Phase II study of cilengitide (EMD 121974, NSC 707544) in patients with non-metastatic castration resistant prostate cancer, NCI-6735. A study by the DOD/PCF prostate cancer clinical trials consortium.
BACKGROUND
Integrins mediate invasion and angiogenesis in prostate cancer bone metastases. We conducted a phase II study of cilengitide, a selective antagonist of α(v)β(3) and α(v)β(5) integrins, in non-metastatic castration resistant prostate cancer with rising PSA.


METHODS
Patients were observed for 4 weeks with PSA monitoring, and then treated with 2,000 mg IV of cilengitide twice weekly until toxicity/progression. PSA, circulating tumor cells (CTCs) and circulating endothelial cells (CECs) were monitored each cycle with imaging performed every three cycles. Primary end point was PSA decline by ≥ 50%. Secondary endpoints were safety, PSA slope, time to progression (TTP), overall survival (OS), CTCs, CECs and gene expression.


RESULTS
16 pts were enrolled; 13 were eligible with median age 65.5 years, baseline PSA 8.4 ng/mL and median Gleason sum 7. Median of three cycles was administered. Treatment was well tolerated with two grade three toxicities and no grade four toxicities. There were no PSA responses; 11 patients progressed by PSA after three cycles. Median TTP was 1.8 months and median OS has not been reached. Median pre- and on-treatment PSA slopes were 1.1 and 1.8 ng/mL/month. Baseline CTCs were detected in 1/9 patients. CTC increased (0 to 1; 2 pts), remained at 0 (2 pts) or decreased (23 to 0; 1 patient) at progression. Baseline median CEC was 26 (0-61) and at progression, 47 (15-148). Low cell counts precluded gene expression studies.


CONCLUSIONS
Cilengitide was well tolerated but had no detectable clinical activity. CTCs are of questionable utility in non-metastatic prostate cancer.
University of Michigan Comprehensive Cancer Center, 7314 Cancer Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109-5946, USA.
Ajjai
A
Alva
Susan
S
Slovin
Stephanie
S
Daignault
Michael
M
Carducci
Robert
R
Dipaola
Ken
K
Pienta
David
D
Agus
Kathleen
K
Cooney
Alice
A
Chen
David C
DC
Smith
Maha
M
Hussain
D000368:Aged; D000726:Androgen Antagonists / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018450:Disease Progression; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007262:Infusions, Intravenous; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009360:Neoplastic Cells, Circulating / Q000187:drug effects / Q000473:pathology; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors / Q000378:metabolism; D012910:Snake Venoms / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D017211:Treatment Failure; D014481:United States
D000726:Androgen Antagonists; D000970:Antineoplastic Agents; D039302:Integrin alphaVbeta3; D019030:Receptors, Vitronectin; D012910:Snake Venoms; C064660:integrin alphaVbeta5; C422910:Cilengitide; D017430:Prostate-Specific Antigen