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1.
Cancer Med ; 9(3): 882-893, 2020 02.
Article in English | MEDLINE | ID: mdl-31821732

ABSTRACT

BACKGROUND: Olaratumab, a fully human monoclonal antibody, selectively binds to human platelet-derived growth factor receptor alpha and blocks ligand binding. This study assessed the effect of olaratumab on the pharmacokinetics (PK) of doxorubicin and the safety of olaratumab alone and in combination with doxorubicin. METHODS: This open-label randomized phase 1 trial enrolled 49 patients ages 27 to 83 with metastatic or locally advanced soft tissue sarcoma (STS). Patients participated in 21-day treatment cycles (up to 8) until they met discontinuation criteria. In cycles 1 and 2, patients received olaratumab (15 mg/kg in Part A, 20 mg/kg in Part B) and doxorubicin (75 mg/m2 ). In cycles 3 through 8, patients continued combination treatment (15 mg/kg olaratumab + doxorubicin). Effect of olaratumab on PK of doxorubicin was determined in patients who received all doses in cycles 1 and 2. RESULTS: PK properties of doxorubicin administered alone or in combination with olaratumab (15 or 20 mg/kg) were similar for AUC(0-tlast ), AUC(0-∞), and Cmax . PK properties of olaratumab (15 or 20 mg/kg) were also similar when administered alone or in combination with doxorubicin. Three patients died (2 of disease progression and 1 of neutropenic enterocolitis). Fatigue and nausea (>75% of patients) were the most common treatment-emergent adverse events (TEAEs). Other common TEAEs included musculoskeletal pain, mucositis, constipation, and diarrhea. CONCLUSIONS: Olaratumab at 15 or 20 mg/kg before doxorubicin infusion had no clinically relevant effect on systemic exposure to doxorubicin compared with doxorubicin alone in patients with metastatic or locally advanced STS.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Doxorubicin/pharmacokinetics , Sarcoma/drug therapy , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/adverse effects , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Disease Progression , Doxorubicin/administration & dosage , Doxorubicin/adverse effects , Drug Interactions , Female , Humans , Infusions, Intravenous , Male , Middle Aged , Neoplasm Staging , Sarcoma/diagnosis , Sarcoma/mortality , Sarcoma/pathology
2.
JAMA Oncol ; 4(6): 814-820, 2018 06 01.
Article in English | MEDLINE | ID: mdl-29710216

ABSTRACT

Importance: Gastrointestinal stromal tumors (GISTs) are life-threatening when metastatic or not amenable to surgical removal. In a few patients with advanced GISTs refractory to imatinib mesylate, treatment with sunitinib malate followed by regorafenib provides tumor control; however, additional active treatments are needed for most patients. Objective: To evaluate the 6-month progression-free survival (PFS), tumor objective response, and overall survival rates in patients with GISTs treated with dasatinib. Design, Setting, and Participants: This single-arm clinical trial used a Bayesian design to enroll patients 13 years or older with measurable imatinib-refractory metastatic GISTs treated at 14 sarcoma referral centers from June 1, 2008, through December 31, 2009. A control group was not included. Patients were followed up for survival for a minimum of 5 years from date of enrollment. Tumor imaging using computed tomography or magnetic resonance imaging was performed every 8 weeks for the first 24 weeks and every 12 weeks thereafter. Tumor response was assessed by local site using the Choi criteria. Treatment was continued until tumor progression, unacceptable toxic effects after reduction in drug dose, or patient or physician decision. Archival tumor tissue was evaluated for expression of the proto-oncogene tyrosine-protein kinase Src (SRC), phosphorylated SRC (pSRC), and succinate dehydrogenase complex iron sulfur subunit B (SDHB) proteins and for mutation in the V-Kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) and platelet-derived growth factor receptor α (PDGFRA) genes. Data analysis was performed from May 19, 2017, through December 20, 2017. Interventions: Dasatinib, 70 mg orally twice daily. Main Outcomes and Measures: The primary end point was the 6-month PFS estimate using greater than 30% as evidence of an active drug and less than 10% as evidence of inactive treatment. Results: In this study, 50 patients were enrolled (median age, 60 years; age range, 19-78 years; 31 [62%] male and 19 [38%] female; 41 [82%] white), and 48 were evaluable for response. The estimated 6-month PFS rate was 29% in the overall population and 50% in a subset of 14 patients with pSRC in GISTs. Objective tumor response was observed in 25%, including 1 patient with an imatinib-resistant mutation in PDGFRA exon 18. Conclusions and Relevance: Dasatinib may have activity in a subset of patients with imatinib-resistant GISTs. Further study is needed to determine whether pSRC is a prognostic biomarker.


Subject(s)
Antineoplastic Agents/therapeutic use , Dasatinib/therapeutic use , Gastrointestinal Neoplasms/drug therapy , Gastrointestinal Stromal Tumors/secondary , Imatinib Mesylate/therapeutic use , Molecular Targeted Therapy , Protein Kinase Inhibitors/therapeutic use , Adult , Aged , Drug Resistance, Neoplasm , Drug Substitution , Female , Follow-Up Studies , Gastrointestinal Neoplasms/chemistry , Gastrointestinal Neoplasms/mortality , Gastrointestinal Stromal Tumors/chemistry , Gastrointestinal Stromal Tumors/drug therapy , Gastrointestinal Stromal Tumors/mortality , Humans , Male , Middle Aged , Neoplasm Proteins/analysis , Progression-Free Survival , Proto-Oncogene Mas , Proto-Oncogene Proteins c-kit/analysis , Receptor, Platelet-Derived Growth Factor alpha/analysis , Receptor, Platelet-Derived Growth Factor alpha/genetics , Succinate Dehydrogenase/analysis , Young Adult , src-Family Kinases/analysis
3.
Cancer ; 123(1): 90-97, 2017 Jan 01.
Article in English | MEDLINE | ID: mdl-27696380

ABSTRACT

BACKGROUND: Alveolar soft part sarcoma (ASPS), chondrosarcoma (CS), chordoma, epithelioid sarcoma, and solitary fibrous tumor (SFT) are malignant tumors that are relatively resistant to chemotherapy and for which more effective drug therapy is needed. METHODS: The 5 listed subtypes were enrolled into a single indolent sarcoma cohort in a phase 2 study of dasatinib using a Bayesian continuous monitoring rule for enrollment. The primary objective was to estimate the 6-month progression-free survival (PFS) rate according to the Choi criteria with a target of ≥50%. Cross-sectional imaging was performed before the start of treatment, every 2 months for 6 months, and then every 3 months during treatment. The 2- and 5-year survival rates were determined. RESULTS: One hundred sixteen patients were enrolled within 45 months, and 109 began treatment with dasatinib. The 6-month PFS rate and the median PFS were 48% and 5.8 months, respectively. The PFS rate at 6 months was highest with ASPS (62%) and lowest with SFT (30%). More than 10% of the patients with ASPS, CS, or chordoma had stable disease for more than 1 year. Collectively, for all 5 subtypes, the 2- and 5-year overall survival rates were 44% and 13%, respectively. An objective response was observed in 18% of the patients with CS or chordoma. CONCLUSIONS: Dasatinib failed to achieve control of sarcoma growth for at least 6 months in more than 50% of the patients in this trial according to the Choi tumor response criteria. An objective tumor response and prolonged stable disease was observed in >10% of patients with CS or chordoma. Cancer 2017;90-97. © 2016 American Cancer Society.


Subject(s)
Bone Neoplasms/drug therapy , Chondrosarcoma/drug therapy , Chordoma/drug therapy , Dasatinib/therapeutic use , Sarcoma, Alveolar Soft Part/drug therapy , Solitary Fibrous Tumors/drug therapy , Adult , Aged , Aged, 80 and over , Bayes Theorem , Bone Neoplasms/mortality , Chondrosarcoma/mortality , Chordoma/mortality , Disease-Free Survival , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Sarcoma, Alveolar Soft Part/mortality , Solitary Fibrous Tumors/mortality , Survival Rate , Young Adult
4.
Oncotarget ; 7(35): 56491-56500, 2016 Aug 30.
Article in English | MEDLINE | ID: mdl-27447854

ABSTRACT

PATIENTS AND METHODS: Patients with metastatic solid tumors who had progressed on at least one line of standard of care therapy were referred to the Indiana University Health Precision Genomics Program. Tumor samples were submitted for DNA & RNA next-generation sequencing, fluorescence in situ hybridization, and immunohistochemistry for actionable targets. A multi-disciplinary tumor board reviewed all results. For each patient, the ratio of progression-free survival (PFS) of the genomically guided line of therapy divided by the PFS of their prior line was calculated. Patients whose PFS ratio was ≥ 1.3 were deemed to have a meaningful improvement in PFS. RESULTS: From April 2014-October 2015, 168 patients were evaluated and 101 patients achieved adequate clinical follow-up for analysis. 19 of 44 (43.2%) patients treated with genomically guided therapy attained a PFS ratio ≥ 1.3 vs. 3 of 57 (5.3%) treated with non-genomically guided therapy (p < 0.0001). Similarly, overall PFS ratios (irrespective of cutoff) were higher for patients with genomically guided therapy vs non-genomically guided therapy (p = 0.05). Further, patients treated with genomically guided therapy had a superior median PFS compared to those treated with non-genomically guided therapy (86 days vs. 49 days, p = 0.005, H.R. = 0.55, 95% C.I.:0.37-0.84). CONCLUSION: Patients with refractory metastatic cancer who receive genomically guided therapy have improved PFS ratios and longer median PFS compared to patients who do not receive genomically guided therapy.


Subject(s)
Medical Oncology/methods , Neoplasms/genetics , Neoplasms/therapy , Precision Medicine/methods , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/genetics , Breast Neoplasms/therapy , Colorectal Neoplasms/genetics , Colorectal Neoplasms/therapy , Disease-Free Survival , Female , Genomics , High-Throughput Nucleotide Sequencing , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Indiana , Male , Middle Aged , Neoplasm Metastasis , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/therapy , Research Design , Sarcoma/genetics , Sarcoma/therapy , Soft Tissue Neoplasms/genetics , Soft Tissue Neoplasms/therapy , Treatment Outcome , Universities
5.
Cancer ; 122(6): 868-74, 2016 Mar 15.
Article in English | MEDLINE | ID: mdl-26710211

ABSTRACT

BACKGROUND: Dasatinib exhibited activity in preclinical models of sarcoma. The Sarcoma Alliance for Research through Collaboration (SARC) conducted a multicenter, phase 2 trial of dasatinib in patients with advanced sarcoma. METHODS: Patients received dasatinib twice daily. The primary objective was to estimate the clinical benefit rate (CBR) (complete response or partial response within 6 months or stable disease duration of ≥6 months) with a target of ≥25%. Patients were enrolled into 1 of 7 different cohorts and assessed by imaging every 8 weeks using Choi criteria tumor response and a Bayesian hierarchical design. For each subtype, enrollment was stopped after a minimum of 9 patients were treated if there was a <1% chance the CBR was ≥25%. RESULTS: A total of 200 patients were enrolled. Accrual was stopped early in 5 cohorts because of low CBR. The leiomyosarcoma (LMS) and undifferentiated pleomorphic sarcoma (UPS) cohorts fully accrued and 6 of 47 and 8 of 42 evaluable patients, respectively, exhibited clinical benefit. The probability that the CBR was ≥25% in the LMS and UPS cohorts was 0.008 and 0.10, respectively. The median progression-free survival ranged from 0.9 months in patients with rhabdomyosarcoma to 2.2 months in patients with LMS. The median overall survival was 8.6 months. The most frequent adverse events were constitutional, gastrointestinal, and respiratory, and 36% of patients required dose reduction for toxicity. Serious adverse events attributed to therapy occurred in 11% of patients. CONCLUSIONS: Dasatinib may have activity in patients with UPS but is inactive as a single agent in the other sarcoma subtypes included herein. The Bayesian design allowed for the early termination of accrual in 5 subtypes because of lack of drug activity.


Subject(s)
Antineoplastic Agents/therapeutic use , Dasatinib/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Sarcoma/drug therapy , Sarcoma/pathology , Adult , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Bayes Theorem , Dasatinib/administration & dosage , Dasatinib/adverse effects , Disease-Free Survival , Drug Administration Schedule , Female , Humans , Kaplan-Meier Estimate , Leiomyosarcoma/drug therapy , Leiomyosarcoma/pathology , Male , Middle Aged , Neoplasm Grading , Osteosarcoma/drug therapy , Osteosarcoma/pathology , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Rhabdomyosarcoma/drug therapy , Rhabdomyosarcoma/pathology , Treatment Outcome
6.
Support Cancer Ther ; 4(4): 241-6, 2007 Sep 01.
Article in English | MEDLINE | ID: mdl-18632523

ABSTRACT

INTRODUCTION: Neuropathic pain has been reported to affect 40%-50% of patients with cancer. PATIENTS AND METHODS: Consecutive patients selected from the outpatient/adult patient palliative care clinic of the Roudebush Veterans Affairs Medical Center and the Indiana University Palliative Clinic were reviewed. A verbal pain linear analogue assessment scale was used to assess neuropathic pain. Pain medication history was also reviewed in addition to percent pain relief. The following variables were extracted from the medical record: pain characteristics, location, cause, date of initiation of therapy, maximal tolerated dose, pain scores on the visit of optimal tolerated dose, other concurrent medications, number of months of pain before initiation of topiramate therapy, and total duration of topiramate therapy. Decrease in worst, best, and average pain was recorded, as were the development of any adverse effects. RESULTS: Of the 13 patients on second- and third-line therapy, 53.8% had >/= 30% decrease in worst pain; 69.2% had >/= 30% decrease in average pain, and 53.8% had >/= 30% decrease in best pain. Eight of 13 patients (61.5%) experienced adverse effects. Five patients discontinued (38.5%) topiramate because of adverse events. CONCLUSION: Because our retrospective study showed topiramate to be a beneficial second- and third-line therapy in patients with cancer who did not experience adequate pain control on previous regimens, further prospective studies are needed to establish this medication in the armamentarium of neuropathic cancer pain management.

8.
Eur Radiol ; 15(7): 1407-14, 2005 Jul.
Article in English | MEDLINE | ID: mdl-15761716

ABSTRACT

The objective of this study was to report the CT and MRI appearances of primary and metastatic gastrointestinal stromal tumor (GIST). The clinical and imaging findings of 31 patients with histological and immunohistochemical diagnosis of GIST were reviewed. The CT and MRI findings were assessed independently for size, location, enhancement characteristics, and pattern of metastatic disease. The tumors were of enteric (n=13), gastric (n=12), duodenal (n=2), and rectal (n=3) origin. In one case the primary site was the mesentery, without involvement of bowel. Primary tumors were typically exophytic (79%), larger than 5 cm (84%), and inhomogeneously enhancing (84%). Central necrosis of all tumors (37%) and aneurysmal dilation of enteric tumors (33%) were less common. Metastases were most commonly to mesentery (26%) or liver (32%). Less common findings were ascites (7%) and omental caking (3%). Liver metastases were hypervascular in 92% of patients and rapidly became cystic following therapy with imatinib mesylate (Gleevec; Novartis, East Hanover, NJ, USA). Lung metastases, bowel obstruction, vascular invasion, and significant lymphadenopathy were not seen in any patient. GISTs have some specific CT findings which could help differentiate them from other gastrointestinal tumors. Liver metastases became cystic following therapy, mimicking simple cysts. MRI was better than single-phase CT for assessing liver metastases, while CT was more sensitive for mesenteric metastases.


Subject(s)
Gastrointestinal Stromal Tumors/diagnosis , Magnetic Resonance Imaging , Tomography, X-Ray Computed , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/therapeutic use , Benzamides , Duodenal Neoplasms/diagnosis , Duodenal Neoplasms/diagnostic imaging , Female , Gastrointestinal Stromal Tumors/diagnostic imaging , Gastrointestinal Stromal Tumors/secondary , Humans , Image Enhancement , Imatinib Mesylate , Intestine, Small/diagnostic imaging , Intestine, Small/pathology , Liver Neoplasms/secondary , Male , Mesentery/pathology , Middle Aged , Peritoneal Neoplasms/secondary , Piperazines/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrimidines/therapeutic use , Radiographic Image Enhancement , Rectal Neoplasms/diagnosis , Rectal Neoplasms/diagnostic imaging , Stomach Neoplasms/diagnosis , Stomach Neoplasms/diagnostic imaging
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