Updated results of phase II trial using escalating doses of neoadjuvant atezolizumab for cisplatin-ineligible patients with nonmetastatic urothelial cancer (NCT02451423).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16510-e16510
Author(s):  
Divya V Natesan ◽  
Li Zhang ◽  
David Yoonsuk Oh ◽  
Sima P. Porten ◽  
Maxwell Meng ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Hearing Loss ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Pathologic Complete Response ◽  
Complete Response ◽  
Treatment Rate ◽  
Carcinoma Of The Bladder ◽  
Muscle Invasive ◽  
To Receive

e16510 Background: Patients (pts) with muscle-invasive bladder cancer (MIBC) ineligible for cisplatin-based chemotherapy have no standard systemic therapy options and are prioritized for radical cystectomy (RC) alone. This prospective clinical trial investigated the safety and efficacy of escalating doses of neoadjuvant atezolizumab (N-ATZ) prior to RC in MIBC pts. Methods: This is a single-institution, phase II trial of escalating doses of N-ATZ (1200 mg IV every 3 weeks) in pts with MIBC. Key inclusion criteria were resectable urothelial carcinoma of the bladder (T2-T4a,N0-1,M0) and inability to receive cisplatin-based treatment (eGFR < 60 mL/min, G≥2 neuropathy/hearing loss, pt decision). Pts with high-risk disease at RC were eligible to receive adjuvant ATZ for up to 16 total doses. Pts were followed for up to 2 years following RC. Primary efficacy endpoint was pathologic complete response (pCR; pT0N0). Secondary endpoints were safety of treatment, rate of pathologic downstaging (≤pT1N0), response based on PD-L1 status, and overall survival (OS) and recurrence-free survival (RFS) at 1 and 2 years from RC. Results: A total of 20 pts were enrolled and sequentially treated with one (n=6), two (n=5), and three (n=9) cycles of N-ATZ prior to RC. Median age was 69 (range 61-81), 75% were male and 85% Caucasian. Pts were cisplatin-ineligible due to low GFR (35%), hearing loss (25%) or neuropathy (10%); the rest refused cisplatin (30%). Most pts had pT2 disease (80%); the remainder, pT3/pT4 (15%/5%), and 10% had cN1. Among 17 pts with available tumor PD-L1 status, 76% had PD-L1 positive (CPS≥10) tumors. pCR was observed in 2 pts (10%) with 1 and 2 ATZ doses, whereas pathologic downstaging was observed in 5 pts (25%) across all 3 doses (Table). All pts completed intended treatment and RC within the trial-defined timeframe. Perioperative TRAEs of any grade occurred in 75%, but only 10% had G3 TRAEs (diarrhea, fecal incontinence). There were no G4/G5 events. Median follow-up from RC was 23.6 months and 75% were still followed at the time of data cutoff in 2/2021. Among evaluable pts, 1-year RFS and OS were 72% and 94% while 2-year RFS and OS were 64% and 69%. PD-L1 positive pts had superior OS (logrank p=0.06) and RFS (p=0.10) relative to PD-L1 negative pts. Conclusions: N-ATZ was well tolerated at all three dose levels and did not delay or prevent surgery. As few as 1 to 2 ATZ doses resulted in pathologic downstaging, including pCR. Although pCR rate in this trial was lower than expected, most pts had a durable recurrence-free period and all evaluable pts with tumor downstaging were alive and recurrence-free at 2 years following RC. Increased tumor PD-L1 expression was suggestive of improved outcomes and further biomarker analyses are ongoing. Clinical trial information: NCT02451423. [Table: see text]

Phase II trial of escalating doses of neoadjuvant atezolizumab for patients with non-metastatic urothelial carcinoma ineligible for cisplatin-based neoadjuvant chemotherapy.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 442-442
Author(s):  
Vadim S Koshkin ◽  
Divya Natesan ◽  
Li Zhang ◽  
David Yoonsuk Oh ◽  
Sima P. Porten ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Hearing Loss ◽  
Urothelial Carcinoma ◽  
Neoadjuvant Therapy ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Prospective Trial ◽  
Safety And Efficacy ◽  
Metastatic Urothelial Cancer ◽  
To Receive

442 Background: For patients (pts) with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-based chemotherapy (cisplatin), the standard of care option is radical cystectomy (RC) alone. This prospective clinical trial investigated the safety and efficacy of escalating doses of atezolizumab (ATZ) as neoadjuvant therapy prior to RC in pts with non-metastatic urothelial cancer. Methods: This single-arm, single institution, phase II trial investigated the administration of one (n = 6), two (n = 5) or three (n = 9) cycles of ATZ (1200 mg IV given every 3 weeks) in pts with MIBC who are either ineligible for or refused cisplatin prior to RC. Key inclusion criteria were urothelial carcinoma of the bladder (T2-T4a,N0-1,M0) and inability to receive cisplatin-based treatment (eGFR < 60 mL/min, G≥2 neuropathy/hearing loss, pt decision). Pts with high-risk disease ( > pT2 or LN+) at the time of RC were eligible to receive adjuvant ATZ for up to 16 total cycles. Primary efficacy endpoint was pathologic complete response (pCR; pT0N0). Important secondary endpoints were safety of treatment, rates of pathologic downstaging and biomarker assessments in serial tissue samples. Pts were followed for up to 2 years following RC. Results: Among 20 pts with MIBC, median age was 69 (range 61-81) and 75% were male. Most commonly pts were cisplatin-ineligible due to low GFR (35%), hearing loss (25%) or neuropathy (10%); remainder refused cisplatin (30%). At trial enrollment, pT2, pT3, and pT4 was present in 80%, 15%, and 5% of pts and 10% had enlarged pelvic lymph nodes ( > 10 mm) on scans. All pts completed intended treatment cycles and all had RC within the defined timeframe ( > 3 weeks from last and < 12 weeks from first treatment). pCR at RC was 10% (2/20 pts), and was observed in pts receiving 1 and 2 cycles of ATZ. Pathologic downstaging (≤pT1N0) was achieved in 25% (5/20 pts) and observed across all three dose levels. Adjuvant ATZ was given to 8 pts. TRAEs of any grade during perioperative period occurred in 75% and G3 TRAEs in 10% (diarrhea, fecal incontinence). There were no G4 or G5 events. Median follow-up from the time of RC was 21.4 months at the time of data cutoff in 10/2020. Among evaluable pts, 1-year RFS and OS were 71% and 94% while 2-year RFS and OS were 64% and 75%. Conclusions: This prospective trial supports the safety and efficacy of ATZ as neoadjuvant therapy in MIBC. Although pCR and rates of downstaging were lower than what was previously reported in comparable neoadjuvant trials of checkpoint inhibitors in MIBC, pCRs in this trial were seen even in pts receiving only 1-2 doses of ATZ. Many pts had a durable recurrence-free period and all 4 evaluable pts who had pathologic downstaging were alive and disease free at 2 years post RC. Translational and biomarker work from this study is also being pursued. Clinical trial information: NCT02451423.

Pathologic response rates between gemcitabine-cisplatin (GC) and methotrexate, vinblastine, doxorubicin hydrochloride, and cisplatin (MVAC) neoadjuvant chemotherapy in muscle-invasive urothelial cell carcinoma of the bladder.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 267-267 ◽  
Author(s):  
Jonathan Lawrence Wright ◽  
Franklin Lee ◽  
William Proctor Harris ◽  
Heather H. Cheng ◽  
Song Zhao ◽  
...  
Keyword(s):  
Neoadjuvant Chemotherapy ◽  
Cardiac Disease ◽  
Clinical Stage ◽  
Pathologic Complete Response ◽  
Response Rates ◽  
Complete Response ◽  
Pathologic Response ◽  
Bcg Therapy ◽  
Carcinoma Of The Bladder ◽  
Muscle Invasive

267 Background: Neoadjuvant chemotherapy for muscle invasive urothelial carcinoma (UC) of the bladder is associated with higher rates of pathologic complete response (CR) and improved disease-specific survival compared to those treated with radical cystectomy (RC) alone. Two standard regimens used are (1) gemcitabine and cisplatin (GC); and (2) methotrexate, vinblastine, adriamycin, and cisplatin (MVAC), with debate on whether there is a difference in clinical efficacy. In this analysis, we compare the pathologic outcomes at cystectomy between neoadjuvant GC and MVAC treatment. Methods: Data was retrospectively collected on patients with T2-T4 UC of the bladder who underwent RC between Sept 2003 and December 2011 at the University of Washington. Clinical and pathologic factors were recorded along with neoadjuvant chemotherapy and comorbidities. Pathologic outcomes included those with CR (pT0) and near CR (nCR = pT0/Ta/Tis). Odds ratio (OR) for CR and nCR were calculated using multivariate logistic regression adjusting for demographic (age, gender, race), medical (creatinine, diabetes mellitus, cardiac disease) and clinical factors (clinical T stage, prior BCG therapy, complete tumor debulking prior to chemotherapy). Results: A total of 78 patients received GC or MVAC neoadjuvant chemotherapy followed by RC, including 46 who received GC and 32 who received MVAC. There was no difference in gender, renal function, cardiac disease or clinical stage between the two groups. Patients over 70 years of age primarily received GC (17/18). CR was achieved in 30% and 25% (p = 0.15) of GC and MVAC patients, respectively (multivariate OR 0.42, 95% CI 0.11-1.63). nCR was more common in those receiving GC (50% vs. 38%, p = 0.04) although non-significant in the multivariate model (OR 0.30, 95% CI 0.07-1.16). Conclusions: We observed similar pathologic response rates for GC and MVAC neoadjuvant chemotherapy in this cohort of bladder cancer patients. These observations support the use of GC as an alternative regimen in the neoadjuvant setting.

Clinical trial in progress: Phase II trial of defactinib (VS-6063) combined with VS-6766 (CH5126766) in patients with metastatic uveal melanoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS9588-TPS9588
Author(s):  
Rino S. Seedor ◽  
Marlana Orloff ◽  
J. Silvio Gutkind ◽  
Andrew E. Aplin ◽  
Mizue Terai ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Uveal Melanoma ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Human Cancer ◽  
Progression Free Survival ◽  
Complete Response ◽  
Total Sample ◽  
Oncogenic Signaling ◽  
Pharmacodynamic Profile

TPS9588 Background: Despite successful treatment of primary uveal melanomas (UM), up to 50% of patients subsequently develop systemic metastasis, with the liver involved in up to 90% of patients. Currently there is no US FDA-approved treatment for metastatic uveal melanoma (MUM). Activating mutations in genes encoding alpha subunits of the heterotrimeric G proteins, GNAQ and GNA11, are found in 80-90% of UM. Recent information suggests that GNAQ/GNA11-oncogenic signaling involves a non-canonical pathway conferring the activation of YAP1, distinct from the activation of PLCβ and PKC-MEK-ERK, which may explain the failure of MEK inhibitors in MUM patients. Focal Adhesion Kinase (FAK) is a tyrosine kinase that provides a direct link between Gαq and tyrosine phosphorylation networks controlling YAP and UM growth. Interestingly, UM represents the human cancer harboring the highest level of FAK overexpression. Recent kinome-wide CRISPR-Cas9 screens revealed that FAK and RAF/MEK co-targeting may provide a new network-based precision therapeutic strategy for MUM treatment. Methods: This is an investigator-initiated, prospective, single arm, single-institution, phase II trial evaluating the combination of a FAK inhibitor (defactinib, VS-6063) with a RAF/MEK inhibitor (VS-6766, CH5126766) for the treatment of patients with metastatic uveal melanoma [NCT04720417]. The primary endpoint of the study is disease control rate (DCR) of 50% including complete response (CR), partial response (PR), and stable disease (SD) as determined by RECIST criteria version 1.1. Secondary endpoints include progression free survival, overall survival, and causality of adverse events. Exploratory endpoints include analysis of the pharmacodynamic profile, mechanism of resistance to the combination, and investigation of circulating free DNA as a biomarker. The efficacy of this combination treatment will be assessed using the Simon’s two stage design. In stage I, a total number of 8 patients are accrued and if there are 2 or fewer overall responses among these 8 patients, further enrollment of patients may be stopped with the conclusion that DCR cannot be 50% or greater. Otherwise, an additional 10 patients will be accrued in stage II, resulting in a total sample size of 18 patients. Patients at 18 years or older with metastases from uveal melanoma will be eligible (any line of therapy). Defactinib (200 mg) will be administered orally twice a day in combination with VS-6766 (3.2 mg) administered orally twice a week for 3 weeks, in 28-day cycles. Dose modification will be considered based on toxicity. Treatment will be continued until maximum clinical benefit is obtained; disease progression or the development of intolerable side effects. Enrollment to stage 1 began in February 2021. Clinical trial information: NCT04720417.

Phase II trial of eribulin in patients who do not achieve pathologic complete response (pCR) following neoadjuvant chemotherapy

2020 ◽  
Vol 180 (3) ◽  
pp. 647-655
Author(s):  
Denise A. Yardley ◽  
Nancy Peacock ◽  
Brooke Daniel ◽  
Betrand Anz ◽  
David C. Molthrop ◽  
...  
Keyword(s):  
Neoadjuvant Chemotherapy ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Pathologic Complete Response ◽  
Complete Response

Oxaliplatin (OXP) plus protracted infusion 5-fluorouracil (PIFU) and external beam radiation (EBRT) prior to surgery (S) for potentially curable esophageal adenocarcinoma (EA): A Southwest Oncology Group (SWOG) phase II trial with molecular correlates (S0356)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4513-4513
Author(s):  
L. Leichman ◽  
B. H. Goldman ◽  
J. K. Benedetti ◽  
K. G. Billingsley ◽  
C. R. Thomas ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Combined Modality Therapy ◽  
Clinical Stage ◽  
Pathologic Complete Response ◽  
Progression Free Survival ◽  
Complete Response ◽  
The United States ◽  
External Beam Radiation ◽  
Beam Radiation

4513 Background: Although neoadjuvant combined modality therapy (NACMTX) has become a standard of care in the United States, median overall survival (OS) for patients (PTS) with EA has changed little over the past 25 years. Progression free survival (PFS) and OS after NACMTX depend on extent of primary tumor response. New regimens to increase pathologic complete response (pCR) are needed. Based on phase I data, SWOG designed a phase II trial (S0356) to test OXP with PI5FU and EBRT for PTS with EA. Objectives included pCR rate ≥ 25%, acceptable toxicity (TOX), PFS, OS and exploration of molecular parameters relevant to pCR. Methods: Eligibility: clinical stage II/III EA, ≥ 18 years, Zubrod PS ≤ 2, standard hematologic/non-hematologic values, and tumor < 2 cm into the gastric cardia. OXP 85 mg/m2 was given day (d) 1, 15 and 29; PI5FU 180 mg/m2/d was given d 8-d43. EBRT 180 cGy/d started d 8 x 25 fractions, 5 d/week to total dose 4500 cGy. S was planned 2–4 weeks after NACMTX, with a second cycle of OXP/ PI5FU after S. Central pathology review of surgical specimens was mandated. The trial used a 2-stage design; the trial was halted at 45 PTS to review pCR rate; it reopened to full accrual. Results: 98 PTS enrolled between 9/15/04 and 8/18/08. 6 PTS were ineligible; 2 PTS did not receive therapy (TX). 90 PTS, 84 men (93%), median age 61.7 years, were analyzed. 4 deaths (4.5%) were due to protocol TX; 2 due to NACMTX, 2 to S. 43% and 18% of PTS had grade 3/4 toxicity, respectively: 39% GI, 22% flu-like/fatigue, 17% pulmonary, 16% hematologic, 14% mucositis and 3% neurologic. 77 PTS (86%) underwent S. 30 PTS (33%) had pCR. 9 PTS (10%) had in-situ cancer or T1N0M0. <50% received postoperative CTX. Conclusions: OXP, PI5FU and EBRT for PTS with EA has produced the highest pCR rate reported to date for a cooperative group trial. Significant but manageable non-hematologic TOX was observed. S mortality is acceptable. Future trials built on this platform should plan to complete all TX before S. Tumor molecular profiles (analyses in progress) may predict benefit from this treatment. Data on PFS and OS will follow. [Table: see text]

Sign in / Sign up

Export Citation Format

Share Document