TRC105 for the treatment of hepatocellular carcinoma: Preclinical data and preliminary results from two clinical trials evaluating monotherapy and combination with sorafenib.

211 Background: Endoglin (CD105), is an endothelial cell membrane receptor highly expressed on proliferating tumor vasculature, including in HCC. CD105 is essential for angiogenesis and its expression is upregulated by hypoxia and VEGF inhibition. TRC105 is a chimeric IgG1 anti-CD105 monoclonal antibody that acts by endothelial cell growth inhibition, ADCC and apoptosis. Methods: Preclinical: Murine BNL HCC cells were grown subcutaneously in wildtype Balb/c mice and treated with antibody to murine CD105, (clone MJ7/18; 10-200ug) ± sorafenib (10 mg/kg daily p.o.) or sorafenib alone. Clinical: Patients with HCC (Childs Pugh A/B7), ECOG 0/1, were enrolled in a phase I study of TRC105 at 3, 6, 10, 15mg/kg q 2wks plus sorafenib 400mg bid; or (if sorafenib-refractory) a phase II study of TRC105 at 10 or 15mg/kg q 2wks. Correlative biomarkers: DCE-MRI; FDG-PET; color Doppler ultrasonography; circulating endothelial and endothelial progenitor cells, plasma levels of angiogenic factors; soluble CD105 and tumor IHC for CD105. Results: Preclinical studies: CD105 expression was increased in BNL HCC tumors of mice treated with sorafenib. Anti-CD105 + sorafenib was more effective than sorafenib alone. Clinical trials (N=16): M:F 13:3; Median age = 55 (range 24-67); Phase I with sorafenib (N=8): 1 DLT (increased AST) occurred at 10mg/kg. The most frequent toxicity has been epistaxis. One patient with coronary stenosis developed a fatal MI and one patient with thrombocytopenia developed G3 cerebral tumor hemorrhage. Phase II (N=8): No grade 3/4 treatment-related toxicities . Most frequent toxicities headache (G2; N=3) and epistaxis (G1; N=4). No patient was progression free at 4 months. Median time on study: Phase I- 4 months; Phase II - 2 months. Preliminary evidence of biologic response seen on DCE-MRI in 1pt (of 3 evaluable) with a reduction in Ktrans and kep and 3pts (of 3 evaluable) with reduction in intra-tumoral color flow on Doppler. Conclusions: TRC105 is well tolerated both as single agent and combined with sorafenib. Evidence of biological activity was observed. Full preclinical, clinical and correlative data will be presented. Clinical trial information: NCT01306058, NCT01375569.

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A phase II study of TR105 in patients with hepatocellular carcinoma (HCC) who have progressed on sorafenib.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e15177 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e15177-e15177

Author(s):

Austin G. Duffy ◽

Osama E. Rahma ◽

Susanna Varkey Ulahannan ◽

Suzanne Fioravanti ◽

Aradhana Venkatesan ◽

...

Keyword(s):

Endothelial Cell ◽

Phase Ii ◽

Phase Ii Study ◽

Color Doppler ◽

Preliminary Evidence ◽

Color Flow ◽

Dce Mri ◽

Second Stage ◽

Circulating Endothelial Progenitor Cells ◽

Biologic Response

e15177 Background: CD105, also known as endoglin, is an endothelial cell membrane receptor that is highly expressed on tumor vasculature, including HCC. CD105 is essential for angiogenesis and its expression is upregulated by hypoxia and VEGF inhibition. TRC105 is a chimeric IgG1 anti-CD105 monoclonal antibody that inhibits angiogenesis and tumor growth by endothelial cell growth inhibition, ADCC and apoptosis. Methods: Patients with HCC and compensated liver function (Childs Pugh A/B7), ECOG 0/1, were enrolled to a single arm phase II study of TRC105 15mg/kg IV every 2 weeks. Patients must have progressed on or been intolerant of prior sorafenib. A Simon optimal 2-stage design was employed with a 50% 4-month PFS target for progression to the second stage. Correlative biomarkers evaluated included: DCE-MRI; FDG-PET; color Doppler ultrasonography; circulating endothelial progenitor cells, plasma levels of angiogenic factors; soluble CD105 and tumor IHC for CD105. Immunogenicity studies were also performed. Results: 8 pts have been treated so far; M:F 6:2; Median age = 58 (range 24-67); 7 pts had progressed following sorafenib (N=1 intolerant). N=1 pt had fibrolammellar HCC. There were no grade 3/4 treatment-related toxicities. Most frequent toxicities were headache (G2; N=3) and epistaxis (G1; N=4). One patient with a history of ischemic heart disease developed acute cardiac syndrome during the first infusion and was replaced. No patient was progression free at 4 months by RECIST criteria. Median time on study was 8 weeks (range 4-16 weeks). Median no. of doses administered was 4 (range 2-7). Preliminary evidence of biologic response was seen on DCE-MRI in 1pt (of 3 evaluable) with a reduction in kTrans and kep and 3pts (of 3 evaluable) who demonstrated reduction in intra-tumoral color flow on color Doppler. Conclusions: TRC105 is well tolerated in this HCC population post-sorafenib. Although there was biological evidence of antiangiogenic activity it is unlikely that the study will proceed to the second stage. Full clinical and correlative data for the first stage of the study will be presented. Future role of TRC105 in HCC will most likely be as combination therapy with sorafenib or other anti-VEGF therapy. Clinical trial information: NCT01375569.

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Pomalidomide Therapy for Myelofibrosis: Analysis of Results From Three Consecutive Clinical Trials

Blood ◽

10.1182/blood.v118.21.1759.1759 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1759-1759 ◽

Cited By ~ 1

Author(s):

Kebede Begna ◽

Animesh Pardanani ◽

Ruben A. Mesa ◽

William J Hogan ◽

Mark R. Litzow ◽

...

Keyword(s):

Clinical Trials ◽

Phase I ◽

Phase Ii ◽

Response Rate ◽

Single Agent ◽

Costal Margin ◽

Median Response ◽

Long Term Treatment

Abstract Abstract 1759 Background: Pomalidomide is a second generation IMiDsÒ immunomodulatory drug that has been shown to be active in the treatment of myelofibrosis (MF)-associated anemia (J Clin Oncol 2009; 27: 4563; Leukemia 2011;25: 301). In the current sponsor-independent analysis, we report long-term follow up data on patients from the Mayo Clinic who had participated in three consecutive clinical trials using single agent pomalidomide for MF. Methods: From May 2007 to January 2010, 94 patients with MF (including primary and post-polycythemia/essential thrombocythemia) were enrolled in three consecutive phase I and II clinical trials involving pomalidomide with or without prednisone. Eight two patients who received only single agent pomalidomide constitute the study population for the current study. Follow up information was updated in July, 2011. Results: Among the 82 study patients, 19 were included in a phase I dose escalation study (2.5-3.5 mg/day), 58 in a phase II low-dose single agent pomalidomide study (0.5 mg/day), and 5 in a phase II randomized study (2 mg/day). Median age was 67 years and 63 (77 %) patients were red blood cell transfusion dependent at study entry. Forty-five (55%), 24 (29%), 7 (9%), and 2 (2%) patients remained on pomalidomide therapy for at least 6, 12, 24, and 36 months, respectively (Table 1). The overall anemia response rate per IWG-MRT criteria was 27% (22/82). Response occurred in the first 6 months in 21 (96%) of the 22 responders. The median time for response was 2.3 months (range, 1–10). The median response duration was 16.5 months (2–40). The anemia response rate in patients with spleen size palpable at less than 10 cm below the costal margin was 44 % (17/39) vs. 10 % (4/39) in those whose spleen was palpable at or above 10 cm (p=0.002). The anemia response rate was twice as likely in JAK2 mutated versus non-mutated cases (30% vs 15% p=0.2). Anemia response rate was also higher in patients with at least 50% increase in absolute basophil count during the first month of therapy: 39% (19/49) vs 6% (2/32) p=0.001). The anemia response rate was not significantly affected by karyotype, transfusion need or leukocyte count. Among the anemia responders (n=22), 3 (14%) relapsed in the first 12 months; relapse was more likely in the presence of baseline leukocytosis (p=0.006). Among the 24 patients who took pomalidomide for at lease 12 months, grade 1 sensory neuropathy developed in 4 (16%) patients. Conclusion: Anemia response to pomalidomide therapy in myelofibrosis often occurs in the first 6 months of treatment and is more likely to occur in the presence of JAK2V617F and absence of marked splenomegaly. Long-term treatment with pomalidomide might be associated with sensory peripheral neuropathy in a subset of treated patients. Disclosures: No relevant conflicts of interest to declare.

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Targeting Intracellular Signaling Cascades for Patients with Relapsed, Refractory Multiple Myeloma: A Systematic Review of Clinical Trials

Blood ◽

10.1182/blood-2018-99-115721 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5659-5659

Author(s):

Shehroz Aslam ◽

Mustafa Nadeem Malik ◽

Abdul Rafae ◽

Rida Riaz ◽

Seren Durer ◽

...

Keyword(s):

Clinical Trials ◽

Phase I ◽

Phase Ii ◽

Intracellular Signaling ◽

Single Agent ◽

Mek Inhibitor ◽

Signaling Cascades ◽

Signaling Cascade ◽

Best Response ◽

Combination Regimens

Abstract Introduction: Intracellular signaling cascades including mTOR (mammalian target of rapamycin), MEK (mitogen-activated protein kinase), BCL2 (B-cell lymphoma 2), MET, AKT, and BTK (Bruton's tyrosine kinase) pathways are involved in the growth, proliferation, and survival of tumor cells. Drugs that inhibit these signaling cascades lead to apoptosis and cell cycle arrest making them an important therapeutic modality for treatment of malignancies. The aim of our review is to analyze the published literature on the clinical efficacy of these intracellular signaling cascade inhibitors in patients with relapsed, refractory multiple myeloma (RRMM). Methods: We performed a comprehensive literature search on articles published after 2010. Four hundred and twenty-three articles were identified using the following five databases (Pubmed, Embase Cochrane, Web of Science and Clinical Trials.gov). After a detailed screening, we finalized 11 studies involving 525 RRMM patients. Clinical trials (phase I/II, II and III) with non-FDA approved drugs were included. Results: mTOR inhibitors (Everolimus and Temsirolimus): A total of 157 RRMM patients were included. All trials were early phase (I/II). Everolimus in combination with panobinostat (n=32) achieved an overall response rate (ORR) of 7%. A total of 82 patients received everolimus in combination with sorafenib and achieved a complete response (CR) of 8.5%. Temsirolimus was used in combination with bortezomib (V) (n=43). CR was observed in 5% patients, very good partial response (VGPR) in 9% and stable disease (SD) in 44% patients. AKT Inhibitors (Perifosine and Uprosertib): A total of 153 RRMM patients were included. Eighty-four patients were tested in phase I/II trials while 69 patients were tested in phase III trials. All patients were given perifosine (50 mg) in combination with V with or without dexamethasone (d). In 142 evaluable patients, the pooled ORR was 31%. Uprosertib is currently under phase II evaluation, no clinical data is available while one ongoing phase I/II trial is summarized in Table 2. MEK inhibitor (Selumetinib): A total of 36 RRMM patients were included. All patients were tested in phase II trials. Single-agent selumetinib (75 mg) was given (n= 32). The ORR was 5.6%, VGPR in 3.12%, partial response (PR) in 3.12%, SD in 53.13% and progressive disease (PD) in 40.63% patients. The median progression-free survival (mPFS) was 3.52 months. BCL2 inhibitor (Venetoclax): A total of 66 RRMM patients were included. All patients were tested in phase I/II trials. Single-agent venetoclax (300-1200 mg) was given. The ORR was 21%, CR in 4%, VGPR in 8% and PR in 6% patients. MET inhibitors (Cabozantinib and Tivantinib): A total of 27 RRMM patients were included. Eleven patients were tested in phase I/II trials while 16 patients were tested in phase II trial. Cabozantinib (20-60 mg) and Tivantinib (360 mg) were given to 11 and 16 patients respectively. SD was seen in 54.5% and 36% patients respectively while PD was seen in 18.2% and 63% patients respectively. BTK inhibitor (Ibrutinib): A total of 86 RRMM patients were included. Patients were tested in phase I/II (n=46) and phase II (n=46) clinical trials. Ibrutinib (560-840 mg) was used in combination regimens in all patients. In 85 evaluable patients, the pooled ORR was 35.29%. The best response was seen when ibrutininb was used in combination with carfilzomib (CFZ) with or without dexamethasone (d) i.e. 67%. Conclusion: In RRMM patients, BTK inhibitor (ibrutinib) and AKT inhibitor (perifosine) when used in combination regimens demonstrated a weak efficacy with an ORR of < 40%. The best response was seen when ibrutinib was used in combination with CFZ +/- d i.e. 67%. MET inhibitor (cabozantinib) and MEK inhibitor (selumetinib) showed SD in more than 50% of patients. mTOR inhibitor (temsirolimus) showed SD in more than 40% of patients. Other intracellular signaling cascade inhibitors (venetoclax, selumetinib, everolimus) when used either as single agents or in combination regimens demonstrated a poor efficacy with an ORR of < 25%. However, data on signaling cascade inhibitors is emerging and future randomized prospective trials are needed. Disclosures No relevant conflicts of interest to declare.

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Phase I to II Multicenter Study of Oblimersen Sodium, a Bcl-2 Antisense Oligonucleotide, in Patients With Advanced Chronic Lymphocytic Leukemia

Journal of Clinical Oncology ◽

10.1200/jco.2005.02.4364 ◽

2005 ◽

Vol 23 (30) ◽

pp. 7697-7702 ◽

Cited By ~ 142

Author(s):

Susan M. O'Brien ◽

Charles C. Cunningham ◽

Anatoliy K. Golenkov ◽

Anna G. Turkina ◽

Steven C. Novick ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Phase I ◽

Phase Ii ◽

Intravenous Infusion ◽

Single Agent ◽

Plasma Concentrations ◽

Parent Drug ◽

Lymphocytic Leukemia ◽

Complete Disappearance ◽

Continuous Intravenous Infusion

Purpose To determine the maximum-tolerated dose (MTD), efficacy, safety, and pharmacokinetics of oblimersen sodium in patients with advanced chronic lymphocytic leukemia (CLL). Patients and Methods Eligible patients had relapsed or refractory CLL after treatment with fludarabine. Oblimersen was administered at doses ranging from 3 to 7 mg/kg/d as a 5-day continuous intravenous infusion in cycle 1 and as a 7-day continuous intravenous infusion in subsequent cycles every 3 weeks in stable or responding patients. Results Forty patients were enrolled and treated (14 patients in phase I and 26 patients in phase II). Dose-limiting reactions in phase I included hypotension and fever, and the MTD for phase II dosing was established at 3 mg/kg/d. Two (8%) of 26 assessable patients achieved a partial response. Other evidence of antitumor activity included ≥ 50% reduction in splenomegaly (seven of 17 patients; 41%), complete disappearance of hepatomegaly (two of seven patients; 29%), ≥ 50% reduction of lymphadenopathy (seven of 22 patients; 32%), and ≥ 50% reduction in circulating lymphocyte counts (11 of 22 patients; 50%). Adverse events included transient hypotension, fever, fatigue, night sweats, diarrhea, nausea, vomiting, hypokalemia, and cough. Plasma concentrations of oblimersen (parent drug) and its major metabolites were variable. Renal clearance represented only a small portion of total parent drug clearance. Conclusion Dosing with oblimersen sodium in patients with CLL is limited by development of a cytokine release syndrome that is characterized by fever, hypotension, and back pain. Oblimersen sodium has modest single-agent activity in heavily pretreated patients with advanced CLL, and further evaluation of its activity in combination with cytotoxic drugs is warranted.

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Single agent activity of rhizoxin in non-small-cell lung cancer: A phase II trial of the EORTC early clinical trials group

Lung Cancer ◽

10.1016/0169-5002(96)84393-5 ◽

1996 ◽

Vol 15 (1) ◽

pp. 155

Keyword(s):

Lung Cancer ◽

Clinical Trials ◽

Small Cell Lung Cancer ◽

Phase Ii ◽

Cell Lung Cancer ◽

Phase Ii Trial ◽

Single Agent ◽

Small Cell ◽

Small Cell Lung

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Unconventional Anticancer Agents: A Systematic Review of Clinical Trials

Journal of Clinical Oncology ◽

10.1200/jco.2005.03.8406 ◽

2006 ◽

Vol 24 (1) ◽

pp. 136-140 ◽

Cited By ~ 20

Author(s):

Andrew J. Vickers ◽

Joyce Kuo ◽

Barrie R. Cassileth

Keyword(s):

Clinical Trials ◽

Phase I ◽

Cancer Patients ◽

Phase Ii ◽

Dose Finding ◽

Phase Iii ◽

High Dose ◽

Free Text ◽

Phase Ii Trials ◽

Off Label

Purpose A substantial number of cancer patients turn to treatments other than those recommended by mainstream oncologists in an effort to sustain tumor remission or halt the spread of cancer. These unconventional approaches include botanicals, high-dose nutritional supplementation, off-label pharmaceuticals, and animal products. The objective of this study was to review systematically the methodologies applied in clinical trials of unconventional treatments specifically for cancer. Methods MEDLINE 1966 to 2005 was searched using approximately 200 different medical subject heading terms (eg, alternative medicine) and free text words (eg, laetrile). We sought prospective clinical trials of unconventional treatments in cancer patients, excluding studies with only symptom control or nonclinical (eg, immune) end points. Trial data were extracted by two reviewers using a standardized protocol. Results We identified 14,735 articles, of which 214, describing 198 different clinical trials, were included. Twenty trials were phase I, three were phase I and II, 70 were phase II, and 105 were phase III. Approximately half of the trials investigated fungal products, 20% investigated other botanicals, 10% investigated vitamins and supplements, and 10% investigated off-label pharmaceuticals. Only eight of the phase I trials were dose-finding trials, and a mere 20% of phase II trials reported a statistical design. Of the 27 different agents tested in phase III, only one agent had a prior dose-finding trial, and only for three agents was the definitive study initiated after the publication of phase II data. Conclusion Unconventional cancer treatments have not been subject to appropriate early-phase trial development. Future research on unconventional therapies should involve dose-finding and phase II studies to determine the suitability of definitive trials.

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