A Phase 2 Trial of Intravesical Gemcitabine and Docetaxel in the Treatment of Bacillus Calmette-Guérin‒Naïve Nonmuscle-Invasive Urothelial Carcinoma of the Bladder.

PURPOSE: Combination intravesical gemcitabine and docetaxel (GemDoce) has demonstrated efficacy as second-line therapy for patients with bacillus Calmette-Guérin (BCG)‒unresponsive nonmuscle-invasive urothelial carcinoma of the bladder (NMIBC). In the context of widespread BCG shortages, we performed a phase 2 prospective trial to assess GemDoce for BCG-naïve NMIBC. MATERIALS AND METHODS: This study is a prospective, single-arm, open-label phase 2 trial for patients with BCG-naïve high-risk NMIBC. Intravesical GemDoce was given weekly for 6 weeks as induction followed by monthly maintenance therapy for 2 years among responders. The primary end point was 3-month complete response, and key secondary end points included adverse events (AEs) and 12-month recurrence-free survival. RESULTS: Twenty-five patients were enrolled between August 2020 and August 2022 with median follow-up of 19.6 months. The pretreatment pathologic stages were high-grade (HG) T1 with carcinoma in situ (CIS; n = 7), HGT1 without CIS (n = 6), HGTa (n = 9), and CIS alone (n = 3). The 3-month complete response rate was 100% and recurrence-free survival at 12 months was 92%. Two patients with pretreatment HGT1 had HGT1 recurrences at 9 and 12 months. No patients progressed to T2 disease, underwent radical cystectomy, or had any radiographic evidence of progressive disease. Grade 1 AEs were common (23/25 patients) including hematuria, urinary frequency, urgency, and fatigue. Five patients (20%) experienced a grade 3 AE including hematuria and UTI. CONCLUSIONS: In this single-arm phase 2 trial, GemDoce was well tolerated with promising efficacy for patients with BCG-naïve high-risk NMIBC.

Phase I study of enzastaurin and bevacizumab in patients with advanced cancer: safety, efficacy and pharmacokinetics.

PURPOSE: Given distinct mechanism of actions of enzastaurin and bevacizumab, preclinical studies suggest enhanced antitumor activity in combination. This phase I study assessed the combination's safety and efficacy. PATIENTS AND METHODS: Six advanced cancer patients could be enrolled in each of 11 cohorts. Patients received an enzastaurin loading dose. Oral enzastaurin (500 mg once daily [QD], 250 mg twice daily [BID], 375 mg BID, 500 mg BID, and 750 mg BID) was escalated in each cohort in combination with bevacizumab dosed at 5 mg/kg every 2 weeks, 10 mg/kg every 2 weeks, or 15 mg/kg every 3 weeks until a dose-limiting toxicity (DLT) occurred in 2 of 6 patients in any cohort. RESULTS: Sixty-seven patients (31, ovarian cancer [ovcar]) were evaluable for safety and efficacy. Six treatment-related DLTs occurred: grade 3 fatigue (n=4), grade 4 cerebral hemorrhage, and grade 3 elevated aspartate transaminase. Common drug-related toxicities included change in color of urine and stool, fatigue, pain, diarrhea, and nausea. The maximum tolerated dose of enzastaurin was 750 mg BID in combination with any tested bevacizumab dose/schedule. Overall response rate was 19.4 % (32.3 % ovcar). Median time to progression was 3.7 months (95 % confidence interval [CI], 2.7-5.5), with 8.3 months (95 % CI, 3.7-11.1) in ovcar. Overall, 35.9 % (50.4 % ovcar) of patients remained without disease progression after 6 months. CONCLUSION: The recommended phase II doses of enzastaurin were 500 mg QD up to 500 mg BID with any tested dose/schedule of bevacizumab. This combination demonstrated encouraging clinical activity, particularly in ovcar.

Phase I study of continuous weekly dosing of dimethylamino benzoylphenylurea (BPU) in patients with solid tumours.

A phase I study of dimethylamino benzoylphenylurea (BPU), a tubulin inhibitor, was performed using a weekly continuous schedule. Patients with refractory solid tumours received oral BPU once weekly without interruption at doses ranging from 5 to 320mg using an accelerated titration design. Nineteen subjects received 54 cycles of BPU. Early pharmacokinetic findings of decreased clearance with increasing dose and plasma accumulation led to the expansion of the 320mg dose level. Two subjects then developed late haematologic dose-limiting toxicities (DLTs) that were associated with the highest plasma exposure to BPU and metabolites. Study enrollment resumed at dose 150mg with real-time pharmacokinetic monitoring. Seven additional subjects (6 evaluable) were treated for a median of 2 cycles (range 1.5-4) without further myelotoxicity. A long half-life and accumulation of BPU and active metabolites were observed, recommending against a continuous administration. Weekly oral BPU therapy should be further tested using an interrupted schedule.

Phase II trial of docetaxel with rapid androgen cycling for progressive noncastrate prostate cancer.

PURPOSE: We evaluated rapid androgen cycling in combination with docetaxel for men with progressive noncastrate prostate cancers. PATIENTS AND METHODS: Noncastrate patients with 150 ng/dL) and an undetectable prostate-specific antigen (PSA;

Preclinical and clinical studies with the multi-kinase inhibitor CEP-701 as treatment for prostate cancer demonstrate the inadequacy of PSA response as a primary endpoint.

PURPOSE: CEP-701 is a potent inhibitor of trk receptors that causes cell death in prostate cancer (PC) models. CEP-701 binds to serum proteins and a preprostatectomy study was performed to assess prostate tissue penetration and clinical response to CEP-701. METHODS: Growth assays and Western blot analyses were performed to evaluate CEP-701 kinase inhibition. In a preprostatectomy study, patients received CEP-701 for five days prior to prostatectomy and prostate tissue analyzed for CEP-701 levels. A phase II dose escalation study was performed in patients with hormone refractory PC with rising PSA and no metastases. Endpoints included PSA response and safety. RESULTS: CEP-701 binds to serum proteins limiting tissue penetration. An oral dose of 40 mg bid of CEP-701 for five days produced levels of 219 +/- 38 nM in prostate at time of prostatectomy. No patients in the Phase II study met the primary response criteria of >50% PSA decline. 7/9 patients had increase in PSA slope on CEP-701 compared to PSA slope prestudy. 5/9 patients had a decrease in PSA levels after stopping CEP-701. Laboratory studies showed increased PSA production by CEP-701 growth arrested human PC cells in vitro and in vivo. CONCLUSIONS: Evaluation of PSA response is an inadequate indicator of response in CEP-701 treated PC patients. Therefore, the effectiveness of CEP-701 as treatment for prostate cancer has not been adequately tested. Based on a strong preclinical rationale, further clinical studies with CEP-701 using alternative endpoints are indicated.