scholarly journals Phase I Study of Cabozantinib and Nivolumab Alone or With Ipilimumab for Advanced or Metastatic Urothelial Carcinoma and Other Genitourinary Tumors

2020 ◽  
Vol 38 (31) ◽  
pp. 3672-3684 ◽  
Author(s):  
Andrea B. Apolo ◽  
Rosa Nadal ◽  
Daniel M. Girardi ◽  
Scot A. Niglio ◽  
Lisa Ley ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Phase Ii ◽  
Objective Response ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Duration Of Response ◽  
Metastatic Urothelial Carcinoma ◽  
Grade 3 ◽  
Recommended Phase Ii Dose ◽  
Phase Ii And Iii

PURPOSE 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.

A phase II study of cabozantinib (XL184) in patients with advanced/metastatic urothelial carcinoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS4589-TPS4589 ◽  
Author(s):  
Andrea Borghese Apolo ◽  
Howard L. Parnes ◽  
Ravi Amrit Madan ◽  
James L. Gulley ◽  
John Joseph Wright ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Objective Response ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
Metastatic Urothelial Carcinoma ◽  
Serum And Urine

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.

scholarly journals Phase II California Cancer Consortium Trial of Gemcitabine-Eribulin Combination in Cisplatin-Ineligible Patients With Metastatic Urothelial Carcinoma: Final Report (NCI-9653)

2019 ◽  
Vol 37 (29) ◽  
pp. 2682-2688 ◽  
Author(s):  
Sarmad Sadeghi ◽  
Susan G. Groshen ◽  
Denice D. Tsao-Wei ◽  
Rahul Parikh ◽  
Amir Mortazavi ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Phase Ii ◽  
Performance Status ◽  
Objective Response ◽  
Evaluation Criteria ◽  
Progression Free Survival ◽  
Median Number ◽  
Final Report ◽  
Curative Surgery ◽  
Metastatic Urothelial Carcinoma

PURPOSE Patients with metastatic urothelial carcinoma are often ineligible for cisplatin-based treatments. A National Cancer Institute Cancer Therapy Evaluation Program–sponsored trial assessed the tolerability and efficacy of a gemcitabine-eribulin combination in this population. METHODS Patients with treatment-naïve advanced or recurrent metastatic urothelial carcinoma of the bladder, ureter, or urethra not amenable to curative surgery and not candidates for cisplatin-based therapy were eligible. Cisplatin ineligibility was defined as creatinine clearance less than 60 mL/min (but ≥ 30 mL/min), grade 2 neuropathy, or grade 2 hearing loss. Treatment was gemcitabine 1,000 mg/m2 intravenously followed by eribulin 1.4 mg/m2, both on days 1 and 8, repeated in 21-day cycles until progression or unacceptable toxicity. A Simon two-stage phase II trial design was used to distinguish between Response Evaluation Criteria in Solid Tumors, version 1.1 objective response rates of 20% versus 50%. RESULTS Between June 2015 and March 2017, 24 eligible patients with a median age of 73 years (range, 62 to 88 years) underwent therapy. Performance status of 0, 1, or 2 was seen in 11, 11, and two patients, respectively. Sites of disease included: lymph nodes, 16; lungs, nine; liver, seven; bladder, five; bones, two. Median number of cycles received was four (range, one to 16). Of 24 patients, 12 were confirmed responders; the observed objective response rate was 50% (95% CI, 29% to 71%). Median overall survival was 11.9 months (95% CI, 5.6 to 20.4 months), and median progression-free survival was 5.3 months (95% CI, 4.5 to 6.7 months). The most common treatment-related any-grade toxicities were fatigue (83% of patients), neutropenia (79%), anemia (63%), alopecia (50%), elevated AST (50%), and constipation, nausea, and thrombocytopenia (42% each). CONCLUSION Gemcitabine-eribulin treatment response and survival for cisplatin-ineligible patients compare favorably to other regimens. Additional research is needed.

Preliminary data from a phase II study of cetuximab with irinotecan in heavily pretreated patients with epidermal growth factor (EGFR)-expressing metastatic colorectal cancer (mCRC): LABEL

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14521-14521 ◽  
Author(s):  
A. Buzaid ◽  
C. de Cerqueira Mathias ◽  
F. Perazzo ◽  
S. Simon ◽  
L. Fein ◽  
...  
Keyword(s):  
Latin American ◽  
Phase Ii ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Treatment Regimens ◽  
Duration Of Response ◽  
Heavily Pretreated ◽  
Grade 3

14521 Background: Cetuximab (Erbitux) is a monoclonal antibody directed against EGFR that is active in combination with irinotecan in patients (pts) with mCRC, who have progressed during or after a prior irinotecan therapy. Methods: This open, single-arm phase II Latin American study investigated this combination in pts with EGFR-expressing mCRC progressing on or within 3 months of chemotherapy containing at least 6 weeks (w) of irinotecan-based therapy. The primary objective was to assess the best overall confirmed response rate (RR). Sample size calculations were based on an expected rate of 20% (±8%). Planned enrollment was 100 pts. Secondary objectives were to explore the duration of response (DOR), progression-free survival (PFS) time, the 12-week PFS rate, and overall survival time. Pts were treated with cetuximab (initial dose 400 mg/m2 then 250 mg/m2 weekly), plus irinotecan at the same dose and schedule (including dose reductions) as pre-study. Preliminary Results: Of 151 pts from 14 centers screened and in the database, 106 (70%, 3 pts missing) were EGFR-expressing and, of these, 79/106 (75%) were treated on-study. Forty (51%) were male; median age was 59 years [27–82]; 70 (89%) pts had a Karnofsky performance status = 90 and 9 (11%) pts = 80. Nineteen (24%) pts had received = 3 prior treatment regimens, 42 (53%) were previously treated with an oxaliplatin-based regimen for metastatic disease. The confirmed overall RR was 26.6% [17.3–37.7]. Median DOR was 23.9 w [17.1–30], median PFS time was 17.7 w [11.7–18.9], and the 12-week PFS rate was 58% [47–69]. Thirty-three (42%) pts were alive at data cut-off. Median survival was 9.7 months [7.9–13.1]. Treatment was well tolerated with the most common grade 3/4 adverse events including: diarrhea, 20%; neutropenia,10%; acne-like rash, 9%. No grade 3/4 infusion-related reactions were reported. Conclusions: The overall confirmed RRs observed in this heavily pretreated population fully met the expectations for the primary endpoint of this study. LABEL confirmed in a Latin American setting the activity and safety of cetuximab plus irinotecan seen in previous studies. No significant financial relationships to disclose.

scholarly journals Camrelizumab Plus Apatinib in Patients With Advanced Cervical Cancer (CLAP): A Multicenter, Open-Label, Single-Arm, Phase II Trial

2020 ◽  
Vol 38 (34) ◽  
pp. 4095-4106
Author(s):  
Chunyan Lan ◽  
Jingxian Shen ◽  
Yin Wang ◽  
Jundong Li ◽  
Zhimin Liu ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Advanced Cervical Cancer ◽  
Open Label ◽  
Duration Of Response ◽  
Grade 3

PURPOSE Camrelizumab is an antibody against programmed death protein 1. We assessed the activity and safety of camrelizumab plus apatinib, a tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2, in patients with advanced cervical cancer. METHODS This multicenter, open-label, single-arm, phase II study enrolled patients with advanced cervical cancer who progressed after at least one line of systemic therapy. Patients received camrelizumab 200 mg every 2 weeks and apatinib 250 mg once per day. The primary end point was objective response rate (ORR) assessed by investigators per RECIST version 1.1. Key secondary end points were progression-free survival (PFS), overall survival (OS), duration of response, and safety. RESULTS Forty-five patients were enrolled and received treatment. Median age was 51.0 years (range, 33-67 years), and 57.8% of patients had previously received two or more lines of chemotherapy for recurrent or metastatic disease. Ten patients (22.2%) had received bevacizumab. Median follow-up was 11.3 months (range, 1.0-15.5 months). ORR was 55.6% (95% CI, 40.0% to 70.4%), with two complete and 23 partial responses. Median PFS was 8.8 months (95% CI, 5.6 months to not estimable). Median duration of response and median OS were not reached. Treatment-related grade 3 or 4 adverse events (AEs) occurred in 71.1% of patients, and the most common AEs were hypertension (24.4%), anemia (20.0%), and fatigue (15.6%). The most common potential immune-related AEs included grade 1-2 hypothyroidism (22.2%) and reactive cutaneous capillary endothelial proliferation (8.9%). CONCLUSION Camrelizumab plus apatinib had promising antitumor activity and manageable toxicities in patients with advanced cervical cancer. Larger randomized controlled trials are warranted to validate our findings.

Avelumab in patients with metastatic urothelial carcinoma: Pooled results from two cohorts of the phase 1b JAVELIN Solid Tumor trial.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 330-330 ◽  
Author(s):  
Manish R. Patel ◽  
John Allan Ellerton ◽  
Jeffrey R. Infante ◽  
Manish Agrawal ◽  
Michael S. Gordon ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Objective Response ◽  
Progression Free Survival ◽  
Pooled Analysis ◽  
Clinical Activity ◽  
Best Response ◽  
Metastatic Urothelial Carcinoma ◽  
Phase 1B ◽  
Grade 3

330 Background: Avelumab is a fully human anti‒PD-L1 IgG1 antibody with promising efficacy and safety in patients (pts) with metastatic urothelial carcinoma (mUC). To further characterize the clinical activity of avelumab in mUC, we report a planned interim pooled analysis of 2 cohorts from a large phase 1b trial (NCT01772004). Methods: Pts with mUC progressed after platinum-based therapy or cisplatin-ineligible, and unselected for tumor PD-L1 expression, received avelumab 10 mg/kg (1 h IV) Q2W. Response was assessed every 6 wks by independent review per RECIST v1.1. Endpoints included objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety (NCI CTCAE v4.0), and tumor PD-L1 expression (clone 73-10). Results: As of Mar 19, 2016, 241 pts received avelumab for a median of 8 wks (range 2-80); median follow-up was 7.3 mos (range 0-18.2). Primary tumor sites were upper tract (renal pelvis/ureter [23.7%]) and lower tract (bladder/urethra [76.3%]). 95.4% of pts had progressed on prior platinum therapy, and 63.4% had received ≥ 2 prior lines for advanced disease (range 0-6). In 153 pts with ≥ 6 mos follow-up, confirmed ORR was 17.6% (95% CI 12.0-24.6) with 9 complete responses and 18 partial responses; 24/27 (88.9%) were ongoing. Median DOR was not reached, and the 24-wk DOR rate was 92.0% (95% CI 71.6, 97.9). 36 pts had stable disease as best response (disease control rate 41.2%). Median PFS was 6.4 wks (95% CI 6.1-11.4), and median OS was 7.0 mos (95% CI 5.6-11.1). Based on a ≥ 5% PD-L1 staining cutoff in evaluable pts with PD-L1+ (n = 56) and PD-L1– (n = 75) tumors, ORR was 25.0% (95% CI 14.4-38.4) vs 14.7% (95% CI 7.6-24.7; p = 0.178). Treatment-related adverse events (TRAE) of any grade occurring in ≥ 10% of pts were infusion-related reaction (22.8%) and fatigue (12.0%). 7.5% had a grade ≥ 3 TRAE; fatigue (1.2%)/asthenia (0.8%) occurred in > 1 pt. 28 pts (11.6%) had an immune-related TRAE (grade ≥ 3 in 2.5%). There was 1 treatment-related death (pneumonitis). Conclusions: Avelumab is well tolerated and shows promising clinical activity, including durable responses, in pts with mUC, regardless of tumor PD-L1 expression status. Follow-up is ongoing. Clinical trial information: NCT01772004.

Phase II trial of vinblastine, ifosfamide, and gallium combination chemotherapy in metastatic urothelial carcinoma.

1994 ◽  
Vol 12 (11) ◽  
pp. 2271-2276 ◽  
Author(s):  
L H Einhorn ◽  
B J Roth ◽  
R Ansari ◽  
R Dreicer ◽  
R Gonin ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Phase Ii ◽  
Combination Chemotherapy ◽  
Phase Ii Trial ◽  
Objective Response ◽  
Gallium Nitrate ◽  
Major Toxicity ◽  
Metastatic Urothelial Carcinoma ◽  
Grade 3 ◽  
Related Mortality

PURPOSE Phase II trial in metastatic urothelial carcinoma using a novel combination chemotherapy regimen consisting of vinblastine, ifosfamide, and gallium nitrate (VIG). PATIENTS AND METHODS Twenty-seven patients were entered onto this phase II study. Dosages were vinblastine 0.11 mg/kg days 1 and 2, ifosfamide 1.2 gm/m2 days 1 through 5 (with mesna), and gallium 300 mg/m2 as a 24-hour infusion days 1 through 5, with calcitriol (1,25-dihydroxycholecalciferol) 0.5 microgram/d orally starting 3 days before each course (except the first) and continuing throughout gallium administration, plus recombinant human granulocyte colony-stimulating factor (rhG-CSF) (filgrastim) 5 micrograms/kg/d days 7 through 16. Courses were repeated every 21 days for a maximum of six cycles. RESULTS The major toxicity was granulocytopenia. Fifteen patients (55.6%) had grade 3 or 4 granulocytopenia, including eight patients with granulocytopenic fevers. Eleven patients had grade 3 or 4 anemia and four had grade 3 or 4 nephrotoxicity, which was reversible. Other grade 3 to 4 toxicities included hypocalcemia (three patients), thrombocytopenia (two), encephalopathy (one), and temporary blindness (one). There was one treatment-related mortality. Toxicity was more severe in patients older than 70 years and those with prior pelvic irradiation, prior cisplatin adjuvant therapy, or prior nephrectomy. We now decrease VIG by 20% in this patient population. Eighteen patients (67%) achieved an objective response, including 11 (41%) who attained a disease-free status (five with VIG alone and six with subsequent surgery). Median duration of remission was 20 weeks, with five patients still in remission at 22+ to 56+ weeks. CONCLUSION VIG combination chemotherapy is very active in patients with metastatic urothelial carcinoma. Toxicity was significant but manageable.

Randomized Phase III Trial of Gemcitabine and Cisplatin With Bevacizumab or Placebo in Patients With Advanced Urothelial Carcinoma: Results of CALGB 90601 (Alliance)

2021 ◽  
pp. JCO.21.00286
Author(s):  
Jonathan E. Rosenberg ◽  
Karla A. Ballman ◽  
Susan Halabi ◽  
Pamela J. Atherton ◽  
Amir Mortazavi ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Controlled Trial ◽  
Objective Response ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Hazard Ratio ◽  
Phase Iii ◽  
Free Survival ◽  
Metastatic Urothelial Carcinoma ◽  
Gemcitabine And Cisplatin

PURPOSE The combination of gemcitabine and cisplatin (GC) is a standard therapy for metastatic urothelial carcinoma. Based on data that angiogenesis plays a role in urothelial carcinoma growth and progression, a randomized placebo-controlled trial was performed with the primary objective of testing whether patients treated with GC and bevacizumab (GCB) have superior overall survival (OS) than patients treated with GC and placebo (GCP). PATIENTS AND METHODS Between July 2009 and December 2014, 506 patients with metastatic urothelial carcinoma without prior chemotherapy for metastatic disease and no neoadjuvant or adjuvant chemotherapy within 12 months were randomly assigned to receive either GCB or GCP. The primary end point was OS, with secondary end points of progression-free survival, objective response, and toxicity. RESULTS With a median follow-up of 76.3 months among alive patients, the median OS was 14.5 months for patients treated with GCB and 14.3 months for patients treated with GCP (hazard ratio for death = 0.87; 95% CI, 0.72 to 1.05; two-sided stratified log-rank P = .14). The median progression-free survival was 8.0 months for GCB and 6.7 months for GCP (hazard ratio = 0.77; 95% CI, 0.63 to 0.95; P = .016). The proportion of patients with grade 3 or greater adverse events did not differ significantly between both arms, although increased bevacizumab-related toxicities such as hypertension and proteinuria occurred in the bevacizumab-treated arm. CONCLUSION The addition of bevacizumab to GC did not result in improved OS. The observed median OS of about 14 months is consistent with prior phase III trials of cisplatin-based chemotherapy.

scholarly journals Efficacy and Safety Outcomes in Patients With Advanced Melanoma Who Discontinued Treatment With Nivolumab and Ipilimumab Because of Adverse Events: A Pooled Analysis of Randomized Phase II and III Trials

2017 ◽  
Vol 35 (34) ◽  
pp. 3807-3814 ◽  
Author(s):  
Dirk Schadendorf ◽  
Jedd D. Wolchok ◽  
F. Stephen Hodi ◽  
Vanna Chiarion-Sileni ◽  
Rene Gonzalez ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Objective Response ◽  
Progression Free Survival ◽  
Pooled Analysis ◽  
Advanced Melanoma ◽  
Induction Phase ◽  
Efficacy And Safety ◽  
Grade 3 ◽  
Phase Ii And Iii

Purpose Approximately 40% of patients with advanced melanoma who received nivolumab combined with ipilimumab in clinical trials discontinued treatment because of adverse events (AEs). We conducted a retrospective analysis to assess the efficacy and safety of nivolumab plus ipilimumab in patients who discontinued treatment because of AEs. Methods Data were pooled from phase II and III trials of patients who received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, every 3 weeks for four doses, followed by nivolumab monotherapy 3 mg/kg every 2 weeks (N = 409). Efficacy was assessed in all randomly assigned patients who discontinued because of AEs during the induction phase (n = 96) and in those who did not discontinue because of AEs (n = 233). Safety was assessed in treated patients who discontinued because of AEs (n = 176) at any time and in those who did not discontinue because of AEs (n = 231). Results At a minimum follow-up of 18 months, median progression-free survival was 8.4 months for patients who discontinued treatment because of AEs during the induction phase and 10.8 months for patients who did not discontinue because of AEs ( P = .97). Median overall survival had not been reached in either group ( P = .23). The objective response rate was 58.3% for patients who discontinued because of AEs during the induction phase and 50.2% for patients who did not discontinue. The vast majority of grade 3 or 4 AEs occurred during the induction phase, with most resolving after appropriate management. Conclusion Efficacy outcomes seemed similar between patients who discontinued nivolumab plus ipilimumab treatment because of AEs during the induction phase and those who did not discontinue because of AEs. Therefore, even after discontinuation, many patients may continue to derive benefit from combination therapy.

Phase Ib/II trial of gemcitabine, cisplatin, plus lenalidomide as first-line therapy for patients with metastatic urothelial carcinoma.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 321-321
Author(s):  
Che-Kai Tsao ◽  
Neeraj Agarwal ◽  
Andrea Borghese Apolo ◽  
Karen M Lee ◽  
James H. Godbold ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Urothelial Carcinoma ◽  
Phase Ii ◽  
Progression Free Survival ◽  
Chronic Administration ◽  
Primary Objective ◽  
Phase Ib ◽  
Frequent Dose ◽  
Metastatic Urothelial Carcinoma ◽  
Dose Reductions

321 Background: Cisplatin-based chemotherapy is standard in patients (pts) with metastatic urothelial carcinoma (MUC), though outcomes remain poor and novel approaches are needed. Lenalidomide, a potent thalidomide analog with antiangiogenic and immunomodulatory properties, has been shown to enhance the antiproliferative properties of standard chemotherapy in nonclinical studies of urothelial cancer (Apolo, ASCO 2011). In this phase Ib/II clinical trial we aimed to determine the safety and efficacy of gemcitabine, cisplatin, plus lenalidomide (GCL) in pts with MUC. Methods: Pts with chemotherapy-naïve MUC received gemcitabine 1000mg/m2 days 1 and 8 and cisplatin 70mg/m2 day 1, of a 21-day cycle. In the phase Ib portion, the dose of lenalidomide was to be dose escalated in successive cohorts starting at 10 mg PO daily, on days 1-14, using standard “3+3” dose escalation rules. The primary objective of the phase II portion was to determine the progression-free survival at one year. Results: A total of 7 pts received GCL (lenalidomide 10 mg dose level) in the phase 1b portion. A single pt experienced a dose limiting toxicity (DLT), grade 4 neutropenia. A decision was made to not dose escalate lenalidomide further due to the frequent need for dose delays and reductions of GC due to cytopenias. An additional 2 pts were enrolled in the phase II portion but the study was terminated due to frequent dose delays/reductions and slow accrual. Among the 9 pts enrolled, 5 required dose reductions of G (4 requiring >1), 4 required dose reductions of C (1 requiring >1), and 6 required at least one dose delay. The most frequent grade ≥ 3 adverse events were: neutropenia (n=7), anemia (n=3), thrombocytopenia (n=3), and diarrhea (n=2). Tumor responses included: partial response (n=3), stable disease (n=3), progressive disease (n=2), and unevaluable (n=1). Conclusions: Chronic administration of the combination of GCL was compromised by overlapping myelosuppression and the need for frequent dose reductions/delays of GC due to cytopenias. Despite promising nonclinical data, combining cytotoxic chemotherapy with “targeted” small molecules faces practical challenges. Clinical trial information: NCT01342172.

scholarly journals TROPHY-U-01: A Phase II Open-Label Study of Sacituzumab Govitecan in Patients With Metastatic Urothelial Carcinoma Progressing After Platinum-Based Chemotherapy and Checkpoint Inhibitors

2021 ◽  
pp. JCO.20.03489
Author(s):  
Scott T. Tagawa ◽  
Arjun V. Balar ◽  
Daniel P. Petrylak ◽  
Arash Rezazadeh Kalebasty ◽  
Yohann Loriot ◽  
...  
Keyword(s):  
Adverse Events ◽  
Urothelial Carcinoma ◽  
Phase Ii ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Open Label ◽  
Free Survival ◽  
Platinum Based Chemotherapy ◽  
Duration Of Response ◽  
Metastatic Urothelial Carcinoma

PURPOSE Patients with metastatic urothelial carcinoma (mUC) who progress on platinum-based combination chemotherapy (PLT) and checkpoint inhibitors (CPIs) have limited options that offer objective response rates (ORRs) of approximately 10% with a median overall survival (OS) of 7-8 months. Sacituzumab govitecan (SG) is a TROP-2–directed antibody-drug conjugate with an SN-38 payload that has shown preliminary activity in mUC. METHODS TROPHY-U-01 (ClinicalTrials.gov identifier: NCT03547973 ) is a multicohort, open-label, phase II, registrational study. Cohort 1 includes patients with locally advanced or unresectable or mUC who had progressed after prior PLT and CPI. Patients received SG 10 mg/kg on days 1 and 8 of 21-day cycles. The primary outcome was centrally reviewed ORR; secondary outcomes were progression-free survival, OS, duration of response, and safety. RESULTS Cohort 1 included 113 patients (78% men; median age, 66 years; 66.4% visceral metastases; median of three [range, 1-8] prior therapies). At a median follow-up of 9.1 months, the ORR was 27% (31 of 113; 95% CI, 19.5 to 36.6); 77% had decrease in measurable disease. Median duration of response was 7.2 months (95% CI, 4.7 to 8.6 months), with median progression-free survival and OS of 5.4 months (95% CI, 3.5 to 7.2 months) and 10.9 months (95% CI, 9.0 to 13.8 months), respectively. Key grade ≥ 3 treatment-related adverse events included neutropenia (35%), leukopenia (18%), anemia (14%), diarrhea (10%), and febrile neutropenia (10%), with 6% discontinuing treatment because of treatment-related adverse events. CONCLUSION SG is an active drug with a manageable safety profile with most common toxicities of neutropenia and diarrhea. SG has notable efficacy compared with historical controls in pretreated mUC that has progressed on both prior PLT regimens and CPI. The results from this study supported accelerated approval of SG in this population.

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