Development and evolution of the Concept

Robert S. Kerbel, PhD

Senior Scientist

Sunnybrook Research Institute

Professor, Dept. of Medical Biophysics University of Toronto

Cancer Metronomic Therapy

Milan, February 26, 2016

Metronomic Chemotherapy:

Evolution and Development of the Concept

Bioessays 13: 31-36, 1991

Inhibition of tumor angiogenesis as a strategy to circumvent acquired

resistance to anti-cancer therapeutic agents

Kerbel RS

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

MTD

“ANTI-ANGIOGENIC”

“ANTI-ANGIOGENIC” (“METRONOMIC”) DOSING AND SCHEDULING OF CHEMOTHERAPY BROWDER ET AL. ( FOLKMAN)

“CONVENTIONAL”

MTD MTD MTD

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: 1878-1886, 2000.

3 wks

“rest”

3 wks

“rest”

3 wks

“rest”

Browder et al.

Cancer Res 60: 1878-1886, 2000

0 10 20 30 40 50 60 70 80 90 190 200 210 0.0

0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0

Control

Vinblastine

DC101

Vbl/DC101

SK-NMC NB Tumor Growth 10 SCID mice

Time (Days)

0 10 20 30 40 50 60 70 80 90 190 200 210 220

5 10 15 20 25 30

Toxicity

Induction:

0.75 mg/m²Vbl ip bolus at start

1 mg/m²/day continuous infusion x 3 wks 800 g DC101 ip bi-weekly

Maintenance:

1.5 mg/m² ip bi-weekly 800 g DC101 ip bi-weekly

“Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity”

Klement G, Baruchel S, Rak J, Man S, Clark K, Hicklin DJ, Bohlen P, Kerbel RS. J.Clin.Invest. 105: R15-R24, 2000

pp 1045-1047

metronomic dosing

Differential Impact of MTD vs Metronomic Chemotherapy on Induction of Pro-tumorigenic BMDC Host Responses

MTD

chemotherapy

The

‘YIN”

tumor response/regression

The

‘YANG”

host response BMDC/EPC mobilization

tumor ‘homing’

and colonization

reduces duration/extent of response

● VEGF(R2) therapy, or....

● metronomic chemotherapy

BMDC = bone marrow derived cells

EPC = endothelial progenitor cells

Paclitaxel + DC101

control Paclitaxel

x200

x600

- 437

Potential Advantages of Metronomic Chemotherapy*

* Kerbel RS & Kamen BA. Antiangiogenic basis of metronomic Chemotherapy. Nature Reviews Cancer 4: 423 - 436, 2004.

reduced acute toxicity

ADVANTAGES

increased convenience

when using oral drugs

practical as long term adjuvant or maintenance

therapy

can be integrated with targeted

therapies for prolonged periods

Pasquier et al. Metronomic chemotherapy: new rationale for

new directions. Nat Rev Clin Oncol. 7: 455-465, 2010.

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

-141

Models (Human Tumor Xenografts) Developed:

hepatocellular breast

melanoma

renal

ovarian colorectal

Lungs Liver

Lymph nodes and mammary fad pad

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)

R. Munoz et al.

Cancer Research 66: 3386-3391, 2006.

Mol Cancer Ther 2: 1011-21, 2003

“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.”

1 Preclinical Research and Experimental Development, SUGEN, Inc., South San Francisco, CA (and other centers)

Spontaneous MMTV-v-H-ras transgenic breast cancer in mice

DMBA-induced mammary carcinoma in rats

IMPACT OF SUNITINIB ON:

T.J. Abram et al. Mol Cancer Ther 2: 1011-21, 2003

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.

FAILED PHASE III TRIALS OF AN ANTIANGIOGENIC TKI (SUNITINIB) IN METASTATIC BREAST CANCER

Trial Therapy

SUN 1064 sunitinib + docetaxel vs docetaxel (1

line)

SUN 1099 sunitinib + capecitabine vs capecitabine (2

line)

SUN 1107 sunitinib vs capecitabine (2

line)

SUN 1094 sunitinib + paclitaxel

(1

line)

30 40 50 60 70 80 90 100 0

10 20 30 40 50 60 70 80 90 100 110

Control Su 60mg/kg

(therapy initiated at day 41) Days after implantation

Percent survival

5 10 15 20 25

0 100 200 300 400 500 600 700

Control 60mg/kg

initiation of therapy

Days

Tumour Volume (mm3)

Contrasting Outcomes of Sunitinib Therapy when Treating

Primary Breast Tumors (LM2-4) vs Advanced Metastatic Disease

Primary (orthotopic)

tumor therapy Postoperative

metastatic therapy

SU 60mg/kg

35 45 55 65 75 85 95 0

10 20 30 40 50 60 70 80 90 100 110

vehicle control sunitinib 60mg/kg paclitaxel 30mg/kg sunitinib + paclitaxel

Days after implantation

Percent survival

Median Survival:

vehicle control: 54 days paclitaxel: 61 days

sunitinib: 65 days

sunitinib + paclitaxel: 50 days

Differential impact of sunitinib plus paclitaxel

chemotherapy when treating established primary tumors versus postsurgical advanced metastatic disease.

E Guerin et al, Cancer Res., accepted, pending minor revision

Treatment of advanced visceral MBC with oral UFT + CTX metronomic chemotherapy

Oral UFT+CTX

CTX (20mg/kg/day via drinking water)

UFT (15mg/kg/day by gavage)

Primary tumor resected day 22;

Treatment initiated day 43;

Therapy terminated at day 183 Repeat experiment

R. Munoz et al. Cancer Research 66: 3386-3391, 2006

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.

Mammary pleural tumor with cuffing around capillaries,  no angiogenesis

P

in collaboration with Hal Dvorak

normal angiogenic NSCLC “non-angiogenic” NSCLC

Is it possible that metronomic chemotherapy regimens target

co-opted tumor vasculature (=“anti-vascular” therapy)?

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

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

Metronomic Chemotherapy: Postulated Mechanisms

“antiangiogenic”

targeting HIF-1α e.g. by topotecan

direct tumor cell targeting

(CSCs?)

stimulation of host immune

system (targeting

Treg’s)

targeting dividing

ECs

targeting BMDCs (including

EPCs)

Some Current Randomized Phase III Trials of “Metronomic” Chemotherapy

NCT01112826  Efficacy of capecitabine metronomic chemotherapy in triple‐

negative breast cancer (SYSCBC‐001)

NCT01131195  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) NCT00442637 Maintenance (metronomic capecitabine plus       

treatment) vs observation in advanced colorectal cancer (CAIRO3) NCT01229813  bevacizumab    (and metronomic capecitabine) chemotherapy 

followed by K‐ras randomization to maintenance treatment for first line treatment of metastatic colorectal cancer (ACT2)

NCT00022516 Study of low dose oral cyclophosphamide and methotrexate maintenance for hormone receptor negative early breast cancer (IBCSG 22‐00)

Clinical trial

identifier # Details / title of trial

bevacizumab

bevacizumab,

bevacizumab

JNCI

104(8):568-9, 2012

~63% of all randomized phase III trials fail to meet

their primary survival endpoint

ACKNOWLEDGMENTS

Yuval Shaked Guido Bocci

Giannoula Klement Raquel Munoz

Eric Guerin

Shan Man

Ping Xu

BACK UP SLIDES

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.”

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