A Phase II Trial of Itraconazole in Improving Pathologic Complete Response in Esophageal Cancer

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]

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Neoadjuvant paclitaxel poliglumex, cisplatin, and radiation for esophageal cancer: A phase II trial

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e15542 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e15542-e15542

Author(s):

T. Ng ◽

T. DiPetrillo ◽

M. Suntharalingam ◽

J. Fontaine ◽

B. McNulty ◽

...

Keyword(s):

Esophageal Cancer ◽

Phase Ii ◽

Single Agent ◽

Pathologic Complete Response ◽

Complete Response ◽

Carcinomatous Meningitis ◽

Carcinoma Of The Esophagus ◽

Radiation Enhancement ◽

Esophagogastric Cancer ◽

Grade 3

e15542 Background: Paclitaxel poliglumex (PPX) is a drug conjugate that links paclitaxel to poly-L-glutamic acid thereby increasing its radiation enhancement factor to 4.0 to 8.0 compared to 1.5–2.0 for paclitaxel. The Brown University Oncology Group previously performed a phase I study establishing the dose of single agent PPX with radiation, and the combination of PPX, cisplatin and radiation for esophagogastric cancer. A phase II study was therefore initiated to evaluate the pathologic response rate of neoadjuvant PPX, cisplatin and radiation for patients with esophageal cancer. Methods: Eligible patients had pathologically confirmed adenocarcinoma or squamous cell carcinoma of the esophagus or GE junction with no evidence of distant metastasis. Celiac nodal disease was allowed. Patients received weekly PPX 50mg/m2 and cisplatin 25mg/m2 for 6 weeks with concurrent with 50.4Gy of radiation. Six to eight weeks after completion of chemoradiotherapy, patients underwent surgical resection. Results: Twenty-three eligible patients have been enrolled. The median age is 63 years. Grade 3/4 treatment related toxicities in the first 15 patients include dehydration (n=5), anorexia (n=5), esophagitis/dysphagia (n=4), electrolyte abnormalities (n=3), nausea (n=2), hypersensitivity (n=2), weight loss (n=1), and anemia (n=1). One patient developed carcinomatous meningitis during treatment. Five of the first 11 patients (45%) undergoing resection had a pathologic complete response. Conclusions: This preliminary data suggests that PPX may provide enhanced radiosensitization as compared to standard paclitaxel, consistent with the preclinical data of PPX and radiation. No significant financial relationships to disclose.

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Phase II trial of paclitaxel, fluorouracil, and cisplatin in patients with advanced carcinoma of the esophagus.

Journal of Clinical Oncology ◽

10.1200/jco.1998.16.5.1826 ◽

1998 ◽

Vol 16 (5) ◽

pp. 1826-1834 ◽

Cited By ~ 131

Author(s):

D H Ilson ◽

J Ajani ◽

K Bhalla ◽

A Forastiere ◽

Y Huang ◽

...

Keyword(s):

Esophageal Cancer ◽

Esophageal Carcinoma ◽

Phase Ii ◽

Metastatic Disease ◽

Combination Chemotherapy ◽

Response Rate ◽

Phase Ii Trial ◽

Complete Response Rate ◽

Squamous Carcinoma ◽

Complete Response

PURPOSE We have previously identified paclitaxel as an active single agent in the treatment of esophageal cancer. We performed a phase II trial of paclitaxel in combination with cisplatin and fluorouracil (5-FU), conventionally used chemotherapy for esophageal cancer. The antitumor response, toxicity, and survival of patients treated with the three-drug regimen were evaluated. PATIENTS AND METHODS Sixty-one patients with advanced, surgically unresectable, or metastatic squamous cell or adenocarcinoma of the esophagus were treated. No prior chemotherapy was allowed. Thirty patients had adenocarcinoma and 31 patients had squamous cell carcinoma. The majority (47 patients; 77%) had metastatic disease and 14 patients (23%) had an unresectable primary or locally recurrent tumor. Patients received paclitaxel 175 mg/m2 by 3-hour infusion day 1; cisplatin 20 mg/m2 daily days 1 through 5, and 5-FU by continuous infusion at a dose of 1,000 mg/m2 daily days 1 through 5. Because of toxicity observed in the first 10 patients treated, the starting dose of 5-FU was subsequently reduced to 750 mg/m2 daily in the remaining patients. A planned attenuation of cisplatin to 15 mg/m2 daily was made after the first three cycles. Granulocyte colony-stimulating factor (G-CSF) was not routinely administered unless the patient had an episode of febrile neutropenia or prolonged grade 4 neutropenia. Treatment was recycled every 28 days. RESULTS Sixty-one patients completed a median of five cycles, and 60 patients were assessable for response. Major responses were seen in 29 patients (48%; 95% confidence intervals, 35 to 61), which included seven complete responses (12%). Comparable response rates were seen for patients with adenocarcinoma (46%) and those with squamous carcinoma (50%), and for patients with metastatic disease (22 of 46 patients; 48%) and those with locally advanced disease (seven of 14 patients; 50%). A significantly higher complete response rate was observed in patients with squamous carcinoma (20%) compared with those with adenocarcinoma (3%; chi2 P=.04). The median duration of response was 5.7 months (range, 1 to 18.6 months). Median survival was 10.8 months (range, 1.5 to 25 months). Toxicity was severe but manageable with dose attenuation, and included 18% of patients with grade 3 neurologic toxicity. Twenty-eight patients (46%) required a dose attenuation for toxicity, and 42 of 275 treatment cycles (15%) required a dose attenuation. Twenty-nine patients (48%) required hospitalization for toxicity, which included 11 patients for neutropenic fever (18%). There were no treatment-related deaths. CONCLUSION The combination of paclitaxel, cisplatin, and 5-FU has substantial antitumor activity in metastatic esophageal carcinoma, with a remarkable complete response rate noted in patients with squamous carcinoma. Paclitaxel is an important new agent in the treatment of esophageal carcinoma, and further evaluation of this agent in combination chemotherapy is warranted. Given the toxicity associated with the current regimen, the optimal dose and schedule of paclitaxel in combination chemotherapy remain to be established.

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

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e16510 ◽

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]

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