Edward Arrowsmith

A Phase II Trial of Panobinostat, a Histone Deacetylase Inhibitor, in the Treatment of Patients with Refractory Metastatic Renal Cell Carcinoma

Purpose: To evaluate the activity of panobinostat in refractory renal carcinoma. Patients and Methods: Patients with advanced clear cell renal carcinoma who had received previous therapy with at least one angiogenesis inhibitor and one mTOR inhibitor were treated with panobinostat 45 mg orally twice a week, and were reevaluated after 8 weeks. Results: Twenty patients were treated with no objective responses. All patients progressed or stopped treatment prior to the 16-week reevaluation. Panobinostat was generally well-tolerated. Conclusion: Panobinostat had no activity in this group of patients with refractory renal carcinoma. Further development of panobinostat in renal carcinoma is not recommended.

Phase I/II study of the combination of panobinostat and carfilzomib in patients with relapsed/refractory multiple myeloma

The purpose of this study was to assess the safety and efficacy of the combination of panobinostat and carfilzomib in patients with relapsed/refractory multiple myeloma. Patients with multiple myeloma who had relapsed after at least one prior treatment were eligible to participate. In the dose escalation part of the study a standard 3+3 design was used to determine the maximum tolerated dose of four planned dose levels of the combination of carfilzomib and panobinostat. Panobinostat was administered on days 1, 3, 5, 15, 17, and 19. Carfilzomib was administered on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Treatment was continued until progression or intolerable toxicity. Forty-four patients were accrued into the trial, 13 in the phase I part and 31 in the phase II part of the study. The median age of the patients was 66 years and the median number of prior therapies was five. The expansion dose was established as 30 mg panobinostat, 20/45 mg/m2 carfilzomib. The overall response rate was 67% for all patients, 67% for patients refractory to prior proteasome inhibitor treatment and 75% for patients refractory to prior immune modulating drug treatment. At a median follow up of 17 months, median progression-free survival was 7.7 months, median time to progression was 7.7 months, and median overall survival had not been reached. The regimen was well tolerated, although there were several panobinostat dose reductions. In conclusion, the combination of panobinostat and carfilzomib is feasible and effective in patients with relapsed/refractory multiple myeloma. (Trial registered at ClinicalTrials.gov: NCT01496118)

Phase 2, multicenter, open-label study of tigatuzumab (CS-1008), a humanized monoclonal antibody targeting death receptor 5, in combination with gemcitabine in chemotherapy-naive patients with unresectable or metastatic pancreatic cancer.

Tigatuzumab is the humanized version of the agonistic murine monoclonal antibody TRA‐8 that binds to the death receptor 5 and induces apoptosis of human cancer cell lines via the caspase cascade. The combination of tigatuzumab and gemcitabine inhibits tumor growth in murine pancreatic xenografts. This phase 2 trial evaluated the efficacy of tigatuzumab combined with gemcitabine in 62 chemotherapy‐naive patients with histologically or cytologically confirmed unresectable or metastatic pancreatic cancer. Patients received intravenous tigatuzumab (8 mg/kg loading dose followed by 3 mg/kg weekly) and gemcitabine (1000 mg/m2 once weekly for 3 weeks followed by 1 week of rest) until progressive disease (PD) or unacceptable toxicity occurred. The primary end point was progression‐free survival (PFS) at 16 weeks. Secondary end points included objective response rate (ORR) (complete responses plus partial responses), duration of response, and overall survival (OS). Safety of the combination was also evaluated. Mean duration of treatment was 18.48 weeks for tigatuzumab and 17.73 weeks for gemcitabine. The PFS rate at 16 weeks was 52.5% (95% confidence interval [CI], 39.3–64.1%). The ORR was 13.1%; 28 (45.9%) patients had stable disease and 14 (23%) patients had PD. Median PFS was 3.9 months (95% CI, 2.2–5.4 months). Median OS was 8.2 months (95% CI, 5.1–9.6 months). The most common adverse events related to tigatuzumab were nausea (35.5%), fatigue (32.3%), and peripheral edema (19.4%). Tigatuzumab combined with gemcitabine was well tolerated and may be clinically active for the treatment of chemotherapy‐naive patients with unresectable or metastatic pancreatic cancer.

Pazopanib as Second-Line Treatment After Sunitinib or Bevacizumab in Patients With Advanced Renal Cell Carcinoma: A Sarah Cannon Oncology Research Consortium Phase II Trial

BACKGROUND This phase II trial examined the activity and toxicity of second-line treatment with pazopanib after failure of first-line single-agent treatment with sunitinib or bevacizumab in patients with advanced clear cell renal carcinoma. PATIENTS AND METHODS Fifty-five patients with metastatic clear cell renal carcinoma who had previously received first-line treatment with sunitinib (39 patients) or bevacizumab (16 patients) were enrolled. Patients received pazopanib 800 mg orally daily and were evaluated for response after 8 weeks of treatment. Responses were measured using Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0, and confirmed with repeated scans after 8 weeks. Patients with objective response or stable disease continued treatment until disease progression or unacceptable toxicity occurred. RESULTS Fifteen of 55 patients (27%) had objective response to pazopanib. An additional 27 patients (49%) had stable disease, for a disease control rate of 76%. After a median follow-up of 16.7 months, the median progression-free survival for the entire group was 7.5 months (95% confidence interval, 5.4-9.4 months). Similar progression-free survival was observed regardless of whether previous treatment was with sunitinib or bevacizumab. The estimated overall survival rate for the entire group at 24 months was 43%. CONCLUSION Pazopanib is an active agent for the treatment of advanced clear cell renal carcinoma, even after failure of sunitinib or bevacizumab. Treatment with pazopanib should be considered early in the sequence of therapy for patients with advanced renal cell carcinoma.

Hormonal Therapy Plus Bevacizumab in Postmenopausal Patients Who Have Hormone Receptor–Positive Metastatic Breast Cancer: A Phase II Trial of the Sarah Cannon Oncology Research Consortium

PURPOSE Preclinical models suggest that addition of anti-vascular endothelial growth factor therapy may improve the efficacy of anti-estrogens in hormone-sensitive breast cancer. This phase II trial evaluated the feasibility and efficacy of bevacizumab added to either anastrozole or fulvestrant in the first-line treatment of patients who have hormone receptor-positive metastatic breast cancer. METHODS Women who had newly diagnosed metastatic hormone receptor-positive breast cancer were eligible. Patients who had relapsed while receiving, or ≤ 12 months after receiving, adjuvant aromatase inhibitor therapy were treated with bevacizumab (10 mg/kg intravenously every 2 weeks) and fulvestrant (loading dose 500 mg intramuscularly [IM], then 250 mg IM 2 weeks later, then 250 mg IM every 4 weeks). All other patients received fulvestrant/bevacizumab or anastrozole (1 mg orally daily)/bevacizumab. Patients who were HER2-positive could also receive trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks). Patients were reevaluated after 8 weeks of therapy; responding or stable patients continued treatment until disease progression or unacceptable toxicity. RESULTS Seventy-nine patients were enrolled (38 were administered anastrozole 41 fulvestrant). Median treatment duration was 8 months in the anastrozole group and 5.5 months in the fulvestrant group. Both regimens were efficacious: overall response rate and median progression-free survival for the entire group were 28% and 13.5 months, respectively. Both regimens were well-tolerated; toxicity was consistent with the known toxicity profiles of each single agent. CONCLUSION Bevacizumab combined with either anastrozole or fulvestrant was feasible and active in the first-line treatment of patients who have hormone receptor-positive metastatic breast cancer. Phase III trials evaluating the efficacy of bevacizumab added to endocrine therapy are in progress.

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

BACKGROUND The 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. PATIENTS AND METHODS Eligible 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. RESULTS One 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. CONCLUSION Although 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.

Phase II Study of Gemcitabine and Bevacizumab As First-Line Treatment in Taxane-Pretreated, HER2-Negative, Locally Recurrent or Metastatic Breast Cancer

BACKGROUND In first-line treatment of metastatic breast cancer, the best use of the available therapeutic agents is unclear. This study evaluated the efficacy and safety of combined therapy with bevacizumab and gemcitabine. PATIENTS Women who were to undergo first-line treatment for locoregionally recurrent or metastatic breast cancer were eligible. Patients must have received a taxane-containing regimen in the neoadjuvant and/or adjuvant setting with a ≥ 12-month disease-free interval. METHODS This was a single-arm, phase II trial. On day 1 of each 14-day cycle, patients received gemcitabine (2500 mg/m(2)) followed by bevacizumab (10 mg/kg). Patients were treated until complete response, progressive disease (PD), or intolerable toxicity. The primary endpoint was progression-free survival (PFS). RESULTS Fifty-two women were enrolled and treated. The median PFS was 4.8 months (95% confidence interval [CI], 3.4-7.6), the 1-year overall survival rate was 68.7% (95% CI, 54.1%-79.5%), and the response rate was 21.4% (95% CI, 10.3%-36.8%). The clinical benefit rate was 35.7%. The median PFS in the triple-negative (n = 19) and non-triple-negative (n = 33) subsets was 3.9 months (95% CI, 2.7-11.7) and 4.9 months (95% CI, 3.4-8.1), respectively. The most common (all grades) drug-related adverse events (AEs) were nausea (51.9%), fatigue (46.2%), decreased appetite (25.0%), and anemia (25.0%). The most common grade 3 or grade 4 drug-related AEs were neutropenia (13.5%), leukopenia (11.5%), and hypertension (7.7%). CONCLUSION Although the gemcitabine-bevacizumab doublet appears active, the median PFS was lower than expected. There were no unexpected safety signals at this dose and schedule of this combination.

A Phase II Study of Higher Dose Weekly Topotecan in Relapsed Small-Cell Lung Cancer

BACKGROUND Five-day topotecan is approved by the US Federal Drug Administration (FDA) for sensitive relapsed small-cell lung cancer (SCLC). We previously found that 4 mg/m(2) intravenous (I.V.) weekly dosing resulted in low-grade 3/4 toxicity but an overall response rate (ORR) < 10%. We hypothesized that higher topotecan dosing could improve ORR without significantly increasing toxicity. PATIENTS AND METHODS This multicenter phase II trial sought a 25% ORR (α = 0.04; β = 0.20). Eligible patients (sensitive or refractory relapsed SCLC; Eastern Cooperative Oncology Group [ECOG] performance status [PS] 0-1; measurable disease) received weekly topotecan (6 mg/m(2) I.V. for 6 weeks) and were restaged every 8 weeks. RESULTS Baseline characteristics were N = 38, enrolled 5/2006-10/2007; median age 64 years (range, 35-82), 47% female, 74% ECOG PS 1, 50% refractory relapsed SCLC. The median follow-up was 15 months (range, 12-24 months). No patients received all planned therapy; only 1 patient was able to receive all planned treatment in cycle 1 because of hematologic toxicity and progressive disease (PD). Among all patients, ORR was 8% (95% confidence interval [CI], 2%-21%), 24% had stable disease, and disease in 47% progressed. Among sensitive relapsed patients ORR was 16% (95% CI, 3%-40%) with no complete responses; median response duration was 3.3 months. Five (26%) patients had stable disease; 8 (42%) patients had PD. Among sensitive relapsed patients, the median time to progression (TTP) and overall survival (OS) was 2.5 months and 8.6 months, respectively. Among refractory relapsed patients there were no ORRs, and median TTP and OS were 1.5 months and 3.7 months, respectively. Grade 3/4 toxicities (> 10%) included neutropenia (53%), leukopenia (42%), thrombocytopenia (37%), anemia (13%), fatigue (13%), and pain (13%). There were no treatment-related deaths. CONCLUSION Weekly topotecan (6 mg/m(2) I.V.) is not feasible because of hematologic toxicity and does not improve efficacy in patients with relapsed SCLC.

A Phase II Trial Evaluating the Safety of Rapid Infusion of Ofatumumab in Patients with Previously Treated Chronic Lymphocytic Leukemia

Lessons Learned. Ofatumumab infusion reactions can be diminished by escalating the dose rate in individual patients in sequential infusions. Background. Ofatumumab (OFA) is a fully humanized, anti‐CD20 antibody approved for use in chronic lymphocytic leukemia (CLL). The recommended administration requires long infusion times. We evaluated an accelerated infusion regimen of 2 hours. Methods. The first dose of OFA (300 mg) was given on week 1 day 1 starting at 3.6 mg/hour and doubling every 30 minutes until a rate of 240 mg/hour was reached. If tolerated, the second dose (1,000 mg) was given on week 1 day 3 starting at 50 mg/hour and doubling every 30 minutes until a rate of 800 mg/hour was reached. If tolerated, the third dose (2,000 mg) was given on week 2 day 1 at 800 mg/hour over the first 30 minutes and, if tolerated, at 1,068 mg/hour over the next 90 minutes (goal infusion time: 120 minutes). Subsequent OFA infusions were administered weekly in the same manner for 8 weeks, and then monthly for 4 months. Results. Thirty‐four patients were treated. Most infusion‐related reactions occurred during the first and second infusion. Eighty‐seven percent (87%) of patients finished the third infusion within 15 minutes of the planned 2 hours and only one had an infusion reaction. Conclusion. Using this stepped‐up dosing regimen, a rapid infusion of OFA is safe and well tolerated.

A Phase II Study with Lead‐In Safety Cohort of 5‐Fluorouracil, Oxaliplatin, and Lapatinib in Combination with Radiation Therapy as Neoadjuvant Treatment for Patients with Localized HER2‐Positive Esophagogastric Adenocarcinomas

Abstract Lessons Learned. Neoadjuvant 5‐fluorouracil, oxaliplatin, and lapatinib in combination with radiation therapy is safe for neoadjuvant treatment for patients with localized human epidermal growth receptor 2‐positive esophagogastric adenocarcinoma. Evaluation of this drug combination in a larger patient pool would allow for more accurate analysis of its efficacy. Background. The optimal design of neoadjuvant chemoradiation for the treatment of localized esophagogastric cancers is the subject of much debate. In this nonrandomized trial, we evaluated neoadjuvant 5‐fluorouracil (5‐FU), oxaliplatin, and lapatinib in combination with radiation therapy as neoadjuvant treatment for patients with localized human epidermal growth receptor 2 (HER2)‐positive esophagogastric adenocarcinomas. Methods. Patients received neoadjuvant 5‐FU (225 mg/m2 continuous intravenous infusion, days 1–42), oxaliplatin (85 mg/m2 intravenously [IV], days 1, 15, and 29), and lapatinib (six patients, 1,000 mg p.o., days 1–42; six patients, 750 mg p.o., days 1–42) plus radiation (1.8 Gy/day Monday through Friday for 50.4 Gy total). Following restaging, eligible patients underwent definitive resection, and pathologic response to neoadjuvant therapy was assessed. Planned enrollment was 42 patients. The primary endpoint was the pathologic complete response (pCR) rate. Results. Twelve patients (median age 64 years; 67% male) received a median of 5.6 weeks of treatment (range: 1.1–8.4). The pCR rate was 8%; four of the 12 patients underwent tumor resection and one patient had a pCR, with pathologic partial response in the remaining three. The most common lapatinib‐related adverse events included (all grades) nausea (67%) and diarrhea (58%), although these were all grade 1 or 2. Enrollment was halted due to low accrual. Conclusion. The treatment regimen was determined to be safe. The study was terminated early due to low accrual.