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  • American Society of Clinical Oncology (ASCO)  (97)
  • 1
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 15 ( 2023-05-20), p. 2701-2705
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 2
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 32, No. 4_suppl ( 2014-02-01), p. 307-307
    Abstract: 307 Background: Translational studies have shown that shed MET levels in serum and urine of pts with UC correlate with stage and visceral metastases and that cabozantinib reverses HGF-driven UC cell growth and invasion. These data support the evaluation of cabozantinib in pts with mUC. Methods: In this phase II study, pts receive cabozantinib 60 mg daily in 28-day cycles. There are 3 study cohorts (1) mUC, (2) bone only mUC (3) metastatic rare bladder histology. The primary objective is to determine the response rate (RR) by RECIST. Response is assessed every 2 cycles. Tissue, blood, and urine were collected on all pts to test for MET/HGF and immune subsets. Results: 26 out of 55 pts have enrolled (19 M, 7 F): median age 62 (42-82) and median KPS of 80%. Primary sites include bladder (77%) and upper tract UC (23%). Prior therapy includes 30% pts with 1 regimen, 39% with 2, 15% with 3, 8% with 4 and 8% with 6. 81% of pts had visceral metastases (lung, liver and bone) and 19% lymph node only metastases. 23 pts (19 in cohort 1, 3 in cohort 2 and 1 in cohort 3) were evaluable for response after completing at least 4 weeks of therapy. In cohort 1, 2 pts achieved PR (1 remained on study for 10 months and 1 remains on study after 〉 12 months of therapy); 7 pts had SD for at least 16 weeks (1 remained on study for 11 months); 10 had PD; 1 is too early to assess for response; 1 was removed before restaging for toxicity and 1 was removed for not meeting eligibility. The objective RR is 11% and SD 37% for a clinical benefit of 48%. In cohort 2, 1 of 3 pts had a near resolution of bone lesions on NaF PET/CT for 11 months. In cohort 3, only pt enrolled (squamous cell carcinoma of the bladder) achieved SD for 16 weeks. Mixed responses with regression of lung, bone or lymph nodes were observed in 30% of pts with PD. Grade 3/4 toxicities included: fatigue (8%), hyponatremia (8%), hypophosphatemia (8%) diarrhea (4%), thromboembolism (4%), transaminitis (4%), hypothyroidism (4%), thrombocytopenia (4%), dysphonia (4%), hypomagnesemia (4%), creatinine increase (4%) and proteinuria (4%). Conclusions: Cabozantinib has clinical activity in pts with relapsed or refractory mUC with manageable toxicities. Further studies are underway to correlate response to therapy with MET expression. Clinical trial information: NCT01688999.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2014
    detail.hit.zdb_id: 2005181-5
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  • 3
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 34, No. 15_suppl ( 2016-05-20), p. e23149-e23149
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2016
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  • 4
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 15_suppl ( 2013-05-20), p. TPS4589-TPS4589
    Abstract: TPS4589 Background: Accumulating evidence supports MET as a therapeutic target in urothelial carcinoma. Activated MET can promote angiogenesis and tumor growth by upregulating VEGF and may play a role in urothelial carcinoma pathogenesis. Cabozantinib inhibits primarily VEGFR2 and MET pathways. Cabozantinib has been approved by the FDA for the treatment of progressive metastatic medullary thyroid cancer, is in Phase 3 trials for metastatic castration-resistant prostate cancer and has demonstrated clinical activity in multiple solid tumors. We previously reported that shed MET levels in serum and urine of patients with urothelial carcinoma correlate with stage, presence of visceral metastases and urinary source and that cabozantinib is effective in reversing HGF-driven urothelial carcinoma cell growth and invasion. These data support the evaluation of cabozantinib in patients with metastatic urothelial carcinoma. Methods: This is a phase II study of oral cabozantinib 60mg daily given continuously in 28-day cycles. There are three study cohorts: [1] metastatic urothelial carcinoma [2] bone only metastatic urothelial carcinoma [3] metastatic non-urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis. A maximum of 55 subjects will be enrolled. Up to 45 patients will be accrued to cohort 1.The remainder will be enrolled on exploratory cohorts 2 & 3. A two-stage single-arm phase II design will be employed. The primary objective is to determine the objective response rate in patients with metastatic urothelial carcinoma who have progressed on prior chemotherapy. Secondary objectives include progression free survival, safety and toxicity, and overall survival. Exploratory objectives include tumor tissue Met expression, shed MET levels in serum and urine, immune subsets, genetic biomarkers, molecular markers of angiogenesis and circulating tumor cells, correlation with clinical response parameters. Finally we will explore treatment evaluation with FDG and NaF PET/CT compared to standard imaging. This study is supported by the Cancer Therapy Evaluation Program (CTEP). NCT01688999 Clinical trial information: NCT01688999.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2013
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  • 5
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 34, No. 2_suppl ( 2016-01-10), p. 203-203
    Abstract: 203 Background: Recently there has been growing evidence that 18 F-Fluoride PET/CT has increased sensitivity relative to technetium-99m diphosphonate (Tc-99m MDP) bone scan for evaluating metastatic bone disease. This analysis studied changes in 18 F-Fluoride PET/CT and evaluated associations with PSA changes for mCRPC patients (pts) on enzalutamide (enz). Methods: As part of a randomized phase II study evaluating enz with or without vaccine therapy, men with mCRPC electively underwent 18 F-Fluoride PET/CT at 3 month (mos) intervals [NCT01867333]. At these points serum PSA was collected. Data was taken on max SUV and volume of presumed cancerous lesions and a variable, Σ SUV*Volume , was calculated which was defined as the sum of the products of SUV max and volume of cancerous lesions. Results: At the time of our analysis, 19 pts had PSA and PET/CT data for at least 2 time points within 1 year of initiating therapy. The median baseline PSA was 19.6 ng/ml (0.76-587). All pts had predominantly bone disease with 10 having small volume lymphadenopathy. Only 1/19 pts progressed by PSA Working Group criteria. An analysis found that 18/19 pts (95%) had an association between changes in PSA and Σ SUV*Volume . Of these 18 pts, 13 had a major ( 〉 50%) and 1 had a minor ( 〉 30%) PSA response and all 14 had an accompanying decrease in Σ SUV*Volume. For 11/14 pts with PSA responses, the change in Σ SUV*Volume paralleled the change in PSA at all time points, while for 3 pts an associated change between Σ SUV*Volume and PSA was delayed by 3 mos. 4/14 pts had short term responses lasting only 3 mos followed by PSA increases. For these 4 pts the changes in Σ SUV*Volume paralleled PSA changes, decreasing at 3 mos and increasing thereafter. Finally 4/18 patients had no PSA response to therapy. All 4 pts had increases in Σ SUV*Volume which paralleled rising PSA values. Conclusions: Preliminary data from a small cohort suggests that findings on 18 F-Fluoride PET/CT are associated with PSA changes. This represents a substantial difference from standard Tc-99m MDP and further suggests that 18 F-Fluoride PET/CT may provide a more sensitive analysis of bone disease. Additional data from this and other studies are required.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2016
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  • 6
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 5_suppl ( 2012-02-10), p. 207-207
    Abstract: 207 Background: Angiogenesis may be vital to mCRPC. Previously, we had shown the potent anti−tumor activity of dual antiangiogenic therapy by combining thalidomide (T) and bevacizumab (B) with docetaxel (D) and prednisone (P) in mCRPC (Ning JCO 2010). We hypothesized that combining lenalidomide (L), an analogue of T, with B, D, and P would have a more favorable efficacy/toxicity profile. Methods: All patients (pts) had chemotherapy−naïve mCRPC. 3 pts received R 15 mg daily, 3 pts had 20 mg daily, and the rest had 25 mg daily for 14 days of every 21−day cycle (C). All pts received D 75 mg/m2 and B 15 mg/kg on day 1 with P 10 mg and enoxaparin daily throughout each C. Pegfilgrastim was given on day 2. PSA was assayed each C with imaging after C2 and then after every 3C. Results: 47 of the planned 51 pts have been enrolled. Median age was 66 (51−82), Gleason score 8 (5−10), on−study PSA 91.6 ng/ml (0.15−3520), pre−study PSA doubling time 1.43 months (0.52−6.73), number of Cs 14 (1−31), and PFS was 19.3 months as of this analysis. Among 45 pts who have completed ≥2 cycles, 39 (86.7%) and 30 (66.7%) had PSA declines of ≥50% and ≥75%, respectively. Of 29 pts with measurable disease there were 2 CR, 21 PR, and 6 SD (79.3% overall RR). 10/47 pts were taken off study for radiographic disease progression and 5/47 for other reasons. Grade ≥3 toxicities included neutropenia (24/47), anemia (9/47), thrombocytopenia (5/47), weight loss (1/47), hypertension (3/47), and febrile neutropenia (4/47). Other toxicities included perianal fistula (3/47), rectal fissure (1/47), myocardial infarction (1/47), and osteonecrosis of the jaw (ONJ) (16/47, 34.0%). At the time of diagnosis of ONJ, 9/16 pts were on bisphosphonates and 3/16 had used bisphosphonates previously. Although the incidence of ONJ was higher than the 18.3% reported by Ning, a recent study of carboplatin plus weekly docetaxel reported an incidence of 29.3%. Conclusions: Dual antiangiogenic therapy with, B and L, plus D and P was associated with high PSA (86.7%) and tumor (79.3%) responses with manageable toxicities. Further studies are underway to explore the high incidence of ONJ.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
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  • 7
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 6_suppl ( 2023-02-20), p. 207-207
    Abstract: 207 Background: Docetaxel with androgen deprivation therapy (ADT) has been shown to improve survival in metastatic castration-sensitive prostate cancer (mCSPC). There is limited data on the immunologic effects of docetaxel in mCSPC. Greater knowledge of the immune impact of docetaxel could inform future trials in prostate cancer. Methods: A clinical trial in mCSPC evaluated sequencing docetaxel and ADT with Prostvac, a poxviral vaccine targeting prostate-specific antigen (PSA). Eligibility criteria included mCSPC within 4 months of ADT and ECOG performance status 0-2. Patients given 6 cycles of docetaxel 75mg/m 2 with ADT alone for mCSPC were included in this analysis. Peripheral blood mononuclear cells (PBMCs) were sampled at baseline and at 3 weeks after commencing docetaxel. Immune cell subsets analyzed included CD4+ and CD8+ T-cells, T regulatory cells (Tregs), natural killer (NK) cells, dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs). Analyses were performed to determine if the baseline immune status or immune changes induced by therapy associate with PSA at 2 years. Results: Fifteen patients were evaluated for peripheral immune responses in this study. Median age was 63 years (range 50-73). Fourteen were white and 1 was black. ECOG performance status was 0 in 11 patients, 1 in 4 patients. Disease volume was high in 7 and low in 8 patients. Among 158 immune cell subsets assessed, only changes in Tregs and activated NK cells with a lytic and cytokine producing phenotype (CD16+ CD56br) were noted after initiation of docetaxel in addition to ADT. Patients with PSA ≤0.2 at 2 years had higher baseline frequencies of total CD4+ T cells, several activated CD4+ T-cell subsets, plasmacytoid DCs, and CD49d- Tregs. They also had lower baseline frequencies of total CD8+ T cells, naïve CD8+ T cells, and CD73+CD8+ T-cells. Patients with PSA ≤0.2 at 2 years also had greater percent increases in CD8+ effector memory (EM) PD-1+ T-cells after treatment. Conclusions: This is the first study to demonstrate increases in activated NK cells with lytic and cytokine producing potential after treatment with docetaxel. Given that NK cells are associated with clinical outcomes in prostate cancer (Zhao SG, JNCI, 2019) and that increased NK cells were seen after treatment with enzalutamide as well (Madan, JITC, 2021), developing immunotherapy combinations to capitalize on NK cell activity may be a path forward for developing immunotherapy in prostate cancer. Clinical trial information: NCT02649855 . [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
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  • 8
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 31 ( 2020-11-01), p. 3672-3684
    Abstract: We assessed the safety and efficacy of cabozantinib and nivolumab (CaboNivo) and CaboNivo plus ipilimumab (CaboNivoIpi) in patients with metastatic urothelial carcinoma (mUC) and other genitourinary (GU) malignances. PATIENTS AND METHODS Patients received escalating doses of CaboNivo or CaboNivoIpi. The primary objective was to establish a recommended phase II dose (RP2D). Secondary objectives included objective response rate (ORR), progression-free survival (PFS), duration of response (DoR), and overall survival (OS). RESULTS Fifty-four patients were enrolled at eight dose levels with a median follow-up time of 44.6 months; data cutoff was January 20, 2020. Grade 3 or 4 treatment-related adverse events (AEs) occurred in 75% and 87% of patients treated with CaboNivo and CaboNivoIpi, respectively, and included fatigue (17% and 10%, respectively), diarrhea (4% and 7%, respectively), and hypertension (21% and 10%, respectively); grade 3 or 4 immune-related AEs included hepatitis (0% and 13%, respectively) and colitis (0% and 7%, respectively). The RP2D was cabozantinib 40 mg/d plus nivolumab 3 mg/kg for CaboNivo and cabozantinib 40 mg/d, nivolumab 3 mg/kg, and ipilimumab 1 mg/kg for CaboNivoIpi. ORR was 30.6% (95% CI, 20.0% to 47.5%) for all patients and 38.5% (95% CI, 13.9% to 68.4%) for patients with mUC. Median DoR was 21.0 months (95% CI, 5.4 to 24.1 months) for all patients and not reached for patients with mUC. Median PFS was 5.1 months (95% CI, 3.5 to 6.9 months) for all patients and 12.8 months (95% CI, 1.8 to 24.1 months) for patients with mUC. Median OS was 12.6 months (95% CI, 6.9 to 18.8 months) for all patients and 25.4 months (95% CI, 5.7 to 41.6 months) for patients with mUC. CONCLUSION CaboNivo and CaboNivoIpi demonstrated manageable toxicities with durable responses and encouraging survival in patients with mUC and other GU tumors. Multiple phase II and III trials are ongoing for these combinations.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
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  • 9
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 34, No. 2_suppl ( 2016-01-10), p. 272-272
    Abstract: 272 Background: AA pts experience greater prostate cancer (PC) incidence and mortality compared to Caucasian (C) pts but are underrepresented in clinical trials (CTs). Greater representation of AAs is required to explore differences in clinical benefit in advanced disease where recent data has reaffirmed the role of D. Methods: In a retrospective analysis, baseline characteristics, Gleason score (GS), ECOG PS, number of cycles (cys), maximum prostate-specific antigen (PSA) declines, radiographic responses, overall survival (OS) and progression-free survival (PFS) were captured in 2 recent D based CTs. Results: Of 136 pts, 28 (21%) self-identified as Black or AA. Median age of AA pts is 66 (50-78 yrs). Median GS is 8 (5-10). Median ECOG PS is 1 (0-2). 15 pts have bone and soft tissue disease; 13 pts have bone only disease. Median number of cys is 28.5 (1-63). Of 27 evaluable pts, 26 had PSA declines (-26 to -99%). Radiographic responses include 11 (39%) partial responses and 16 (57%) pts with stable disease. Median OS for AAs is 29.0 months (mos) (95% CI: 20.9-34.7 mos); median PFS is 21.5 mos (95% CI: 13.7-28.9 mos). Median OS for all non-AA pts is 24.8 mos (95% CI: 21.8-29.5 mos); median PFS is 16.1 mos (95% CI: 14.1-20.1 mos). The VEGF-634G 〉 C SNP, associated with a more aggressive phenotype of PC, was evaluated in 54 pts. No evidence was found that genotype frequency varies between C and AA pts. Conclusions: In this analysis, AA pts did not have inferior OS (29 mos) or PFS (21.5 mos) outcomes compared to non-AA pts (24.8, 16.1 mos). Further analysis from larger studies is required to determine differential benefits of D for AA pts compared to non-AA pts. Clinical trial information: NCT00089609, NCT00942578.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2016
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  • 10
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 6_suppl ( 2013-02-20), p. 314-314
    Abstract: 314 Background: Mounting evidence supports Met as a target in urothelial cancer (UC). Activated Met can promote angiogenesis and tumor growth by upregulating VEGF and may play a role in UC pathogenesis. Cabozantinib inhibits both VEGFR2 and Met pathways. In this study, we assessed shed Met (sMet) levels in the urine and serum of UC patients (pts) and cabozantinib’s effects on HGF-driven UC cell growth and invasion. Methods: sMet levels in serum and urine samples from 31 pts with UC (23 metastatic, 8 muscle-invasive) were correlated with stage, presence of visceral metastases and urinary source. The effects of cabozantinib on 4 human UC-derived cell lines were studied in vitro. Intact RT4, TCC-SUP, T24M2 and T24M3 cells at 80% confluence were serum deprived 16 h, then left untreated or treated with hepatocyte growth factor (HGF) and/or cabozantinib prior to analysis of Met, phospho- (p)Met, pAkt, Akt, pMAPK and MAPK by immunoassay or immunoblotting. Cabozantinib effects on basal and HGF-induced UC cell invasion, proliferation and soft agar growth were measured. Results: Median serum Met levels were modestly higher in pts with metastatic versus muscle-invasive disease. Urinary Met levels were clearly higher in pts with visceral metastasis (p=0.0111) and in urine from ileal conduits and neobladders compared to normally voided urine, regardless of stage (p=0.0489). Met content in UC cell lines was low in RT4 and higher in T24M2, T24M3 and TCC-SUP. Basal pMet content was universally low, increased significantly by HGF and this was reversed by cabozantinib. HGF-driven increases in pAkt/Akt and pMAPK/MAPK in all 4 cell lines were reversed by cabozantinib, as were HGF-enhanced UC cell invasion, proliferation and anchorage independent growth. Conclusions: Median urinary sMet is significantly higher in pts with visceral metastasis and in specimens from ileal conduits and neobladders relative to normally voided urine. UC cell Met content in culture increased with disease grade; HGF stimulated activation of Met and known effectors, and enhanced invasion, growth rate and anchorage-independent growth; cabozantinib effectively reversed these HGF-driven effects. These data support evaluation of cabozantinib in pts with metastatic UC.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2013
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