scholarly journals Cabozantinib in Patients With Advanced Prostate Cancer: Results of a Phase II Randomized Discontinuation Trial

2013 ◽  
Vol 31 (4) ◽  
pp. 412-419 ◽  
Author(s):  
David C. Smith ◽  
Matthew R. Smith ◽  
Christopher Sweeney ◽  
Aymen A. Elfiky ◽  
Christopher Logothetis ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Soft Tissue ◽  
Phase Ii ◽  
Stable Disease ◽  
Objective Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Random Assignment ◽  
Soft Tissue Lesions ◽  
Randomized Discontinuation Trial

Purpose Cabozantinib (XL184) is an orally bioavailable tyrosine kinase inhibitor with activity against MET and vascular endothelial growth factor receptor 2. We evaluated the activity of cabozantinib in patients with castration-resistant prostate cancer (CRPC) in a phase II randomized discontinuation trial with an expansion cohort. Patients and Methods Patients received 100 mg of cabozantinib daily. Those with stable disease per RECIST at 12 weeks were randomly assigned to cabozantinib or placebo. Primary end points were objective response rate at 12 weeks and progression-free survival (PFS) after random assignment. Results One hundred seventy-one men with CRPC were enrolled. Random assignment was halted early based on the observed activity of cabozantinib. Seventy-two percent of patients had regression in soft tissue lesions, whereas 68% of evaluable patients had improvement on bone scan, including complete resolution in 12%. The objective response rate at 12 weeks was 5%, with stable disease in 75% of patients. Thirty-one patients with stable disease at week 12 were randomly assigned. Median PFS was 23.9 weeks (95% CI, 10.7 to 62.4 weeks) with cabozantinib and 5.9 weeks (95% CI, 5.4 to 6.6 weeks) with placebo (hazard ratio, 0.12; P < .001). Serum total alkaline phosphatase and plasma cross-linked C-terminal telopeptide of type I collagen were reduced by ≥ 50% in 57% of evaluable patients. On retrospective review, bone pain improved in 67% of evaluable patients, with a decrease in narcotic use in 56%. The most common grade 3 adverse events were fatigue (16%), hypertension (12%), and hand-foot syndrome (8%). Conclusion Cabozantinib has clinical activity in men with CRPC, including reduction of soft tissue lesions, improvement in PFS, resolution of bone scans, and reductions in bone turnover markers, pain, and narcotic use.

scholarly journals Pembrolizumab for Treatment-Refractory Metastatic Castration-Resistant Prostate Cancer: Multicohort, Open-Label Phase II KEYNOTE-199 Study

2020 ◽  
Vol 38 (5) ◽  
pp. 395-405 ◽  
Author(s):  
Emmanuel S. Antonarakis ◽  
Josep M. Piulats ◽  
Marine Gross-Goupil ◽  
Jeffrey Goh ◽  
Kristiina Ojamaa ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Antitumor Activity ◽  
Disease Control ◽  
Phase Ii ◽  
Objective Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Duration Of Response

PURPOSE Pembrolizumab has previously shown antitumor activity against programmed death ligand 1 (PD-L1)–positive metastatic castration-resistant prostate cancer (mCRPC). Here, we assessed the antitumor activity and safety of pembrolizumab in three parallel cohorts of a larger mCRPC population. METHODS The phase II KEYNOTE-199 study included three cohorts of patients with mCRPC treated with docetaxel and one or more targeted endocrine therapies. Cohorts 1 and 2 enrolled patients with RECIST-measurable PD-L1–positive and PD-L1–negative disease, respectively. Cohort 3 enrolled patients with bone-predominant disease, regardless of PD-L1 expression. All patients received pembrolizumab 200 mg every 3 weeks for up to 35 cycles. The primary end point was objective response rate per RECIST v1.1 assessed by central review in cohorts 1 and 2. Secondary end points included disease control rate, duration of response, overall survival (OS), and safety. RESULTS Two hundred fifty-eight patients were enrolled: 133 in cohort 1, 66 in cohort 2, and 59 in cohort 3. Objective response rate was 5% (95% CI, 2% to 11%) in cohort 1 and 3% (95% CI, < 1% to 11%) in cohort 2. Median duration of response was not reached (range, 1.9 to ≥ 21.8 months) and 10.6 months (range, 4.4 to 16.8 months), respectively. Disease control rate was 10% in cohort 1, 9% in cohort 2, and 22% in cohort 3. Median OS was 9.5 months in cohort 1, 7.9 months in cohort 2, and 14.1 months in cohort 3. Treatment-related adverse events occurred in 60% of patients, were of grade 3 to 5 severity in 15%, and led to discontinuation of treatment in 5%. CONCLUSION Pembrolizumab monotherapy shows antitumor activity with an acceptable safety profile in a subset of patients with RECIST-measurable and bone-predominant mCRPC previously treated with docetaxel and targeted endocrine therapy. Observed responses seem to be durable, and OS estimates are encouraging.

scholarly journals A Phase II Study of Glembatumumab Vedotin for Metastatic Uveal Melanoma

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2270
Author(s):  
Merve Hasanov ◽  
Matthew J. Rioth ◽  
Kari Kendra ◽  
Leonel Hernandez-Aya ◽  
Richard W. Joseph ◽  
...  
Keyword(s):  
Overall Survival ◽  
Uveal Melanoma ◽  
Phase Ii ◽  
Stable Disease ◽  
Objective Response Rate ◽  
Response Rate ◽  
Phase Ii Study ◽  
Objective Response ◽  
Progression Free Survival ◽  
Free Survival

Glembatumumab vedotin (CDX-011, GV) is a fully human Immunoglobulin G2 monoclonal antibody directed against glycoprotein NMB coupled via a peptide linker to monomethyl auristatin E (MMAE), a potent cytotoxic microtubule inhibitor. This phase II study evaluated the overall response rate and safety of GV, glycoprotein NMB (GPNMB) expression, and survival in patients with metastatic uveal melanoma. Eligible patients with metastatic uveal melanoma who had not previously been treated with chemotherapy received GV 1.9 mg/kg every three weeks. The primary endpoint was the objective response rate (ORR). Secondary endpoints included GPNMB expression, progression-free survival (PFS), overall survival (OS), and toxicity analysis. GPNMB expression was assessed pre- and post-treatment via immunohistochemistry for patients with available tumor tissue. Out of 35 patients who received treatment, two patients had confirmed partial responses (PRs; 6%), and 18 patients had a stable disease (SD; 51%) as the best objective response. 38% of the patients had stable disease >100 days. The grade 3 or 4 toxicities that occurred in two or more patients were neutropenia, rash, hyponatremia, and vomiting. The median progression-free survival was 3.1 months (95% CI: 1.5–5.6), and the median overall survival was 11.9 months (95% CI 9.0–16.9) in the evaluable study population. GV is well-tolerated in metastatic uveal melanoma. The disease control rate was 57% despite a low objective response rate. Exploratory immune correlation studies are underway to provide insight into target saturation, combination strategies, and antigen release.

scholarly journals Pyrotinib in HER2-Mutant Advanced Lung Adenocarcinoma After Platinum-Based Chemotherapy: A Multicenter, Open-Label, Single-Arm, Phase II Study

2020 ◽  
Vol 38 (24) ◽  
pp. 2753-2761 ◽  
Author(s):  
Caicun Zhou ◽  
Xingya Li ◽  
Qiming Wang ◽  
Guanghui Gao ◽  
Yiping Zhang ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Phase Ii ◽  
Objective Response Rate ◽  
Response Rate ◽  
Phase Ii Study ◽  
Objective Response ◽  
Unmet Need ◽  
Open Label ◽  
Platinum Based Chemotherapy ◽  
Grade 3

PURPOSE Targeted therapies against non–small-cell lung cancer (NSCLC) harboring HER2 mutations remain an unmet need. In this study, we assessed the efficacy and safety of pyrotinib in patients with HER2-mutant advanced NSCLC in a prospective, multicenter, open-label, single-arm, phase II study. PATIENTS AND METHODS Patients with stage IIIB or IV HER2-mutant lung adenocarcinoma who were previously treated with platinum-based chemotherapy were enrolled to receive pyrotinib at a dose of 400 mg/d for 21-day cycles. The primary end point was objective response rate per independent review committee (IRC). RESULTS Between October 20, 2016, and December 10, 2018, 60 patients received pyrotinib monotherapy. At baseline, 58 (96.7%) were stage IV, and 25 (41.7%) received at least 2 lines of prior chemotherapy. As of data cutoff on June 20, 2019, IRC-assessed objective response rate was 30.0% (95% CI, 18.8% to 43.2%). All subgroups of patients with different HER2 mutation types showed a favorable objective response rate. The objective response rates were similar between patients with and without brain metastases (25.0% v 31.3%). The median duration of response was 6.9 months (95% CI, 4.9 to 11.1 months). The median progression-free survival was 6.9 months (95% CI, 5.5 to 8.3 months) per IRC. The median overall survival was 14.4 months (95% CI, 12.3 to 21.3 months). Treatment-related adverse events of grade 3 or 4 occurred in 28.3% of patients, with the most common being diarrhea (20.0%; all grade 3). No treatment-related deaths were reported. CONCLUSION Pyrotinib showed promising antitumor activity and an acceptable safety profile in chemotherapy-treated patients with HER2-mutant NSCLC.

Phase II Results of Bendamustine in Combination with Rituximab in Relapsed Indolent and Mantle-Cell Non-Hodgkin’s Lymphoma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2710-2710 ◽  
Author(s):  
Richard H. Van der Jagt ◽  
Philip Cohen ◽  
Bruce D. Cheson ◽  
Anil Tulpule ◽  
Jordan A. Herst ◽  
...  
Keyword(s):  
Phase Ii ◽  
Objective Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Complete Response ◽  
Hodgkin's Lymphoma ◽  
Prior Chemotherapy ◽  
Non Hodgkin's Lymphoma ◽  
Mantle Cell ◽  
Grade 3

Abstract Objective: The objective of this study was to evaluate the efficacy and safety of bendamustine HCl (TREANDA®) in combination with rituximab in patients with relapsed non-Hodgkin’s lymphoma (NHL). Background: Bendamustine is a novel hybrid, alkylating agent with single-agent activity in multiple hematologic and solid tumors. It induces cell death via both apoptosis and the apoptosis-independent pathway of mitotic catastrophe. The combination of bendamustine and rituximab has been shown to exhibit a synergistic antitumor effect on NHL cells. Methods: This Phase II, multicenter study enrolled adult patients with relapsed, indolent B-cell or mantle-cell NHL who were not refractory to rituximab (defined as progression ≤6 months of last rituximab dose). Patients received rituximab 375 mg/m2 intravenously (IV) on day 1 and bendamustine 90 mg/m2 IV on days 2 and 3 of a 28-day cycle for 4 to 6 cycles. An additional dose of rituximab 375 mg/m2 IV was given 1 week before the first cycle of bendamustine and 4 weeks after the last cycle. Results: The intent-to-treat (ITT) population included 66 patients (59% men) with a median age of 60 years (range, 40–84). Indolent histologic phenotype was seen in 54 patients with the following histologic subtypes: follicular center cell (61%), small lymphocytic (15%), lymphoplasmacytic (3%), and marginal zone (3%); 18% had mantle-cell lymphoma (MCL). A total of 85% of patients had stage III/IV disease. These patients relapsed from a median of 1 prior chemotherapy (range: 0–5), with 56% having had prior treatment with rituximab. Patients with no prior chemotherapy relapsed following biologic therapy. In the ITT population, the overall objective response rate (ORR) was 94% (complete response [CR]/complete response unconfirmed [CRu], 41%; partial response [PR], 53%); 6% had stable disease. The ORR for the 12 MCL patients was 92% (CR/CRu, 42%; PR 50%). For all patients, the median duration of response and progression-free survival has not been reached after a median follow-up of 8.3 months (range, 0.14–31 months). Grade 3/4 neutropenia was seen in 41% of patients (7%, febrile neutropenia). Common nonhematologic toxicities (grade 1/2, grade 3, grade 4) were nausea (68%, 0%, 0%) and fatigue (53%, 5%, 0%); one patient had grade 3 sepsis. No alopecia was observed. Conclusions: Bendamustine administered in combination with rituximab produced a high objective response rate and was generally well tolerated in patients with relapsed indolent and mantle-cell NHL who were not refractory to rituximab. These results suggest that the combination of bendamustine and rituximab may be comparable in activity to R-CHOP, and further studies of this combination are warranted.

CETUFTIRI, a new combination of UFT with leucovorin (LV), irinotecan, and cetuximab as first-line treatment for patients (pts) with unresectable metastatic colorectal cancer (mCRC): Preliminary results from a multicenter phase II trial

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4087-4087 ◽  
Author(s):  
J. Bennouna ◽  
R. Faroux ◽  
E. François ◽  
C. Ligeza ◽  
C. El Hannani ◽  
...  
Keyword(s):  
Phase Ii ◽  
Objective Response Rate ◽  
Response Rate ◽  
Phase Ii Study ◽  
Objective Response ◽  
New Combination ◽  
Line Treatment ◽  
First Line ◽  
Egfr Expression ◽  
First Line Treatment

4087 Background: A phase II study (ASCO 2004) established that the combination of UFT (tegafur-uracil) with LV and irinotecan (TEGAFIRI) could be safely administered to pts with unresectable mCRC, with an objective response rate (ORR) of 34% and a median time to progression (TTP) of 5.7 months. We initiated CETUFTIRI, a phase II study, to evaluate the efficacy and tolerability of cetuximab added to TEGAFIRI in chemonaïve pts with unresectable mCRC. Methods: Patients in this single-stage study were aged =18 years, with histologically or cytologically confirmed, bidimensionally measurable mCRC, ECOG performance status 0 or 1, and adequate bone marrow, renal, and hepatic function. EGFR expression was not an inclusion criterion. Treatment consisted of UFT 250 mg/m2/day d1–14, LV 90 mg/day d1–14, and irinotecan 250 mg/m2 d1 every 3 weeks, plus cetuximab 400 mg/m2 week 1 then 250 mg/m2 weekly thereafter. The primary endpoint was ORR and the planned sample size was 61 pts. The study is now closed to accrual. Results: To date, 48 patients are evaluable for safety and 31 are evaluable for efficacy. Patient characteristics (n=48): median age 65 years (range 45–84 years); ECOG PS 0/1: 73/27%; male 65%; tumor sites: colon 69%; rectum 17%; junction 14%; liver metastasis 83%; lung metastasis 46%; other 27%. Adverse events per patient (n=48) after a total of 230 cycles were: grade G3 mucositis 10%; G3/4 neutropenia 10%; G3 nausea/vomiting 8%; G3 asthenia 6%; febrile neutropenia 6%; G3 hypokalemia 6%; G3/4 anemia 4%; G3 diarrhea 2%; acne-like rash G1/2 50% (G3 4%); infusion- related reaction to cetuximab 6%. Two of 31 evaluable pts had a complete response and 11 had a partial response, for an ORR of 42%; 5 pts had stable disease (16%) and 11 pts had progressive disease (35.5%). An independent radiologist review is planned for all 61 pts included up to December 2006. Conclusions: The CETUFTIRI combination seems to have an acceptable toxicity profile with an attractive objective response rate in the first-line treatment of pts with mCRC. No significant financial relationships to disclose.

Phase II study of hydroxyurea for unresectable meningioma (Southwest Oncology Group S9811)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2063-2063 ◽  
Author(s):  
L. J. Swinnen ◽  
C. Rankin ◽  
E. J. Rushing ◽  
H. F. Laura ◽  
D. M. Damek ◽  
...  
Keyword(s):  
Phase Ii ◽  
Objective Response Rate ◽  
Response Rate ◽  
Phase Ii Study ◽  
Objective Response ◽  
Disease Rate ◽  
Hematologic Toxicity ◽  
Benign Meningioma ◽  
Small Series ◽  
Grade 3

2063 Background: Meningiomas account for 15%-18% of CNS tumors. Although benign, recurrence is seen in 16%-39% of cases, depending on the extent of resection possible. Tumor location may make further resection hazardous. Chronic hydroxyurea (HU) was reported to produce well documented objective responses in a small series of patients, with gradual regression occurring over 6–10 months. Induction of apoptosis was furthermore demonstrated with HU in primary benign meningioma explant cultures. The S9811 phase II trial was undertaken to estimate the objective response rate, if any, of unresectable benign meningioma to this HU regimen. Methods: Eligibility required unresectable, measurable, residual or recurrent, histologically-proven benign meningioma. Progressive tumor or progressive neurologic deficit was required. No prior cytotoxics, no radiation therapy for >1 year. Age > 18, adequate hematologic reserve, PS 0–2. HU 20 mg/kg/day po was given for up to 2 years if there was no progressive disease. Single-stage accrual of 38 pts would have allowed detection of 5% null hypothesis response probability vs. 20% with 90% power; the 28 pts actually accrued provide 81% power. Results: Between November 98 and June 2005, 29 pts were accrued, with study closure due to slow accrual. 1 ineligible. Response assessment showed CR+PR 0% (95% CI 0–12%); SD 71% (95% CI 51–87%); PD 21% (95% CI 8–41%); undetermined 7%. Median PFS was 27 months. (95% CI 12–29 months.); 3-year PFS 43% (95% CI 25–61%). Median OS has not been reached. Seven patients were removed from study for toxicity (5/7 hematological). Toxicity was mainly hematologic: 11/28 (39%) grade 3, 2/28 (11%) grade 4. Grade 3 non-hematologic toxicity was seen in 7/28 (25%). Conclusions: Chronic HU therapy for unresectable benign meningioma resulted in an estimated objective response rate of < 12%. Whether the stable disease rate seen differs in any way from what can be expected from the natural history of meningioma cannot be determined from this phase II study design. No significant financial relationships to disclose.

Irinotecan plus temozolomide in children with recurrent or refractory neuroblastoma: A phase II Children's Oncology Group study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 10011-10011
Author(s):  
R. Bagatell ◽  
L. M. Wagner ◽  
S. L. Cohn ◽  
J. M. Maris ◽  
C. P. Reynolds ◽  
...  
Keyword(s):  
Phase Ii ◽  
Stable Disease ◽  
Bone Marrow Aspirate ◽  
Response Rate ◽  
Objective Response ◽  
Response Assessment ◽  
Stage Design ◽  
Combination Methods ◽  
Grade 3 ◽  
Experienced Grade

10011 Background: Treatment of children with relapsed or refractory neuroblastoma (NB) remains a challenge. Responses to irinotecan (IRN) + temozolomide (TEM) were seen in NB xenograft-bearing mice, and objective responses were observed in patients with NB treated on a phase I study of this combination. Methods: A phase II study of IRN (10 mg/m2/dose IV daily × 5 days times; 2 weeks) + TEM (100 mg/m2/dose PO daily × 5 days) for children with relapsed or refractory NB was conducted. A one-stage design (endpoint: best overall response) required 5 or more responders out of the first 25 evaluable patients on each of two strata: 1) patients with disease measurable by CT or MRI; and 2) patients with disease detected only by bone marrow aspirate/biopsy and/or MIBG scan. Patients with stable disease or better after 3 cycles could receive an additional 3 cycles of study therapy. International Neuroblastoma Response Criteria were used for response assessment. Radiographic responses were centrally reviewed. Results: Fifty-five eligible and evaluable patients were enrolled, 28 on stratum 1 and 27 on stratum 2. Four responses were observed in the first 25 evaluable stratum 1 patients, and five responses were observed in the first 25 evaluable stratum 2 patients. Three patients had complete responses, but the overall objective response rate (CR+PR) was 16% (9/55). Eleven (stratum 1) and 13 (stratum 2) patients had stable disease. Less than 5% of patients experienced Grade 3 or 4 diarrhea. Although 18% of patients on stratum 1 and 35% of patients on stratum 2 experienced Grade 3 or 4 neutropenia during the first 3 cycles of therapy, <10% of all patients developed evidence of infection while neutropenic. Thrombocytopenia (Grade 3 or 4) was observed in only 7% of patients on stratum 1 and 12% on stratum 2. Conclusions: The combination of IRN+TEM was well tolerated in patients with recurrent or refractory NB. There were 9 objective responses, including 3 complete responses. The minimum desired response rate was attained within stratum 2, but not stratum 1. IRN+TEM may be an appropriate backbone for further study in the relapse setting in combination with novel, targeted agents. No significant financial relationships to disclose.

Combined analysis of two phase II trials of imatinib in advanced dermatofibrosarcoma protuberans (DFSP)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 10520-10520 ◽  
Author(s):  
S. Schuetze ◽  
P. Rutkowski ◽  
M. M. Van Glabbeke ◽  
C. Rankin ◽  
B. P. Rubin ◽  
...  
Keyword(s):  
Phase Ii ◽  
Objective Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Locally Advanced ◽  
Chromosome 17 ◽  
Low Grade ◽  
Time To Progression ◽  
Phase Ii Trials ◽  
Two Phase

10520 Background: DFSP is an infiltrative, low-grade, dermal tumor with propensity to recur locally and occasionally metastasize. Translocation between COL1A1 on chromosome 17 and PDGFB on chromosome 22, which results in transcriptional upregulation of PDGFB, is characteristic of DFSP. Autocrine/paracrine PDGFB-mediated activation of PDGFRB drives DFSP proliferation. Two distinct phase II trials of imatinib in patients (pts) with locally advanced or metastatic DFSP were conducted, 1 in North America (SWOG) with confirmed objective response rate and 1 in Europe (EORTC) with 14 week progression-free rate as primary end-points. Methods: Pts with locally advanced or metastatic DFSP were eligible. In the EORTC trial confirmation of t(17;22) by FISH was prospectively required for participation, imatinib was started at 400mg bid, surgery was undertaken after 14 weeks if feasible and response was assessed at 14 weeks. Full accrual was to be 44 pts in one step. In the SWOG trial confirmation of t(17;22) by RT-PCR was performed after enrollment, imatinib was started at 400mg daily and response was assessed every 8 weeks. Full accrual was to be 40 pts in 2 steps. Results: 16 pts were enrolled in EORTC and 8 pts enrolled in SWOG trial. The studies were closed early because of slow accrual and regulatory approval of imatinib in DFSP. Pts age ranged from 24 to 70 yrs, DFSP was located on head/neck, trunk and extremity in 7, 11 and 6 pts, respectively, ranged in size from 1.2–49 cm and was classic, pigmented and fibrosarcomatous DFSP in 13, 1 and 7 pts, respectively. One patient did not have DFSP on central review, lacked t(17;22) and thus was ineligible. Metastases were present in 7 pts involving lung in 6 pts. 11 pts (46%) had partial response, 9 pts had stable disease and 4 pts had progressive disease as best response. Median time to progression was 1.7 yrs. Response and progression-free at 1 yr rates were similar between studies. Imatinib was stopped in 11 pts for progression, 1 pt for toxicity, 2 pts resected free of gross disease and 1 pt withdrew. Conclusions: Imatinib is active in DFSP harboring t(17;22) with an objective response rate approaching 50% and is active in fibrosarcomatous DFSP. Response rates and time to progression did not appear to differ between pts taking 400 mg daily versus 400 mg bid. [Table: see text]

A phase II trial of the aurora kinase A inhibitor MLN8237 in patients with metastatic castrate resistant and neuroendocrine prostate cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS5096-TPS5096 ◽  
Author(s):  
Himisha Beltran ◽  
Mark A. Rubin ◽  
Juan Miguel Mosquera ◽  
Paul J. Christos ◽  
Olivera Calukovic ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Objective Response ◽  
Neuron Specific Enolase ◽  
Aurora Kinase ◽  
Response To Therapy ◽  
Aurora Kinase A ◽  
Kinase A

TPS5096 Background: NEPC can rarely arise de novo but more commonly arises as a mechanism of resistance in the setting of advanced prostate cancer. Transformation to NEPC is likely promoted by potent hormonal therapies and is currently under-recognized. There is no effective therapy for NEPC and most patients (pts) survive less than one year. We have found that Aurora kinase A (AURKA) and N-myc (MYCN) are significantly overexpressed and amplified in NEPC compared to prostate adenocarcinoma, and cooperate to induce neuroendocrine (NE) differentiation in prostate cancer (Beltran et al, Cancer Disc 2011). In preclinical models, aurora kinase inhibition results in dramatic and preferential anti-tumor activity in NEPC. Methods: In this single arm, multi-institutional Phase II trial, pts with metastatic prostate cancer need to meet at least one NEPC entry criterion: 1) histologic diagnosis of small cell or NEPC, 2) >50% immunohistochemical staining for NE markers, 3) development of liver metastases in absence of PSA progression, or 4) serum chromogranin >5x normal or neuron specific enolase >2x normal. Study will be open at 10 institutions including PCCTC sites. After a mandatory on-study research biopsy, pts will be treated with MLN8237, an orally administered Aurora kinase A inhibitor at 50 mg twice daily for 7 days repeated every 21 days. The primary endpoint is objective response rate (ORR). Secondary endpoints include overall survival, progression free survival, PSA response rate, circulating tumor cell response, and serum NE marker response to therapy. A number of correlative studies including AURKA, MYCN, AR, and exome and RNAseq are embedded in this trial in order to molecularly define this aggressive and poorly characterized disease. A Simon 2-stage design will be employed with up to 60 subjects providing 80% power to determine if the true ORR is >30% and 95% power if the true ORR is <15%, assuming a 5% level of significance. A subset of at least 20% meeting histologic entry criteria is embedded.

Bevacizumab and albumin-bound paclitaxel treatment in metastatic breast cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1101-1101 ◽  
Author(s):  
J. S. Link ◽  
J. R. Waisman ◽  
B. Nguyen ◽  
C. I. Jacobs
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Stable Disease ◽  
Objective Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Brain Lesion ◽  
Metastatic Breast ◽  
Significant Activity ◽  
Pet Ct

1101 Background: Miller, et al demonstrated the combination of bevacizumab and paclitaxel has significant activity in metastatic breast cancer. Because paclitaxel albumin bound (PAB) has been shown to have less toxicity, a better tumor delivery and possibly better response for metastatic breast cancer, we combined it with bevacizumab (B) to treat women with metastatic breast cancer. Methods: This is a retrospective analysis. Billing records from March 2005 through December 2006 were reviewed to obtain all patients treated consecutively with a combination of PAB (80–125mg/m2 days 1,8,15 or 170–200 mg/m2 every 14 days on a 28 day cycle) and B (10mg/kg every 14 days). A total of 40 women were identified. A minimum of two courses were given. All women had received a minimum of 3 prior chemotherapy regimens including anthracyclines 34/40 and taxanes 35/40. Patients were monitored for response using RECIST criteria based on PE, and PET/CT imaging. Six women with bone only disease were monitored with PET, CT/MRI and tumor markers. All response data were confirmed by independent review. Results: 20 women had objective responses to the PAB/B regimen (3CRs and 17PRs) for an overall response rate of 50%. Another seven women had stable disease (SD) for a mean duration of 212 days. Thirteen women progressed. The mean time to progression for the responders was 132 days. Toxicity was acceptable with fatigue (9 gr 2), neuropathy (4 gr 2, 1 gr 3), anemia (2 gr 2, 2 gr 3), and hypertension (3 gr 2) being the most common complaints. Two patients were discontinued due to a possible CNS hemorrhage into a metastatic brain lesion. There were no other treatment discontinuations due to non-tolerance Conclusions: In our limited series of consecutive woman with advanced, heavily pretreated metastatic breast cancer treated with PAB (Abraxane) and bevacizumab (Avastin), we saw a 50% objective response rate (3CR, 17PR). The regimen was well tolerated with acceptable toxicity. Another seven women had stable disease for an average duration of >200days giving an objective response rate + SD of 67%. No significant financial relationships to disclose.

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