Cancer Metronomic Therapy Milan, February 26, 2016

Transcription

1 Cancer Metronomic Therapy Milan, February 26, 2016 Metronomic Chemotherapy: Evolution and Development of the Concept Robert S. Kerbel, PhD Senior Scientist Sunnybrook Research Institute Professor, Dept. of Medical Biophysics University of Toronto

2 Bioessays 13: 31-36, 1991 Inhibition of tumor angiogenesis as a strategy to circumvent acquired resistance to anti-cancer therapeutic agents Kerbel RS

3 Chemotherapy Drugs Should Have Vascular Targeting/ Antiangiogenic Effects - Why? chemotherapy drugs kill cycling cells dividing endothelial cells are present in the growing tumor neovasculature therefore chemotherapy should have vascular targeting/ antiangiogenic effects and cause a tumor response even when the tumor cells are resistant to the chemotherapy

4 ANTI-ANGIOGENIC ( METRONOMIC ) DOSING AND SCHEDULING OF CHEMOTHERAPY BROWDER ET AL. ( FOLKMAN) CONVENTIONAL 3 wks rest 3 wks rest 3 wks rest MTD MTD MTD MTD ANTI-ANGIOGENIC Low(er) dose given once a week Browder T. et al. Antiangiogenic scheduling of chemotherapy improes efficacy against experimental drug-resistant cancer Cancer Res. 60: , 2000.

5 Browder et al. Cancer Res 60: , 2000

6 Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity SK-NMC NB Tumor Growth 10 SCID mice Control Vinblastine DC101 Vbl/DC Toxicity Induction: 0.75 mg/m 2 Vbl ip bolus at start 1 mg/m 2 /day continuous infusion x 3 wks 800 g DC101 ip bi-weekly Maintenance: 1.5 mg/m 2 ip bi-weekly 800 g DC101 ip bi-weekly Time (Days) Klement G, Baruchel S, Rak J, Man S, Clark K, Hicklin DJ, Bohlen P, Kerbel RS. J.Clin.Invest. 105: R15-R24, 2000

7 pp metronomic dosing

8 Differential Impact of MTD vs Metronomic Chemotherapy on Induction of Pro-tumorigenic BMDC Host Responses The YIN MTD chemotherapy tumor response/regression reduces duration/extent of response tumor homing and colonization The YANG host response BMDC/EPC mobilization VEGF(R2) therapy, or... metronomic chemotherapy BMDC = bone marrow derived cells EPC = endothelial progenitor cells

9

10 control Paclitaxel Paclitaxel + DC101 x200 x600

11 - 437

12 Potential Advantages of Metronomic Chemotherapy* ADVANTAGES reduced acute toxicity increased convenience when using oral drugs practical as long term adjuvant or maintenance therapy can be integrated with targeted therapies for prolonged periods * Kerbel RS & Kamen BA. Antiangiogenic basis of metronomic Chemotherapy. Nature Reviews Cancer 4: , Pasquier et al. Metronomic chemotherapy: new rationale for new directions. Nat Rev Clin Oncol. 7: , 2010.

13 Negative Perceptions or Concerns About Metronomic Chemotherapy administering lower doses of chemotherapy facilitates development of resistance if toxicity is less, then anti-tumor efficacy will be less too mechanisms especially molecular remain vague... oral chemotherapy has some disadvantages compared to i.v. chemotherapy (PK heterogeneity, patient compliance.) chronic metronomic chemotherapy may be carcinogenic secondary tumors empiricism regarding defining the optimal dose (in contrast to non-empiric MTD chemotherapy) the preclinical / mouse therapy results may not be clinically relevant

14 -141 Models (Human Tumor Xenografts) Developed: breast melanoma ovarian renal hepatocellular colorectal

15 A Model to Study Treatment of High Volume MDA-MB-231/LM2-4 Spontaneous Metastases (one month after surgical removal of orthotopic transplanted primary tumor) Lungs Liver Lymph nodes and mammary fad pad R. Munoz et al. Cancer Research 66: , 2006.

16 Mol Cancer Ther 2: , Preclinical Research and Experimental Development, SUGEN, Inc., South San Francisco, CA (and other centers) These results demonstrate that SU11248 is effective in preclinical breast cancer models and suggest that it may be useful in the treatment of breast cancer in the clinic.

17 IMPACT OF SUNITINIB ON: Spontaneous MMTV-v-H-ras transgenic breast cancer in mice DMBA-induced mammary carcinoma in rats T.J. Abram et al. Mol Cancer Ther 2: , 2003

18 IMPACT OF SUNITINIB AND DOCETAXEL* ON TRANSPLANTED MXI HUMAN BREAST CANCER PRIMARY TUMOR XENOGRAFTS * Similar results obtained with 5-FU or adriamycin by Abram et al.

19 FAILED PHASE III TRIALS OF AN ANTIANGIOGENIC TKI (SUNITINIB) IN METASTATIC BREAST CANCER Trial SUN 1064 (1 st line) SUN 1099 (2 nd line) SUN 1107 (2 nd line) SUN 1094 (1 st line) Therapy sunitinib + docetaxel vs docetaxel sunitinib + capecitabine vs capecitabine sunitinib vs capecitabine sunitinib + paclitaxel

20 Contrasting Outcomes of Sunitinib Therapy when Treating Primary Breast Tumors (LM2-4) vs Advanced Metastatic Disease Tumour Volume (mm 3) Control SU 60mg/kg 60mg/kg Primary (orthotopic) tumor therapy Days Percent survival Postoperative metastatic therapy Days after implantation initiation of therapy Control Su 60mg/kg (therapy initiated at day41)

21 Differential impact of sunitinib plus paclitaxel chemotherapy when treating established primary tumors versus postsurgical advanced metastatic disease. Percent survival vehicle control sunitinib 60mg/kg paclitaxel 30mg/kg sunitinib + paclitaxel Days after implantation Median Survival: vehicle control: 54 days paclitaxel: 61 days sunitinib: 65 days sunitinib + paclitaxel: 50 days E Guerin et al, Cancer Res., accepted, pending minor revision

22 Treatment of advanced visceral MBC with oral UFT + CTX metronomic chemotherapy Primary tumor resected day 22; Treatment initiated day 43; Therapy terminated at day 183 Repeat experiment Oral UFT+CTX CTX (20mg/kg/day via drinking water) UFT (15mg/kg/day by gavage) R. Munoz et al. Cancer Research 66: , 2006

23 Effect of Metronomic CTX/UFT on Primary Orthotopic Transplant Conclusion: Addition of metronomic UFT to CTX has no effect on primary tumor, in profound contrast to metastatic disease.

24 Mammary pleural tumor with cuffing around capillaries, no angiogenesis P in collaboration with Hal Dvorak

25 normal angiogenic NSCLC non-angiogenic NSCLC Is it possible that metronomic chemotherapy regimens target co-opted tumor vasculature (= anti-vascular therapy)?

26 Sci Transl Med 7(282):282ra50, 2015

27 Sci Transl Med 7(282):282ra50, 2015 (Guido Bocci / Teresa di Desidero) uptake of topotecan by RCC cells is elevated by treatment with pazopanib greater direct tumor cell kill

28 Metronomic Chemotherapy: Postulated Mechanisms antiangiogenic targeting dividing ECs targeting BMDCs (including EPCs) direct tumor cell targeting (CSCs?) targeting HIF-1α e.g. by topotecan stimulation of host immune system (targeting Treg s)

29 Some Current Randomized Phase III Trials of Metronomic Chemotherapy Clinical trial identifier # NCT NCT NCT NCT NCT Details / title of trial Efficacy of capecitabine metronomic chemotherapy in triplenegative breast cancer (SYSCBC 001) bevacizumab and paclitaxel or bevacizumab, cyclophosphamide and capecitabine as first line therapy in treating women with locally advanced, recurrent or metastatic breast cancer (SAKK 04/29) Maintenance (metronomic capecitabine plus bevacizumab treatment) vs observation in advanced colorectal cancer (CAIRO3) bevacizumab, (and metronomic capecitabine) chemotherapy followed by K ras randomization to maintenance treatment for first line treatment of metastatic colorectal cancer (ACT2) Study of low dose oral cyclophosphamide and methotrexate maintenance for hormone receptor negative early breast cancer (IBCSG 22 00)

30 JNCI JOURNAL OF THE NATIOANL CANCER INSTITUTE 104(8):568-9, 2012 ~63% of all randomized phase III trials fail to meet their primary survival endpoint

31 ACKNOWLEDGMENTS Yuval Shaked Guido Bocci Giannoula Klement Raquel Munoz Eric Guerin Shan Man Ping Xu

32 BACK UP SLIDES

33 J Mateo et al (JS de Bono) Conclusions: Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate.

34 Shivaani Kummar et al (James H Doroshow) Conclusion: This is the first trial that evaluated single-agent low-dose cyclophosphamide in HGSCO, peritoneal fallopian tube, and BBCA-mutant ovarian cancers It was well tolerated and clinical activity was observed The addition of veliparib at 60 mg daily did not improve either the response rate or the median progression-free survival