Lina Asmar

Phase III study of mitoxantrone plus low dose prednisone versus low dose prednisone alone in patients with asymptomatic hormone refractory prostate cancer

PURPOSEnWe compared median time to treatment failure of men with asymptomatic, hormone refractory, progressive prostate cancer treated with mitoxantrone plus prednisone versus prednisone alone.nnnMATERIALS AND METHODSnIn a multicenter phase III trial 120 men with asymptomatic, progressive, hormone refractory prostate cancer were randomly assigned to treatment with mitoxantrone and prednisone or prednisone alone. Patients received 12 mg./m. mitoxantrone intravenously once every 3 weeks for 6 cycles and 5 mg. prednisone twice daily with or without mitoxantrone. Time to treatment failure was assessed as an aggregate end point comprised of time to disease progression, time to toxicity or death, or time to initiation of alternate therapy.nnnRESULTSnMedian followup was 21.8 months. Median time to treatment failure and median time to progression were the same: time to treatment failure and time to progression in the mitoxantrone and prednisone group was 8.1 months compared to 4.1 months in the prednisone alone group (p = 0.017 versus p = 0.018). More patients (27 or 48%) treated with mitoxantrone and prednisone achieved a 50% or greater reduction in prostate specific antigen levels than those who received only prednisone (15 or 24%, p = 0.007). There was no significant difference in median survival between the 2 groups, which was 23 and 19 months, respectively. Death was mainly attributable to disease progression.nnnCONCLUSIONSnPatients with hormone refractory prostate cancer who are asymptomatic but had progressive disease had a significantly higher response rate when treated with mitoxantrone and prednisone as demonstrated by the 50% or greater decrease in prostate specific antigen compared to treatment with prednisone alone. Time to treatment failure was significantly prolonged in the chemotherapy treated group but survival rates were not different.

Phase II trial of single-agent weekly docetaxel in hormone-refractory, symptomatic, metastatic carcinoma of the prostate.

The purpose of this study was to assess the efficacy of weekly administration of docetaxel as a single agent in patients with hormone-refractory, symptomatic, metastatic prostate cancer with respect to symptom palliation, tumor response, time to progression, and survival. Sixty men with progressive metastatic prostate cancer that had progressed on at least one hormonal regimen were enrolled in this multicenter phase II study. Twenty-one percent of patients had received prior palliative radiotherapy, and 25% had received prior chemotherapy for hormone-refractory disease. Patients were scheduled to receive three 8-week cycles of docetaxel (36 mg/m(2) on days 1, 8, 15, 22, 29, and 36) with 2-week intervals between cycles. The docetaxel dose could be decreased in the event of toxicity, but no dose escalation was permitted. A > or =50% decrease in serum prostate-specific antigen (PSA) levels from baseline with stabilization or improvement of performance status lasting 2 months or longer occurred in 24 (41%) patients, of whom 16 (27%) had a > or =80% decrease for 2 months or more. The median time to progression for all patients was 5.1 months (range, 0.9 to 18.2 months). The estimated median time to progression for patients who had and those who did not have a > or =50% reduction in serum PSA level with stable or improved performance status was 6.65 and 4.3 months, respectively. The median overall survival was 9.4 months (range, 1.6 to 18.2 months). Treatment toxicity was considered acceptable. Single-agent docetaxel at 36 mg/m(2) weekly was associated with a PSA response rate of 41%, increased time to progression and survival, and minimal myelosuppression in patients with hormone-refractory metastatic prostate cancer.

Randomized Phase III Trial of Gemcitabine-Based Chemotherapy With In Situ RRM1 and ERCC1 Protein Levels for Response Prediction in Non–Small-Cell Lung Cancer

PURPOSEnWe evaluated the efficacy of gemcitabine versus gemcitabine and carboplatin in patients with advanced non-small-cell lung cancer (NSCLC) and a performance status (PS) of 2 and assessed if tumoral RRM1 and ERCC1 protein levels are predictive of response to therapy.nnnPATIENTS AND METHODSnA randomized phase III trial was conducted in community-based oncology practices. Tumor specimens were collected a priori and shipped to a single laboratory for blinded determination of in situ RRM1 and ERCC1 protein expression levels by an automated quantitative immunofluorescent-based technology.nnnRESULTSnOne hundred seventy patients were randomly assigned. Overall median survival was 5.1 months for gemcitabine and 6.7 months for gemcitabine and carboplatin (P = .24). RRM1 (range, 5.3 to 105.6; median, 34.1) and ERCC1 (range, 5.2 to 131.3; median, 34.7) values were significantly and inversely correlated with disease response (r = -0.41; P = .001 for RRM1; r = -0.39; P = .003 for ERCC1; ie, response was better for patients with low levels of expression). A model for response prediction that included RRM1, ERCC1, and treatment arm, was highly predictive of the treatment response observed (P = .0005). We did not find statistically significant associations between survival and RRM1 or ERCC1 levels.nnnCONCLUSIONnSingle-agent chemotherapy remains the standard of care for patients with advanced NSCLC and poor PS. Quantitative analysis of RRM1 and ERCC1 protein expression in routinely collected tumor specimens in community oncology practices is predictive of response to gemcitabine and gemcitabine and carboplatin therapy. Oncologists should consider including in situ expression analysis for these proteins into their therapeutic decisions.

Gemcitabine, cisplatin, and sunitinib for metastatic urothelial carcinoma and as preoperative therapy for muscle-invasive bladder cancer

BACKGROUNDnData support chemotherapy combined with antiangiogenic therapy in metastatic urothelial cancer (mUC) and muscle-invasive bladder cancer (MIBC). We investigated the efficacy and safety of gemcitabine, cisplatin, and sunitinib (GCS) in mUC and MIBC in parallel phase II trials.nnnPATIENTS AND METHODSnTrial 1 enrolled 36 patients with mUC who were chemotherapy naive; trial 2 enrolled 9 patients with MIBC. The primary endpoints for trials 1 and 2 were response rate and pathologic complete response, respectively. GCS was given as first-line treatment for patients with mUC and as neoadjuvant therapy for patients with MIBC. The Simon minimax 2-stage design was used for an objective response rate in trial 1 and for the pathologic complete response rate in trial 2.nnnRESULTSnThe initial trial 1 GCS dose was gemcitabine 1000 mg/m(2) intravenously, days 1 and 8; cisplatin 70 mg/m(2) intravenously, day 1; and sunitinib 37.5 mg orally daily, days 1 to 14 of a 21-day cycle. These doses proved intolerable. The doses of gemcitabine and cisplatin were subsequently reduced to 800 and 60 mg/m(2), respectively, without an improvement in drug delivery, and the trial was closed. This lower-dose regimen was applied in trial 2, which was stopped early due to excess toxicity. Grade 3 to 4 hematologic toxicities occurred in 70% (23/33) of patients in trial 1 and 22% (2/9) of patients in trial 2. In trial 1, the response rate was 49% (95% CI, 31%-67%); in trial 2, the pathologic complete response was 22% (2/9). Due to early closure secondary to toxicity, the sample sizes of both trials were small.nnnCONCLUSIONSnDelivery of GCS was hampered by excessive toxicity in both advanced and neoadjuvant settings.

Azacitidine favorably modulates PSA kinetics correlating with plasma DNA LINE-1 hypomethylation in men with chemonaïve castration-resistant prostate cancer.

BACKGROUNDnAzacitidine is a hypomethylating agent that activates genes repressed by promoter methylation. Preclinically, demethylating agents reverse resistance of prostate cancer to androgen ablation. A phase II trial evaluated azacitidine for men with castration-resistant prostate cancer (CRPC) progressing on combined androgen blockade (CAB).nnnMETHODSnChemonaïve patients with CRPC on CAB and PSA-doubling time (DT) < 3 months were eligible. The primary endpoint was prolongation of PSA-DT to ≥ 3 months. Correlation of biologic activity (fetal hemoglobin, plasma DNA LINE-1 methylation) with prolongation of PSA-DT was tested. CAB was continued and azacitidine 75 mg/m(2) was administered subcutaneously on days 1-5 of each 28-day cycle up to 12 cycles or until clinical progression/intolerable toxicities.nnnRESULTSnThirty-six patients were enrolled, 80.6% had metastatic disease, and 34 were evaluable. A PSA-DT ≥ 3 months was attained in 19 patients (55.8%). Overall median PSA-DT was significantly prolonged compared to baseline (2.8 vs. 1.5 months, P < 0.01). Fourteen patients had some PSA decline during therapy and 1 patient had a ≥ 30% decline compared with baseline. The median clinical progression-free survival was 12.4 weeks. Grade 3 toxicities included fatigue (12%), and neutropenia (6%), with 4 patients discontinuing due to toxicities. A trend in decreasing plasma DNA LINE-1 methylation was seen with longer treatment duration (P = 0.06), which significantly correlated with prolongation of PSA-DT (P = 0.02).nnnCONCLUSIONSnAzacitidine favorably modulates PSA kinetics in chemonaïve CRPC that correlates with decreasing plasma DNA LINE-1 methylation. Given the excellent tolerability, further development of azacitidine for CRPC may be warranted, with exploration of combination regimens.

Phase II study of gemcitabine, cisplatin, and sunitinib in patients with advanced urothelial carcinoma (UC).

282 Background: Sunitinib (S) has single-agent activity in patients with advanced urothelial carcinoma (UC). Preclinical studies in UC demonstrate at least additive antitumor activity combining S with gemcitabine (G) or cisplatin (C).nnnMETHODSnPatients with chemonaïve metastatic UC were enrolled in a multicenter phase II trial with overall response rate (ORR) as the primary endpoint. The initial dosing regimen, based on a phase I trial (Reck, 2010), was G 1000 mg/m2 IV (Days 1 & 8), C 70 mg/m2 IV (Day 1), and S 37.5 mg PO daily (Days 1-14)/each 21-day cycle (up to 6 cycles), followed by S 37.5 mg daily until progression.nnnRESULTSnFrom December 2008 to August 2009, 15 eligible patients enrolled. Seven of 15 patients discontinued treatment early (median: 3 cycles) due to toxicity, most often due to recurrent neutropenia and thrombocytopenia. Intrapatient dose reductions were required for G (12/15), C (8/15), and S (10/15). Eight of 15 patients experienced serious adverse events. Based on the toxicity profile, enrollment was held and the dosing regimen was revised to G 800 mg/m2 IV (Days 1 and 8), C 60 mg/m2 IV (Day 1), S 37.5 mg PO daily (Days 1-14). From December 2009 to April 2011, 18 additional patients were enrolled. Despite the reduced starting doses, intrapatient dose reductions were required for G (13/18), C (9/18), and S (15/18). The most frequent Grade 3-4 toxicities for both groups were neutropenia (70%), thrombocytopenia (58%), and anemia (30%). Antitumor activity is shown in the Table. Median PFS was 7.9 and median OS was 13.8 months.nnnCONCLUSIONSnCombination G+C+S is poorly tolerated and results in activity comparable to historical results with G+C alone. Supported in part by a grant from Pfizer Inc. [Table: see text].

Association of rash with outcomes in a randomized phase II trial evaluating cetuximab in combination with mitoxantrone plus prednisone after docetaxel for metastatic castration-resistant prostate cancer

PURPOSEnCetuximab (C), a chimeric monoclonal antibody that binds epidermal growth factor receptor (EGFR), is active against androgen-independent prostate cancer cell lines and might enhance the activity of chemotherapy. The efficacy of combining cetuximab with mitoxantrone (M) plus prednisone (MP) was evaluated in progressive metastatic castrate-resistant prostate cancer (CRPC) after receiving docetaxel.nnnMATERIALS AND METHODSnPatients with progression after receiving docetaxel were eligible and randomized 2:1 to CMP or MP. Therapy was mitoxantrone 12 mg/m(2) intravenously (I.V.) on day 1, oral prednisone 10 mg daily in both arms, and cetuximab 250 mg/m(2) I.V. (400 mg/m(2) day 1, cycle 1) on days 1, 8, and 15 in the CMP arm. Cycles were repeated every 21 days. Radiologic assessments of disease and PSA (prostate-specific antigen) occurred every 4 cycles. The primary endpoint was time to progression (TTP).nnnRESULTSnA total of 115 patients were enrolled, 75 in the CMP and 40 in the MP arm: the median TTP was 4.9 and 6.6 months, respectively; the measurable disease response rate was 2% and 4%, the PSA response rate 7.7% and 17.6%, and median survival 11.9 and 15.7 months, respectively. Key grade 3-4 toxicities were neutropenia 44% and 25.6%, anemia 6.7% and 7.7%, thrombocytopenia 6.7% and 2.6%, and fatigue 8% in both arms. In an unplanned exploratory analysis, median TTP with (n = 24) and without rash (n = 51) in the CMP arm was 10.3 months vs. 2.8 months (P = .004). On multivariable analysis,rash was significantly associated with TTP (hazard ratio [HR] = 0.43; P = .01).nnnCONCLUSIONSnThe treatment with CMP is not recommended in unselected men with docetaxel-treated CRPC, although rash might help develop tailored therapy.

Results of a phase II study of weekly paclitaxel plus carboplatin in advanced carcinoma of unknown primary origin : A reasonable regimen for the community-based clinic?

Optimal treatment for cancer of unknown primary (CUP) can challenge clinicians. This study sought to determine the efficacy and toxicity of weekly paclitaxel and carboplatin in CUP. Forty-two subjects enrolled. Treatment was intravenous paclitaxel (80 mg/m2) plus carboplatin (AUC = 2) on Days 1, 8, and 15 every 28 days. Seven (18 percent) responded (complete = 2, partial = 5); median survival was 8.5 months; estimated survival (12 and 24-month) was 33 and 17 percent, respectively. Median time to progression was 3.7 months, and estimated progression-free survival (12 and 24 months) was 14 and 7 percent, respectively. Median duration of response was 17.3 months. This combination produced modest antitumor activity in advanced CUP.

Phase II Trial of Sunitinib for the Therapy of Progressive Metastatic Castration-Refractory Prostate Cancer After Previous Docetaxel Chemotherapy

Effective options are lacking for progressive castration-refractory prostate cancer (CRPC) after conventional chemotherapy. Sunitinib is an orally administered multitargeted tyrosine kinase inhibitor that is approved multinationally for renal cell carcinoma and gastrointestinal stromal tumors. A phase II trial was conducted to examine the efficacy and toxicities of sunitinib in metastatic CRPC progressing after 1-2 previous chemotherapy regimens including docetaxel. The primary objective was clinical progression-free survival (PFS) with a 12-week PFS > or = 30% assumed to be of interest. Secondary objectives included prostate-specific antigen (PSA) response, modulation of PSA kinetics, objective response, quality of life, pain, survival, and toxicities. Sunitinib 50 mg daily was administered orally on days 1-28 of each 6-week cycle. Patients were treated to a maximum of 8 cycles or until clinically progressive disease or intolerable toxicity.

Phase II study of azacitidine to restore responsiveness of prostate cancer to hormonal therapy.

Epigenetic alterations, including methylation of key tumor suppressor genes, may play a role in the progression of prostate cancer to a castration-refractory state. Azacitidine, an agent approved for the treatment of myelodysplastic syndromes, appears to exert its antineoplastic effects partly by hypomethylating DNA that leads to the reversal of gene silencing. It is hypothesized that the addition of azacitidine to complete androgen blockade may restore the responsiveness of progressive prostate cancer to hormonal therapy. A phase II trial was designed to evaluate the activity of azacitidine to primarily modulate PSA kinetics, with supportive secondary clinical endpoints. Correlative studies will be performed to detect the biologic activity of azacitidine (increased fetal hemoglobin, plasma DNA methylation) and examine any association with anti-tumor clinical activity.