Syntéza prekurzorov a N-arylaminooxazolkarboxamidových inhibítorov VEGFR2 TK
Best of ASCO in Gyn Oncology Adnan R Munkarah. Biologics in Recurrent Ovarian Ca Cediranib- highly...
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Transcript of Best of ASCO in Gyn Oncology Adnan R Munkarah. Biologics in Recurrent Ovarian Ca Cediranib- highly...
Best of ASCO in Gyn Best of ASCO in Gyn OncologyOncology
Adnan R MunkarahAdnan R Munkarah
Biologics in Recurrent Ovarian Biologics in Recurrent Ovarian CaCa
CediranibCediranib- highly selective and potent oral - highly selective and potent oral TK inhibitor of VEGFR1, VEGFR2, VEGFR3 TK inhibitor of VEGFR1, VEGFR2, VEGFR3 and c-Kit(and c-Kit(Matulanis #5501, Hirte#5521Matulanis #5501, Hirte#5521))
SunitinibSunitinib- multitargeted RTK inhibitor - multitargeted RTK inhibitor ((Biagi #5522Biagi #5522))
PertuzumabPertuzumab- monoclonal ab prevents - monoclonal ab prevents HER2 dimerization + CBDCA (HER2 dimerization + CBDCA (Kaye #5520, Kaye #5520, Lalla #5550Lalla #5550))
SorafenibSorafenib- oral TKI targeting raf & VEGFR, - oral TKI targeting raf & VEGFR, PDGFR, Flt3, c-kit ( PDGFR, Flt3, c-kit ( Matei D, GOG #5537Matei D, GOG #5537))
Folate Receptor Folate Receptor FRFR Overexpressed in majority of EOC, absent in Overexpressed in majority of EOC, absent in
nomrla tissuesnomrla tissues MORAb-003 humanized monoclonal ab to FRAMORAb-003 humanized monoclonal ab to FRA Armstrong D #5500Armstrong D #5500
52 patients with platinum sensitive EOC in first 52 patients with platinum sensitive EOC in first relapserelapse
Asymptomatic patients treated with single agent Asymptomatic patients treated with single agent ab (SA)ab (SA)
Symptomatic patients or those with progression on Symptomatic patients or those with progression on SA receive ab with platinum & TaxaneSA receive ab with platinum & Taxane
MOAb-003 significantly increased overall response MOAb-003 significantly increased overall response and duration of responseand duration of response
Folate Receptor Folate Receptor FRFR
Bell-McGuinn #5517Bell-McGuinn #5517 Phase I trrial in platinum resistant Phase I trrial in platinum resistant
EOC patientsEOC patients Well toleratedWell tolerated + response+ response
BelinostatBelinostat Histone deacetylase inhibitorHistone deacetylase inhibitor Preclinical studiesPreclinical studies
Synergy with carboplatinum and taxolSynergy with carboplatinum and taxol Effect in platinum resistant and sensitive Effect in platinum resistant and sensitive
EOCEOC Well tolerated in combination with Well tolerated in combination with
taxol/carbo and clinical benefit in heavily taxol/carbo and clinical benefit in heavily pretreated patients (pretreated patients (Finkler #5519Finkler #5519))
Promising activity in LMP ovarian Promising activity in LMP ovarian tumors (tumors (Mackay # 5518Mackay # 5518))
Seiji Isonishi,Seiji Isonishi,1 1 Makoto Yasuda, Makoto Yasuda,1 1 Fumiaki Fumiaki Takahashi,Takahashi,22 Noriyuki Katsumata, Noriyuki Katsumata,33 Eizo Kimura, Eizo Kimura, 1 1
Daisuke Aoki,Daisuke Aoki,44 Toshiko Jobo, Toshiko Jobo,55 Fumitoshi Fumitoshi Terauchi,Terauchi,66 Hiroshi Tsuda, Hiroshi Tsuda,44 Toru Sugiyama Toru Sugiyama77
1.The jikei University1.The jikei University School of Medicine, 2. Kitasato School of Medicine, 2. Kitasato University,3. National Cancer CenterUniversity,3. National Cancer Center Hospital, 3.Hospital, 3. Kousei Kousei General Hospital, 4. Keio University School of Medicine, 5. General Hospital, 4. Keio University School of Medicine, 5. Social Insurance Sagamino Hospital, 6. Tokyo Medical Social Insurance Sagamino Hospital, 6. Tokyo Medical University, 7.University, 7. Iwate Medical University School of MedicineIwate Medical University School of Medicine
jjgog0606@[email protected]
Conventional administration of paclitaxel and carboplatin Conventional administration of paclitaxel and carboplatin (c-TC) every 21 days is a standard therapy for advanced (c-TC) every 21 days is a standard therapy for advanced epithelial ovarian cancer.epithelial ovarian cancer.
Several phase II clinical trials of dose-dense weekly Several phase II clinical trials of dose-dense weekly administration of paclitaxel and carboplatin (dd-TC) in administration of paclitaxel and carboplatin (dd-TC) in ovarian cancer have demonstrated promising efficacy and ovarian cancer have demonstrated promising efficacy and favorable tolerabilityfavorable tolerability ((Gynecol Oncol 2005; 96: 296, Cancer Chemother Pharmacol 2008; 61: 243Gynecol Oncol 2005; 96: 296, Cancer Chemother Pharmacol 2008; 61: 243))..
Recent randomized phase III trials for breast cancer Recent randomized phase III trials for breast cancer demonstrated weekly paclitaxel improved survivaldemonstrated weekly paclitaxel improved survival ((NEJM 2008;358:1663-71, JCO 2008; 26:1642-1649NEJM 2008;358:1663-71, JCO 2008; 26:1642-1649))..
Conventional administration of paclitaxel and carboplatin Conventional administration of paclitaxel and carboplatin (c-TC) every 21 days is a standard therapy for advanced (c-TC) every 21 days is a standard therapy for advanced epithelial ovarian cancer.epithelial ovarian cancer.
Several phase II clinical trials of dose-dense weekly Several phase II clinical trials of dose-dense weekly administration of paclitaxel and carboplatin (dd-TC) in administration of paclitaxel and carboplatin (dd-TC) in ovarian cancer have demonstrated promising efficacy and ovarian cancer have demonstrated promising efficacy and favorable tolerabilityfavorable tolerability ((Gynecol Oncol 2005; 96: 296, Cancer Chemother Pharmacol 2008; 61: 243Gynecol Oncol 2005; 96: 296, Cancer Chemother Pharmacol 2008; 61: 243))..
Recent randomized phase III trials for breast cancer Recent randomized phase III trials for breast cancer demonstrated weekly paclitaxel improved survivaldemonstrated weekly paclitaxel improved survival ((NEJM 2008;358:1663-71, JCO 2008; 26:1642-1649NEJM 2008;358:1663-71, JCO 2008; 26:1642-1649))..
Ovarian Epithelial, Primary Ovarian Epithelial, Primary Peritoneal, or Fallopian Tube cancerPeritoneal, or Fallopian Tube cancer
FIGO Stage II-IVFIGO Stage II-IV
Ovarian Epithelial, Primary Ovarian Epithelial, Primary Peritoneal, or Fallopian Tube cancerPeritoneal, or Fallopian Tube cancer
FIGO Stage II-IVFIGO Stage II-IV
Conventional TC (c-TC)Conventional TC (c-TC) Paclitaxel 180mg/mPaclitaxel 180mg/m22, day 1, day 1 Carboplatin AUC 6.0, day 1Carboplatin AUC 6.0, day 1 every 21 days for 6-9 every 21 days for 6-9 cyclescycles
Conventional TC (c-TC)Conventional TC (c-TC) Paclitaxel 180mg/mPaclitaxel 180mg/m22, day 1, day 1 Carboplatin AUC 6.0, day 1Carboplatin AUC 6.0, day 1 every 21 days for 6-9 every 21 days for 6-9 cyclescycles
Dose-dense weekly TC (dd-TC)Dose-dense weekly TC (dd-TC) Paclitaxel 80mg/mPaclitaxel 80mg/m22, days 1,8,15, days 1,8,15 Carboplatin AUC 6.0, day 1Carboplatin AUC 6.0, day 1 every 21 days for 6-9 cyclesevery 21 days for 6-9 cycles
Dose-dense weekly TC (dd-TC)Dose-dense weekly TC (dd-TC) Paclitaxel 80mg/mPaclitaxel 80mg/m22, days 1,8,15, days 1,8,15 Carboplatin AUC 6.0, day 1Carboplatin AUC 6.0, day 1 every 21 days for 6-9 cyclesevery 21 days for 6-9 cycles
RandomizationRandomizationStratification; Stratification;
Residual disease: Residual disease: <<1cm, > 1cm1cm, > 1cmFIGO StageFIGO Stage : : II vs. III vs. IVII vs. III vs. IVHistologyHistology : : clear cell/mucinous vs.serous/others clear cell/mucinous vs.serous/others
NNewew OvOvarianarian ElElaborateaborate trialtrial:: NOVEL NOVEL trialtrialNNewew OvOvarianarian ElElaborateaborate trialtrial:: NOVEL NOVEL trialtrial
I.I. Histologically or cytologically* confirmed stage II-IV ovarian epithelial, primary Histologically or cytologically* confirmed stage II-IV ovarian epithelial, primary
peritoneal, or fallopian tube cancerperitoneal, or fallopian tube cancer
II.II. No prior chemotherapy No prior chemotherapy
III.III. Age: 20 and more Age: 20 and more
IV.IV. Performance status: ECOG 0-3Performance status: ECOG 0-3
V.V. 1) Absolute neutrophil count at least 1,500/mm1) Absolute neutrophil count at least 1,500/mm33
2) Platelet count at least 100,000/mm2) Platelet count at least 100,000/mm33
3) Bilirubin less than 1.5mg/dL3) Bilirubin less than 1.5mg/dL
4) SGOT less than 100 IU/l4) SGOT less than 100 IU/l
5) Serum creatinine less than 1.5mg/dL5) Serum creatinine less than 1.5mg/dL
VI. VI. Written informed consentWritten informed consent
I.I. Histologically or cytologically* confirmed stage II-IV ovarian epithelial, primary Histologically or cytologically* confirmed stage II-IV ovarian epithelial, primary
peritoneal, or fallopian tube cancerperitoneal, or fallopian tube cancer
II.II. No prior chemotherapy No prior chemotherapy
III.III. Age: 20 and more Age: 20 and more
IV.IV. Performance status: ECOG 0-3Performance status: ECOG 0-3
V.V. 1) Absolute neutrophil count at least 1,500/mm1) Absolute neutrophil count at least 1,500/mm33
2) Platelet count at least 100,000/mm2) Platelet count at least 100,000/mm33
3) Bilirubin less than 1.5mg/dL3) Bilirubin less than 1.5mg/dL
4) SGOT less than 100 IU/l4) SGOT less than 100 IU/l
5) Serum creatinine less than 1.5mg/dL5) Serum creatinine less than 1.5mg/dL
VI. VI. Written informed consentWritten informed consent
*CA125/CEA >25, and GI cancer should be ruled out*CA125/CEA >25, and GI cancer should be ruled out
Primary endpoint:Primary endpoint:
Progression-free SurvivalProgression-free Survival
Secondary endpoints:Secondary endpoints:Overall survival (OS)Overall survival (OS)Response rateResponse rateAdverse eventsAdverse eventsQuality of life (FACT)Quality of life (FACT)
Primary endpoint:Primary endpoint:
Progression-free SurvivalProgression-free Survival
Secondary endpoints:Secondary endpoints:Overall survival (OS)Overall survival (OS)Response rateResponse rateAdverse eventsAdverse eventsQuality of life (FACT)Quality of life (FACT)
Hypothesis:Hypothesis: 5 months improvement in median 5 months improvement in median PFS (from 16 to 21 months)PFS (from 16 to 21 months)
Statistical test:Statistical test: 2 sided log-rank with α=0.05, 2 sided log-rank with α=0.05, β=0.2β=0.2
Sample size:Sample size: 380 patients initially on Apr. 2003380 patients initially on Apr. 2003
600 patients with one interim 600 patients with one interim analysisanalysis after amendment on Jan. 2005after amendment on Jan. 2005
Progression defined as:Progression defined as:
appearance of any measurable or appearance of any measurable or evaluable lesionevaluable lesion
OROR
CA125 level CA125 level >> 2 times UNL or 2 times UNL or nadir nadir for 2 consecutive for 2 consecutive measurements at measurements at least 1 week apartleast 1 week apart
Hypothesis:Hypothesis: 5 months improvement in median 5 months improvement in median PFS (from 16 to 21 months)PFS (from 16 to 21 months)
Statistical test:Statistical test: 2 sided log-rank with α=0.05, 2 sided log-rank with α=0.05, β=0.2β=0.2
Sample size:Sample size: 380 patients initially on Apr. 2003380 patients initially on Apr. 2003
600 patients with one interim 600 patients with one interim analysisanalysis after amendment on Jan. 2005after amendment on Jan. 2005
Progression defined as:Progression defined as:
appearance of any measurable or appearance of any measurable or evaluable lesionevaluable lesion
OROR
CA125 level CA125 level >> 2 times UNL or 2 times UNL or nadir nadir for 2 consecutive for 2 consecutive measurements at measurements at least 1 week apartleast 1 week apart
637 Patients enrolled and randomly assigned
320 Assigned to c-TC 317 Assigned to dd-TCdd-TC 317 Assigned to dd-TCdd-TC
319 Eligible Patients
312 Eligible Patients
1 Ineligible
5 Ineligible
6 cycles of treatmentAdditional 3 cycles should be given if clinical responses were observed.Interval or secondary debulking surgery were allowed.
319 Primary intention to treat efficacy analysis
314 Safety analysis
312 Primary intention to treat efficacy analysis
312 Safety analysis
CharacteristicCharacteristic Conventional TCConventional TC(n = 319) (n = 319)
Dose-dense TCDose-dense TC(n = 312)(n = 312)
Median age Median age (range)(range) 57 (25-84)57 (25-84) 57 (25-87)57 (25-87)
FIGO stage, %FIGO stage, %IIIIIIIIIIIVIV
171767671616
202065651515
ECOG PS, %ECOG PS, %0 or 10 or 12233
90906644
90907722
Disease, %Disease, %OvarianOvarianFallopian tubeFallopian tubePrimary Primary
peritonealperitoneal
87876688
8383551212
CharacteristicCharacteristicConventional Conventional
TCTC(n = 319) (n = 319)
Dose-dense TCDose-dense TC(n = 312)(n = 312)
Surgery, %Surgery, % Primary debulkingPrimary debulking Interval debulkingInterval debulking Secondary/Second Secondary/Second LookLook
8989991818
898911111212
Residual disease, %Residual disease, %<< 1cm 1cm> 1cm> 1cm
45455555
46465454
Histologic type, %Histologic type, %Clear or MucinousClear or MucinousSerous or othersSerous or others
16168484
17178383
MeasurableMeasurable% of patients% of patients
c-TCc-TC(n = 135) (n = 135)
dd-TCdd-TC(n = 147)(n = 147)
Objective Objective
responseresponse
CRCR
PRPR
NCNC
PDPD
NENE
5353
1616
3838
3131
77
99
5656
2020
3636
2929
33
1212
P=0.72
Evaluated by WHO criteria
Clinical Response
Adverse EventAdverse Event c-TCc-TC(n = 314) (n = 314)
dd-TCdd-TC(n = 312)(n = 312) P valueP value
no. (%)no. (%)
NeutropeniaNeutropenia 276 (80)276 (80) 286 (92)286 (92) 0.150.15
ThrombocytopeniaThrombocytopenia 120 (38)120 (38) 136 (44)136 (44) 0.190.19
AnemiaAnemia 137 (44)137 (44) 214 (69)214 (69) < 0.0001< 0.0001
Febrile neutropeniaFebrile neutropenia 29 (9)29 (9) 29 (9)29 (9) 1.001.00
Neuropathy-motorNeuropathy-motor 43 (14)43 (14) 37 (12)37 (12) 0.550.55
Neuropathy-sensoryNeuropathy-sensory 86 (27)86 (27) 71 (23)71 (23) 0.200.20
Evaluated by NCI-CTC ver.2.0
c-TC c-TC (n = 319) (n = 319)
dd-TCdd-TC(n = 312)(n = 312)
>> 6 cycles (all patients) 6 cycles (all patients)9 cycles (responding 9 cycles (responding patients)patients)
231231 (72%)(72%)5050
186186 (60%)(60%)3737
Completed protocol therapyCompleted protocol therapy
Discontinued protocol Discontinued protocol
therapytherapy
progression/deathprogression/death
toxicitytoxicityhematologichematologicneuropathyneuropathyallergyallergypatient refusal for patient refusal for
toxicitytoxicityothersothers
patient refusalpatient refusal
other reasonsother reasons
UnknownUnknown
200200 (63%)(63%)
117117 (37%)(37%)
2828
69693030557712121313
88
1111
22
147147 (47%)(47%)
165165 (53%)(53%)
2828
1131136868334413132525
66
1717
00
TreatmeTreatmentnt nn EventEvent Median PFSMedian PFS P valueP value HR HR 95%CI 95%CI
c-TCc-TC 319 319 200 200 17.2 mos.17.2 mos.
dd-TCdd-TC 312 312 160 160 28.0 mos.28.0 mos. 0.0015 0.0015 0.7140.714 0.581-0.581-
0.8790.879
TreatmeTreatmentnt nn EventEvent 2-yr survival2-yr survival P P
valuevalue HR HR 95%CI 95%CI
c-TCc-TC 319 319 95 95 77.7%77.7%
dd-TCdd-TC 312 312 7070 83.6%83.6% 0.04960.0496 0.7350.735 0.540-0.540-1.0001.000
nnPS 2-3PS 2-3 6161PS 0-1PS 0-1 570570
Age > 60Age > 60 368368Age Age << 60 60 263263
Primary peritonealPrimary peritoneal 6363Fallopian tubeFallopian tube 3232OvarianOvarian 536536
Serous/OthersSerous/Others 527527Clear Clear cell/Mucinouscell/Mucinous 104104
FIGO stage IVFIGO stage IV 9898FIGO stage IIIFIGO stage III 417417FIGO stage IIFIGO stage II 116116
Residual disease > Residual disease > 1cm1cm 342342
Residual disease Residual disease << 1cm1cm 289289
OverallOverall 631631 dd-TC better c-TC better
0.0 0.5 1.0 1.5 2.0
PFS was improved with dose-dense weekly PFS was improved with dose-dense weekly TC compared to conventional TC in patients TC compared to conventional TC in patients with advanced epithelial ovarian cancer.with advanced epithelial ovarian cancer.
Analysis of overall survival is ongoing.Analysis of overall survival is ongoing.
Hematologic toxicity was increased in dose-Hematologic toxicity was increased in dose-dense TC.dense TC.
Neurotoxicity was similar in both groups.Neurotoxicity was similar in both groups.
PFS was improved with dose-dense weekly PFS was improved with dose-dense weekly TC compared to conventional TC in patients TC compared to conventional TC in patients with advanced epithelial ovarian cancer.with advanced epithelial ovarian cancer.
Analysis of overall survival is ongoing.Analysis of overall survival is ongoing.
Hematologic toxicity was increased in dose-Hematologic toxicity was increased in dose-dense TC.dense TC.
Neurotoxicity was similar in both groups.Neurotoxicity was similar in both groups.
AZD2281 (KU-0059436), a PARPAZD2281 (KU-0059436), a PARP(poly ADP-ribose polymerase) (poly ADP-ribose polymerase)
inhibitorinhibitorwith single agent anticancer activity with single agent anticancer activity
in patients with BRCA deficient in patients with BRCA deficient ovarian cancer:ovarian cancer:
Results from a phase I studyResults from a phase I studyPeter C Fong1, David S Boss2, Craig P Carden1, Marja Mergui-Roelvink2,
Jacques De Greve3, Charles M Gourley4, James Carmichael5,Johann S de Bono1, Jan H Schellens2, Stan B Kaye1
1The Royal Marsden Hospital and The Institute of Cancer Research, UK, 2The Netherlands Cancer Institute, The Netherlands, 3UZ Brussel Oncologisch Centrum, Belgium,
4Edinburgh Cancer Research Centre, UK, 5KuDOS Pharmaceuticals/AstraZeneca, UK
PARPPARP Poly(ADP-ribose) polymerase-1- member Poly(ADP-ribose) polymerase-1- member
of PARP enzymesof PARP enzymes Abundant nuclear proteinAbundant nuclear protein Binds to DNA breaksBinds to DNA breaks Activated PARP cleaves NAD+ into Activated PARP cleaves NAD+ into
nictoinamide and ADP-ribose and nictoinamide and ADP-ribose and polymerizes the latter onto nuclear polymerizes the latter onto nuclear receptor proteins including histones, receptor proteins including histones, transcription factors and PARP itselftranscription factors and PARP itself
Contributes to repair of single strand Contributes to repair of single strand breaks in DNAbreaks in DNA
Poly ADP-Ribose Polymerase Poly ADP-Ribose Polymerase (PARP)(PARP)
PARP inhibitors & BRCAPARP inhibitors & BRCA
10 -9 10 -8 10 -7 10 -6 10 -5 10 -40-4
-3
-2
-1
0
conc (M)
BRCA2-/-
BRCA2+/+
BRCA2+/-
Increased sensitivity of BRCA1-/- and BRCA2-/- cells to PARP inhibition
10 -9 10 -8 10 -7 10 -6 10 -5 10 -40-4
-3
-2
-1
0
conc (M)
BRCA1-/-
BRCA1+/+
BRCA1+/-
No difference in sensitivity between heterozygous and wild-type BRCA cells
Farmer et al. Nature 2005; 434:917-21
Targeted inhibition selective and less toxic therapy
From targeted therapy to the From targeted therapy to the AZD2281 Phase I study AZD2281 Phase I study
Oral, small molecule PARP inhibitorOral, small molecule PARP inhibitor ICIC5050 for PARP1 enzyme in the low nM range for PARP1 enzyme in the low nM range
Phase I trial began at RMH then NKI; later expanded to Phase I trial began at RMH then NKI; later expanded to other centresother centres
Escalation phaseEscalation phase: All tumour types: All tumour types Primary objectives of safety and tolerabilityPrimary objectives of safety and tolerability
Expansion phaseExpansion phase: BRCA mutation carriers (HR deficient) : BRCA mutation carriers (HR deficient) especially ovarian cancerespecially ovarian cancer Further assessment of efficacyFurther assessment of efficacy
Overall recruitmentOverall recruitment
Escalation PhaseEscalation Phase (n=46) (n=46)1,21,2
Various tumour types; BRCA carrier status not mandatoryVarious tumour types; BRCA carrier status not mandatory 10 dose level cohorts:10 dose level cohorts:
10mg daily given for 2 out of 3 weeks 10mg daily given for 2 out of 3 weeks 600mg bid continuous dosing600mg bid continuous dosing
11 BRCA carrier ovarian cancer11 BRCA carrier ovarian cancer
Expansion phaseExpansion phase (n=52) at 200mg bid continuous (n=52) at 200mg bid continuous22
Confirmed BRCA mutation carriersConfirmed BRCA mutation carriers 39 ovarian cancer39 ovarian cancer
1Fong et al. Proceedings of ASCO 20062Yap et al. Proceedings of ASCO 2007
ToxicitiesToxicities(first 60 patients, all tumour types)(first 60 patients, all tumour types)
Most toxicities were Grade 1-2 (Most toxicities were Grade 1-2 (≥95%)≥95%) Most common toxicities were:Most common toxicities were:
nausea 28%, vomiting 18%, dysgeusia 13%, anorexia 12%nausea 28%, vomiting 18%, dysgeusia 13%, anorexia 12% fatigue 28%fatigue 28%
Grade 3-4 toxicities were rare:Grade 3-4 toxicities were rare: myelosuppression (myelosuppression (≤≤5%) 5%) nausea and vomiting (2-3%)nausea and vomiting (2-3%) CNS: dizziness or mood changes (2-3%)CNS: dizziness or mood changes (2-3%)
Pattern of toxicity similar in BRCA mutation carriersPattern of toxicity similar in BRCA mutation carriers
Dose limiting toxicities (DLT)Dose limiting toxicities (DLT)
Dose Dose (mg)/ (mg)/
ScheduleSchedule
Tumour Tumour typetype DLTDLT OutcomeOutcome
400 bid 400 bid continuoucontinuou
ssOvarian CaOvarian Ca
G3 low mood G3 low mood andand
G3 fatigueG3 fatigue
Resolved within 24 Resolved within 24 hours of drug hours of drug
discontinuationdiscontinuation
Recurred with re-Recurred with re-challengechallenge
600 bid 600 bid continuoucontinuou
ss
MesothelioMesotheliomama
G4 G4 thrombocytopethrombocytope
niania
Resolved 2 weeks after Resolved 2 weeks after drug discontinuationdrug discontinuation
600 bid 600 bid continuoucontinuou
ssBreast CaBreast Ca G3 somnolenceG3 somnolence
Resolved within 24 Resolved within 24 hours of drug hours of drug
discontinuationdiscontinuation
G1 on lower doseG1 on lower dose
Maximum Tolerated Dose (MTD) = 400mg bid
DemographicsDemographicsBRCA-mutated ovarian cancer BRCA-mutated ovarian cancer
subpopulationsubpopulation
PatientsPatientsDose (mg bid)Dose (mg bid)
≤ ≤ 100100 200200 400400 600600Total = 50Total = 50 44 3939 66 11
No. evaluable for No. evaluable for efficacy = 46efficacy = 46 44 3737 44 11
Includes Includes primary peritoneal cancer (2 pts), fallopian tube primary peritoneal cancer (2 pts), fallopian tube carcinoma (1 pt) and 1 ovarian cancercarcinoma (1 pt) and 1 ovarian cancer pt with compelling pt with compelling family family historyhistory for BRCA mutation for BRCA mutation
Excluded pts:Excluded pts: 1 pt died from disease-related non-neutropenic sepsis after 1 cycle 1 pt died from disease-related non-neutropenic sepsis after 1 cycle 1 pt had DLT on day 1 and again on day 8 with re-challenge of drug1 pt had DLT on day 1 and again on day 8 with re-challenge of drug 2 pts had PD within 2-3 weeks after commencement2 pts had PD within 2-3 weeks after commencement
DemographicsDemographicsBRCA-mutated ovarian cancer BRCA-mutated ovarian cancer
subpopulationsubpopulationCharacteristicsCharacteristics NumberNumber
BRCA1 / BRCA2 / Family historyBRCA1 / BRCA2 / Family history 41 / 8 / 141 / 8 / 1
Median age (range)Median age (range) 52 (37-80) yrs52 (37-80) yrs
ECOG PS 0-1ECOG PS 0-1 4747
Median duration from diagnosis to treatment Median duration from diagnosis to treatment (range)(range) 4.7 (0.5–16) yrs4.7 (0.5–16) yrs
Platinum statusPlatinum statusSensitive (PD > 6 months after platinum)Sensitive (PD > 6 months after platinum)Resistant (PD Resistant (PD ≤≤ 6 months after platinum)6 months after platinum)Refractory (PD on platinum or on Refractory (PD on platinum or on completion of platinum)completion of platinum)
101027271313
Median no. of prior systemic therapies Median no. of prior systemic therapies (range)(range) 3 (1-8)3 (1-8)
23 mm
21mm
16mm
TotalTotal Platinum Platinum sensitivesensitive
Platinum Platinum resistantresistant
Platinum Platinum refractorrefractor
yy
No. of evaluable No. of evaluable patientspatients 4646 1010 2525 1111
Responders by Responders by RECISTRECIST 13 (28%)13 (28%) 5 (50%)5 (50%) 8 (32%)8 (32%) 0 (0%)0 (0%)
Responders by GCIG Responders by GCIG CA125CA125 18 (39%)18 (39%) 8 (80%)8 (80%) 8 (32%)8 (32%) 2 (18%)2 (18%)
Responders by either Responders by either RECIST or GCIG RECIST or GCIG criteriacriteria
2121 (46%) (46%) 8 (80%)8 (80%) 11 (44%)11 (44%) 2 (18%)2 (18%)
SD (> 4 cycles)SD (> 4 cycles) 6 (13%)6 (13%) 1 (10%)1 (10%) 4 (16%)4 (16%) 1 (9%)1 (9%)
Median duration of Median duration of response in weeks response in weeks (range)(range)
2424 (10-77) (10-77) 23 (16-77)23 (16-77) 24 (10-65)24 (10-65) 26 (20-32)26 (20-32)
Response to AZD2281 byResponse to AZD2281 byplatinum-free intervalplatinum-free interval
TotalTotal Platinum Platinum sensitivesensitive
Platinum Platinum resistantresistant
Platinum Platinum refractorrefractor
yy
No. of evaluable No. of evaluable patientspatients 4646 1010 2525 1111
Responders by Responders by RECISTRECIST 13 (28%)13 (28%) 5 (50%)5 (50%) 8 (32%)8 (32%) 0 (0%)0 (0%)
Responders by GCIG Responders by GCIG CA125CA125 18 (39%)18 (39%) 8 (80%)8 (80%) 8 (32%)8 (32%) 2 (18%)2 (18%)
Responders by either Responders by either RECIST or GCIG RECIST or GCIG criteriacriteria
21 (46%)21 (46%) 8 8 (80%)(80%) 11 (44%)11 (44%) 2 (18%)2 (18%)
SD (> 4 cycles)SD (> 4 cycles) 6 (13%)6 (13%) 1 (10%)1 (10%) 4 (16%)4 (16%) 1 (9%)1 (9%)
Median duration of Median duration of response in weeks response in weeks (range)(range)
2424 (10-77) (10-77) 23 (16-77)23 (16-77) 24 (10-65)24 (10-65) 26 (20-32)26 (20-32)
Response to AZD2281 byResponse to AZD2281 byplatinum-free intervalplatinum-free interval
TotalTotal Platinum Platinum sensitivesensitive
Platinum Platinum resistantresistant
Platinum Platinum refractorrefractor
yy
No. of evaluable No. of evaluable patientspatients 4646 1010 2525 1111
Responders by Responders by RECISTRECIST 13 (28%)13 (28%) 5 (50%)5 (50%) 8 (32%)8 (32%) 0 (0%)0 (0%)
Responders by GCIG Responders by GCIG CA125CA125 18 (39%)18 (39%) 8 (80%)8 (80%) 8 (32%)8 (32%) 2 (18%)2 (18%)
Responders by either Responders by either RECIST or GCIG RECIST or GCIG criteriacriteria
21 (46%)21 (46%) 8 (80%)8 (80%) 1111 (44%) (44%) 2 (18%)2 (18%)
SD (> 4 cycles)SD (> 4 cycles) 6 (13%)6 (13%) 1 (10%)1 (10%) 4 (16%)4 (16%) 1 (9%)1 (9%)
Median duration of Median duration of response in weeks response in weeks (range)(range)
2424 (10-77) (10-77) 23 (16-77)23 (16-77) 24 (10-65)24 (10-65) 26 (20-32)26 (20-32)
Response to AZD2281 byResponse to AZD2281 byplatinum-free intervalplatinum-free interval
TotalTotal Platinum Platinum sensitivesensitive
Platinum Platinum resistantresistant
Platinum Platinum refractorrefractor
yy
No. of evaluable No. of evaluable patientspatients 4646 1010 2525 1111
Responders by Responders by RECISTRECIST 13 (28%)13 (28%) 5 (50%)5 (50%) 8 (32%)8 (32%) 0 (0%)0 (0%)
Responders by GCIG Responders by GCIG CA125CA125 18 (39%)18 (39%) 8 (80%)8 (80%) 8 (32%)8 (32%) 2 (18%)2 (18%)
Responders by either Responders by either RECIST or GCIG RECIST or GCIG criteriacriteria
21 (46%)21 (46%) 8 (80%)8 (80%) 11 (44%)11 (44%) 22 (18%) (18%)
SD (> 4 cycles)SD (> 4 cycles) 6 (13%)6 (13%) 1 (10%)1 (10%) 4 (16%)4 (16%) 1 (9%)1 (9%)
Median duration of Median duration of response in weeks response in weeks (range)(range)
2424 (10-77) (10-77) 23 (16-77)23 (16-77) 24 (10-65)24 (10-65) 26 (20-32)26 (20-32)
Response to AZD2281 byResponse to AZD2281 byplatinum-free intervalplatinum-free interval
AZD2281 key messagesAZD2281 key messages Well tolerated oral therapy not associated with the Well tolerated oral therapy not associated with the
typical toxicities of chemotherapytypical toxicities of chemotherapy
Clear evidence of beneficial tumour response in Clear evidence of beneficial tumour response in BRCA BRCA mutated ovarian cancer patients mutated ovarian cancer patients
46% (21/46 pts) response rate (RECIST or GCIG CA125) 46% (21/46 pts) response rate (RECIST or GCIG CA125)
13% meaningful disease stabilisation 13% meaningful disease stabilisation
Total clinical benefit rate of 59%Total clinical benefit rate of 59%
A randomised phase II trial in BRCA ovarian cancer A randomised phase II trial in BRCA ovarian cancer pts with platinum-free interval of 0-12 months pts with platinum-free interval of 0-12 months
AZD2281 vs pegylated liposomal doxorubicinAZD2281 vs pegylated liposomal doxorubicin