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Rudin C.M.,Johns Hopkins University | Poirier J.T.,Johns Hopkins University | Senzer N.N.,Mary Crowley Cancer Research Center | Burroughs K.D.,Neotropix | And 3 more authors.
Clinical Cancer Research | Year: 2011

Purpose: Seneca Valley Virus (SVV-001) is a novel naturally occurring replication-competent picornavirus with potent and selective tropism for neuroendocrine cancer cell types, including small cell lung cancer. We conducted a first-in-human, first-in-class phase I clinical trial of this agent in patients with cancers with neuroendocrine features, including small cell lung cancer. Experimental Design: Clinical evaluation of single intravenous doses in patients with cancers with neuroendocrine features was performed across five log-increments from 107 to 1011 vp/kg. Toxicity, viral titers and clearance, neutralizing antibody development, and tumor response were assessed. Results: A total of 30 patients were treated with SVV-001, including six with small cell carcinoma at the lowest dose of 107 vp/kg. SVV-001 was well tolerated, with no dose-limiting toxicities observed in any dose cohort. Viral clearance was documented in all subjects and correlated temporally with development of antiviral antibodies. Evidence of in vivo intratumoral viral replication was observed among patients with small cell carcinoma, with peak viral titers estimated to be >103-fold higher than the administered dose. One patient with previously progressive chemorefractory small cell lung cancer remained progression-free for 10 months after SVV-001 administration, and is alive over 3 years after treatment. Conclusions: Intravenous SVV-001 administration in patients is well tolerated at doses up to 1011 vp/kg, with predictable viral clearance kinetics, intratumoral viral replication, and evidence of antitumor activity in patients with small cell lung cancer. Phase II clinical evaluation in small cell lung cancer is warranted, and has been initiated. ©2011 AACR.


PubMed | Temple University, University of Houston, Rutgers Cancer Institute of New Jersey, Amgen and 7 more.
Type: Journal Article | Journal: Head & neck | Year: 2016

Cutaneous head and neck melanoma has poor outcomes and limited treatment options. In OPTiM, a phase 3 study in patients with unresectable stage IIIB/IIIC/IV melanoma, intralesional administration of the oncolytic virus talimogene laherparepvec improved durable response rate (DRR; continuous response 6 months) compared with subcutaneous granulocyte-macrophage colony-stimulating factor (GM-CSF).Retrospective review of OPTiM identified patients with cutaneous head and neck melanoma given talimogene laherparepvec (n=61) or GM-CSF (n=26). Outcomes were compared between talimogene laherparepvec and GM-CSF treated patients with cutaneous head and neck melanoma.DRR was higher for talimogene laherparepvec-treated patients than for GM-CSF treated patients (36.1% vs 3.8%; p=.001). A total of 29.5% of patients had a complete response with talimogene laherparepvec versus 0% with GM-CSF. Among talimogene laherparepvec-treated patients with a response, the probability of still being in response after 12 months was 73%. Median overall survival (OS) was 25.2 months for GM-CSF and had not been reached with talimogene laherparepvec.Treatment with talimogene laherparepvec was associated with improved response and survival compared with GM-CSF in patients with cutaneous head and neck melanoma. 2016 Wiley Periodicals, Inc. Head Neck 38: 1752-1758, 2016.


PubMed | Sloan Kettering Cancer Center, University of Minnesota, Biothera and Mary Crowley Cancer Research Center
Type: Journal Article | Journal: Clinical colorectal cancer | Year: 2016

Imprime PGG ((1,6)-[poly-(1,3)-D-glucopyranosyl]-poly-(1,3)-D-glucopyranose) is an innate immune cell modulator that primes neutrophils and monocytes/macrophages to exert antitumor activity against complement opsonized tumor cells. In patients with KRAS-mutant colorectal cancer (CRC), cetuximab alone is ineffective; however, it can bind to tumor cells and induce opsonization for recognition by Imprime PGG-bound innate immune cells. The primary objective of this study was to determine the antitumor activity of Imprime PGG in combination with cetuximab in patients with KRAS-mutant metastatic CRC.The study had a 2-stage Simon optimal design with 80% power to detect a target objective response rate (ORR) of10% at a 10% significance level. Patients received weekly Imprime PGG (4 mg/kg) and cetuximab (loading dose, 400 mg/m(2), then 250 mg/m(2)) intravenously. The primary end point was ORR; secondary end points included duration of response (DOR), time to progression (TTP), overall survival (OS), disease control rate, progression-free survival, and safety. Stage 1 of the study was to enroll 17 evaluable patients.One partial response (5.6%) was observed among 18 patients enrolled into stage 1. Median DOR was 4.2 months, TTP 2.7 months, and OS 6.6 months. Overall, observed toxicity was as expected from cetuximab alone. The most common (20%) adverse events related to Imprime PGG were fatigue (7 patients; 38.9%), infusion reaction (4 patients; 22.2%), and headache (4 patients; 22.2%). There was no Grade 4 toxicity nor treatment-related deaths.Imprime PGG in combination with cetuximab treatment in patients with KRAS-mutant CRC showed compelling, albeit modest, clinical activity. This study provides proof of principle that Imprime PGG, in combination with complement-activating antibodies, is associated with clinical activity.


Bowles D.W.,University of Colorado at Denver | Senzer N.,Mary Crowley Cancer Research Center | Hausman D.,Oncothyreon | Peterson S.,Oncothyreon | And 4 more authors.
Investigational New Drugs | Year: 2014

Background This phase I, dose-finding study determined the safety, maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), and antitumor activity of PX-866, a phosphatidylinositol 3-kinase inhibitor, combined with cetuximab in patients with incurable colorectal cancer or squamous cell carcinoma of the head and neck. Methods PX-866 was administered at escalating doses (6-8 mg daily) combined with cetuximab given at a 400 mg/m2 loading dose followed by 250 mg/m2 weekly. A "3 + 3" study design was used. Prior therapy with anti-EGFR therapies, including cetuximab, was allowed. Results Eleven patients were enrolled. The most frequent treatment-emergent adverse event was diarrhea (90.1 %), followed by hypomagnesemia (72.2 %), vomiting (72.2 %), fatigue (54.5 %), nausea (54.5 %), rash (45.5 %) and peripheral edema (40 %). No dose limiting toxicities were observed. The RP2D was 8 mg, the same as the single-agent PX-866 MTD. Best responses in 9 evaluable patients were: 4 partial responses (44.4 %), 4 stable disease (44.4 %), and 1 disease progression (11.1 %). The median progression free survival was 106 days (range: 1-271). Conclusion Treatment with PX-866 and cetuximab was tolerated with signs of anti-tumor activity. Further development of this combination is warranted. © 2014 Springer Science+Business Media New York.


PubMed | Mary Crowley Cancer Research Center and University of California at Los Angeles
Type: | Journal: The surgeon : journal of the Royal Colleges of Surgeons of Edinburgh and Ireland | Year: 2016

Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer with an overall 5-year survival rate less than 5% due to the poor early diagnosis and lack of effective therapeutic options. The most effective therapy remains surgery, however post-operative survival could be enhanced with effective adjuvant therapy. The massive information gained from Omics techniques on PDAC at the beginning of the 21st century is a remarkable accomplishment. However, the information gained from the omics data, including next generation sequencing data, has yet to successfully affect care of patients suffering with PDAC. Therefore, we propose the development of an actionable genomic platform that matches a patients PDAC clinically actionable genes with potential targeted adjuvant therapies. Using this platform, PDX1 has been identified as a potential actionable gene for PDAC, therefore, RNAi therapy, gene therapy and small inhibitory drugs, all targeting PDX1, serve as potential targeted adjuvant therapies. Preclinical studies support the hypothesis that identification of PDAC actionable genes could permit translation of a patients genomic information into precision targeted adjuvant therapy for PDAC.


PubMed | Northern California Melanoma Center, Amgen Inc., University of Louisville, Amgen and 6 more.
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2017

LBA9008 Background: T-VEC is an oncolytic immunotherapy (OI) derived from herpes simplex virus type-1 designed to selectively replicate within tumors and to produce GM-CSF to enhance systemic antitumor immune responses. OPTiM is a randomized, phase III trial of T-VEC or GM-CSF in patients (pts) with unresected melanoma with regional or distant metastases. We report the primary results of the first phase III study of OI.Key criteria: age 18 yrs; ECOG 1; unresectable melanoma stage IIIB/C or IV; injectable cutaneous, SC, or nodal lesions; LDH 1.5X upper limit of normal; 3 visceral lesions (excluding lung), none >3 cm. Pts were randomized 2:1 to intralesional T-VEC (initially 4 mL x10436 pts are in the ITT set: 295 (68%) T-VEC, 141 (32%) GM-CSF. 57% were men; median age was 63 yrs. Stage distribution was: IIIB/C 30%, IVM1a 27%, IVM1b 21%, IVM1c 22%. Objective response rate with T-VEC was 26% (95% CI: 21%, 32%) with 11% CR, and with GM-CSF was 6% (95% CI: 2%, 10%) with 1% CR. DRR for T-VEC was 16% (95% CI: 12%, 21%) and 2% for GM-CSF (95% CI: 0%, 5%), p<0.0001. DRR by stage (T-VEC, GM-CSF) was IIIB/C (33%, 0%), M1a (16%, 2%), M1b (3%, 4%), and M1c (8%, 3%). Interim OS showed a trend in favor of T-VEC; HR 0.79 (95% CI: 0.61, 1.02). Most common adverse events (AEs) with T-VEC were fatigue, chills, and pyrexia. Serious AEs occurred in 26% of T-VEC and 13% of GM-CSF pts. No grade 3 AE occurred in 3% of pts in either arm.T-VEC demonstrated both a statistically significant improvement in DRR over GM-CSF in pts with unresectable stage IIIB-IV melanoma and a tolerable safety profile; an interim analysis showed a trend toward improved OS. T-VEC represents a novel potential tx option for melanoma with regional or distant metastases.NCT00769704.


PubMed | California Cancer Associates for Research and Excellence, Millennium Pharmaceuticals Inc., University of Utah and Mary Crowley Cancer Research Center
Type: Journal Article | Journal: Journal of clinical pharmacology | Year: 2016

Ixazomib is the first oral proteasome inhibitor to be investigated in the clinic. This clinical study assessed whether the pharmacokinetics of ixazomib would be altered if administered after a high-calorie, high-fat meal. In a 2-period, 2-sequence, crossover study design, adult patients with advanced solid tumors or lymphoma received a 4-mg oral dose of ixazomib as immediate-release capsules on day 1 without food (fasted, administered following an overnight fast) or with food (fed, following consumption of a high-calorie, high-fat meal), followed by another dose on day 15 in the alternate food intake condition (fasted to fed or fed to fasted). Twenty-four patients were enrolled; of these, 15 were included in the pharmacokinetic-evaluable population. Administration of ixazomib after a high-fat meal reduced both the rate and extent of absorption of ixazomib. Under fed conditions, the median time to peak plasma concentration (Tmax ) of ixazomib was delayed by approximately 3 hours compared with administration in the fasted state (1.02 hours vs 4.0 hours), and there was a 28% reduction in total systemic exposure (area under the curve, AUC) and a 69% reduction in peak plasma concentration (Cmax ). Together, the results support the administration of ixazomib on an empty stomach, at least 1 hour before or at least 2 hours after food. These recommendations are reflected in the United States Prescribing Information for ixazomib (clinicaltrials.gov identifier NCT01454076).


Hong D.,University of Houston | Kurzrock R.,University of California at San Diego | Kim Y.,Isis Pharmaceuticals | Woessner R.,Astrazeneca | And 21 more authors.
Science Translational Medicine | Year: 2015

Next-generation sequencing technologies have greatly expanded our understanding of cancer genetics. Antisense technology is an attractive platform with the potential to translate these advances into improved cancer therapeutics, because antisense oligonucleotide (ASO) inhibitors can be designed on the basis of gene sequence information alone. Recent human clinical data have demonstrated the potent activity of systemically administered ASOs targeted to genes expressed in the liver. We describe the preclinical activity and initial clinical evaluation of a class of ASOs containing constrained ethyl modifications for targeting the gene encoding the transcription factor STAT3, a notoriously difficult protein to inhibit therapeutically. Systemic delivery of the unformulated ASO, AZD9150, decreased STAT3 expression in a broad range of preclinical cancer models and showed antitumor activity in lymphoma and lung cancer models. AZD9150 preclinical activity translated into single-agent antitumor activity in patients with highly treatment-refractory lymphoma and non-small cell lung cancer in a phase 1 doseescalation study. © 2015 American Association for the Advancement of Science. All rights Reserved.


Hong D.S.,University of Houston | Kurzrock R.,University of Houston | Wheler J.J.,University of Houston | Naing A.,University of Houston | And 12 more authors.
Clinical Cancer Research | Year: 2015

Purpose: This "3+3" phase I study evaluated the safety, biologic, and clinical activity of lenvatinib, an oral multikinase inhibitor, in patients with solid tumors. Experimental Design: Ascending doses of lenvatinib were administered per os twice daily in 28-day cycles. Safety and response were assessed for all patients. Angiogenic and apoptotic factors were tested as possible biomarkers in an expanded melanoma cohort. Results: Seventy-seven patients were treated in 3 cohorts: 18 with intermittent twice-daily dosing (7 days on, 7 days off) of 0.1-3.2 mg; 33 with twice-daily dosing of 3.2-12 mg; and 26 with twice-daily dosing of 10 mg (expanded melanoma cohort). Maximum tolerated dose was established at 10 mg per os twice daily. Prominent drug-related toxicities included hypertension (43%), fatigue (42%), proteinuria (39%), and nausea (25%); dose-limiting toxicities included hypertension, fatigue, and proteinuria. Twelve patients (15.6%) achieved partial response (PR, n = 9) or unconfirmed PR (uPR, n = 3), and 19 (24.7%) achieved stable disease (SD) ≥23 weeks. Total PR/uPR/SD ≥23 weeks was 40.3% (n = 31). Responses (PR/uPR) by disease were as follows: melanoma, 5 of 29 patients (includes 1 patient with NRAS mutation); thyroid, 3 of 6 patients; pancreatic, 1 of 2 patients; lung, 1 of 1 patients; renal, 1 of 1 patients; endometrial, 1 of 4 patients; and ovarian, 1 of 5 patients. AUC0-24 and Cmax increased dose proportionally. In multivariate Cox proportional hazard model analyses, increased baseline systolic blood pressure and decreased angiopoietin-1 ratio (2 hours:baseline) were associated with longer progression-free survival (PFS) in the expanded melanoma cohort (P = 0.041 and P = 0.03, respectively). Conclusions: The toxicity profile, pharmacokinetics, and antitumor activity of lenvatinib are encouraging. Decreases in the angiopoietin-1 ratio correlated with longer PFS in melanoma patients. ©2015 AACR.


PubMed | Mary Crowley Cancer Research Center, University of Houston, Eisai Inc and Sarah Cannon Research Institute at HealthONE
Type: Clinical Trial, Phase I | Journal: Oncotarget | Year: 2016

In this phase 1b study, patients with stage 4 or unresectable stage 3 melanoma were treated with escalating doses of lenvatinib (once daily) and temozolomide (TMZ) (days 1-5) in 28-day cycles, to determine the maximum tolerated dose (MTD) of the combination. Dose Level (DL)1: lenvatinib 20 mg, TMZ 100 mg/m2; DL2: lenvatinib 24 mg, TMZ 100 mg/m2; DL3: lenvatinib 24 mg, TMZ 150 mg/m2. Adverse events (AEs) were recorded and tumor response assessed per RECIST 1.0.Dose-limiting toxicity occurred in 1 of 32 treated patients (DL1); MTD was not reached. The highest dose administered was lenvatinib 24 mg + TMZ 150 mg/m2. Most common treatment-related AEs included fatigue (56.3%), hypertension (53.1%), and proteinuria (46.9%). Overall objective response rate was 18.8% (6 patients), all partial response; (DL1, n = 1; DL3, n = 5). Stable disease (SD) 16 weeks was observed in 28.1% of patients (DL1 and DL2, n = 1 each; DL3, n = 7); 12.5% of patients had SD 23 weeks. Single and repeat-dose pharmacokinetics of lenvatinib were comparable across cycles and with concomitant TMZ administration.Lenvatinib 24 mg/day + TMZ 150 mg/m2/day (days 1-5) demonstrated modest clinical activity, an acceptable safety profile, and was administered without worsening of either lenvatinib- or TMZ-related toxicities in this patient group.

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