Phase II study of copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or aggressive lymphoma.

BACKGROUND: Copanlisib is a pan-class I phosphatidylinositol 3-kinase inhibitor with predominant activity against the α- and δ-isoforms. PATIENTS AND METHODS: This phase II study evaluated the response rate of copanlisib administered intravenously on days 1, 8, and 15 of a 28-day cycle, in patients with indolent or aggressive malignant lymphoma. Archival tumor tissues were used for immunohistochemistry, gene-expression profiling, and mutation analysis. RESULTS: Thirty-three patients with indolent lymphoma and 51 with aggressive lymphoma received copanlisib. Follicular lymphoma (48.5%) and peripheral T-cell lymphoma (33.3%) were the most common histologic subtypes. Most patients (78.6%) had received prior rituximab and 54.8% were rituximab-refractory. Median duration of treatment was 23 and 8 weeks in the indolent and aggressive cohorts, respectively (overall range 2-138). Eighty patients were evaluated for efficacy. The objective response rate was 43.7% (14/32) in the indolent cohort and 27.1% (13/48) in the aggressive cohort; median progression-free survival was 294 days (range 0-874) and 70 days (range 0-897), respectively; median duration of response was 390 days (range 0-825) and 166 days (range 0-786), respectively. Common adverse events included hyperglycemia (57.1%; grade ≥3, 23.8%), hypertension (54.8%; grade ≥3, 40.5%), and diarrhea (40.5%; grade ≥3, 4.8%), all generally manageable. Neutropenia occurred in 28.6% of patients (grade 4, 11.9%). Molecular analyses showed enhanced antitumor activity in tumors with upregulated phosphatidylinositol 3-kinase pathway gene expression. CONCLUSION: Intravenous copanlisib demonstrated promising efficacy and manageable toxicity in heavily pretreated patients with various subtypes of indolent and aggressive malignant lymphoma. Subtype-specific studies of copanlisib in patients with follicular, peripheral T-cell, and mantle cell lymphomas are ongoing. This trial is registered with ClinicalTrials.gov number NCT01660451 (Part A).

Phase I/II study of sagopilone (ZK-EPO) plus carboplatin in women with recurrent platinum-sensitive ovarian cancer.

BACKGROUND: Sagopilone is the first fully synthetic epothilone in clinical development and has demonstrated promising preclinical activity. This phase I/II, prospective, open-label trial investigated the efficacy and safety of sagopilone plus carboplatin in patients with recurrent platinum-sensitive ovarian cancer (OC). METHODS: In phase I (dose-escalation stage), patients with OC recurring at least 6 months after platinum-containing chemotherapy received 3-h infusions of sagopilone (initial dose of 12 mg m(-2)) followed by carboplatin every 3 weeks, for 2-6 treatment courses. Patients enrolled in phase II received 3-h infusions of 16 mg m(-2) sagopilone. Efficacy was assessed using modified Response Evaluation Criteria in Solid Tumors (modRECIST) and Gynecologic Cancer InterGroup CA125 criteria. The safety and tolerability of sagopilone were also evaluated. RESULTS: In all, 45 patients received sagopilone at 12 mg m(-2) or 16 mg m(-2). There were 29 confirmed tumour responses (21 modRECIST and 8 CA125) across both treatment groups, indicating that the primary objective of the study was reached. The main adverse events (AEs) reported were peripheral neuropathy (75.6%), fatigue (71.1%) and nausea (64.4%). Grade ≥3 AEs occurred in 35 patients (77.8%). No deaths related to the study drug were reported. CONCLUSION: Sagopilone in combination with carboplatin was effective and toxicities were manageable in patients with recurrent platinum-sensitive OC.

Phase II study of first-line sagopilone plus prednisone in patients with castration-resistant prostate cancer: a phase II study of the Department of Defense Prostate Cancer Clinical Trials Consortium.

BACKGROUND: Preclinical studies in prostate cancer (PC) models demonstrated the anti-tumour activity of the first fully synthetic epothilone, sagopilone. This is the first study to investigate the activity and safety of sagopilone in patients with metastatic castration-resistant PC (CRPC). METHODS: Chemotherapy-naïve patients with metastatic CRPC received sagopilone (one cycle: 16 mg m(-2) intravenously over 3 h q3w) plus prednisone (5 mg twice daily). The primary efficacy evaluation was prostate-specific antigen (PSA) response rate (≥50% PSA reduction confirmed ≥28 days apart). According to the Simon two-stage design, ≥3 PSA responders were necessary within the first 13 evaluable patients for recruitment to continue until 46 evaluable patients were available. RESULTS: In all, 53 patients received ≥2 study medication cycles, with high compliance. Mean individual dose was 15.1±1.4 mg m(-2) during initial six cycles, mean dose intensity 94±9%. The confirmed PSA response rate was 37%. Median overall progression-free survival was 6.4 months. The most commonly reported adverse events (>10% of patients) were peripheral neuropathy (94.3%), fatigue (54.7%) and pain in the extremities (47.2%). Sagopilone was associated with very little haematological toxicity. CONCLUSION: This study shows that first-line sagopilone has noteworthy anti-tumour activity and a clinically significant level of neuropathy for patients with metastatic chemotherapy-naïve CRPC.

A phase II trial evaluating two schedules of sagopilone (ZK-EPO), a novel epothilone, in patients with platinum-resistant ovarian cancer.

BACKGROUND: Sagopilone, the first fully synthetic epothilone, has shown promising preclinical activity in tumour models. This open-label randomised phase II study investigated two infusion schedules of sagopilone in women with ovarian cancer. PATIENTS AND METHODS: Women with ovarian cancer recurring within 6 months of end of last platinum-containing treatment received sagopilone 16 mg/m(2) as a 3- or 0.5-h i.v. infusion every 21 days for up to 6 weeks. RESULTS: Sixty-three patients received sagopilone as a 3-h (n=38) or 0.5-h (n=25) infusion. There were nine confirmed tumour responses [by modified RECIST (n=8) and by Gynecologic Cancer Intergroup CA-125 criteria (n=1)] in 57 patients assessable for efficacy overall [three (13%) with 0.5-h and six (18%) with 3-h infusions]. The 0.5-h arm was closed when it failed to meet its target efficacy. Main drug-related adverse events were peripheral sensory neuropathy (73%; 16% grade 3), nausea (37%; 2% grade 3), fatigue (35%; 3% grade 3) and arthralgia (30%; 5% grade 3). Overall incidence of peripheral sensory neuropathy was similar in both treatment arms, with no grade 4 neuropathy events. No acute allergic infusion reactions were observed. CONCLUSION: Sagopilone is effective, with balanced tolerability, in patients with recurrent platinum-resistant ovarian cancer.

Phase I study of the novel, fully synthetic epothilone sagopilone (ZK-EPO) in patients with solid tumors.

BACKGROUND: Sagopilone (ZK-EPO) is a fully synthetic microtubule-stabilizing agent that has demonstrated high antitumor activity in preclinical models. This first-in-human phase I study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxic effects (DLTs) of 3-weekly sagopilone treatment. PATIENTS AND METHODS: A total of 52 patients with advanced solid tumors received a 30-min infusion of escalating doses of sagopilone (0.6-29.4 mg/m(2)) every 3 weeks. Nine additional patients were recruited to a 3-h infusion arm (16.53- or 22.0-mg/m(2) dose) to assess the incidence of neuropathy with prolonged infusion. RESULTS: The MTD was established as 22.0 mg/m(2). DLTs comprised peripheral sensory neuropathy (PNP), infection, hyponatremia, diarrhea, and central ataxia. PNP was the most common grade 3 event, with a similar incidence in the 30-min and 3-h arms. Hematologic adverse events were rare and of low intensity. One confirmed partial response (PR) and one unconfirmed PR were reported in the 30-min arm, and a further unconfirmed PR was observed in the 3-h arm. Eleven patients achieved disease stabilization. Sagopilone showed high levels of tissue binding and no obvious serum accumulation in both arms. CONCLUSIONS: These data demonstrate that sagopilone therapy is feasible and well tolerated. The recommended dose for phase II studies is 16.53 mg/m(2), once every 3 weeks.

Weekly administration of sagopilone (ZK-EPO), a fully synthetic epothilone, in patients with refractory solid tumours: results of a phase I trial.

BACKGROUND: Epothilones are a novel class of microtubule-stabilising agents, and sagopilone is a fully synthetic epothilone that has shown marked in vivo and in vitro preclinical activity. METHODS: This phase I, open-label study investigated the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of weekly sagopilone. Twenty-three patients with malignancy resistant or refractory to standard treatment were enrolled into this study evaluating sagopilone doses from 0.6 to 7.0 mg m(-2). RESULTS: The incidence of drug-related haematological adverse events (AEs) was low, with two grade 3 events observed. Nonhaematological AEs were generally mild and reversible; increased gamma-GT was the only grade 4 event and grade 3 events comprised peripheral neuropathy (n=2), diarrhoea (n=1) and fatigue (n=1). Two grade 3 events were DLTs (diarrhoea and peripheral neuropathy at 7.0 mg m(-2)). The MTD of weekly sagopilone was therefore established as 5.3 mg m(-2). Stable disease was the best overall response (n=3). Microtubule bundle formation in peripheral blood mononuclear cells increased post-treatment, peaking after 1 h. Sagopilone disposition was similar across treatment courses and showed rapidly decreasing serum concentrations after infusion end and a long terminal disposition phase with no obvious accumulation in the serum, probably reflecting a fast uptake into tissues followed by a slow release. CONCLUSION: Weekly administration of sagopilone could represent an alternative to the 3-weekly administration currently evaluated in phase II trials.

Predictive factors of upstaging DCIS to invasive carcinoma in BCT vs mastectomy.

BACKGROUND: Upstaging from DCIS to invasive ductal carcinoma varies widely from 0 to 59%. We aim to identify risk factors associated with upstaging in all DCIS patients and based on specific surgical intervention. METHODS: Patients with a pre-operative diagnosis of DCIS undergoing BCT or mastectomy were reviewed. Multivariable analysis was performed to identify risk factors for upstaging. RESULTS: In total, 623 patients had a preoperative diagnosis of DCIS. Upstaging occurred in 74 patients (12%) overall. There was no difference in upstaging rates between mastectomy and BCT (11% v 14% p = 0.27). Sentinel lymph node biopsy was positive in 4/212 patients (1%). Multivariable analysis revealed suspicion of microinvasion (OR 5.7 95%CI2.2-14.9), surgeon suspicion of invasive disease (OR 2.7, 95% CI 1.2-6.4) and larger size/multicentric/extensive tumor (OR 1.9 95% CI 1.1-3.4) increase risk of upstaging. CONCLUSIONS: Suspicion of microinvasion, surgeon suspicion, and tumor size can be used to help guide the use of sentinel lymph node biopsy. For patients without these high risk characteristics, it is hard to justify the use of concurrent SLN biopsy for patients who undergo BCT.

Influence of treatment with onapristone on the IGF-system in breast cancer patients.

The influence of the novel antiprogestin onapristone on the serum insulin-like growth factor (IGF) system was studied in a group of 13 postmenopausal women with metastatic breast cancer. Blood samples were obtained before treatment and subsequently after 1, 2 and 3 months on therapy. IGF-I, IGF-II and IGF-binding protein (IGFBP)-2 were measured by radioimmunoassay (RIA). In addition, the IGFBP profile was evaluated by Western ligand blotting (WLB), and IGFBP-3 fragmentation determined by immunoblotting. A moderate (29%) but significant increase in IGF-I was observed after 3 months on treatment (p < 0.05). IGFBP-2 showed a significant, progressive increase during treatment when evaluated both by WLB (44% increase over baseline at 3 months) and by RIA (33% increase over baseline at 3 months). There was a non-significant trend towards an initial decrease in IGFBP-3 fragmentation. No significant alterations were observed in IGF-II or any of the binding proteins (except IGFBP-2) determined by Western ligand blotting. Due to the observation that onapristone treatment caused a moderate suppression of serum cortisol and androstenedione, we postulate the observed increase in IGF-I to be due to a slight glucocorticoid agonistic effect of the drug. On the contrary, the increase in IGFBP-2 may be related to disease progression as has been observed in patients suffering from prostatic cancer.

Clinical importance of unilaterally enlarging lymph nodes on otherwise normal mammograms.

PURPOSE: To determine the clinical importance of unilateral enlargement of axillary or intramammary lymph nodes on otherwise normal mammograms. MATERIALS AND METHODS: Twenty-four patients (aged 33-76 years) with unilaterally enlarging lymph nodes on otherwise normal mammograms were identified in a review of mammographic reports from 1991 to 1995. Mammograms, medical history, follow-up findings, and biopsy results were reviewed. RESULTS: The initial nodal size was 3-17 mm. The size increased by 20%-312%. Seven patients had a history of malignancy. Six patients had a clinical history suggestive of a benign cause of nodal enlargement. Seven patients underwent biopsy. Two patients had results positive for malignancy (one, melanoma; one, lymphoma). Both patients had a known history of malignancy and a size increase of greater than 100%. In 17 patients, mammographic follow-up findings at 6-58 months (mean, 26 months) showed decreased nodal size in 13 and no change in four patients. CONCLUSION: Enlarging lymph nodes on otherwise normal mammograms are usually benign. Clinical history can reveal possible causes of nodal enlargement. If the patient has no history of malignancy, the amount of nodal size increase is small, and the node maintains a benign appearance, mammographic follow-up is a reasonable alternative to biopsy.