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Clinical and pharmacological background

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  1. Clinical and pharmacological background • Microtubule stabilizing (and destabilizing) agents have relevant role in the treatment of breast cancer (and other tumors) • They are natural compounds discovered serendipitously or in large-scale screens from plant, microbial, and marine sources • Increased knowledge of the molecular bases of their mechanisms of action and tumor resistance has allowed rational approaches to the development of new analogues or chemotypes with innovative pharmacological and clinical properties

  2. Why target microtubules? • Microtubules are key components of the cytoskeleton • Perform multiple basic cellular functions (maintenance of cell shape, transport of vesicles, mitochondria throughout cells, cell signaling, cell division and mitosis) • Fill the area from nucleus to plasma membrane • Their polymerization dynamics are tightly regulated both spatially and temporally • At least 3 distinct binding sites for tubulin-targeting drugs • Disruption of microtubule dynamics leads to mitotic arrest and cell death

  3. Vinca alkaloids (destabilizers) (+) end Microtubules -tubulin Mitotic chromosome Microtubules Centriole -tubulin Tubulin Tubulin dimers Mitotic center Subunits 8 nm (-) end Taxanes (stabilizers) Top view 24 nm Structure and function of microtubulesand mechanism of action of tubulin-binding agents  Polymerization  Polymerization From Morris PG & Fornier MN, 2008, modified

  4. Effect of microtubule-targeting agents on cell cycle Prometaphase Early metaphase Telophase Anaphase Metaphase with vinflunine* Metaphase with paclitaxel* Chromosomes Microtubules Kinetochores • The reduced dynamic movements of chromosomes reduces the tension on the kinetochores, centromeres and the conjoined chromosomes. • These changes are associated with the blocking of mitosis at the metaphase–anaphase transition. *Some chromosomes remain at spindle poles Jordan MA, et al. Nat Rev Cancer. 2004

  5. Effects of tubulin targeting drugs on cancer cells MDR = multidrug-resistance phenotype; Pgp = P-glycoprotein; MRP = multidrug resistance-associated proteins; MAP = microtubule-associated proteins. Kavallaris M et al., Drug Resit Updat 4:392-401, 2001

  6. Antimitotic drugs bind to microtubules at diverse sites a | A few molecules of vinblastine bound to high-affinity sites at the microtubule plus end suffice to suppress microtubule dynamics. b | Colchicine forms complexes with tubulin dimers and copolymerizes into the microtubule lattice, suppressing microtubule dynamics. c | A microtubule cut away to show the interior surface is shown. Paclitaxel binds along the interior surface of the microtubule, suppressing its dynamics. Jordan Ma & Wilson L, Nat Rev Cancer 4:253-265, 2004

  7. Taxanes in clinical uses Docetaxel Paclitaxel • Indications: • adjuvant treatment of breast cancer • locally advanced or metastatic breast cancer • locally advanced or metastatic NSCLC • hormone refractory metastatic prostate cancer • metastatic gastric adenocarcinoma • locally advanced squamous cell carcinom of the • head & neck • Indications: • advanced ovarian cancer • adjuvant treatment of node positive breast • cancer • metastatic breast cancer • advanced NSCLC • advanced AIDS-related Kaposi’s sarcoma From EMEA/FDA product information

  8. Disadvantages of first-generation taxanes • Poor bioavailability • Low solubility in water • Need of surfactant agents (cremophor EL, Tween80) believed to be responsible for severe allergic reactions • Relevant toxicity • Treatment failure due to intrinsic or acquired multidrug resistance

  9. Cellular changes associated with multidrug and taxane resistance • Overexpression of members of the ATP-binding cassette family of drug transporters • eg, p-glycoprotein • Alterations in microtubule/tubulins • Tubulin mutations • Overexpression of tubulin isotypes with more dynamicity (-III) • Changes in the expression ofmicrotubule-associated proteins (MAPs) Fojo AT, et al. 2005; Dumontet C, et al. 1999

  10. Microtubule destabilizers and stabilizersand their binding sites on tubulin MICROTUBULE DESTABILIZERS MICROTUBULE STABILIZERS Vinca alkaloids Vincristine Vinblastine Vinorelbine Vinflunine Halicondrins (eribulin mesylate) Cryptophycins Dolastatins Hemiasterlins Laulimalide Peloruside A Laulimalide binding site Eleutherobin Sarcodictyins A+B Cyclostreptin Discodermolide Dictyostatin Vinca binding site Taxanes • Paclitaxel • Docetaxel • ABI-007 • CT-2103 • Taxoprexin • Larotaxel • Cabazitaxel Colchicine binding site Taxane binding site Epothilones Colchicine Epothilone D (KOS-862) Ixabepilone Sagopilone BMS-310705 Epothilone B (Patupilone) Combrestatins 2-Methoxyestradiol • Dehydelone • (KOS-1584) Sulphonamides Morris PG & Fornier MN, Clin Cancer Res 22:7167-7172, 2008

  11. Natural-product microtubule-stabilizing agents and their sources * semi-synthetic analogue from 10-deacetyl baccatin III

  12. Summary of defined microtubule stabilizing agents MDR: Multi-drug resistance; P-gp: P-glycoprotein From Zhao Y et al., 2009, modified

  13. New paclitaxel formulations

  14. nab-paclitaxel (ABI-007) • Paclitaxel bound to albumin nanoparticles • Advantages: • Cremophor free formulation • Lower risk of hypersensitivity reactions • No premedications needed • Shorter infusion time • Linear, predictable PK • Greater amount of drug delivered to the target cells • Might make use of gp60-albumin mediated receptor transport across endothelial cells Morris and Fornier, 2008; Ibrahim et al., 2002; Desai et al Clin Cancer Res 2006

  15. nab-paclitaxel Significant differences in RR = response rate (p=0.001) and TTP= time to progression (p=0.006); NR= not reported 1Ibrahim, JCO 2005; 2Mirtsching Breast Ca Res Treat Suppl 2006; 3Gradishar JCO 2005

  16. Adverse events B) grade 3 and 4 reported in ≥ 5% of patients in either group A) all grades reported in more than 20% of patients in either treatment group • The incidence of grade 4 neutropenia was significantly lower for ABI-007 compared with standard paclitaxel (9% vs 22%, p=0.001) • Grade 3 sensory neuropathy was more common in the ABI-007 arm than in the standard pazlitaxel arm (10% vs 2%, p=0.001) but was easily managed and improved rapidly (median 22 days) • No hypersensitivity reactions occurred with ABI-007 despite the absence of premedication and shorter administration time SD, standard deviation; ANC, absolute neutrophil count; * p<0.05 Gradishar WJ et al., J Clin Oncol 23:7794-7803, 2005

  17. nab-paclitaxel • ABI-007 showed superior efficacy to paclitaxel in a phase III study in metastatic breast cancer. • Although ABI-007 use was associated with less neutropenia, its use did increase the risk of peripheral neuropathy. • ABI-007 is now approved by FDA and EMEA for the treatment of metastatic breast cancer. • A phase II study of ABI-007 in combination with trastuzumab and carboplatin in patients with metastatic breast cancer is ongoing. • An adjuvant phase II trial of doxorubicin and cyclophosphamide followed by ABI-007, all in combination with bevacizumab, for breast cancer patients has recently completed accrual. • The incorporation of ABI-007 into standard taxane-based regimens could potentially remove the need for premedication with steroids and could allow more rapid infusion times.

  18. Phase II study nab-paclitaxel vs. docetaxel first-line metastatic breast cancer patients randomized to 4 arms: Comparisons (N=300) nab-paclitaxel vs. docetaxel (A, B, Cvs. D) weekly vs. every-3-weeks nab-paclitaxel (B, Cvs.A) low vs. high dose weekly nab-paclitaxel (Bvs. C) R A N D O M I Z E Arm A: nab-paclitaxel 300 mg/m2 q3w (n=76) Arm B:nab-paclitaxel 100 mg/m2weekly 3 out of 4 (n=76) Arm C: nab-paclitaxel 150 mg/m2weekly 3 out of 4 (n=74) Arm D: docetaxel 100 mg/m2 q3w (n=74) Arms A, C and D administered at the MTD Gradishar W, et al. ASCO 2007. Abstract 1032.

  19. Phase II study evaluating various doses of nab-paclitaxel vs. docetaxel ABX 300 mg/m2 q3w ABX 100 mg/m2 qw3/4 ABX 150 mg/m2 qw3/4 Docetaxel 100 mg/m2 q3w P = .002 100 90 P = .007 P = .003 80 P = .016 70 70 62 60 Response Rate (%) 50 43 38 40 30 20 10 n = 76 76 74 74 0 Treatment Gradishar W, et al. ASCO 2007. Abstract 1032.

  20. AB CD Phase II study evaluating various doses of nab-paclitaxel vs. docetaxel • PFS statistically superior with 150 mg/m2 (P = .002) and 300 mg/m2nab-paclitaxel (P = .046) compared with docetaxel in MBC • PFS statistically superior with 150 mg/m2nab-paclitaxel compared with 100 mg/m2nab-paclitaxel (P = .009) • Lower incidence of neutropenia and fatigue with all schedules of nab-paclitaxel compared with docetaxel • Randomized phase III trial comparing weekly nab-paclitaxel 150 mg/m2 vs. docetaxel 100 mg/m2 in MBC planned Progression-free SurvivalInvestigator Assessments 1.0 0.75 Proportion Not Improved 0.50 0.25 75% of patients off-study 0.0 0 3 6 9 12 15 18 Months Gradishar W, et al. ASCO 2007. Abstract 1032.

  21. New taxanes in phase III clinical trials Larotaxel (XRP9881, RPR 109881A) Cabazitaxel (XRP-6258, TXD258) • A phase III trial completed in combination with prednisone for the treatment of hormone-refractory metastatic prostatic cancer • Results recently published (ASCO GU 2010) • Oral route • Phase III trials completed for the treatment of breast and pancreatic cancer – results not yet published • Phase III trials ongoing for the treatment of bladder cancer • Favorable therapeutic index in taxane-pretrated metastatic breast cancer • (Dieras V et al., 2008)

  22. New taxanes in phase II trials Milataxel (MAC-321) Ortataxel (BAY 59-8862/IDN5109) TPI-287 (NBT-287) Phase II trials ongoing for the treatment of mesothelioma, NSCLC and colorectal cancer IV/Oral route Phase II trials ongoing for the treatment of pancreatic, prostate cancer and melanoma Phase II trials ongoing for the treatment of NHL, NSCLC, breast, kidney, renal cell carcinoma Oral route BMS-275183 Tesetaxel (DJ-927) Phase II trials ongoing for the treatment of NSCLC Oral route Phase II trials ongoing for the treatment of colorectal, gastric cancer and melanoma. IV/Oral route

  23. New taxanes in phase I trials TL-310 Simotaxel (TL909) BMS-188797 BMS-184476

  24. Chemical structures of the natural epothilones and the synthetic epothilones currently in clinical development Natural epothilones Epothilone B (Patupilone) Epothilone A Epothilone C Epothilone D (KOS-862) Semi- & Fully Synthetic Derivatives Sagopilone (ZK-EPO) Ixabepilone (Aza-epothilone B) Dehydelone KOS-1584 BMS 310705 Structural differences among the natural moieties are indicated with gray circles. Within epothilone B and D derivatives, structural differences from natural epothilones are indicated using gray ellipses. From Michaud LB, Ann Pharmacother 43:1249-309, 2009, modified

  25. Epothilones: mechanism of action • Induce microtubule stabilization • Bind to -tubulin • Compete with same binding site as paclitaxel on  -tubulin • Binding mode different from above • Accumulate in G2/M • Induces conformational changes in Bax (pro-apoptotic protein) • Bcl-2-dependent • Potential for synergism with Bcl-2 inhibitors

  26. Pharmacologic considerations • Epothilone A and B • High in vitro tumor activity • Modest in vivo activity • Metabolic instability • Unfavorable PK • Narrow therapeutic window • Analogs developed to optimize product

  27. Class-specific advantages • Low susceptibility to tumor resistance mechanisms • MRP-1 and P-gp efflux pumps •  (III) tubulin overexpression • -tubulin mutations

  28. Summary of phase II trials of ixabepilone in metastatic breast cancer 45 42 40 35 30 30 Overall Response Rate(%) 25 22 18a 20 12b 15 12 10 5 0 Roché1 After adjuvant anthracycline Low2 Taxane-pretreated MBC Thomas3 Taxane-resistant MBC Perez4Anthracycline-, taxane-, and capecitabine-resistant Bunnell5 Multiresistant MBC w/capecitabine aInvestigator assessed; bIndependent assessed. 1. Roché H, et al. J Clin Oncol. 2007;25:3415. 2. Low JA, et al. J Clin Oncol. 2005;23:2726. 3. Thomas E, et al. J Clin Oncol. 2007;25:3399. 4. Perez EA, et al. J Clin Oncol. 2007;25:3407. 5. Bunnell CA, et al. J Clin Oncol. 2006;24:Abstract 10511. Graphic courtesy of Hope S. Rugo, MD.

  29. Ixabepilone phase II trialsGrade 3/4 toxicity in metastatic breast cancer Severe myalgias range from 3-26% Grade 3/4 neutropenia 35 to 58% Fatigue variable at 6 to 34% Febrile neutropenia 3-14% with 14 % on NCI0229 Sensory neuropathy ranged from 3-22% Diarrhea at 1 to 11% 1. Thomas E, et al. J Clin Oncol. 2007;25:3399. 2. Low JA, et al. J Clin Oncol. 2005;23:2726. 3. Roché H, et al. J Clin Oncol. 2007;25:3415. 4. Perez EA, et al. J Clin Oncol. 2007;25:3407. 5. Bunnell CA, et al. J Clin Oncol. 2006;24:Abstract 10511.

  30. FDA approved ixabepilone in October 2007 as a single agent for triple-resistant metastatic breast cancer, and in combination with capecitabine for anthracycline- and taxane-resistant disease IxabepilonePhase III data EMEA CHMP gave a negative opinion and did not recommend a marketing authorization for ixabepilone for the treatment of locally advanced breast cancer (November 20, 2008) BMS Pharma EEIG withdrawn its marketing authorization application for ixabepilone (March 18, 2009)

  31. What were the main concerns of the CHMP? • The CHMP was concerned that ixabepilone’s benefits in terms of increasing the time until the cancer got worse did not outweigh the concerns over the medicine’s safety. • In particular, the Committee was concerned over the risk of patients developing neuropathy (damage to nerve cells), which was a severe and common side effect in patients taking the medicine. • Therefore, at the time of the withdrawal, the CHMP’s view was that the benefits of ixabepilone in the treatment of breast cancer did not outweigh the identified risks.

  32. Study Design: International, Randomized, Open-label, Phase III Trial Ixabepilone (40 mg/m2 IV over 3 hr d1 q3wk) + Capecitabine (2000 mg/m2/dayPO 2 divided doses d1-d14 q3wk) N = 375 Metastatic or locally advanced breast cancer RESISTANT to anthracyclines and taxanes N = 752 Capecitabine (2500 mg/m2/day PO 2 divided doses d1-d14 q3wk) N = 377 • Stratification • Visceral metastases • Prior chemotherapy for MBC • Anthracycline resistance • Study site

  33. Strict definition: patients whose tumors rapidly progressed in the adjuvant or metastatic setting after receiving both anthracyclines and taxanes Resistance to Prior Therapy

  34. Progression-free Survival by Independent Radiologic Review 1.0 0.8 0.6 0.4 0.2 0 HR: 0.75 (0.64–0.88) Proportion Progression Free P=0.0003 0 4 8 12 16 20 24 28 32 36 Months

  35. Response Rate

  36. Toxicity (%)a Ixabepilone + Capecitabine N = 369 Capecitabine N = 368 P Value Leukopenia 57 6 <.0001 Anemia 10 4.5 .005 Neutropenia 68 11 <.0001 Thrombocytopenia 8 4 .011 Febrile neutropenia 5 <1 .001 Grade 3/4 Hematologic Toxicities aBy worst CTCAE v3 grade. Thomas E, et al. J Clin Oncol. 2007;25:5210.

  37. Grade 3/4 Nonhematologic toxicities 80 Ixabepilone + capecitabine (n = 369) Capecitabine (n = 368) 60 % Patients 40 23 18 17 20 9 9 8 6 4 3 3 3 2 2 2 2 0.3 0 0 0 Myalgia Hand-foot syndrome Diarrhea Arthralgia Fatigue Nausea Vomiting Peripheral neuropathy Mucositis Thomas E, et al. J Clin Oncol. 2007;25:5210

  38. Ixabepilone for metastatic breast cancer is an example of a cancer drug that adds "a small benefit at a high cost“ • This editorial accompanies a new cost-efficacy study in the same issue of the journal that found that the addition of ixabepilone to capecitabine adds about $31,000 to the overall medical costs of metastatic breast cancer while providing about 1 more month of "quality-adjusted" survival (Reed et al., 2009).

  39. Epothilones in clinical development a, dose limiting toxicity; mBC, metastatic breast cancer; A&T, anthracycline & taxane