Cassie M. Lane

Bevacizumab and everolimus in the treatment of patients with metastatic melanoma: a phase 2 trial of the Sarah Cannon Oncology Research Consortium.

In this phase 2 study, the activity and tolerability of the combination of bevacizumab, an inhibitor of angiogenesis, and everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), was evaluated in the treatment of patients with metastatic melanoma.

A Phase II Trial of Dose-Dense Neoadjuvant Gemcitabine, Epirubicin, and Albumin-Bound Paclitaxel With Pegfilgrastim in the Treatment of Patients With Locally Advanced Breast Cancer

BACKGROUND Neoadjuvant anthracycline/taxane combinations, with or without gemcitabine, produce pathologic complete responses (pCRs) in 15%-25% of patients. In this multicenter phase II study, we attempted to increase efficacy and decrease toxicity of a 3-drug gemcitabine-containing neoadjuvant regimen by administering dose-dense therapy with pegfilgrastim, and including albumin-bound paclitaxel as the taxane. PATIENTS AND METHODS A total of 123 patients with locally advanced breast cancer were enrolled. Patients were treated with 6 doses of neoadjuvant gemcitabine 2000 mg/m2, epirubicin 50 mg/m2, and albumin-bound paclitaxel 175 mg/m2 intravenously administered at 14-day intervals. Following neoadjuvant chemotherapy, patients underwent either mastectomy or breast conservation surgery; pathologic response to treatment was assessed. Postoperatively, patients received 4 doses of gemcitabine 2000 mg/m2 with albumin-bound paclitaxel 220 mg/m2 at 14-day intervals. Pegfilgrastim 6 mg was administered subcutaneously on day 2 following each dose of chemotherapy. RESULTS A total of 116 patients (95%) completed neoadjuvant chemotherapy and had subsequent surgical resection. Twenty-three patients (20%) had a pCR. The estimated 3-year progression-free survival (PFS) and overall survival rates were 48% and 86%, respectively. Neoadjuvant treatment was well tolerated; only 11% of the patients had grade 3/4 neutropenia, with 1 episode of neutropenic fever. Other grade 3/4 toxicities occurred in < 10% of the patients. CONCLUSION Neoadjuvant biweekly chemotherapy with gemcitabine/epirubicin/albumin-bound paclitaxel with pegfilgrastim is feasible and well tolerated. The pCR rate of 20% and the 3-year PFS rate of 48% are similar to results achieved with other commonly used neoadjuvant regimens.

Phase II Study of Cetuximab, Docetaxel, and Gemcitabine in Patients With Previously Untreated Advanced Non-Small-Cell Lung Cancer

BACKGROUND Targeting epidermal growth factor receptors (EGFRs) has been a novel strategy in treating non-small-cell lung cancer (NSCLC). This multicenter, community-based trial was designed to examine the role of cetuximab in combination with a nonplatinum regimen. PATIENTS AND METHODS Eligibility criteria were newly diagnosed unresectable stage III/IV NSCLC, all histologies, measurable disease, and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2. Treatment premedication included dexamethasone 20 mg orally 12 and 6 hours before treatment, and 4 mg 12 hours following treatment; diphenhydramine 50 mg intravenously (I.V.) and cimetidine 300 mg I.V. before cetuximab. Treatment medication included docetaxel 30 mg/m2 I.V. days 1 and 8; gemcitabine 1000 mg/m2 I.V. days 1 and 8; and cetuximab 400 mg/m2 I.V. day 1, then 250 mg/m2 I.V. weekly. Patients received up to 6 cycles with restaging every 6 weeks. The primary endpoint was an overall response rate (ORR) > or = 25%. RESULTS Sixty-nine patients enrolled from July 2005 to October 2007. Patients had a median age of 69 years; 70% were male and 30% were female; ECOG PS was 0 in 42%, 1 in 51%, and 2 in 7%; patients had adenocarcinoma (42%), squamous cell (30%), large cell (6%), mixed (1%), and not otherwise specified (20%) disease. The ORR was 17% (95% CI, 9%-29%). Thirty-five patients (54%) had stable disease; 14 patients (22%) had progressive disease. With a median follow-up of 17.8 months, the median progression-free and overall survivals were 4 months and 9.4 months, respectively. The most common (> 10%) grade 3/4 toxicities were neutropenia (25%), rash (22%), and fatigue (12%). Accrual in our middle Tennessee offices was temporarily suspended and ultimately stopped because of a higher-than-anticipated rate of cetuximab-related severe hypersensitivity reactions (HSRs) in 4 patients among the first 12 enrolled, including 1 fatal event. CONCLUSION Cetuximab/docetaxel/gemcitabine was relatively well-tolerated and associated with efficacy similar to chemotherapy alone. Additional study with cetuximab/chemotherapy in NSCLC should focus on new potentially predictive biomarkers. Also, additional study is needed to better understand and prevent the severe HSRs that appear to be endemic to specific regions of the United States.

A Phase 2 Study of the Hsp90 Inhibitor AUY922 as Treatment for Patients with Refractory Gastrointestinal Stromal Tumors

ABSTRACT Background: AUY922 is an inhibitor of heat shock protein 90 (Hsp90). Hsp90 inhibitors induce kit degradation in preclinical gastrointestinal stromal tumor (GIST) models. This trial was designed to determine the progression-free survival (PFS) of patients with GIST refractory to or intolerant of imatinib and sunitinib. Methods: Eligible patients received AUY922 70 mg/mg2 by intravenous (IV) infusion on days 1, 8, and 15 of 21-day cycles. Treatment continued until progression or unacceptable toxicity. Results: Between December 2011 and January 2015, 25 patients were enrolled (median age, 63 years; 56% male) and received a median of 2 cycles (range: 1–12) of AUY922 treatment. Thirty-four patients were planned, but enrollment was stopped early due to slow accrual. Median PFS was 3.9 months (95% CI: 2.5, 5.3) and median OS was 8.5 months (95% CI: 5.2, 16.7). Radiographic response was evaluated in 21 patients; one patient achieved PR (4%) with another 15 having best response of stable disease (60%). The most common treatment-related adverse event was diarrhea (60% all grades). Reversible ocular toxicities that resulted in drug hold (24%) or reduction (8%) were also observed. Conclusion: AUY922 produced a median PFS which compares favorably to historical controls of placebo (6 weeks) for patients refractory to treatment with imatinib. While diarrhea and ocular toxicities were common, the majority of patients received treatment until disease progression.

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.

Phase II Trial of Vinflunine in Relapsed Small Cell Lung Cancer

Background: Vinflunine is a new microtubule inhibitor with preclinical activity in small cell lung cancer (SCLC). In this phase II trial, we evaluated vinflunine in patients with relapse-sensitive and refractory SCLC. Methods: This trial aimed to achieve a 20% objective response rate (ORR) in platinum-sensitive patients. Patients with Eastern Cooperative Oncology Group performance status 0 to 2 and measurable disease received vinflunine (320 mg/m2 IV) every 21 days (≤6 cycles; response evaluation every 6 weeks). Results: Patient characteristics (N = 51): median age 63 years (range, 37–85 years); male, 55%; Eastern Cooperative Oncology Group performance status 2, 16%; relapse-sensitive SCLC, 53%. The overall ORR was 19.6% (95% confidence interval [CI] 10–33%). Twelve (23.5%) patients had stable disease; 18 (35.3%) patients had progressive disease. Among relapse-sensitive patients, ORR was 22.2% (95% CI 9–42%). Among relapse-refractory patients, ORR was 16.7% (95% CI 5–37%). Median follow-up was 15 months (range, 12–18 months); median progression-free survival (PFS) was 1.6 months (95% CI 1.3–3.9 months); median overall survival (OS) was 4.9 months (95% CI 3.2–6.5 months). Among relapse-sensitive patients, PFS and OS were 1.6 and 4.9 months, respectively. Among relapsed-refractory patients, PFS and OS were 1.4 and 4.0 months, respectively. In general, vinflunine was well tolerated, although neutropenia was a notable toxicity. Grade 3/4 toxicities (>5%): neutropenia (32%), arthralgia/myalgia (16%), fatigue (16%), hyponatremia (12%), leukopenia (12%), nausea/vomiting (12%), constipation (6%), and thrombocytopenia (6%). The rates of toxicities were relatively well balanced among relapse-sensitive and refractory patients; one patient died of sepsis that was possibly treatment related. Conclusions: Vinflunine has activity in relapsed SCLC, including refractory relapsed patients. Neutropenia was common but associated with rare febrile episodes. Additional study in relapse-refractory SCLC is indicated.

Single Agent Vinflunine in the Salvage Treatment of Patients with Castration-Resistant Prostate Cancer: A Phase II Trial of the Sarah Cannon Research Consortium

ABSTRACT Patients with metastatic prostate cancer resistant to hormones and docetaxel were treated with vinflunine (320 mg/m2 every 21 days), a new vinca alkaloid with improved preclinical activity. Only 1 of 36 patients (3%) had partial response; the median progression-free survival (PFS) was 2.1 months. Treatment was well tolerated, with myelosuppression as the only frequent toxicity. Vinflunine has a low level of activity in the treatment of refractory metastatic prostate cancer, and should not be further developed for this indication.

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.

A Phase-2 Trial of Single Agent Axitinib as Maintenance Therapy Following First-Line Treatment With Modified FOLFOX/Bevacizumab in Patients With Metastatic Colorectal Cancer

ABSTRACT This phase-2 trial evaluated the efficacy of axitinib as maintenance therapy for patients with metastatic colorectal cancer (mCRC) following first-line treatment with FOLFOX/bevacizumab. Patients with mCRC received mFOLFOX/bevacizumab followed by axitinib maintenance after four cycles. The primary endpoint was progression-free survival (PFS). Seventy patients were enrolled. Common treatment-related toxicities were fatigue, nausea, diarrhea, and peripheral neuropathy during FOLFOX/bevacizumab treatment; and fatigue, hypertension, diarrhea, and peripheral neuropathy during axitinib treatment. Median PFS was 8.3 months. Treatment with FOLFOX/bevacizumab followed by maintenance axitinib as first-line treatment for mCRC produced a median PFS consistent with historical controls of other first-line regimens.

A Phase 2 Study of 5-Fluorouracil (5-FU), Ziv-Aflibercept, and Radiation for the Preoperative and Adjuvant Treatment of Patients with Stage II/III Rectal Cancer

ABSTRACT Background: This phase II study combined aflibercept with preoperative chemoradiation for patients with stage II/III rectal cancer, followed by mFOLFOX6/aflibercept. Methods: Patients received preoperative 5-FU (days 1–43), radiation (weeks 1–6), and aflibercept (days 1–15) each 28 day cycle for 6 weeks. Six weeks following the last aflibercept dose, patients underwent surgical resection. Four cycles of mFOLFOX6 plus aflibercept began 8 weeks after surgery. Results: Common treatment-related toxicities included diarrhea, fatigue, and mucositis. The pCR rate was 23%. Discussion: Afilbercept plus 5-FU-based chemoradiation was tolerated in patients with localized rectal cancer and showed a pCR rate within range of historical data.