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  • 1
    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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  • 2
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 34, No. 15_suppl ( 2016-05-20), p. 4534-4534
    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
    detail.hit.zdb_id: 2005181-5
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  • 3
    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
    detail.hit.zdb_id: 2005181-5
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  • 4
    Online Resource
    Online Resource
    American Society of Clinical Oncology (ASCO) ; 2014
    In:  Journal of Clinical Oncology Vol. 32, No. 4_suppl ( 2014-02-01), p. LBA400-LBA400
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 32, No. 4_suppl ( 2014-02-01), p. LBA400-LBA400
    Abstract: LBA400 Background: Carbonic Anydrase IX (CAIX) has been identified as a potential marker for clear cell renal cell carcinoma (ccRCC). We report the results of a phase II clinical trial of a novel small molecule radiotracer that binds to CAIX in clinically localized kidney tumors or biopsy proven metastases. Methods: Between October 2012 and May 2013, patients with kidney tumors underwent imaging with the 18F-VM4-037 radiotracer within 4 weeks of biopsy or surgery for kidney tumors. Imaging characteristics with the radiotracer were collected. All H & E pathology was centrally reviewed by a single pathologist. Immunohistochemistry of the surgical specimens for CAIX and Carbonic Anhydrase XII (CAXII) was reviewed by two experienced pathologists. Primary objectives were to evaluate the biodistribution of the radiotracer within tumor and non-tumor tissues as well to assess the safety of the radiotracer in patients. Results: 12 patients were enrolled and 11 received radiotracer and images were obtained. All patients tolerated the radiotracer well with no significant adverse events. 10 of the 11 patients had histologically confirmed malignancy. 1 patient had a complex cyst with no tumor found at surgery. Two patients had extrarenal disease and 9 had tumors in the kidney only. 100% had ccRCC and 4/11 had germline VHL mutations. Mean SUV for the entire group as 5.44 in the index lesions; in patients with histologically confirmed ccRCC the mean SUV was 5.91. 12 samples were stained for CAIX and CAXII including a biopsy obtained from a lung metastasis in one patient. The concordance between pathologists for CAIX IHC was 75%, for CAXII was 67%. Of the CAIX IHC slides, 67% had 3+ staining, 25% had 2+ and one specimen did not demonstrate CAIX staining. Only one specimen demonstrated 3+ staining for CAXII; 2 specimens had no detectable staining for CAXII and the remainder stained 1-2+ for CAXII. Conclusions: The 18F-VM4-037 was well tolerated and demonstrated modest signal uptake in tumors within the kidney. Immunohistochemistry staining for CAIX and CAXII was robust in nearly all tumors making correlation with radiotracer signal difficult. Larger studies are needed to evaluate the diagnostic performance of this radiotracer. Clinical trial information: NCT01712685.
    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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  • 5
    In: Journal of Nuclear Medicine, Society of Nuclear Medicine, Vol. 61, No. 6 ( 2020-06), p. 881-889
    Type of Medium: Online Resource
    ISSN: 0161-5505 , 2159-662X
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    Language: English
    Publisher: Society of Nuclear Medicine
    Publication Date: 2020
    detail.hit.zdb_id: 2040222-3
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  • 6
    Online Resource
    Online Resource
    American Society of Clinical Oncology (ASCO) ; 2015
    In:  Journal of Clinical Oncology Vol. 33, No. 7_suppl ( 2015-03-01), p. 115-115
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 33, No. 7_suppl ( 2015-03-01), p. 115-115
    Abstract: 115 Background: 18 F-FDG PET/CT is widely used to diagnose malignancy, but is not recommended for localized prostate cancer. This study explores the value of multi-parametric MRI (mpMRI) in characterizing incidentally detected prostate FDG uptake. Methods: Thirty-one patients who underwent FDG PET/CT and prostate MRI were eligible for this study. 14 patients were excluded (n=8 insufficient histopathology, n=6 radical prostatectomy before PET), with final analysis of 17 patients. The mpMRI sequences included T2-weighted, dynamic contrast enhancement (DCE), apparent diffusion coefficient (ADC), and MR spectroscopy (MRS). Nuclear medicine physicians, blinded to clinicopathologic findings, identified suspicious areas and maximum standardized uptake values (SUVmax) on FDG PET/CT. The lesion and sector-based imaging findings were correlated with annotated histopathology from whole-mount or MRI/TRUS fusion biopsy samples. Positive predictive values (PPVs) were estimated using generalized estimating equations with logit link. Results were evaluated with Kruskal-Wallis and Dunn’s multiple comparisons tests. Results: The PPV of FDG PET alone in detecting prostate cancer was 0.56. Combining FDG (base parameter) with mpMRI modalities (T2, DCE, ADC, MRS) increased the sector-based PPV to 0.79, 0.82, 0.80, and 0.89, respectively. All benign lesions had SUVmax 〈 5, and malignant lesions had higher mean SUVmax values that correlated with Gleason scores [Table]. This relationship between SUVmax and Gleason score was significant, with p=0.012 on the Kruskal-Wallis test and p=0.015 on the Dunn’s multiple comparisons test for Gleason 0 vs Gleason ≥ 4+5. Conclusions: Incidental prostate FDG uptake has low clinical utility alone, but these areas may harbor high-grade prostate cancer, especially if the SUVmax is greater than 5. [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: 2015
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  • 7
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 3274-3274
    Abstract: Introduction: Multiple myeloma (MM) is a patchy bone marrow based malignancy of plasma cells, resulting in painful bone lytic lesions that can be visualized by 18F-FDG-PET-CT. We treated 45 NDMM patients with CRd-R therapy that resulted in high rates of minimal residual disease (MRD) negativity (62%)(Korde et al. JAMA Onc 2015). In this study, we assessed longitudinal FDG response through lenalidomide (Len) maintenance period and aimed to correlate with clinical findings and MRD status. Methods: The details of treatment received, study design and patients' characteristics have already been published. As part of the study design, all patients had serial PET imaging at baseline, after achievement of CR and/or at completion of 8 cycles of CRd, and at year-1 and -2 of Len maintenance, or termination of protocol therapy. Whole body (vertex to toes) static FDG imaging was performed at 1-hour post injection, implemented according to institutional practice. Focal lesions on FGD were defined as: increased uptake (above background reference) within the bone, (excluding articular regions due to high prevalence and likelihood of confounding arthritic disease), maximum standardized uptake value (SUV) 〉 1.5 for lesion size on CT ranging from 0.5-1.0 cm, or maximum SUV 〉 2.5 for lesions 〉 1.0 cm. Results: At baseline, 37/45(82.2%) patients had FDG-positive lesions and 8/45(17.8%) were negative. Median follow-up for longitudinal analysis is 30.1 months. Among initial FDG-negative patients, 7/8 (87.5%) patients remained negative throughout follow-up; 1/8 (12.5%) patients developed a sclerotic FDG-positive lesion deemed not to be progression (rib 5 SUV 1.7). Among the 37 patients with baseline FDG-positive lesions, 12/37(32.4%) patients had complete resolution of FDG-PET-CTs (FDG-responders); 25/37(67.5%) remained FDG-long-term positive at time of last protocol scan. Eight of the 25(32%) FDG-long-term positive patients met IMWG criteria for progression, compared to 0/12 FDG-responders (p value=0.04). For patients with available data, MRD negative status after initial CRd (prior to Len maintenance) was not associated with long-term PET-CT response [19/24(79.2%) vs. 8/11(72.7%), FDG-long-term positive vs. FDG-responders, p=NS]. For the remaining FDG-long-term positive patients not meeting progression criteria, all 17 patients had low-positive persistent FDG with decreased or partial SUV response that decreased over time while on Len maintenance. Conclusions: In patients receiving CRd followed by long-term Len maintenance, 68% of baseline FDG-positive patients have persistent longitudinal FDG-positive myeloma lesions. While there is an increased risk of clinical progression among these patients, the majority showed low-positive FDG lesion uptake that decreased over time with long-term Len maintenance. Long-term resolution of FDG-positive lesions is not associated with MRD status after initial CRd therapy. Further follow-up is needed to examine the significance of persistent FDG-positive lesions in relationship to residual disease and mechanisms of resistance. Figure Figure. Disclosures Korde: Medscape: Honoraria. Hassoun:Takeda: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy; Binding Site: Research Funding. Landgren:Medscape Myeloma Program: Honoraria; BMS: Honoraria; Merck: Honoraria; Takeda: Honoraria; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
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    detail.hit.zdb_id: 80069-7
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  • 8
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 33, No. 15_suppl ( 2015-05-20), p. 2552-2552
    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: 2015
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  • 9
    In: European Journal of Nuclear Medicine and Molecular Imaging, Springer Science and Business Media LLC, Vol. 47, No. 1 ( 2020-01), p. 178-184
    Abstract: We evaluated the prognostic value of 18 F-sodium fluoride (NaF) PET/CT in patients with urological malignancies treated with cabozantinib and nivolumab with or without ipilimumab. Methods We prospectively recruited patients with advanced urological malignancies into a phase I trial of cabozantinib plus nivolumab with or without ipilimumab. NaF PET/CT scans were performed pre- and 8 weeks post-treatment. We measured the total volume of fluoride avid bone (FTV) using a standardized uptake value (SUV) threshold of 10. We used Kaplan-Meier analysis to predict the overall survival (OS) of patients in terms of SUVmax, FTV, total lesion fluoride (TLF) uptake at baseline and 8 weeks post-treatment, and percent change in FTV and TLF. Result Of 111 patients who underwent NaF PET/CT, 30 had bone metastases at baseline. Four of the 30 patients survived for the duration of the study period. OS ranged from 0.23 to 34 months (m) (median 6.0 m). The baseline FTV of all 30 patients ranged from 9.6 to 1570 ml (median 439 ml). The FTV 8 weeks post-treatment was 56–6296 ml (median 448 ml) from 19 available patients. Patients with higher TLF at baseline had shorter OS than patients with lower TLF (3.4 vs 14 m; p  = 0.022). Patients with higher SUVmax at follow-up had shorter OS than patients with lower SUVmax (5.6 vs 24 m; p  = 0.010). However, FTV and TLF 8 weeks post-treatment did not show a significant difference between groups (5.6 vs 17 m; p  = 0.49), and the percent changes in FTV (12 vs 14 m; p  = 0.49) and TLF (5.6 vs 17 m; p  = 0.54) also were not significant. Conclusion Higher TLF at baseline and higher SUVmax at follow-up NaF PET/CT corresponded with shorter survival in patients with bone metastases from urological malignancies who underwent treatment. NaF PET/CT may be a useful predictor of OS in this population.
    Type of Medium: Online Resource
    ISSN: 1619-7070 , 1619-7089
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2098375-X
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  • 10
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 11519-11519
    Abstract: 11519 Background: Recurrent ES carries a poor prognosis, and systemic therapies have limited efficacy. Preclinical models suggested that trabectedin (T) could achieve serum concentrations high enough to suppress the dominant oncogene of ES (i.e. EWS::FLI1 transcription factor), and that this effect is sustained by subsequent administration of low dose irinotecan (I). We conducted a phase I study of T+I in patients (pts) with ES. Methods: This multicenter dose escalation study employed a standard 3+3 design. T was given as a 1-h infusion on day (D)1 with low dose I intravenously on D2 and 4 of a 21D cycle. Dose limiting toxicities (DLTs) were evaluated in cycle one. Eligibility required confirmed EWS::FLI1 fusion transcript, age ≥10 years, ECOG performance status ≤2, adequate organ function and willing to have a research biopsy if safely accessible. Primary objectives were to determine the recommended dose (RD) and safety of T+I. Secondary objectives comprised efficacy of T+I and avidity of ES for 3'-Deoxy-3'- 18 F Fluorothymidine ( 18 F-FLT) PET. Results: 20 pts enrolled from 1/2021-12/2022 across 5 sites, 5F/15M, median age 18 years (range 10-59). Pts had received a median of 4 (range 2-9) prior therapy lines including irinotecan in 60% of pts. Grade (G) 3/4 treatment-emergent adverse events (TEAEs) occurring in ≥10% of pts were: elevated ALT/AST, elevated creatinine phosphokinase, febrile neutropenia, anemia, lymphopenia, neutropenia, and thrombocytopenia. There were 2 G5 respiratory TEAEs. 18 F-FLT PET scans were obtained in 5 pts. ES tumors were 18 F-FLT PET avid. Dose level (DL)2 was the RD. At DL 2 and above, there were 4 PRs, 6 SD in 14 evaluable pts (Table). Conclusions: T+I can be safely administered to heavily pretreated pts with ES, demonstrating activity at the RD with 3 PRs (n=5 evaluable). The 18 F-FLT PET may be useful to understand patterns of disease progression in ES. Correlative studies will be critical to understanding the mechanism of drug activity. Given the clinical benefit seen with T+I at RD, a phase II portion in pts with ES ≥6 years old is actively accruing. Clinical trial information: NCT04067115 . [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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