D. M. Waterhouse

Treatment of Advanced Renal Cell Carcinoma with the Combination Bevacizumab/Erlotinib/Imatinib: A Phase I/II Trial

PURPOSEnThe aim of this study was to evaluate the efficacy and toxicity of imatinib, a platelet-derived growth factor-beta receptor antagonist, when added to the combination bevacizumab/erlotinib in the treatment of patients with advanced clear cell renal carcinoma.nnnPATIENTS AND METHODSnNinety-four patients with metastatic clear cell renal carcinoma were treated with bevacizumab 10 mg/kg intravenously every 2 weeks, erlotinib 150 mg orally daily, and imatinib 400 mg orally daily. Patients were reevaluated after 8 weeks of treatment; patients with objective response or stable disease (SD) continued to receive treatment until they experienced tumor progression.nnnRESULTSnFifteen of 88 evaluable patients (17%; 95% confidence interval, 10%-26%) had partial responses, whereas an additional 54 patients (61%) had SD. The median progression-free and overall survival for all patients was 8.9 months and 17.2 months, respectively. The addition of imatinib markedly increased toxicity compared with the bevacizumab/erlotinib regimen; the most common grade 3/4 toxicities were diarrhea, rash, and fatigue.nnnCONCLUSIONnBevacizumab/erlotinib/imatinib was unacceptably toxic in this group of patients. Inhibition of the PDGF receptor (PDGFR) with imatinib did not appear to improve efficacy compared retrospectively with the results of treatment with bevacizumab/erlotinib. The importance of PDGFR inhibition in the treatment of advanced clear cell renal carcinoma remains unclear. Further development of this particular combination is not planned or recommended.

Efficacy and Safety of Oral Topotecan and Bevacizumab Combination as Second-Line Treatment for Relapsed Small-Cell Lung Cancer: An Open-Label Multicenter Single-Arm Phase II Study

BACKGROUNDnTopotecan is currently the only US Federal Drug Administration (FDA)-approved drug for second-line treatment of relapsed small-cell lung cancer (SCLC). We investigated the efficacy and safety of a novel topotecan-bevacizumab combination in treating relapsed SCLC.nnnPATIENTS AND METHODSnEach 21-day treatment cycle consisted of bevacizumab (15 mg/kg) administration on day 1 and oral topotecan (2.3 mg/m(2)/d) administration on days 1 to 5. Treatment was continued for 8 cycles or until disease progression/toxicity. The primary objective was evaluation of 3-month progression-free survival (PFS). Overall response rate (ORR), duration of response, time to response (TTR), and overall survival (OS) were secondary objectives.nnnRESULTSnThe study enrolled 50 patients between July 2008 and May 2010. The 3-month PFS was 65% (95% confidence interval [CI], 49.3%-76.9%), which was promising compared with the historical control of 50% (P = .017) but did not meet the predefined criteria for clinically meaningful improvement. Median PFS was 6.24 months for the sensitive subgroup (progression time from end of previous chemotherapy > 90 days; n = 27) and 2.91 months for the resistant subgroup (progression time ≤ 90 days; n = 23). No patient achieved complete response (CR), and the ORR was 16%. Twenty (40%) patients had stable disease (SD) and 13 (26%) had progressive disease (PD). Median OS, TTR, and duration of response were 7.4, 1.3, and 4.7 months, respectively. The worst reported adverse events (AEs) were grade 1/2 in 11 (22%) patients and grade 3/4/5 in 39 (78%) patients.nnnCONCLUSIONnImprovement in the 3-month PFS after treatment with topotecan-bevacizumab was promising compared with the historical control and justifies additional studies with this regimen.

A phase II study of two dose levels of ofatumumab induction followed by maintenance therapy in symptomatic, previously untreated chronic lymphocytic leukemia

Despite the recent advances in treatment of CLL with targeted agents such as ibrutinib, availability of nonchemotherapy based therapies is desired. Given the 58% response rate (1996 NCI‐WG criteria) of single agent ofatumumab in CLL refractory to fludarabine and alemtuzumab, we initiated a phase II trial examining response, safety, and progression‐free survival (PFS) of ofatumumab as front‐line monotherapy. Patients enrolled included untreated, symptomatic CLL patients over the age of 65 or those who were inappropriate/did not desire chemotherapy. Two cohorts were enrolled sequentially examining either 1 g (33 patients) or 2 g (44 patients) weekly for 8 weeks followed by maintenance dosing every 2 months for a total of 24 months. Patients receiving 1 g were older than those receiving 2 g, but there were no significant differences in other clinical characteristics. The best overall response rates in the 1 and 2 g patient cohorts were 72 and 89% (1996 NCI‐WG criteria), respectively (54 and 68%, respectively, using 2008 IWCLL criteria). All but two responses were partial. The 24‐month estimated PFS rates were 46 and 78%, respectively. Response and PFS was lower in del(17p) and del(11q) CLL patients. Differences in PFS between dose cohorts were statistically significant and remained so when adjusting for age or high‐risk cytogenetics. Toxicity of this treatment was mild with only six patients not completing therapy due to toxicity. Ofatumumab induction followed by maintenance therapy in untreated CLL represents a well‐tolerated and active regimen, particularly with the 2 g of ofatumumab. Am. J. Hematol. 91:1020–1025, 2016.

High-Dose Bevacizumab in the Treatment of Patients With Advanced Clear Cell Renal Carcinoma: A Phase II Trial of the Sarah Cannon Oncology Research Consortium

BACKGROUNDnThe dose of bevacizumab necessary to optimally inhibit tumor angiogenesis in advanced renal cell carcinoma is unknown. In this phase II trial, we evaluated the efficacy and safety of 2 escalated doses of bevacizumab in patients with advanced clear cell renal carcinoma.nnnPATIENTS AND METHODSnEligible patients had metastatic or locally advanced unresectable clear cell renal carcinoma. Patients who were previously untreated or who had previously received vascular endothelial growth factor receptor (VEGFR)-targeted therapy were eligible and were considered separately in the efficacy evaluation. Two doses of bevacizumab were evaluated in sequential cohorts: 15 mg/kg every 2 weeks and 15 mg/kg weekly. The initial reevaluation was at 8 weeks; responding and stable patients continued treatment, with reevaluations every 8 weeks until tumor progression or unacceptable toxicity occurred.nnnRESULTSnOne hundred nineteen eligible patients were enrolled and received bevacizumab 15 mg/kg every 2 weeks (n = 61) or bevacizumab 15 mg/kg weekly (n = 58). Seventy patients were previously untreated with VEGFR-targeted therapy. In previously untreated patients, the overall response rate was 19%, with a median progression-free survival (PFS) of 7.8 months. Less activity was seen in patients previously treated with VEGFR-targeted agents (overall response rate, 4%; median PFS, 3.7 months). There was no suggestion of any difference in efficacy between the 2 dose levels tested. Both dose levels were tolerated well by most patients, with a spectrum of toxicity typical for bevacizumab. Grade 3/4 proteinuria was more frequent with both of these escalated doses, particularly with 15 mg/kg weekly.nnnCONCLUSIONnAlthough administration of escalated doses of bevacizumab was feasible in patients with advanced clear cell renal carcinoma, there was no suggestion that these doses were more efficacious than bevacizumab administered at the standard dose of 10 mg/kg every 2 weeks.

Lenalidomide in combination with gemcitabine as first-line treatment for patients with metastatic carcinoma of the pancreas: A Sarah Cannon Research Institute phase II trial

Objectives: To evaluate the 6-mo overall survival, safety and tolerability of lenalidomide in combination with standard gemcitabine as first-line treatment for patients with metastatic pancreatic cancer. Methods: Eligibility included: previously untreated metastatic adenocarcinoma of the pancreas with metastases incurable by surgery/radiation therapy; ECOG PS 0–2; adequate organ function; prophylactic anticoagulation for venous thromboembolic events (VTEs). Patients received lenalidomide 25 mg PO (days 1–21) and gemcitabine 1,000 mg/m2 IV (days 1, 8 and 15) each 28-day cycle, with response evaluations every eight weeks. Results: Between 5/2009–4/2010, 72 patients (median age 64 years; 68% male; 42% ECOG PS 0) were enrolled in this multicenter, community-based study. Six-month OS was 37% (95% CI 26–48%). Median PFS and OS were 2.3 (95% CI 1.9–3.5) and 4.7 (95% CI 3.4–5.7) months, respectively. Eight partial responses (11%) were documented. Thirty-nine patients (54%) experienced thrombocytopenia (2 patients, 3% grade 4). Hematologic toxicities resulted in dose modifications for the majority of patients. Twenty patients (28%) developed VTEs during treatment. Conclusions: The observed 6-month OS (37%) of lenalidomide with gemcitabine does not suggest improvement compared with historical results with gemcitabine alone. Toxicities and dose modifications likely limited dose intensity. Further development of this regimen in pancreas cancer is not recommended.

A Phase II Study of the Combination of Bevacizumab, Pertuzumab, and Octreotide LAR for Patients with Advanced Neuroendocrine Cancers

ABSTRACT Purpose: To evaluate efficacy and safety of bevacizumab, pertuzumab, and octreotide depot for advanced neuroendocrine tumors. Methods: Patients received bevacizumab 15 mg/kg and pertuzumab 420 mg IV q21 days with octreotide depot 30 mg IM q28 days. Results: Toxicities in 43 patients included diarrhea (63%), fatigue (63%), hypertension (44%), and nausea (44%). Reversible G3 hypertension (26%) and LVEF decline (9%) occurred. 7/43 patients achieved objective response (typical carcinoid, 5; pancreatic NET, 2). Median PFS and OS were 6.5 and 26.4 months, respectively. Discussion: Bevacizumab, pertuzumab, and octreotide depot was well-tolerated with a 16% ORR. Results in the well-differentiated carcinoid tumors are thought provoking.

Phase II trial of preoperative pemetrexed plus carboplatin in patients with stage IB-III nonsquamous non-small cell lung cancer (NSCLC)

OBJECTIVESnThe combination of pemetrexed and carboplatin is a standard first-line treatment for patients with advanced NSCLC. In this pilot phase II trial, we evaluated the feasibility of using pemetrexed and carboplatin as neoadjuvant therapy, prior to definitive surgical resection, for patients with localized NSCLC.nnnPATIENTS AND METHODSnPatients with potentially resectable, previously untreated, clinical stage IB-III, nonsquamous NSCLC were eligible for this trial. All patients received 4 cycles of pemetrexed (500u202fmg/m2) and carboplatin (AUC 6.0) administered at 21u202fday intervals. Three to 6 weeks after completion of chemotherapy, definitive surgical resection was attempted. The primary endpoint of this trial was the 3-year survival rate.nnnRESULTSnForty-six patients began protocol treatment, and 40 completed 4 courses of pemetrexed/carboplatin. Surgical resection was performed in 27 patients (59%); all had pathologic partial responses. The estimated 3-year survival rate for the entire group was 46%. Toxicity of neoadjuvant therapy was consistent with toxicity previously reported with pemetrexed/carboplatin.nnnCONCLUSIONSnAdministration of 4 courses of pemetrexed/carboplatin was feasible. The efficacy was similar to neoadjuvant regimens previously investigated. A significant number of patients 19 of 46 (41%) in this trial did not have surgical resection after neoadjuvant therapy. Further investigation of the role of neoadjuvant pemetrexed/carboplatin requires a larger, randomized clinical trial.