Clinical Benefit Response Rate Research Articles

Clinical Profile Of Single-Agent Modified-Release Oprozomib Tablets In Patients (Pts) With Hematologic Malignancies: Updated Results From a Multicenter, Open-Label, Dose Escalation Phase 1b/2 Study

Clinical Profile Of Single-Agent Modified-Release Oprozomib Tablets In Patients (Pts) With Hematologic Malignancies: Updated Results From a Multicenter, Open-Label, Dose Escalation Phase 1b/2 Study

Abstract C295: Update on first-in-man trial of novel oral PARP inhibitor BMN 673 in patients with solid tumors.

Abstract Background: BMN 673 is the most potent and specific inhibitor of PARP1/2 in clinical development (IC50<1nM). In tumors genetically dependent on DNA repair by homologous recombination PARP inhibition induces synthetic lethality. PARP inhibition has also been shown to be effective in preclinical models of small cell lung cancer and Ewing sarcoma, possibly related to high PARP expression. Methods: Pharmacokinetics (PK), pharmacodynamics (PD), safety and anti-tumor activity of BMN 673 were evaluated in a 2-stage escalation/expansion study. Expansion included cohorts of pts with BRCA-related cancers, small cell lung cancer (SCLC) and Ewing sarcoma (ES). Results: (As of July 29, 2013) In escalation, 39 pts were enrolled in 9 cohorts from 25 to 1100 µg/d with 1000 µg/d being the MTD related to dose-limiting hematologic toxicity. 38 pts have been enrolled in expansion including 25 patients with BRCA related cancers. For all 77 (63F/14M) pts, median age (range) is 52 (18-81), PS, 0 (0-1) and # of prior therapies 4 (1-13). Eight ES, 7 SCLC and 48 patients with deleterious BRCA mutations and breast (n=18), ovarian (n=28) or pancreatic (n=2) cancer were enrolled. BMN 673 demonstrated good oral bioavailability and a long half-life supporting daily dosing (ASCO 2013 Abstract 2580). One related grade 4 toxicity (thrombocytopenia) occurred. Related grade 3 adverse events have included fatigue, anemia, neutropenia and thrombocytopenia, all in fewer than 15% of patients. Dose-related inhibition of PARP activity in PBMC's was observed. Response, reduction in neutrophils and platelets and the need for blood transfusions and dose reductions appear to correlate with BMN 673 exposure.Overall, the objective response (including CA-125) and clinical benefit response rates are for all BRCA patients are 60.4% and 81%, respectively. Treatment is ongoing in 5 of 7 SCLC patients and 2 of 8 ES patients with no objective responses observed yet. Conclusions: BMN 673 is well tolerated with high objective and clinical benefit response rates in heavily pre-treated ovarian and breast cancer pts with deleterious germline BRCA mutations. A phase 3 trial in metastatic breast cancer is underway. Clinicaltrial.gov ID: NCT01286987 BRCA Breast and Ovarian CancerNBRCA Tumor TypeResponse18BreastCRPRSD > 12 weeksCBR*18Breast1 (6%)9 (50%)∧14 (78%)Response - 25 RECIST evaluable; 27 CA-125 evaluable28Ovarian28OvarianCRPRCA-1251 (4%)10 (40%)19 (70%)2PancreasCRPRSD ≥ 12 weeks2Pancreas0 (0%)0 (0%)2 (100%)**∧3 breast cancer responses are not yet confirmed; *CBR: clinical benefit response; **CA19-9 normalized in 1 patient Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C295. Citation Format: Zev A. Wainberg, Johann S. de Bono, Lida Mina, Jasgit Sachdev, Lauren Averett Byers, Rashmi Chugh, Charlie Zhang, Joshua W. Henshaw, Andrew Dorr, John Glaspy, Ramesh Ramanathan. Update on first-in-man trial of novel oral PARP inhibitor BMN 673 in patients with solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C295.

Phase Ib Dose-Escalation Study (PX-171-006) of Carfilzomib, Lenalidomide, and Low-Dose Dexamethasone in Relapsed or Progressive Multiple Myeloma

Carfilzomib, a selective proteasome inhibitor, has shown safety and efficacy in relapsed and/or refractory multiple myeloma. This phase I study in patients with relapsed or progressive multiple myeloma assessed the safety and tolerability of escalating doses of carfilzomib in combination with lenalidomide and low-dose dexamethasone (CRd) to identify the dose for a phase II expansion study. Patients with multiple myeloma who relapsed after 1 to 3 prior regimens enrolled into dose-escalation cohorts. CRd was administered on 28-day dosing cycles: carfilzomib 15 to 27 mg/m(2) on days 1, 2, 8, 9, 15, and 16; lenalidomide 10 to 25 mg on days 1 to 21; and dexamethasone 40 mg weekly. Forty patients enrolled in six cohorts. Prior treatment included bortezomib (75%) and lenalidomide (70%); 20% and 36% were refractory overall. The maximum tolerated dose was not identified, and the highest dose combination tested was recommended for the phase II study. The most common toxicities of any grade were fatigue (62.5%), neutropenia (55.5%), and diarrhea (52.5%). Grade 3/4 toxicities included neutropenia (42.5%), thrombocytopenia (32.5%), and lymphopenia (27.5%), with no grade 3/4 neuropathy reported. Proteasome inhibition 1-hour after dose was more than 80% in cycles 1 and 2. Among all patients, the overall response rate was 62.5%, the clinical benefit response rate was 75.0%, and the median duration of response and progression-free survival were 11.8 and 10.2 months, respectively. The maximum planned CRd dose, carfilzomib 27 mg/m(2), lenalidomide 25 mg, and dexamethasone 40 mg, was recommended for further study, with promising safety and efficacy.

Resistance to BRAF-targeted therapy in melanoma

BRAF mutations are identified in 40–50% of patients with melanoma. Treatment of these patients with either of two BRAF inhibitors (vemurafenib, dabrafenib) or the MEK inhibitor trametinib is associated with improved clinical benefit (response rate, progression free survival, and overall survival) compared with treatment with chemotherapy in three phase III trials. Unfortunately, most patients, including those who experience initial, profound tumour regression, have evidence of disease progression within 6–8months after commencing therapy with one of these agents. The mechanisms of resistance are varied and include activation of alternative signalling pathways as well as reactivating the MAP kinase pathway through alternative means. This review describes relevant aspects of MAP kinase pathway signalling, summarises the clinical data with BRAF and MEK inhibitors, presents the known resistance mechanisms to BRAF inhibitor therapy, and provides some strategies for how resistance may be overcome.

Very Low to Low Doses of Continuous Azacitidine in Combination with Standard Doses of Lenalidomide and Low-Dose Dexamethasone (Rd) in Patients with Relapsed or Refractory Multiple Myeloma (RRMM): Interim Results of a Phase I/II Study

AbstractAbstract 5031 Background:Myeloma inevitably becomes refractory to available agents primarily due to accumulation of genetic and epigenetic mutations in the aberrant clone. The s-phase dependent DNA methylation inhibitor azacitidine may help overcome epigenetically mediated resistance in myeloma cells that cycle despite treatment and reactivate alternate growth control programs in cells with genetic apoptosis resistance. Here we present interim results of an ongoing phase I/II study that explores the safety, antimyeloma activity, and epigenetic effects of continuous azacitidine at predicted non-cytotoxic doses in combination with Rd in RRMM Methods:Entry criteria included measurable disease, relapsed or refractory state, and glomerular filtration rate ≥ 60ml/min (Cockroft-Gault). Lenalidomide 25mg d1–21 every 28d and dexamethasone 40mg weekly were fixed. In phase I (3×3 design) azacitidine was escalated from 30 to 40mg/m2 SC weekly (DL 1 and 2) to 30, 40, and maximally 50mg/m2 SC twice a week (DL 3–5). Dose limiting toxicity (DLT) was assessed during cycle 1 and response every 28 days according to IMWG uniform response criteria (partial response, PR, or better) and adapted EBMT criteria (minor response, MR). Plasma activity of cytidine deaminase (CDA) was measured in dose levels 3–5, using HPLC to quantify deamination of added cytidine (Wilcoxon exact test). Phase II enrolls 10 additional patients at the highest tolerated dose and includes global gene expression and DNA methylation arrays before and after cycle 1 in CD138+, CD34+, and remaining bone marrow cells. Results:Twenty patients with relapsed (n=1) or refractory (n=19) MM were enrolled after they had received a median of 4 prior regimens (range 1–10). Their disease was refractory to lenalidomide (n=17), bortezomib and/or carfilzomib (n=16), or both lenalidomide and proteasome inhibitors (n=14). 18 patients had received alkylators, 8 high dose chemotherapy, and 6 anthracyclines. One DLT was observed in 1 out of 6 patients treated at DL 4; neutropenic fever without other evidence for infection. No DLT occurred in 4 patients treated so far at DL 5. Grade 3 and 4 toxicities were seen in 11 patients, neutropenia in 9 (lowest ANC 0. 24K/mm3), thrombocytopenia in 4 (lowest 16K/mm3, transfusions used in 1 to avoid treatment delay), neutropenic fever in 2 (1 after cycle 1), and diarrhea, depression, deep venous thrombosis, and a possibly related pleural effusion with hypoxemia in 1 patient each. DL 1 and 2 (n=6) yielded only one MR, but as azacitidine was increased to twice a week (DL 3–5, n=14) the clinical benefit response rate (CBRR, ≥MR) and response rate (RR, ≥PR) increased to 35. 7% and 28. 6%, respectively with 1 very good partial response (VGPR), 3 PR and 1 MR. The patient with MR had secondary plasma cell leukemia (sPCL) after 7 prior regimens and had to be taken off trial due to cytopenias but was continued on reduced azacitidine (20mg/m2), lenalidomide (5–10mg), and prednisone (50mg TIW) reaching PR off trial and achieving a 10 month time to progression (TTP). Of all other responding patients, only the one treated with weekly azacitidine progressed while receiving azacitidine (TTP 3 months), one patient with sPCL progressed during azacitidine interruption for neutropenic fever, another patient was taken off trial due to pleural effusion with hypoxemia, 2 are still on study, currently for 8 and 3 months. The median time to response was 1 cycle (range 1–7). Responders in DL 3–5 had similar treatment histories as the entire cohort, refractory to last Rx: 80%, median previous regimens: 4 (range 1–7), refractory to lenalidomide: 60%, to proteasome inhibitors: 80%, and to both: 60%; but their plasma CDA activity was lower than in non-responders (Figure 1). Women treated at DL 3–5 (n=6) responded better than men (n=8), likely related to lower plasma CDA activity (Figure 2). Conclusions:Azacitidine was generally well tolerated up to the target maximal dose of 50mg/m2SC twice a week (BIW) in combination with Rd given to 4 out of 6 patients required for establishing the phase 2 dose. Encouraging response rates in refractory MM correlated with low plasma activity of the azacitidine inactivating enzyme CDA found predominantly in women. Results support development of azacitidine in RRMM and argue for testing combination with the competitive inhibitor of CDA, tetrahydrouridine. Until then, dose escalation in non-responding but tolerating patients will be explored. [Display omitted] [Display omitted] Disclosures:Reu:Celgene: Research Funding. Off Label Use: Azacitidine in multiple myeloma. Kindwall-Keller:Celgene: Speakers Bureau; TEVA: Speakers Bureau. Duong:Celgene: Research Funding.

A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma

AbstractCarfilzomib is a next-generation, selective proteasome inhibitor being evaluated for the treatment of relapsed and refractory multiple myeloma. In this open-label, single-arm phase 2 study (PX-171-003-A1), patients received single-agent carfilzomib 20 mg/m2 intravenously twice weekly for 3 of 4 weeks in cycle 1, then 27 mg/m2 for ≤ 12 cycles. The primary endpoint was overall response rate (≥ partial response). Secondary endpoints included clinical benefit response rate (≥ minimal response), duration of response, progression-free survival, overall survival, and safety. A total of 266 patients were evaluable for safety, 257 for efficacy; 95% were refractory to their last therapy; 80% were refractory or intolerant to both bortezomib and lenalidomide. Patients had median of 5 prior lines of therapy, including bortezomib, lenalidomide, and thalidomide. Overall response rate was 23.7% with median duration of response of 7.8 months. Median overall survival was 15.6 months. Adverse events (AEs) were manageable without cumulative toxicities. Common AEs were fatigue (49%), anemia (46%), nausea (45%), and thrombocytopenia (39%). Thirty-three patients (12.4%) experienced peripheral neuropathy, primarily grades 1 or 2. Thirty-three patients (12.4%) withdrew because of an AE. Durable responses and an acceptable tolerability profile in this heavily pretreated population demonstrate the potential of carfilzomib to offer meaningful clinical benefit. This trial was registered at www.clinicaltrials.gov as #NCT00511238.

Bevacizumab Plus Chemotherapy in Metastatic Colorectal Cancer Patients Treated in Clinical Practice

The effect of KRAS status on response to bevacizumab plus chemotherapy in metastatic colorectal cancer is still unclear. We aimed to evaluate the overall clinical response to such a therapy in clinical practice and assess the role of KRAS status on therapy response. This was a retrospective study enrolling 108 metastatic colorectal cancer patients. KRAS mutation analysis was performed by PCR. Overall, 41.7% of patients had stable disease, 39.8% a partial response, 3.7% a complete response and 14.8% disease progression. Both clinical benefit and objective response rate tended to be higher in patients with only hepatic metastases than those with extrahepatic or multiple metastases. Response to therapy would appear to be independent of KRAS status, but larger studies are needed. Bevacizumab plus chemotherapy provides clinical benefit and objective response rate in patients with metastatic colorectal cancer independently of KRAS expression, especially in those patients with only liver metastases.

LBA11 - Cerebel (EGF111438): An Open Label Randomized Phase III Study Comparing the Incidence of CNS Metastases in Patients (PTS) with HER2+ Metastatic Breast Cancer (MBC), Treated with Lapatinib Plus Capecitabine (LC) Versus Trastuzumab Plus Capecitabine (TC)

ABSTRACT Background In HER2+ MBC, central nervous system (CNS) metastases (mets) occur in 28 - 43% of cases. Systemic therapies with potential to prevent or reduce CNS mets are of current interest. Based on lapatinib promising activity in CNS mets, CEREBEL evaluated the prophylactic impact on CNS mets incidence in HER2+ MBC pts treated with Lapatinib plus capecitabine (LC) in comparison to Trastuzumab plus capecitabine (TC). Methods CEREBEL was a multicenter study in HER2+ MBC pts without CNS mets at baseline, confirmed centrally by MRI. Prior treatment must include anthracyclines or taxanes in (neo)adjuvant or metastatic setting. Pts were randomized to LC (L-1250 mg daily + C-2000 mg/m2/day for 14 days [21-day cycle]) or TC (T loading dose 8 mg/kg followed by 6 mg/kg q3weekly + C-2500 mg/m2/day for 14 days [21-day cycle]). Primary endpoint was incidence of CNS as first site of relapse. Secondary endpoints were progression free survival (PFS), overall survival (OS), CNS progression at any time, overall response rate (ORR), clinical benefit response rate, duration of response and safety. Results A pre-specified interim analysis (IA) including 475 pts was performed by an IDMC convened on June 2012. A total of 43% and 46% of pts had not received prior treatment for MBC, 38% and 40% of pts had not received prior T, in LC and TC arms, respectively. Adverse events were similar in both arms with the exception of diarrhoea, nausea and rash (higher with LC). The incidence of CNS metastasis as site of first relapse was 3% for LC versus 4% for TC (OR 95% CI = 0.75 (0.25, 2.20) in modified ITT population (N = 218 pts per arm). The median PFS was 6.6 and 8.0 months in LC and TC arms (HR: 1.3; 95% CI: 1.0, 1.7; ) and median OS was 22.4 and 27.3 months (HR:1.58; 95% CI:1.07,2.32)(ITT) Conclusions Based on these results, the IDMC recommended study termination. Final results and updated survival data will be presented at ESMO with the 535 patients included in CEREBEL. EudraCT number 2008-000673-38 Disclosure X. Pivot: I am consultant and I have received honorariums for the sponsor GSK. R. Allerton: Roche advisory boad for use of Pertuzumab in breast cancer. R. Parikh: Employee of GSK M. DeSilvio: Employee of GSK S. Santillana: Employees of GSK, Director Clinical Development R. Swaby: Employee of GSK. All other authors have declared no conflicts of interest.

An open‐label, single‐arm, phase 2 study of single‐agent carfilzomib in patients with relapsed and/or refractory multiple myeloma who have been previously treated with bortezomib

Carfilzomib is a next-generation proteasome inhibitor that selectively and irreversibly binds to its target. In clinical studies, carfilzomib has shown efficacy in patients with relapsed and/or refractory multiple myeloma (MM) and has demonstrated a tolerable safety profile. In this phase 2, open-label, multicentre clinical trial, 35 patients with relapsed and/or refractory MM following 1-3 prior therapies, including at least one bortezomib-based regimen, received carfilzomib 20 mg/m(2) in a twice-weekly, consecutive-day dosing schedule for ≤12 monthly cycles. The best overall response rate (ORR) was 17·1% and the clinical benefit response rate (ORR + minimal response) was 31·4%. The median duration of response was >10·6 months and the median time to progression was 4·6 months. The most common adverse events were fatigue (62·9%), nausea (60·0%), and vomiting (42·9%). No exacerbation of baseline peripheral neuropathy was observed. Single-agent carfilzomib was generally well tolerated for up to 12 treatment cycles and showed activity in patients with relapsed and/or refractory MM who had received prior treatment with bortezomib. These data, combined with an acceptable toxicity profile, support the potential use of carfilzomib in patients with relapsed and/or refractory MM and warrant continued investigation of carfilzomib as single agent or in combination with other agents.

Clinical experience with oral vinorelbine (NVBO) plus prednisone as first- or second-line chemotherapy of metastatic hormone-refractory prostate cancer (HRPC).

e15144 Background: IV NVB plus hydrocortisone (HC) compared with HC alone resulted in improved clinical benefit, progression-free survival (PFS) and PSA response rate in HRPC. The oral formulation of NVB avoids the side effects associated with the IV injection, may reduce administration and toxicity-related costs and is easy to administer. Due to these advantages, single agent NVBO treatment could be considered as an optimal option for patients (p) with HRPC previously treated with a taxane or as first-line treatment when a taxane is not indicated. We retrospectively evaluated efficacy and toxicity or NVBO administered as single agent as first or second-line chemotherapy of metastatic HRPC. Methods: Retrospectively data was collected from p with metastatic HRPC treated with NVBO 80 mg/m2 on days 1 and 8, with a prior test of myelosensitivity at 60 mg/m2 for the 1st cycle (cy), plus prednisone 10 mg/day. Patients had received either a taxane as 1st-line treatment or had a documented contraindication to receiving docetaxel. 1 cy was equivalent to a 3-week period. Results: Data on 67 p treated in 13 Spanish centres were included. Median age 73 years (range 54-86). ECOG PS 0, 16.4%; 1, 56.7%; 2, 11.9%. Median PSA 88.9 ng/mL. Prior chemotherapy, 58.2%. Median number of cy was 4 (range 1-6). 56.9% of p could escalate NVBO to 80 mg/m2. 265 cy were performed, 9.1% were delayed and 2.3% had a dose reduction. Grade 3-4 events were infrequent and mainly hematological: neutropenia (6% of p), anemia (4.5%), pain (3%), infection (1.5%), asthenia (3%), respiratory (1.5%), cystitis (1.5%), rectal bleeding (1.5%), febrile syndrome (1.5%), renal (1.5%). No febrile neutropenia was reported. PSA response rate 16.1%, PSA stable was reported in 41.9%. 39 p were evaluable for measurable disease; among them, PR 17.9%, SD 48.7%. Median follow-up, 7.1 months. Median overall survival, 11 months [95% CI: 7.3-14.7]. Median PFS, 2.9 months [95% CI: 2.2-3.6]. Conclusions: NVBO is a safe and active regimen in previous chemotherapy treated HRPC. For those p who cannot receive a taxane as first-line therapy, NVBO can also be considered as an effective first-line treatment.

Metronomic oral combination chemotherapy with capecitabine and cyclophosphamide: a phase II study in patients with HER2-negative metastatic breast cancer

Metronomic combination chemotherapy with the oral fluoropyrimidine doxifluridine/5'-deoxy-5-fluorouridine (5 -DFUR) and oral cyclophosphamide (C) showed promising efficacy in a single-arm study. The oral fluoropyrimidine capecitabine was designed to deliver 5-fluorouracil preferentially to tumors, potentially improving efficacy over doxifluridine. We conducted a phase II multicenter study to evaluate an all-oral XC combination in patients with HER2-negative metastatic breast cancer (MBC). Patients received capecitabine 828mg/m(2) twice daily with cyclophosphamide 33mg/m(2) twice daily, days 1-14 every 3weeks. The primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Between May 2007 and April 2009, 51 patients were enrolled and 45 were included in the efficacy analysis. The median follow-up was 18.1months. ORR was 44.4% and stable disease (≥24weeks) was achieved in 13.4%, resulting in a 57.8% clinical benefit response rate. Median PFS was 12.3months (95% confidence interval: 8.9-18.9months). Median PFS was 10.7months in triple-negative disease and 13.2months in estrogen-receptor positive, HER2-negative disease. The 1- and 2-year OS rates were 86 and 71%, respectively. Median OS has not been reached. Grade 3 adverse events comprised leukopenia (26%), neutropenia (16%), and decreased hemoglobin (2%). There was no grade 3 hand-foot syndrome. Oral XC is an effective first- or second-line therapy for MBC, demonstrating high activity in both luminal A and triple-negative disease with few severe side effects. This metronomic oral combination chemotherapy could be beneficial for the treatment of HER2-negative MBC.

Unfavorable Cytogenetic Characteristics Do Not Adversely Impact Response Rates in Patients with Relapsed and/or Refractory Multiple Myeloma Treated with Single-Agent Carfilzomib on the 003 (A1) Study

Unfavorable Cytogenetic Characteristics Do Not Adversely Impact Response Rates in Patients with Relapsed and/or Refractory Multiple Myeloma Treated with Single-Agent Carfilzomib on the 003 (A1) Study

Final Results From the Bortezomib-naïve Group of PX-171-004, a Phase 2 Study of Single-Agent Carfilzomib in Patients with Relapsed and/or Refractory MM

Final Results From the Bortezomib-naïve Group of PX-171-004, a Phase 2 Study of Single-Agent Carfilzomib in Patients with Relapsed and/or Refractory MM

Phase II Study of the Mammalian Target of Rapamycin Inhibitor Ridaforolimus in Patients With Advanced Bone and Soft Tissue Sarcomas

Ridaforolimus is an inhibitor of mammalian target of rapamycin, an integral component of the phosphatidyl 3-kinase/AKT signaling pathway, with early evidence of activity in sarcomas. This multicenter, open-label, single-arm, phase II trial was conducted to assess the antitumor activity of ridaforolimus in patients with distinct subtypes of advanced sarcomas. Patients with metastatic or unresectable soft tissue or bone sarcomas received ridaforolimus 12.5 mg administered as a 30-minute intravenous infusion once daily for 5 days every 2 weeks. The primary end point was clinical benefit response (CBR) rate (complete response or partial response [PR] or stable disease ≥ 16 weeks). Safety, progression-free survival (PFS), overall survival (OS), time to progression, and duration of response were also evaluated. A total of 212 patients were treated in four separate histologic cohorts. In this heavily pretreated population, 61 patients (28.8%) achieved CBR. Median PFS was 15.3 weeks; median OS was 40 weeks. Response Evaluation Criteria in Solid Tumors (RECIST) confirmed response rate was 1.9%, with four patients achieving confirmed PR (two with osteosarcoma, one with spindle cell sarcoma, and one with malignant fibrous histiocytoma). Archival tumor protein markers analyzed were not correlated with CBR. Related adverse events were generally mild or moderate and consisted primarily of stomatitis, mucosal inflammation, mouth ulceration, rash, and fatigue. Single-agent ridaforolimus in patients with advanced and pretreated sarcomas led to PFS results that compare favorably with historical metrics. A phase III trial based on these data will further define ridaforolimus activity in sarcomas.

Combination of recombinant adenovirus-p53 with radiochemotherapy in unresectable pancreatic carcinoma

To assess the safety and efficacy of the combination of recombinant adenovirus-p53 (rAd-p53) with radiochemotherapy for treating unresectable pancreatic carcinoma. The eligible patients received concurrent rAd-p53 intratumoral injection and radiochemotherapy. Intratumoral injection of rAd-p53 was guided by B ultrasound. Radiochemotherapy consisted of intensity-modulated radiotherapy (IMRT) at two dose levels and intravenous gemcitabine (Gem). For radiotherapy, gross target volume (GTV) and clinical target volume (CTV) were 55-60 Gy and 45-55 Gy in 25-30 fractions, respectively. Concurrent intravenous gemcitabine was administered at 350 mg/m(2), weekly, for 6 weeks. The primary end points included toxicity, clinical benefit response (CBR) and disease control rate (DCR). The secondary end points included progression-free survival (PFS) and overall survival (OS). Fifteen eligible patients were enrolled. Eight patients (53.3%) were evaluated as CBR and 12 (80%) achieved DCR. The median PFS and OS were 6.7 and 13.8 months, respectively. One-year PFS and OS were 40.0% and 51.1%, respectively. There were 8 (53.3%) patients reported grade 3 toxicities including neutropenia (6 patients, 40%), fever (1 patient, 6.7%) and fatigue (1 patient, 6.7%). There was no grade 4 toxicity reported. Combination of rAd-p53 in unresectable pancreatic carcinoma showed encouraging efficacious benefit and was well tolerated. Long-term follow-up is needed to confirm the improvement of PFS and OS.

A phase II trial of sorafenib (S) and dacarbazine (D) in leiomyosarcoma (LMS), synovial sarcoma (SS), and malignant peripheral nerve sheath tumor (MPNST).

10025 Background: Sorafenib has a low single agent RR in sarcoma. Other angiogenesis inhibitors are more effective when combined with standard chemotherapy. Sorafenib has been safely combined with dacarbazine for treatment of melanoma. As PRs, MRs and prolonged SD were seen in LMS, SS and MPNST in our single agent S study, we chose to investigate S+D in those histologies. Methods: Patients with LMS, SS or MPNST with up to 2 priors, and adequate hepatic, renal and marrow function receive S at 400 mg BID and D at 1000mg/m2 every 3 weeks. Pts are restaged every 2 cycles. The primary objective of this trial is to determine Clinical Benefit Response rate (CBR=CR+PR + SD x18 weeks) of S+D in these subtypes. A Simon two stage design to distinguish between a CBR rate of 20% and 40% required 4 CBRs out of the first 17 pts to expand to a second cohort, and 11/37 (29.7%) CBRs to be considered positive. Results: From 2/09-12/10, 31 pts have been enrolled: 17 F, 14 M; median age 55, range 27-80; ECOG PS 0 16, 1 14; 20...

A phase II study of lonafarnib (LF) in patients with locally advanced and metastatic breast cancer (MBC): Hoosier Oncology Group BRE07-126.

598 Background: LF is a potent, specific, reversible farnesyl transferase inhibitor (FTI). FT is an enzyme that catalyzes the covalent attachment of a 15-carbon farnesyl group to conserved amino acid residues at the carboxy terminus of certain proteins. FTIs were initially developed to target the ras family of oncoproteins (H-ras, K-ras, and N-ras), G-proteins that exist in a mutated (oncogenic) form in about 30% of human cancers. Oral administration of LF blocked tumor growth of a variety of human xenografts (glioblastoma, lung, pancreatic, prostate, colon, bladder, and CML) in nude mice. LF inhibits growth both ER+ and ER−, as well as HER2+ and HER2− breast cancer. We conducted a nonrandomized, open label study of LF in pts with advanced and MBC. Methods: Primary objective was to determine progression-free survival (PFS) of LF in pts with locally advanced and MBC, unlimited prior treatment, and ECOG PS 0-1. Secondary objectives included the evaluation of clinical benefit response rate (CR+PR+SD > 180 day duration), overall response rate (ORR), and toxicity. Pts 1- 4 were treated with 200mg PO BID daily on days 1-21 of every 21 day cycle until PD or unacceptable toxicity. However, due to early onset of intolerable diarrhea, the study design was modified to a dose escalation model. Pts were pre-treated with Loperamide and started on LF 200mg total daily dose (TDD). If LF was tolerated for 7 days, pts were escalated to 300mg TDD and then 400mg TDD. Results: 29 eligible pts were treated with a median of 2 cycles (range 1-7). Median age was 56 yrs (range 41-76 years), and 100% were female and ECOG PS 1. Median # of prior regimens was 8 (range 0-20). 15/24 (63%), 11/24 (46%) and 3/20 (15%) were ER, PR and HER2 positive, respectively. The most frequent grade 3/4 toxicities comprised diarrhea (23%) and dehydration (8%). Two grade 5 toxicities: PD NOS and encephalopathy. The best response data for the 17 evaluable pts are 5 (29%) stable disease (SD) and 12 (71%) progressive disease (PD). Median PFS was 9 wks. Conclusions: Results based on the first 17 pts does not support improved PFS or ORR compared to historical controls. Further follow up and biomarker correlations are ongoing and will be presented at the meeting.

Gene Regulatory and Clinical Effects of Interferon β in Patients with Metastatic Melanoma: A Phase II Trial

Interferon (IFN)-β in preclinical studies, compared to IFN-α2, bound with higher affinity to its receptor, induced to higher levels of IFN-stimulated gene products, induced more apoptosis in melanoma cells, and had antitumor effects against melanoma. A maximally tolerated dose of 12 × 10(6) international units/m(2) after 2 weeks subcutaneously daily with dose escalation to 18 × 10(6) international units/m(2) was thus used in a phase II trial of IFN-β1a in cutaneous metastatic melanoma (n = 17) and uveal melanoma (n = 4). It resulted in expected but reversible drug-related severe (grade 3) adverse events in 13/21 patients; anorexia and fatigue were mostly of mild or moderate severity and infrequently needed dose reduction. Although a single patient had a sustained regression, overall IFN-β1a did not have clinical benefit (response rate <10%; median progression-free survival 1.8 months). Effective and potent induction in peripheral blood cells and into serum of products of IFN-stimulated genes such as the pro-apoptotic cytokine, TRAIL, and the immunomodulatory and anti-angiogenic chemokines, CXCL10 and CCL8, confirmed gene regulatory actions. To probe further anti-angiogenic mechanisms, both VEGF-A and CXCL-5 were assessed; compared to before treatment, both proteins decreased. Continued improvements in understanding of antitumor mechanisms will enhance usefulness of IFNs for nodal or distant metastases from melanoma.

Baseline Peripheral Neuropathy Does Not Impact the Efficacy and Tolerability of the Novel Proteasome Inhibitor Carfilzomib (CFZ): Results of a Subset Analysis of a Phase 2 Trial In Patients with Relapsed and Refractory Multiple Myeloma (R/R MM)

Baseline Peripheral Neuropathy Does Not Impact the Efficacy and Tolerability of the Novel Proteasome Inhibitor Carfilzomib (CFZ): Results of a Subset Analysis of a Phase 2 Trial In Patients with Relapsed and Refractory Multiple Myeloma (R/R MM)

Mature Results of MM011: A Phase I/II Trial of Lenalidomide, Liposomal Doxorubicin, Dexamethasone, and Vincristine, Followed by Lenalidomide Maintenance (DVd-R) for Relapsed or Refractory Multiple Myeloma

AbstractAbstract 1967 Background:An initial report of MM011 described the MTD and promising activity in the first 62 patients (pts) (Baz R et al, Ann Oncol 2006). Here we report complete outcomes of the entire study cohort (n=77) with over four years since the enrollment of the last patient. Methods:Pts with relapsed or refractory myeloma after at least 2 cycles of previous therapy were treated with lenalidomide at increasing dose levels (5mg – 10mg – 15mg, MTD 10mg) d1-21 every 28 days, liposomal doxorubicin 40mg/m2 d1, dexamethasone 40mg d1-4, and, if no significant neuropathy was present, vincristine 2mg IV for 4–6 cycles (2 cycles beyond best response) followed by lenalidomide maintenance at 10mg d1-21 every 28 days. Prednisone 50 mg every other day was allowed during maintenance, dexamethasone was not. DVT prophylaxis with aspirin 81 mg daily was mandated. All pts were included in PFS and OS analyses. Patient mortality was verified via social security death index as of July 20, 2010. Pts who developed progressive disease after at least one dose of study drug or who had measurable disease and stayed on study for at least 60 days were considered evaluable for response. Results:From 03/2003 to 04/2006 77 pts of median age 62 years (range, 41–81) were enrolled, median follow up on study was 16.4 months (range, 0.2–80.4). Median time from diagnosis to enrollment was 39 months (range, 4–118); 67 pts (87%) had Salmon-Durie stage III at diagnosis; median previous therapies were 3 (range 1–7); 49 pts (64%) were refractory to last induction (46 after previous response, 3 primary refractory). Karyotype analysis at study entry revealed abnormal cytogenetics in 28 (36.4%), with del13 in 13 (17.1%) and del17p in 5 pts (6.6%). Previous therapies included doxorubicin (n=60, 78%), thalidomide (n=56, 73%), bortezomib (n=20, 26%), high dose chemotherapy with ASCT (n=17, 22%), and lenalidomide (n=4, 5%). During induction, grade 3 and 4 adverse events occurred in 37 pts (48.1%), with hematologic AEs, VTEs, and infections observed in 32.5%, 6.5%, and 3.9% of pts, respectively. 43 pts (56%) reached maintenance and 41 of them received prednisone in addition to lenalidomide. During maintenance 11 out of 43 pts (25.6%) experienced grade 3 or 4 AEs, (hematologic: 16.3%, infections: 4.7%, VTEs: 4.7%). One patient experienced heart failure that was attributed to severe aortic stenosis. 64 out of 77 pts (83%) were evaluable for response. According to uniform international response criteria with adapted EBMT criteria for MR, their rates of CR, VGPR, PR, and MR were 5%, 16%, 33%, and 20%, respectively, resulting in a 54% response rate (RR=CR+VGPR+PR) and a 74% clinical benefit response rate (CBRR=RR+MR). Median PFS and OS were 12.1 and 21 months, respectively. In the subgroup of 46 pts with relapsed and refractory myeloma, 37 were evaluable for response and achieved a RR of 49% and a CBRR of 65% (VGPR 14%, PR 35%, MR 16%). Median PFS and OS in pts with relapsed and refractory disease (n=46) were 9.7 and 14 months, respectively. Pts with disease relapsed after or refractory to prior thalidomide or lenalidomide and refractory to or relapsing within 60 days after bortezomib (n=14; median age=62.5 years, median previous therapies=4) experienced median PFS and OS of 7.3 and 9.6 months, respectively, as compared to median EFS of 1 and OS of 6 months in a comparable patient population (Kumar S et al, ASH 2009 #2878). Among 12 pts evaluable for response in this highest risk group, RR and CBRR were 25% and 50%, respectively. Their median duration of response was 5.8 months. Conclusion:DVd-R yielded impressive long-term outcomes in relapsed and refractory myeloma pts, even if their myeloma was refractory to bortezomib. [Display omitted] Disclosures:Baz:Celgene: Research Funding. Hussein:Celgene: Employment. Srkalovic:EPIC: Speakers Bureau; Physicians Connect: Speakers Bureau. Dean:Celgene: Research Funding. Knight:Celgene: Employment. Zeldis:Celgene Corp: Employment. Reu:Celgene: Research Funding.