We evaluated two dose levels of cilengitide, an inhibitor of αvβ3 and αvβ5 integrins, in chemotherapy naïve patients with asymptomatic, metastatic CRPC using a six month non-progression endpoint. The choice of this endpoint represents a shift in paradigm from using PSA decline rates or response rates to a clinically meaningful endpoint. The rational was further supported by the hypothesized cytostatic mechanism of action. Recognizing the difficulties in interpreting early changes, this trial pioneered a trial design that allowed patients with evidence of asymptomatic progression at first assessment to continue on study with an interim follow up scan to confirm progression. Both approaches proved feasible.
Since neither arm, at the time of prespecified interim analysis (after first stage of accrual), met the prespecified cutoff of 6 (27%) or more patients progression free at the six month evaluation, the study did not proceed to second stage. Although neither arm reached the prespecified activity level, clinical (a trend towards less progression at the six month assessment; 91% and 77% on the 500mg arm and the 2000mg dose arm, respectively) and correlative studies results suggest that the 2000mg dose level has more but modest activity over the 500 mg dose.
Markers of bone turnover are indicative of bone resorption and formation reflecting osteoclastic and osteoblastic activity, respectively and are proving to be a useful tool for measuring the efficacy of bone targeted therapy.[8
] Increased N-telopeptide and bone specific alkaline phosphatase have been associated with adverse clinical outcomes, including shorter time to skeletal events, disease progression and death.[6
] In this trial, bone turnover markers of patients treated on the 2000mg arm tended not to increase as much at time of progression although was not statistically significant. Additionally, patients on both arms that obtained stable disease at six months showed a similar trend suggesting an effect of cilengitide on the bone microenvironment in some patients. Another promising biomarker in CRPC investigated in this study is CTCs. Recent studies of CTCs in CRPC have evaluated the ability of CTCs to be used as a surrogate for overall survival.[14
] Less than 5 CTCs/7.5 mL at baseline and post-treatment has correlated with improved overall survival. In this study, there was a trend towards increased time to progression in patients on the 2000mg dose arm with less than or equal to five CTCs at first assessment. In all patients, there was a non-significant trend towards increased time to progression in patients with 0–5 CTCs at cycle 2 compared to those with >5 CTCs at cycle 2, again suggestive of possible activity in some patients though the numbers are too small for any major conclusion.
It is possible that significant clinical activity was not demonstrated despite a signal of biologic activity because of incomplete integrin inhibition which could have been impacted by dose or schedule. In phase I testing, no clear pattern of cilengitide toxicity could be determined and no maximum tolerated dose was reached [18
] with responses achieved at both low and high dose levels.[1
] However, disease specific phase II testing points towards a modest increased efficacy at higher dose levels [32
] which is supported in our current trial. In a phase IIa study investigating 500mg and 2000mg dosing in patients with recurrent glioblastoma,[37
] pharmacokinetic studies revealed significantly greater exposures among the 2000mg cohort. However, in prostate cancer, which is not known to be as vascular as brain tumors, it is possible that even the 2000mg dose may not have been sufficient to effectively block integrin receptors to result in a biologic effect due to the short plasma half-life of cilengitide of 2.5–4 hours.[28
] Therefore dosing chosen for this trial may not have been optimal with the potential need for continuous infusion or more frequent administration to observe a significant biologic effect. It is also possible that alternative integrins not blocked by cilengitide may have a more significant role in prostate cancer. To date, the specific functions of integrins, their ligands, and their modulators in prostate cancer progression are incompletely understood.[3
] This study suggests that inhibition of integrins may have some biologic effect but perhaps alternative or more inhibition is necessary. Because tumors can overcome integrin requirements through upregulation of integrin-initiated intracellular signaling pathways, inhibition of integrin-dependent signaling components, including FAK, Src, and P13K may serve as complimentary chemotherapeutic targets[46
Because of the lessons learned investigating other bone targeted therapies suggesting patients may have been taken off therapy prematurely, we pioneered this study design to avoid premature withdrawal of the agent. Patients were permitted to continue on trial until confirmed progression. Twenty-five patients had asymptomatic progression at first assessment (12 weeks). Of these 24 patients, 13 (54%) elected to continue treatment. Thirty-one percent of these 13 patients achieved a best response of SD. 69% experienced confirmed progression at the second assessment after cycle 3 (18 weeks). This is one of the first trials to test the feasibility of this concept. Since this trial was designed in 2004, the Prostate Cancer Clinical Trials Working Group has published consensus recommendations for clinical trial conduct including this concept.[42