m+ +,-h intravenous (i%v%!infusion every "ee.s (/".!0 "ith antiemetic and liver-protectin prophylaxis(dexamethasone +3 m i%v%! 3 min before (Arm A!0 Doxorubicin "as


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administered at 1* m#m+ i%v% /".0 sinle aent0 or at 23 m#m+ i%v% plusifosfamide (rane0 245 #m+! i%v% /".0 "ith proper hydration and mesnaadministration (Arm 6!% 'ermuted-bloc. randomi>ation method "as used0 "ithstratication by baseline @9H '$ score (3 versus )4+! and patholoical subtype(&R versus other TR$!% In Arm A0 treatment could continue until diseaseproression or discontinuation for other reasons (e%% unacceptable toxicity orconsent"ithdra"al!% In Arm 60 treatment "as stopped if maximum doxorubicincumulative dose "as reached or if L@7 "as abnormally reduced% In bothtreatment arms0 a maximum of t"o dose reductions "ere allo"ed in the event of febrile neutropenia rade , neutropenia M* days rade , thrombocytopenia -"ee. delay for recovery from rade #, AT or A$T A' or bilirubin increases ofany rade rade #, nausea#vomitin (except if reversible "ith ade/uatesupportive #symptomatic therapy!0 or any other rade #, toxicity%

+%% @8cacy end-points and tumour assessment 'rimary e8cacy end-point "asproression-free survival ('7$! evaluated in the e8cacy population (i%e% patientsrandomised "ith conrmed patholoical dianosis of TR$ and evidence oftranslocation by Juorescence in situ hybridisation!% '7$ and obKective tumourresponse "ere assessed by an Independent @xternal Revie" ommittee (I@R!accordin to R@I$T v%)%3 B),C% Disease assessments "ere done symmetricallyacross treatment arms "ithin , "ee.s before randomisation0 every 2 "ee.sdurin the rst 5 months and every 5 "ee.s thereafter% @xploratory evaluationsaccordin to hoi criteria B)*C "ere predenedper protocol and they "ere also performed by the I@R% $econdary analysis ofe8cacy "as basedon the population of all randomised patients accordin to the investiators

assessment0 as anintent-to-treat evaluation%

+%,% $afety assessment$afety "as evaluated in all patients receivin at least one dose of study dru0 byassessment of adverse events (A@s!0 laboratory test results0 physicalexaminations and vital sins% A@s and laboratory values "ere raded accordinto the ational ancer Institute-ommon

Toxicity riteria for Adverse @vents0 v%%3%

+%*% $tatistical methodsA Jexible adaptive desin "ith sample si>e reassessment0 if necessary0 "as

used% A priori assumptions "ere a t"o-sided *? sinicance level "ith ;3?po"er0 expected median '7$ "ith DXT = )) months and **? reduction inrelative ris. of proression or death Bha>ard ratio (FR! = 3%,*C% At rst stae0 aminimum of ;3 evaluable patients "as re/uired Bat least *3? (i%e% ,3 patients!"ith &RC% An interim analysis of primary end-point ('7$! to reKect F3 (FR = )!"as planned in the rst stae of the trial0 "ith approximately ,* '7$ eventsassessed by independent revie" the adKusted 'ococ. boundary p-value to reKectF3 "ith ,* events should be N3%3,+% omparison bet"een treatment arms "as


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done by a stratied lo-ran. test and sinicance level determined by actualobserved number of events% After interim analysis0 sample si>e could beincreased if thedesired po"er "as not achieved "ith the observed FR but "as still clinicallymeaninful%Response rates "ere compared by 7ishers exact test% Enstratied lo ran. test

and ox reression "ere also used to evaluate secondary time-to-event end-points0 such as overall survival (9$!%@A$T v%, and $A$ v%5%+ "ere used to calculate sample si>e and for all statisticalanalysis outputs0respectively%'atients "ill be follo"ed for overall survival until Auust +3),%

% Result%)'atient disposition

The rst patient "as enrolled on );th ovember +33;% As of +3th 7ebruary+3)+0 a total of )+) patients had been randomised (trabectedin0 n = 2) DXT n= 23! (7i% )! ;; patients "ere evaluable for the primary e8cacy end-point(trabectedin0 n = *) DXT0 n = 1! and ,3 of them had &R% Therefore0accrual "as put on hold% At the time of interim analysis (Auust +3)+!0 +2 '7$events assessed by independent revie" "ere reached (trabectedin0 n = )2DXT0 n = )3!% 6ecause recalculation of the patient population needed toachieve a sinicant diard ratio "asFR = 3%;2 (5*? condence interval (I!0 3%,4)%;! (p = 3%255+! (Table +!%


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$econdary e8cacy analysis (n = )+)! "as also non-statistically sinicant:unstratied lo ran. test p = 3%** (7i% +b! and FR = 3%;* (5*? I0 3%*4)%*! (p= 3%***)! (Table +!% &ultivariate step"ise ox reression sho"ed &R subtypeas the most favourable pronostic factor0 alon "ith a lo" number of sitesinvolved and no prior surery0for patients treated "ith both trabectedin and DXT% Importantly0 a hih

percentae of patients "ere censored in both treatment arms renderin theanalyses underpo"ered (Table !% &ain censorin reason in primary e8cacypopulation (n = ;;! "as surical lesion removal (curative or palliative! beforedisease proression: +%*? (trabectedin arm! and )2%+? (DXT arm!% 9therfre/uent censorin reason "as the administration of ne" anticancer therapybefore disease proression: )1%2? (trabectedin arm: chemotherapy in ))%;?and radiotherapy in *%5?! and +,%? (DXT arm: chemotherapy in );%5? andradiotherapy in *%,?!% Administration of other therapies "ithout diseaseproression "as not addressed in the protocol0 but it "as assumed that treatinInvestiators "ould manae the patients in their best benet%

%*% Response rateIn e8cacy population0 R@I$T v%)%3 response rate "as sinicantly hiher inDXT arm (Table ,! disease control rate "as similar: ;+%,? (trabectedin arm!versus ;2%*? (DXT arm!% hoi response criteria sho"ed no sinicantdi


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As expected0 most common severe non-haematoloical laboratory abnormalityassociated "ith trabectedin "as transaminases elevation0 "hich occurredinfre/uently "ith DXT (*%? for AT and %? for A$T "ith trabectedinversus )%5? for both AT and A$T "ith DXT!% In areement "ith previous trials0severe transaminase increases had a transient pattern0 "ith a pea. elevation onDay ; and return to rade N) before Day ++ of each cycle0 and sho"ed a cleartrend to reduction in subse/uent cycles of treatment%

,% DiscussionAdvanced $T$ are a heteroeneous roup of tumours that re/uire medicaltreatment tailored accordin to histoloical and molecular subtypes% Entil no"0no clinical trials have investiated a novel treatment option in $T$ "ithtranslocations that produce ne" or dereulated transcription factors% This clinicaltrial "as desined to evaluate trabectedin versus DXT as rst-line therapy inunresectable locally advanced or metastatic0 patholoically conrmed TR$ bymeans of externallyassessed '7$% To date0 no other phase III randomi>ed trials have been conducted

comparin rst-line standard doxorubicin or doxorubicin plus ifosfamide versusother therapies in adult $T$ only one phase II randomi>edtrial has beenpreviously published B)2C% This trial started "ith the rst stae0 to be expandedin the second stae0 dependin on results of interim analysis% 7or this interimevaluation0 taret population "as ;3 evaluable patients0 and ,* '7$ events "ereexpected% The analysis had to be conducted before reachin this event rate%7inally0 +5 independently assessed '7$ events "ere reached from ;; evaluablepatients in &ay +3) (** '7$ events in all randomised patients!% Fih attritionrate of evaluable patients from all randomised populations (+1%?! due toinaccurate dianosis and#or lac. of specic translocation0 toether "ith hihcensorin rate (21%3?in e8cacy population! resulted in fe"er '7$ events than expected and0

therefore0 the analysis "as underpo"ered for statistical comparisons% 7irst-linesettin larely contributed to hih censorin% 'atients suitable for surery afterseveral treatment cycles under"ent tumour removal in both arms and0 in Arm 60many patients "ho completed 24; DXT cycles per protocol received a ne"anticancer therapy% As a conse/uence0 results of this trial do not allo"conrmin superiority of either treatment arm as rst-line chemotherapy in thissarcomasubset% There "as no statistically sinicant di


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disease control rate "as similar "ith both therapies: ;+%,? (trabectedin! versus;2%*? (DXT! and hoi response assessment sho"ed no sinicant di


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DXT arm0 "hile it "as manaed "ith administration delay in patients receivintrabectedin%&ost common laboratory disorder associated "ith trabectedin "as elevatedtransaminases0 "hich is uncommon in patients treated "ith DXT% Incidence oftrabectedin associated rade #, increase (*%? and %? for AT and A$T0respectively! in this trial "as similar to those previously reported AT and ,3%1?

for A$T! B)5C% Transaminase increase "as the most fre/uent reason for dosereductions% Fo"ever0 the occurrence of hepatobiliary adverse events "as lo"0further supportin the observation that the liver dysfunction induced bytrabectedin is mostly transient0 non-cumulative and mostly "ithout clinicalconse/uences%In conclusion0 this phase III randomised trial performed in a selected subset of

TR$ sho"ed nosinicant di I0 ha"la $'% Randomised multicenter phase IIItrial of trabectedin (T! versus doxorubicin-based chemotherapy as rst-line

therapy in patients "ith translocationrelated sarcoma (TR$!% O lin 9ncol 30+3)+ (suppl% abstr% T'$)3)3)!% 'reliminary results of this study "ere presentedat the American $ociety of linical 9ncoloy (A$9! +3) &eetin% QFendifar A@0ha"la $'0 eahy &H0 Italiano A0 'atel $0 $antoro A0 $taddon A'0 'enel 0'iperno-eumann $0 Demetri HD0 Fay"ard 0 Shite O0 Hou" H0 De &iuel 60ardelli '0 $oto A0 ieto A0 6lay OP% Results of the randomi>ed phase III trial oftrabectedin (T! versus doxorubicinbased chemotherapy (DXT! as rst-line


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therapy in patients (pts! "ith translocation-related sarcoma (TR$!% O lin 9ncol)0 +3) (suppl% abstr% )3*)1

randomised phase iii trial of trabectedin versus doxorubicin

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