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Amrubicin

New Drugs in Cancer Therapy Mediterranean School of Oncology Roma, 13th May 2011. Amrubicin. Francesco Grossi S.S. Tumori Polmonari Istituto Nazionale per la Ricerca sul Cancro Genova. Chemical structures of amrubicin and amrubicinol.

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Amrubicin

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  1. New Drugs in CancerTherapy MediterraneanSchoolofOncology Roma, 13th May 2011 Amrubicin Francesco Grossi S.S. Tumori Polmonari Istituto Nazionale per la Ricerca sul Cancro Genova

  2. Chemical structures of amrubicin and amrubicinol Amrubicin is an antracycline current approved in Japan since 2002 in SCLC and NSCLC produced by Sumitomo Pharmaceuticals under the brand name Calsed. Amrubicin acts by inhibiting topoisomerase II

  3. Activity and toxicity in preclinicalmodels • Itsantitumor activity was found to be superior to that of doxorubicin in experimental therapeutic models using human tumor xenografts. Morisada S,Jpn J Cancer Res 1989 • AMR showed much less cardiotoxicity than doxorubicin in chronic experimental models using rabbits and dogs. Suzuki T, Invest New Drugs 1997; Noda T, Invest New Drugs 1998

  4. Amrubicin vs anthracyclines • In contrast to other anthracyclines, the in vitro cytotoxicactivity of amrubicinol is 18–220 times more potent than that of its parent compound, amrubicin.Yamaoka T,Jpn J Cancer Res 1998 • In mice experiments, Noguchi et al showed that amrubicinol has more potent antitumor activity than itsparentcompound, amrubicin. The levelsofamrubicinolin the tumors of these mice were higher than doxorubicin levels in doxorubicin-treatedmice.Noguchi T,Jpn J Cancer Res 1998 • In contrast, the levels of amrubicin and amrubicinol were lower than those of doxorubicin in several non-tumortissues, including the heart.Noda T, Invest New Drugs 1998

  5. Canine Cardiotoxicity: Effect of AMR on DOX-Induced Cardiomyopathy Experimental Design Continued DOX IV (1.5 mg/kg 1x q 3 wks) 18th Week: Sacrifice Score lesions DOX2 IV (1.75 mg/kg first treatment, then 1.5 mg/kg 1x q 3 wks x 4 cycles) 30th Week: Sacrifice Score lesions >19 Heart sections/animal Vehicle 1 q 3 wks IV; 4 cycles 9-Week interval (no treatment) AMR3 2.5 mg/kg q 3 wks IV; 4 cycles DOX 1.5 mg/kg q 3 wks IV; 4 cycles Noda T, Invest New Drugs 1998

  6. Canine Cardiotoxicity: Effect of AMR on DOX-Induced Cardiomyopathy Less Cardiotoxicity Observed With AMR1 DOX (18 wks) 1.98 * 0.42 DOX + Vehicle (9 + 9 wks) 3.42 DOX + DOX (9 + 9 wks) ** 0.40 DOX + AMR (9 + 9 wks) Mean Scores *P<0.01 DOX + DOX vs DOX + vehicle. **P<0.01 DOX + AMR vs DOX + DOX. Noda T, Invest New Drugs 1998

  7. Japanese Data on Amrubicin Show Minimal Signs of Cardiotoxicity • N ≥ 600 Patients • 6% Of patients who received treatment with Amrubicin experienced transient electrocardiogram (ECG) abnormalities1 • Anthracycline-induced cardiomyopathy was not observed at cumulative doses tested1,2 • 17 Patients from various clinical trials received greater than Amrubicin 900 mg/m2 and reported no cardiomyopathy2 • Amrubicin 600 mg/m2 is the equivalent of the recommended maximum dose of Doxorubicin (300 mg/m2) 1 Amrubicin Investigator’s Brochure, 22 Jun 07, Edition 3, p. 120. 2 Amrubicin Investigator’s Brochure, 22 Jun 07, Edition 3, pp. 114-115.

  8. Japanese Postmarketing Data • N = Approximately 6500 Patients • Rare cardiotoxic events noted • Acute heart failure: 1 reported case from a patient who received 15 cycles of AMR; reversed after 10 days • Transient ECG changes occurred • Asymptomatic ST-T depression • Acute changes only 1Data on file (2006 periodic safety report).

  9. AMR Is Potentially Devoid of Cardiotoxicity • Preclinical data show that cardiotoxicity profiles are similar between AMR and control/vehicle comparators • Only background incidences of cardiac events were documented in the Japanese clinical data • Cardiac events in ongoing phase 2 trials in amrubicin-treated patients are comparable to topotecan-treated patients

  10. Amrubicin in preclinicalmodels • Synergistic effects were obtained for the simultaneous use of amrubicinol with CDDP, CPT-11, gefitinib and trastuzumab. • The combination of amrubicinol with gemcitabine was antagonistic.

  11. Phase I trialswithamrubicinmonotherapy • AMR given on day 1 of every 3-week. Myelosuppression was the dose-limitingmtoxicity (DLT) and the maximum tolerated dose (MTD) was 130 mg/m2. The recommended dose (RD) and schedule for a phase II trial was 100 mg/m2 every 3 weeks. • Infusion for three consecutive days (3 trials) every 3 weeks, the MTD was 40-50 mg/m2/day and the DLTs were leukopenia, neutropenia, thrombocytopenia, and gastrointestinal complications. The RD in these phase I study was 35-45 mg/m2 for three consecutive days every 3 weeks. Inoue K, Invest New Drugs 1989; Sugiura T, Invest New Drugs 2005; Okamoto I, CancerChemotherPharmacol 2006; Igawa S, J ThoracOncol. 2007

  12. Amrubicin story (a Japanese story) • 1986-1998 Phase I-II trials • 1998-99 Preclinical studies • 2002 Drugs approval in Japan, preclinical Lung cancer • 2005-06 Phase I SCLC and NSCLC • 2007 SCLC phase II • 2008 SCLC random phase II • 2009-2011 SCLC-NSCLC random phase II and III (ongoing)

  13. Overview of Clinical Studies Used for Approval of Amrubicin in Japan (1-12) andPost-Marketing Studies in SCLC (13-15)

  14. ResponsestoCrizotinib in ALK + NSCLC Kwak EL, NEJM 2010

  15. Study A8081007: Crizotinib vs CT i ALK +Study design R A N D O M I S E Pemetrexed 500 mg/m2 d1 q 3 weeks OR Docetaxel 75 mg/m2 d1 q 3 weeks Crizotinib 250 mg BID till PD Primary endpoint: PFS Enrollment 318 patients ALK + ClinicalTrials.gov record

  16. PFS for patients on pemetrexed (ALK+ vs triple negative) Camidge DR, JTO 2011

  17. Phase II studies of amrubicinmonotherapy for recurrent SCLC

  18. Side effects (grade 3-4) • Hematologictoxicities • Neutropenia (67-85%) - Febrile neutropenia (14-5%) • Thrombocytopenia (20-41%) • Anemia (21-42%) • Non-Hematologictoxicities • Anorexia (7-15%) • Fatigue(15-22%) • Hyponatremia (8%) • Nausea (3-5%)

  19. Amrubicin vs Topotecan Jotte R, JCO 2010 Inoue A, JCO 2008

  20. Clinical trials with amrubicin-based combination therapy

  21. Amrubicin + carboplatin in ED- SCLC • Carboplatin AUC 4 + Amrubicin 35 mg/m2 d 1-3 q 21 • RR sensitive relapse (58.3%) vs refractory relapse (15.4%) p 0.03. • MST sensitive relapse (10 months) refractory relapse(5months: p = 0.004) • PFS sensitive relapse (5 months) refractoryrelapse (2 months; p = 0.01). • Neutropenia g 3-4 (88%), anemia g 3-4 (56%) thrombocyopenia g 3-4 (44%) Hirose T, Lung Cancer 2011

  22. Amrubicin + topotecan in ED-SCLC • Amrubicin 35 mg/m2 d 3-5 q 21, topotecan 0.75 mg/m2 d 1-5 q 21 • RR naive (74%) vs relapse (43%). • MST naive (14.9 months) relapse (10.2 months) • PFS naive (5.3 months) relapse (4.7 months). • Neutropenia g 3-4 (97%), febrile neutropenia (41%, 2 TD) Nogami k, Lung Cancer 2011 (in press)

  23. Survivalforptswith LD/ED, refractory/ sensitive with vs w/o Amrubicin Survival curves for pts with LD Survival curves for pts with ED Survival curves for LD patients with refractory relapse Survival curves for LD patients with sensitive relapse Suzuki H, Med Oncol 2010

  24. Randomized phase II study of amrubicin as single agent or in combination with cisplatin versus etoposidecisplatin as first-line treatment in patients with extensive stage SCLC (ES) Investigate the activity and safety of amrubicin alone versus amrubicin in combination with cisplatin versus standard treatment for extensive disease (ED) small-cell lung cancer in the first line setting.

  25. EORTC protocol 08062: study design • Twenty-seven eligible patients who start their treatment will be entered in each of the 3 arms. • In either of the two experimental arms, if at least 19 patients show a response (a response rate of 69% or higher), the treatment will be declared sufficiently active for taking forward to a phase III study. • Non-eligible/non-assessable patients will be replaced up to a maximum of 85 patient

  26. Grazie per l’attenzione! francesco.grossi@istge.it

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