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  • American Society of Clinical Oncology (ASCO)  (15)
  • George, Thomas J.  (15)
  • 1
    Online Resource
    Online Resource
    Phase II trial of the PARP inhibitor, niraparib, in BRCA1-Associated Protein 1 (BAP1) and other DNA damage response (DDR) pathway deficient neoplasms including cholangiocarcinoma.
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 3_suppl ( 2021-01-20), p. TPS354-TPS354
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 3_suppl ( 2021-01-20), p. TPS354-TPS354
    Abstract: TPS354 Background: BRCA1-Associated Protein 1 (BAP1) is a critical regulator of the cell cycle, cellular differentiation, cell death, and DNA damage response. It also acts as a tumor suppressor. Preclinical models demonstrate significant synthetic lethality in BAP1 mutant cell lines and patient xenografts when treated with PARP inhibitors, independent of underlying BRCA status, suggesting this mutation confers a BRCA-like phenotype. BAP1 is mutated, leading to a loss of functional protein, in up to 30% of cholangiocarcinomas as well as several other solid tumors. Methods: This phase 2, open-label, single arm multicenter study aims to exploit the concept of synthetic lethality with the use of the PARP inhibitor niraparib in pts with metastatic relapsed or refractory solid tumors. Eligible pts with measurable metastatic and incurable solid tumors are assigned to one of two cohorts: Cohort A (histology-specific): tumors harboring suspected BAP1 mutations including cholangiocarcinoma, uveal melanoma, mesothelioma or clear cell renal cell carcinoma with tissue available for BAP1 mutational assessment via NGS or Cohort B (histology-agnostic): tumors with known DNA damage response (DDR) mutations (Table) confirmed by CLIA-approved NGS. Other key eligibility criteria include age ≥18 years, adequate cardiac, renal, hepatic function and Eastern Cooperative Oncology Group performance status of 0 to 1. Pts with known BRCA1 or BRCA2 mutations or prior PARPi exposure are excluded. Pts receive niraparib 200-300mg daily (depending on weight and/or platelet count) continuously. Primary endpoint is objective response rate with secondary endpoints of PFS, OS, toxicity and exploratory biomarker determinations. Radiographic response by RECIST criteria is measured every 8 weeks while on treatment. Cohort A has fully enrolled. Cohort B enrollment continues to a maximum of 47 total evaluable subjects with expansion cohorts allowable for histologic or molecular subtypes meeting pre-specified responses. NCT03207347 Clinical trial information: NCT03207347. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.3_suppl.TPS354
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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  • 2
    Online Resource
    Online Resource
    Results of a phase II trial of the PARP inhibitor, niraparib, in BAP1 and other DNA damage response pathway deficient neoplasms.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. 3122-3122
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 3122-3122
    Abstract: 3122 Background: BRCA1-Associated Protein 1 (BAP1) acts as a tumor suppressor and critical regulator of the cell cycle and DNA damage response (DDR). PARP inhibitors (PARPi) demonstrate synthetic lethality in BAP1 mutant (mBAP1) preclinical models, independent of underlying germline BRCA status. mBAP1 leads to a loss of functional protein in several solid tumors. This study aimed to explore the clinical activity of niraparib in patients (pts) with advanced tumors likely to harbor mBAP1. Methods: Eligible adult pts with measurable metastatic solid tumors having exhausted approved therapies, adequate organ function, and ECOG PS 0-1 were assigned to Cohort A (histology-specific): tumors likely to harbor mBAP1 (i.e., cholangiocarcinoma, uveal melanoma, mesothelioma, or clear cell renal cell carcinoma) with tissue available for mBAP1 confirmation; or Cohort B (histology-agnostic): tumors with other known non-BRCA confirmed DDR mutations. Known BRCA1 or 2 mutations or prior PARPi exposure were excluded. All pts received niraparib 200-300mg daily, depending on weight and/or platelet count. Radiographic response was assessed by RECIST v1.1 measured every 8 weeks while on treatment. The primary endpoint was ORR with secondary endpoints of PFS, OS, clinical benefit (CR+PR+SD), toxicity, and exploratory biomarker determinations. Cohort A employed Simon's optimal two-stage design to assess a 30% ORR increase (a = 0.05; power = 90%). Cohort B aimed to assess a 40% ORR increase for this molecularly selected/enriched patient population. Results: From 08/13/2018 to 12/21/2021, 37 pts enrolled from two different centers, with 32 evaluable for response (Cohort A n = 18; Cohort B n = 14). In Cohort A, best ORR was 1 PR (6%), 8 SD (44%; median 5.7 mo; range 2 - 9.4 mo), and 9 PD (50%). Cohort A was stopped at the first stage following the pre-specified Simon’s design. mBAP1 was confirmed in 7/9 pts (78%) with PR or SD but in only 2/9 (22%) in those with PD. In Cohort B, best ORR was 6 SD (43%; median 7.5 mo; range 3.3 - 8.6 mo) and 8 PD (57%). Mutations in those with SD included ATM, CHEK2, PTEN, RAD50, and ARID1A. Common grade 3/4 AEs observed were anemia (16%), thrombocytopenia (16%), nausea (11%), and vomiting (8%). There were no unexpected nor grade 5 toxicities. Conclusions: The use of niraparib was well tolerated in pts with advanced treatment refractory solid tumors but failed to meet pre-specified efficacy threshold of ORR. However, clinical benefit was identified in 78% of patients in cohort A who had a confirmed mBAP1 tumor. Further correlative analyses are ongoing and additional clinical development restricted to mBAP1 tumors may be justified. Clinical trial information: NCT03207347.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.3122
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 3
    Online Resource
    Online Resource
    Phase II trial of the PARP inhibitor, niraparib, in BAP1 and other DNA damage response (DDR) pathway deficient neoplasms (NCT03207347).
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 15_suppl ( 2020-05-20), p. e22061-e22061
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. e22061-e22061
    Abstract: e22061 Background: BRCA-associated protein-1 (BAP1) is a ubiquitin ligase associated with regulating cell cycle, cell proliferation, DNA damage pathway, and cell death. It also acts as a tumor suppressor gene as seen in hereditary cancer syndrome associated with germline mutations in BAP1. Preclinical studies have shown that PARP-inhibitor treatment of BAP1 mutant cell lines demonstrated significant synthetic lethality, independent of underlying BRCA status suggesting this mutation confers a BRCA-like phenotype. BAP1 is mutated, leading to a loss of functional protein, in up to 30% of several solid tumors including cholangiocarcinoma, mesothelioma, uveal melanoma, and clear cell renal cell carcinoma. Methods: This phase 2, open-label, single arm study aims to exploit the concept of synthetic lethality with the use of the PARP inhibitor niraparib in two biologically distinct cohorts. Eligible patients (pts) with measurable metastatic and incurable solid tumors are assigned to one of the two cohorts: Cohort A (histology-specific): tumors harboring suspected BAP1 mutations including cholangiocarcinoma, uveal melanoma, mesothelioma or clear cell renal cell carcinoma with tissue available for BAP1 mutational assessment via Next Generation Sequencing (NGS); or Cohort B (histology-agnostic): tumors with known DNA damage response (DDR) mutations (Table) confirmed by CLIA-approved NGS. Key inclusion criteria also include age ≥18 years, adequate cardiac, renal, hepatic function and ECOG PS of 0 to 1. Key exclusion criteria include known BRCA1 or BRCA2 mutations or prior PARPi exposure. Pts receive niraparib 200-300mg daily (depending on weight and/or platelet count) continuously. Primary endpoint is objective response rate (ORR), and secondary endpoints are progression free survival (PFS), overall survival (OS), toxicity and exploratory biomarker determinations. Radiographic response by RECIST criteria is measured every 8 weeks while on treatment. Cohort B enrollment is closed. Enrollment in Cohort A continues. A maximum of 47 evaluable subjects is planned with expansion cohorts allowable for histologic or molecular subtypes meeting pre-specified responses. Clinical trial information: NCT03207347. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.15_suppl.e22061
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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  • 4
    Online Resource
    Online Resource
    A phase II, open-label pilot study evaluating the safety and activity of liposomal irinotecan (Nal-IRI) in combination with 5-FU and oxaliplatin (NALIRIFOX) in preoperative treatment of pancreatic adenocarcinoma (NEO-Nal-IRI Study).
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 3_suppl ( 2021-01-20), p. TPS446-TPS446
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 3_suppl ( 2021-01-20), p. TPS446-TPS446
    Abstract: TPS446 Background: Neoadjuvant treatment for potentially curable pancreatic cancer (PDAC) is increasing in acceptability, but a standard regimen has yet to be established. Multiple studies have demonstrated feasibility and effectiveness of the FOLFIRINOX (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) regimen in the perioperative setting. However, FOLFIRINOX often requires dose modifications, delays and growth factor support due to excessive toxicity which can complicate care delivery when given neoadjuvantly. Liposomal irinotecan injection (Nal-IRI) is FDA approved with a well-tolerated safety profile in relapsed, refractory metastatic PDAC. The current study aims to substitute Nal-IRI for traditional irinotecan in the standard FOLFIRINOX regimen (NALIRIFOX) and to demonstrate safe and effective neoadjuvant delivery. Methods: This phase II, open-label, multicenter single-arm study focuses on patients (pts) with operable PDAC without metastatic disease. Other key eligibility criteria include age ≥18 years, resectability confirmed by multiD GI tumor board (resectable vs. borderline), adequate cardiac, renal, hepatic function and ECOG performance status of 0 to 1. Pts receive NALIRIFOX regimen as per the table below every 2 weeks for four months followed by disease reassessment. Pts who remain surgical candidates will undergo surgical resection within 4 to 8 weeks following last dose of therapy. The primary endpoint is to assess safety and feasibility of regimen in perioperative setting. Secondary endpoints include R0 resection rate, clinical, biochemical and radiological response rate and patient-reported quality of life during treatment as measured by the NCI validated FACT-G scale. Enrollment continues to a maximum of 28 evaluable pts to demonstrate a reduction in historical 30 day postoperative complication rate. Clinical trial information: NCT03483038. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.3_suppl.TPS446
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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  • 5
    Online Resource
    Online Resource
    A phase Ib/II study (IMMCO-1) of atezolizumab plus tivozanib in immunologically cold pancreatic, gallbladder, and biliary cancers.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 4_suppl ( 2022-02-01), p. TPS491-TPS491
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 4_suppl ( 2022-02-01), p. TPS491-TPS491
    Abstract: TPS491 Background: Checkpoint inhibition (CPI) represents a significant advance in cancer care however it is not effective in the treatment of several immunologically cold tumors including pancreatic, gallbladder, and biliary cancers where checkpoint inhibitors have produced objective response rates of 〈 5%. VEGF is thought to play a key role in modulating the anti-tumor immune response. Secreted by tumors, it leads to endothelial cell proliferation, vascular permeability, and vasodilation that together leads to the development of an abnormal vasculature with excessive permeability and poor blood flow, thus limiting immune surveillance. In addition, VEGF inhibits dendritic cell differentiation, limiting the presentation of tumor antigens to CD4 and CD8 T cells. Through the inhibition of VEGF, it may be possible to potentiate the effect of immune checkpoint blockade. Combined use of a VEGF tyrosine kinase inhibitor (TKI) and checkpoint inhibitor is already standard of care in advanced kidney, cervical and endometrial cancers. There has been suggestion that such a combination may have clinical activity in some microsatellite stable (MSS) GI malignancies. This signal seeking study aims to build upon those observations by incorporating a pan-VEGF axis inhibitor (tivozanib) with CPI. Methods: This is an open-label non-randomized phase Ib/II signal seeking basket study in multiple immunologically cold tumors. The co-primary endpoints are safety and efficacy of the combination of the VEGF-TKI tivozanib and CPI atezolizumab. Key eligibility criteria includes patients with MSS pancreatic, biliary (cholangiocarcinoma and gallbladder), well-differentiated grade 2 and 3 neuroendocrine tumors, ovarian and vulvar cancer, soft tissue sarcoma, castrate resistant prostate cancer, and HER2 positive hormone receptor negative breast cancer, that is metastatic and progressed on at least one line of therapy. Key exclusion criteria will include patients with known mismatch repair deficiency, microsatellite instability, or high tumor mutational burden. The phase Ib portion will assess the safety profile of the combination of tivozanib and atezolizumab with a potential dose de-escalation of tivozanib using a 3+3 study design. Starting doses include tivozanib 1.34 mg per day for 21 days of each 28-day cycle and atezolizumab 1680 mg on day 1 of every 28-day cycle. The phase II portion will enroll up to 26 additional patients using the dose of tivozanib found to be safe in the Ib portion. Disease response assessments are every 12 weeks with CT Chest, Abdomen, and Pelvis via RECIST 1.1. Treatment will continue until progression or intolerance. This signal seeking study is looking to confirm the best objective response rate for evaluable patients increasing from 〈 7% (null hypothesis) to 25% (one-sided alpha = 0.05; 80% power). Active enrollment continues. Clinical trial information: NCT05000294.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.4_suppl.TPS491
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 6
    Online Resource
    Online Resource
    A phase II, open-label, pilot study evaluating the safety and activity of liposomal irinotecan (Nal-IRI) in combination with 5-FU and oxaliplatin (NALIRIFOX) in preoperative treatment of pancreatic adenocarcinoma: NEO-Nal-IRI study.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. TPS4196-TPS4196
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. TPS4196-TPS4196
    Abstract: TPS4196 Background: Neoadjuvant treatment for potentially curable pancreatic cancer (PDAC) is increasing in acceptability, but a standard regimen has yet to be established. Multiple studies have demonstrated feasibility and effectiveness of the FOLFIRINOX (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) regimen in the perioperative setting. However, FOLFIRINOX often requires dose modifications, delays and growth factor support due to excessive toxicity which can complicate care delivery when given pre-op. Liposomal irinotecan injection (Nal-IRI) is FDA approved in combination with 5-FU/LV with a well-tolerated safety profile in relapsed, refractory metastatic PDAC. The current study aims to substitute Nal-IRI for traditional irinotecan in the standard FOLFIRINOX regimen (NALIRIFOX) and to demonstrate safe and effective neoadjuvant delivery. Methods: This phase 2, open-label, multicenter single-arm study focuses on patients (pts) with operable PDAC without metastatic disease. Other key eligibility criteria include age ≥18 years, resectability confirmed by multiD GI tumor board (resectable vs. borderline), adequate cardiac, renal, hepatic function and ECOG performance status of 0 to 1. Pts receive NALIRIFOX regimen as per the table every 2 weeks for four months followed by disease reassessment. Pts who remain surgical candidates will undergo surgical resection within 4 to 8 weeks following last dose of therapy. The primary endpoint is to assess safety and feasibility of regimen in pre-op setting. Secondary endpoints include R0 resection rate, clinical, biochemical and radiological response rate and patient-reported quality of life during treatment as measured by the NCI validated FACT-G scale. Enrollment continues to a maximum of 28 evaluable pts to demonstrate a reduction in historical 30-day post-op complication rate. Clinical trial information: NCT03483038. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.TPS4196
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 7
    Online Resource
    Online Resource
    A phase II, open-label pilot study evaluating the safety and activity of Nal-IRI in combination with 5-FU and oxaliplatin in preoperative treatment of pancreatic adenocarcinoma (NEO-Nal-IRI Study) (NCT03483038).
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 4_suppl ( 2020-02-01), p. TPS790-TPS790
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 4_suppl ( 2020-02-01), p. TPS790-TPS790
    Abstract: TPS790 Background: Neoadjuvant treatment for borderline resectable pancreatic cancer (PCa) is increasing in acceptability, but a standard regimen has yet to be established. Multiple studies have demonstrated feasibility and effectiveness of the FOLFIRINOX (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) regimen in the perioperative setting. However, FOLFIRINOX often requires dose modifications, delays and growth factor support due to excessive toxicity which can complicate care delivery when given neoadjuvantly. Irinotecan liposomal injection (Nal-IRI) is FDA approved with a well-tolerated safety profile in relapsed, refractory metastatic PCa. The current study aims to substitute Nal-IRI for traditional irinotecan in the standard FOLFIRINOX regimen and to demonstrate safe and effective neoadjuvant delivery. Methods: This phase 2, open-label, multicenter single-arm study focuses on patients (pts) with borderline resectable PCa without metastatic disease. Other key eligibility criteria include age ≥18 years, resectability confirmed by multiD GI tumor board, adequate cardiac, renal, hepatic function and ECOG performance status of 0 to 1. Pts receive FOLFNal-IRINOX regimen as per Table every 2 weeks for four months followed by disease reassessment. Pts who remain surgical candidates will undergo surgical resection within 4 to 8 weeks following last dose of therapy. The primary endpoint is to assess safety and feasibility of regimen in perioperative setting. Secondary endpoints include R0 resection rate, clinical, biochemical and radiological response rate and patient-reported quality of life during treatment as measured by the NCI validated FACT-G scale. Enrollment continues to a maximum of 28 evaluable pts to demonstrate a reduction in historical 30 day postoperative complication rate. Clinical trial information: NCT03483038 . [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.4_suppl.TPS790
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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    Online Resource
  • 8
    Online Resource
    Online Resource
    A phase II, open-label pilot study evaluating the safety and activity of liposomal irinotecan (Nal-IRI) in combination with 5-FU and oxaliplatin (NALIRIFOX) in preoperative treatment of pancreatic adenocarcinoma: NEO-Nal-IRI study.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 4_suppl ( 2022-02-01), p. TPS619-TPS619
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 4_suppl ( 2022-02-01), p. TPS619-TPS619
    Abstract: TPS619 Background: Neoadjuvant treatment for potentially curable pancreatic cancer (PDAC) is increasing in acceptability, but a standard regimen has yet to be established. Multiple studies have demonstrated feasibility and effectiveness of the FOLFIRINOX (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) regimen in the perioperative setting. However, FOLFIRINOX often requires dose modifications, delays and growth factor support due to excessive toxicity which can complicate care delivery when given pre-op. Liposomal irinotecan injection (Nal-IRI) in combination with 5FU/LV is FDA approved with a well-tolerated safety profile in relapsed, refractory metastatic PDAC. The current study aims to substitute Nal-IRI for traditional irinotecan in the standard FOLFIRINOX regimen (NALIRIFOX) and to demonstrate safe and effective neoadjuvant delivery. Methods: This phase 2, open-label, multicenter single-arm study focuses on patients (pts) with operable PDAC without metastatic disease. Other key eligibility criteria include age ≥18 years, resectability confirmed by multiD GI tumor board (resectable vs. borderline), adequate cardiac, renal, hepatic function and ECOG performance status of 0 to 1. Pts receive NALIRIFOX regimen as per the table every 2 weeks for four months followed by disease reassessment. Pts who remain surgical candidates will undergo surgical resection within 4 to 8 weeks following last dose of therapy. The primary endpoint is to assess safety and feasibility of regimen in pre-op setting. Secondary endpoints include R0 resection rate, clinical, biochemical and radiological response rate and patient-reported quality of life during treatment as measured by the NCI validated FACT-G scale. Exploratory ctDNA and stool microbiome analyses are also planned. Enrollment continues to a maximum of 28 evaluable pts to demonstrate a reduction in historical 30-day post-op complication rate. Clinical trial information: NCT03483038. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.4_suppl.TPS619
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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    Online Resource
  • 9
    Online Resource
    Online Resource
    A phase Ib/II study (IMMCO-1) of atezolizumab plus tivozanib in castrate-resistant prostate cancer and certain other immunologically cold tumors.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 6_suppl ( 2022-02-20), p. TPS208-TPS208
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 6_suppl ( 2022-02-20), p. TPS208-TPS208
    Abstract: TPS208 Background: Castrate resistant prostate cancer (CRPC) is an immunologically cold tumor, with a 5% response rate reported to the PD-L1 inhibitor pembrolizumab. VEGF secreted by tumors may play a key role in hindering the anti-tumor immune response, leading to the development of an abnormal vasculature that may limit immune surveillance. VEGF also inhibits dendritic cell differentiation, limiting the presentation of tumor antigens. The inhibition of VEGF may therefore potentiate the effect of PD-1/L1 directed therapy by enabling immune surveillance and antigen presentation. VEGF-TKI and checkpoint inhibitor combinations are currently approved in the treatment of advanced kidney, cervical, and endometrial cancers. This signal-seeking study aims to determine whether the combination of the VEGF-TKI tivozanib and the PD-L1 inhibitor atezolizumab may be effective in CRPC and certain other immunologically cold tumors. Methods: The trial is a single center phase Ib/II basket study in multiple immunologically cold tumors. Co-primary endpoints are safety and the overall response rate as measured via RECIST v1.1. The tivozanib dose will be determined via a 3+3 dose de-escalation phase Ib portion. Patients treated in the phase Ib portion will be included as study subjects for phase the II portion. The study is designed to test for a 25%+ response rate as compared to a null hypothesis of 〈 7% (one-sided alpha = 0.05; 80% power). A Simon’s two-stage design will be utilized and if ≥2 responses among the first 16 evaluable patients, a further 10 evaluable patients will be accrued for a total of 26. Up to 33 subjects will be enrolled to account for a 20% dropout rate. The null hypothesis will be rejected if at least 5 responses are observed. The University of Florida's Data Integrity and Safety Committee will review significant adverse events. Tivozanib will be given at a dose of 1.34 mg/day for 21 days of each 28-day cycle (potential dose reduction is to 0.89 mg/day). Atezolizumab is given at a dose of 1,680 mg every 28 days. Treatment is until disease progression or intolerance. Key inclusion criteria include a diagnosis of certain advanced and unresectable or metastatic immunologically cold tumors (CRPC previously treated with an androgen inhibitor or cytotoxic chemotherapy in the advanced or metastatic setting, bile duct or gallbladder cancer, certain HR-negative HER2-positive breast cancers, ovarian cancer, pancreatic adenocarcinoma, soft tissue sarcoma, or vulvar cancer), at least one prior systemic therapy in this setting, ECOG 0-1 (phase Ib) or ECOG 0-2 (phase II), age ≥ 18, adequate hematologic and end-organ function, life expectancy of at least 12 weeks, and measurable disease by RECIST v1.1. Key exclusion criteria include known mismatch repair deficiency, microsatellite instability, or high tumor mutational burden. Active enrollment continues. Clinical trial information: NCT05000294.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.6_suppl.TPS208
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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  • 10
    Online Resource
    Online Resource
    A phase Ib/II study of atezolizumab plus tivozanib in pancreatic, gallbladder, and bile duct malignancies.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 4_suppl ( 2023-02-01), p. TPS625-TPS625
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 4_suppl ( 2023-02-01), p. TPS625-TPS625
    Abstract: TPS625 Background: Immune checkpoint inhibitor (ICI) therapy represents a significant advance in cancer care however it is not an effective intervention in the treatment of several immunologically cold tumors including pancreatic, gallbladder, and bile duct malignancies where ICIs have produced objective response rates of 0-6%. VEGF is thought to play a key role in modulating the anti-tumor immune response as it is secreted by tumors and leads to endothelial cell proliferation, vascular permeability, and vasodilation. This in turn leads to the development of an abnormal vasculature with excessive permeability and poor blood flow, thus limiting immune surveillance. In addition, VEGF inhibits dendritic cell differentiation, limiting the presentation of tumor antigens to CD4 and CD8 T cells. Through the inhibition of VEGF, it may be possible to potentiate the effect of ICIs. Combined use of a VEGF receptor tyrosine kinase inhibitor (TKI) and ICI is already approved for advanced kidney and endometrial cancer. Methods: This is a single institution, single arm, open-label phase Ib/II study with the co-primary endpoints of safety and efficacy of the combination of the VEGFR-TKI tivozanib and the ICI atezolizumab. Eligible patients are those with metastatic cancer progressing on at least one line of therapy of the following organs: pancreatic, gallbladder, bile duct, well-differentiated grade 2 and 3 neuroendocrine tumors, ovarian, vulvar, soft tissue sarcoma, castrate resistant prostate, and HER2 positive hormone receptor negative breast. Key exclusion criteria will include patients with known mismatch repair deficiency, microsatellite instability, or high tumor mutational burden. The phase Ib portion will assess the safety profile of the combination of tivozanib and atezolizumab with a potential dose de-escalation of tivozanib using a 3+3 study design. Three patients will be treated with tivozanib 1.34 mg per day (dose level 0) for 21 days of each 28-day cycle and atezolizumab 1680 mg on day 1 of every 28-day cycle. If one dose limiting toxicity (DLT) is found then 3 more patients will be enrolled at dose level 0. If 〉 1 DLT occurs in the first 3 patients or 〉 1 DLT in the first 6, another 3+3 study will begin at dose level -1 (0.89 mg of tivozanib). If 1 DLT occurs in these 3 patients at dose level -1 then another 3 will be enrolled at this dose. The study will be stopped for toxicity if there is 〉 1 DLT in the first 3 patients at dose level -1 or if there are 〉 1 DLT in the 6 patients at dose level -1. A subsequent protocol amendment was made to reduce tivozanib dose level 0 to 0.89 mg per day and dose level -1 to 0.89 mg every other day. The phase II portion will enroll up to 26 patients using the dose of tivozanib found to be safe in the Ib portion. Disease response assessment every 12 weeks with CT Chest, Abdomen, and Pelvis via RECIST 1.1. Treatment will continue until progression or intolerance. Enrollment is ongoing. Clinical trial information: NCT05000294 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.4_suppl.TPS625
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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