scholarly journals Cabozantinib in Chemotherapy-Pretreated Metastatic Castration-Resistant Prostate Cancer: Results of a Phase II Nonrandomized Expansion Study

2014 ◽  
Vol 32 (30) ◽  
pp. 3391-3399 ◽  
Author(s):  
Matthew R. Smith ◽  
Christopher J. Sweeney ◽  
Paul G. Corn ◽  
Dana E. Rathkopf ◽  
David C. Smith ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Soft Tissue ◽  
Tumor Cells ◽  
Phase Ii ◽  
Bone Scan ◽  
Castration Resistant Prostate Cancer ◽  
Bone Biomarkers ◽  
Castration Resistant ◽  
Analgesic Use

Purpose Cabozantinib (XL184), an oral inhibitor of multiple receptor tyrosine kinases such as MET and VEGFR2, was evaluated in a phase II nonrandomized expansion study in castration-resistant prostate cancer (CRPC). Patients and Methods Patients received open-label cabozantinib at daily starting doses of 100 mg or 40 mg until disease progression or unacceptable toxicity. The primary end point was bone scan response, defined as ≥ 30% reduction in bone scan lesion area. Other efficacy end points included overall survival, pain, analgesic use, and biomarkers. Results One hundred forty-four patients sequentially enrolled in either a 100-mg (n = 93) or 40-mg (n = 51) study cohort. Ninety-one patients (63%) had a bone scan response, often by week 6. Treatment resulted in clinically meaningful pain relief (57% of patients) and reduction or discontinuation of narcotic analgesics (55% of patients), as well as improvements in measurable soft tissue disease, circulating tumor cells, and bone biomarkers. Improvements in each of these outcomes were observed in both cohorts: bone scan response in 73% and 45%, respectively; reductions in measurable soft tissue disease in 80% and 79%, respectively. Median overall survival was 10.8 months for the entire population. Most common grade 3 or 4 adverse events were fatigue (22%) and hypertension (14%). Fewer dose reductions because of toxicity were required in the 40-mg group. Conclusion The evidence suggests that cabozantinib has clinically meaningful activity in CRPC. Cabozantinib resulted in improvements in bone scans, pain, analgesic use, measurable soft tissue disease, circulating tumor cells, and bone biomarkers. Taken together, these phase II observations warrant further development of cabozantinib in prostate cancer.

Quantitative bone scan lesion area as an early surrogate outcome measure indicative of overall survival in metastatic castration-resistant prostate cancer.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 179-179
Author(s):  
Matthew S. Brown ◽  
Hyun J. Kim ◽  
Gregory H. Chu ◽  
Martin Allen-Auerbach ◽  
Cheryce Fischer ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Bone Scan ◽  
Post Treatment ◽  
Whole Body ◽  
Treatment Trial ◽  
Castration Resistant Prostate Cancer ◽  
Lesion Area ◽  
Surrogate Outcome ◽  
Castration Resistant

179 Background: Bone Scan Lesion Area (BSLA) is a biomarker that can be computed semi-automatically from whole-body scintigraphic imaging as a measure of overall bone tumor burden. Initial development and validation, including correlation with outcomes, was performed in trial cohorts from a single drug treatment with controls in subjects with metastatic castrate-resistant prostate cancer (CRPC). A 30% increase/decrease in BSLA was defined as progression/response on bone scan. We hypothesize that, when applied to an independent treatment trial cohort with a different mechanism of drug action, baseline BSLA and Week 12 change post-treatment are predictive of a subject's overall survival. Methods: From an anonymized imaging research database a cohort of 198 CRPC subjects was identified who enrolled in a treatment trial (127 treated, 71 placebo). This cohort was independent of those used for biomarker development and initial validation, and involved a different mechanism of drug action. Subjects underwent standard of care whole-body bone scintigraphy with 99mTc-Methyl diphosphonate (99mTc-MDP). BSLA was calculated at baseline and response at Week 12. Multivariate Cox regression was used to test whether (1) baseline BSLA, and (2) early changes in BSLA (12 weeks post treatment) were predictive of overall survival. Results: BSLA < 2000 mm2 at baseline was a prognostic factor (HR=0.6; p=0.003) and predictive of longer survival (HR=0.4; p<0.001). Subjects without PD by BSLA at Week 12 had significantly longer survival than subjects with PD: median 170 days vs. 186 days in the placebo group and 260 days vs. 392 days in the treatment group. The overall survival rates between non-PD and PD subjects were statistically different (HR=0.64, p=0.007). Conclusions: BSLA is calculated semi-automatically from bone scans and provides a quantitative and objective treatment response assessment. Baseline BSLA and early changes post treatment were found to be predictive of overall survival in patients with metastatic castration-resistant prostate cancer. BSLA has now been demonstrated to be an early surrogate outcome for overall survival in different drug treatments.

scholarly journals Phase II Trial of Bevacizumab, Thalidomide, Docetaxel, and Prednisone in Patients With Metastatic Castration-Resistant Prostate Cancer

2010 ◽  
Vol 28 (12) ◽  
pp. 2070-2076 ◽  
Author(s):  
Yang-Min Ning ◽  
James L. Gulley ◽  
Philip M. Arlen ◽  
Sukyung Woo ◽  
Seth M. Steinberg ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Combination Therapy ◽  
Phase Ii ◽  
Specific Antigen ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
Time To Progression ◽  
Castration Resistant ◽  
Phase Ii Studies

Purpose We previously demonstrated that thalidomide appears to add to the activity of docetaxel in metastatic castration-resistant prostate cancer (CRPC). Phase II studies combining docetaxel with bevacizumab have had substantial antitumor activity. We hypothesized that the combination of docetaxel plus these antiangiogenic drugs with different targets would have substantial clinical activity. To explore safety and efficacy, this was tested in mice and in human patients. Patients and Methods Preclinical efficacy of the combination therapy was evaluated in PC3 xenograft mice. Sixty patients with progressive metastatic CRPC received intravenous docetaxel and bevacizumab plus oral thalidomide and prednisone. The primary end point was a prostate-specific antigen (PSA) decline of ≥ 50%. Secondary end points included time to progression, overall survival, and safety. Results In the mouse model, combination therapy of docetaxel, bevacizumab, and thalidomide inhibited tumor growth most effectively. In the clinical trial, 90% of patients receiving the combination therapy had PSA declines of ≥ 50%, and 88% achieved a PSA decline of ≥ 30% within the first 3 months of treatment. The median time to progression was 18.3 months, and the median overall survival was 28.2 months in this group with a Halabi-predicted survival of 14 months. While toxicities were manageable, all patients developed grade 3/4 neutropenia. Conclusion The addition of bevacizumab and thalidomide to docetaxel is a highly active combination with manageable toxicities. The estimated median survival is encouraging, given the generally poor prognosis of this patient population. These results suggest that definitive clinical trials combining antiangiogenic agent combinations with docetaxel are warranted to improve treatment outcomes for patients with metastatic CRPC.

Phase II clinical study of radium-223 chloride (BAY 88-8223) in Japanese patients with symptomatic castration-resistant prostate cancer (CRPC) with bone metastases.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 167-167
Author(s):  
Hiroji Uemura ◽  
Satoshi Nagamori ◽  
Yoshiaki Wakumoto ◽  
Hirotsugu Uemura ◽  
Go Kimura ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Bone Metastases ◽  
Phase Ii ◽  
Japanese Patients ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Radium 223 ◽  
Phase Ii Clinical Study ◽  
Secondary Endpoints

167 Background: The ALSYMPCA study was conducted to evaluate the alpha-emitting radiopharmaceutical Radium-223 Chloride (BAY 88-8223) in patients with symptomatic bone metastases in Castration resistant prostate cancer (CRPC). This trial met its primary endpoint of overall survival at the time of pre-planned interim analysis. Post hoc analysis showed a reduction from baseline in total ALP at 12 weeks (32% reduction in the BAY 88-8223 arm vs. 37% increase in placebo arm, P < 0.001) (Sartor et al. ASCO 2013). We are reporting here a single-arm, open-label, multicenter, phase II clinical study of BAY 88-8223 in Japanese patients with symptomatic CRPC with bone metastases. Methods: Eligible patients had progressive, symptomatic CRPC with at least 2 bone metastases on bone scintigraphy and no known visceral metastases; were receiving Best Standard of Care; and either had previously received docetaxel, were docetaxel ineligible, or had refused docetaxel. Patients received 6 injections of radium-223 (50 kBq/kg IV) every 4 weeks. The primary endpoint was percentage of change in total ALP from baseline at 12 weeks. Secondary endpoints included overall survival, time to symptomatic skeletal event, percentage of change in bone ALP/PSA/biomarkers, and safety. Results: A total of 67 subjects were enrolled; 18 were screening failures, and 49 were received to the study treatment and received at least one administration from September 2013 to May 2014. The mean percent change in total ALP from baseline at 12 weeks was -19.3% (95%CI: -28.0% to -10.7%). The results of secondary endpoints will be presented. The safety and tolerability profile for BAY 88-8223 were highly favorable and only 1 subject (2.0%) experienced lymphocyte count decreased as a Grade 4 adverse event, and there was no death during the study treatment and within 30 days after the last injection of study treatment. Conclusions: The reduction from baseline in total ALP at 12 weeks seen in this phase II study is consistent with the results shown in ALSYMPCA study. Overall, BAY 88-8223 was well tolerated in Japanese patients with CRPC and bone metastases. Clinical trial information: NCT01929655.

scholarly journals Circulating tumor cells and γH2AX as biomarkers for responsiveness to radium-223 in advanced prostate cancer patients

2020 ◽  
Vol 6 (1) ◽  
pp. FSO437
Author(s):  
Jonathan Chatzkel ◽  
Jesse Mocha ◽  
Johnna Smith ◽  
Jun-Min Zhou ◽  
Youngchul Kim ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Castration Resistant Prostate Cancer ◽  
Dna Breaks ◽  
Risk Of Death ◽  
Castration Resistant ◽  
Radium 223 ◽  
Potential Biomarker

Aim: Radium-223 improves overall survival in patients with metastatic castration-resistant prostate cancer to the bone. Radium-223 causes double-strand DNA breaks and produces γH2AX, a potential biomarker for response. We examined the feasibility of tracking γH2AX positivity and numeration in circulating tumor cells. Patients & methods: Ten patients with biopsy-confirmed symptomatic M1b castration-resistant prostate cancer received radium-223 as standard of care and were assessed for γH2AX level changes following doses 1, 3 and 6. Results: Trend tests confirmed that patients with ≥50% increase in circulating tumor cells positive for γH2AX postradium-223 therapy had a lower risk of death (p = 0.035). Conclusion: Regular interval measurements of γH2AX are feasible. The potential correlation between γH2AX changes and overall survival warrants further investigation.

scholarly journals Overall Survival Analysis of a Phase II Randomized Controlled Trial of a Poxviral-Based PSA-Targeted Immunotherapy in Metastatic Castration-Resistant Prostate Cancer

2010 ◽  
Vol 28 (7) ◽  
pp. 1099-1105 ◽  
Author(s):  
Philip W. Kantoff ◽  
Thomas J. Schuetz ◽  
Brent A. Blumenstein ◽  
L. Michael Glode ◽  
David L. Bilhartz ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Phase Ii ◽  
Viral Vectors ◽  
Controlled Trial ◽  
Specific Antigen ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Randomized Controlled ◽  
Castration Resistant

PurposeTherapeutic prostate-specific antigen (PSA) –targeted poxviral vaccines for prostate cancer have been well tolerated. PROSTVAC-VF treatment was evaluated for safety and for prolongation of progression-free survival (PFS) and overall survival (OS) in a randomized, controlled, and blinded phase II study.Patients and MethodsIn total, 125 patients were randomly assigned in a multicenter trial of vaccination series. Eligible patients had minimally symptomatic castration-resistant metastatic prostate cancer (mCRPC). PROSTVAC-VF comprises two recombinant viral vectors, each encoding transgenes for PSA, and three immune costimulatory molecules (B7.1, ICAM-1, and LFA-3). Vaccinia-based vector was used for priming followed by six planned fowlpox-based vector boosts. Patients were allocated (2:1) to PROSTVAC-VF plus granulocyte-macrophage colony-stimulating factor or to control empty vectors plus saline injections.ResultsEighty-two patients received PROSTVAC-VF and 40 received control vectors. Patient characteristics were similar in both groups. The primary end point was PFS, which was similar in the two groups (P = .6). However, at 3 years post study, PROSTVAC-VF patients had a better OS with 25 (30%) of 82 alive versus 7 (17%) of 40 controls, longer median survival by 8.5 months (25.1 v 16.6 months for controls), an estimated hazard ratio of 0.56 (95% CI, 0.37 to 0.85), and stratified log-rank P = .0061.ConclusionPROSTVAC-VF immunotherapy was well tolerated and associated with a 44% reduction in the death rate and an 8.5-month improvement in median OS in men with mCRPC. These provocative data provide preliminary evidence of clinically meaningful benefit but need to be confirmed in a larger phase III study.

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