VTX-2337, a TLR8 agonist, plus chemotherapy in recurrent ovarian cancer: Preclinical and phase I data by the Gynecologic Oncology Group.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3077-3077 ◽  
Author(s):  
Bradley J. Monk ◽  
William E. Brady ◽  
Heather A. Lankes ◽  
Andrea Facciabene ◽  
Kristi Manjarrez ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Mouse Model ◽  
Phase I ◽  
Gynecologic Oncology ◽  
Single Agent ◽  
Injection Site Reaction ◽  
Pegylated Liposomal Doxorubicin ◽  
Recurrent Ovarian Cancer ◽  
Preclinical Model ◽  
Gynecologic Oncology Group

3077 Background: Given the absence of clear molecular drivers in high-grade serous ovarian cancer, targeting the tumor micro-environment with immunotherapy is an emerging approach. VTX-2337 is a potent, small molecule agonist of TLR8 which stimulates the innate immune response, and was previously evaluated as a single agent in cancer patients. We report data combining VTX-2337 with chemotherapy in recurrent ovarian cancer. Methods: VTX-2337 was tested in an ovarian cancer mouse model with an intact human immune system. Additionally, an open-label phase I study of VTX-2337 + pegylated liposomal doxorubicin (PLD) in recurrent ovarian cancer (NCT01294293, N=13) was performed. PLD (40 mg/m2) was given on day 1 of a 28-day cycle. Three dose levels of VTX-2337 (2.5, 3.0, 3.5 mg/m2, N=13) were serially tested and given by SC injection on days 3, 10, and 17. VTX-2337 (3.0 mg/m2) was also tested with paclitaxel (80 mg/m2; N=7) given on days 1, 8, and 15 of a 28 day cycle. Responses were evaluated using RECIST1.1. PK and serum immune cytokines were measured. Patients remained on therapy until toxicity or progression. Results: In the mouse model, clinical responses to PLD were increased. Innate immunity along with CD8+ T cell responses were also induced. In humans, treatment with PLD + VTX-2337 increased various cytokines and chemokines (G-CSF, MCP-1, MIP-1β, TNF-α). The PK of PLD was not affected by VTXE2337. The combination was well tolerated with no DLTs. AEs consisted of those seen with single-agent PLD (Gr 3/4 toxicities, N=6) or VTXE2337 (Gr 1/2 injection site reaction, transient fever, flu-like symptoms). There was 1 partial response (13%) and 63% had stable disease. Paclitaxel + VTX-2337 was also well tolerated. Conclusions: VTX-2337 enhances the effect of PLD in a preclinical model of ovarian cancer, and the combination is well-tolerated in patients. Clinical data and biomarkers consistent with immunostimulation, provide rationale for the on-going randomized, placebo-controlled, phase II trial comparing PLD vs PLD + VTX-2337 (GOG-3003, NCT01666444). Clinical trial information: NCT01666444.

Phase I trial and pharmacologic trial of sequences of paclitaxel and topotecan in previously treated ovarian epithelial malignancies: a Gynecologic Oncology Group study.

1997 ◽  
Vol 15 (1) ◽  
pp. 177-186 ◽  
Author(s):  
S O'Reilly ◽  
G F Fleming ◽  
S D Barker ◽  
J R Walczak ◽  
M A Bookman ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase I ◽  
Gynecologic Oncology ◽  
Single Agent ◽  
Recurrent Ovarian Cancer ◽  
Gynecologic Oncology Group ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Stimulating Factor ◽  
Pharmacologic Study

PURPOSE A phase I and pharmacologic study to evaluate the feasibility of administering paclitaxel (PTX) in combination with topotecan (TPT) without and with granulocyte colony-stimulating factor (G-CSF) in women with recurrent or refractory ovarian cancer. PATIENTS AND METHODS TPT was administered as a 30-minute infusion daily for 5 days and PTX was given as a 24-hour infusion (PTX-24) either before TPT on day 1 or after TPT on day 5. Each patient received both schedules on an alternating basis every 3 weeks. Sequential dose escalation of TPT or PTX-24 without and with G-CSF resulted in five dosage permutations of TPT/PTX (mg/ m2): 0.75/135 without G-CSF and 0.75/135, 1.25/135, 1.50/135, and 1.25/170 with G-CSF. RESULTS Twenty-two patients received 109 courses of therapy. Dose-limiting myelosuppression consistently occurred at the first TPT/PTX-24 dose level (0.75/135 mg/m2) in the absence of G-CSF support. Although the addition of G-CSF resulted in reduced rates of complicated neutropenia, the incidences of dose-limiting neutropenia and thrombocytopenia were unacceptably high after the doses of either TPT or PTX-24 were increased. Paired analysis showed similar hematologic toxicities between the two sequences of drug administration. The pharmacologic behavior of both TPT and PTX-24 was not altered by drug sequencing. Major antitumor responses occurred in 40% of patients with measurable and assessable disease, including 45% and 9% of patients with potentially cisplatin-sensitive and -resistant tumors, respectively. CONCLUSION The recommended doses of TPT on a daily times-five schedule combined with PTX-24 in these patients were 0.75 mg/m2/d and 135 mg/m2, respectively, with G-CSF support. Although this dose of PTX has significant single-agent activity in ovarian cancer, the dose of TPT is much lower than the TPT dose at which single-agent activity has been observed. Due to the inability to administer near relevant single-agent doses of both drugs in combination, as well as the requirement for G-CSF support, further evaluations of this regimen in women with refractory or recurrent ovarian cancer are necessary before it can be recommended for previously treated patients in this setting.

scholarly journals Low-dose abdominal radiation as a docetaxel chemosensitizer for recurrent epithelial ovarian cancer: A phase I study of the Gynecologic Oncology Group

2011 ◽  
Vol 120 (2) ◽  
pp. 224-228 ◽  
Author(s):  
Charles A. Kunos ◽  
Michael W. Sill ◽  
Thomas E. Buekers ◽  
Joan L. Walker ◽  
Jeanne M. Schilder ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase I ◽  
Epithelial Ovarian Cancer ◽  
Phase I Study ◽  
Low Dose ◽  
Gynecologic Oncology ◽  
Gynecologic Oncology Group ◽  
Oncology Group

Phase I and pharmacokinetic study of the novel VEGF-directed fusion protein, aflibercept, in combination with docetaxel in women with recurrent ovarian, fallopian tube, and primary peritoneal cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5549-5549
Author(s):  
R. L. Coleman ◽  
A. Kamat ◽  
R. Iyer ◽  
V. Kundra ◽  
M. Garcia ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Fusion Protein ◽  
Phase I ◽  
Cancer Patients ◽  
Fdg Pet ◽  
Single Agent ◽  
Recurrent Ovarian Cancer ◽  
Circulating Endothelial Cells ◽  
Efficacy Evaluation ◽  
Dce Mri

5549 Background: VEGF blockade has proved to be a promising therapeutic strategy in solid tumors, including ovarian. Aflibercept, a novel fusion protein consisting of the extracellular domains of VEGFR1/2 binds VEGF A, B and PlGF. Aflibercept has been studied as a single agent in heavily pretreated ovarian cancer patients. We hypothesized that the combination of aflibercept and docetaxel could be safely administered to women with recurrent ovarian cancer. Correlative biomarker and imaging studies of anti-angiogenesis targeting, pharmacokinetics (PK) and preliminary efficacy were additional objectives. Methods: Eligible patients had measurable, recurrent disease with no more than 3 prior chemotherapeutic regimens. Study design was a “lead-in” phase I trial; cycle 0, administered aflibercept IV as a single agent in 1 of 3 dose levels (2, 4, or 6 mg/kg) in a 3+3 design. Aflibercept was given in subsequent cycles with docetaxel (75 mg/m2); each cycle was 21 days. Correlative studies in cycle 0 were: PK (single agent), circulating endothelial cells and precursors (CEC, CEP), and imaging FDG-PET, DCE-MRI (baseline, day 2 and day 21). Efficacy evaluation (RECIST) was conducted q2 cycles of combination therapy. Results: Nine patients were recruited, 3 at each dose level. All are evaluable. No DLTs were observed in cycles 0 and 1; The most common hematological toxicities were myelosuppression (1 Grade 4 ANC) and anemia (Grade 2). Non-hematological toxicities (Gr 3) included headache, hypertension, fatigue and ulceration. One patient each with hypertension and ulceration lead to treatment discontinuation after 4 and 13 cycles, respectively. FDG-PET defined SUVmax in target lesions within 25% of baseline in 7 patients; 2 others had >25% increase at 48 hours post treatment. CECs, CEPs, DCE-MRI and PK are being analyzed. Confirmed PR was observed in 2 (22%) with 1 additional near PR. Median number of cycles: 5 (range 3–15). All have now progressed, median time to progression: 15 weeks. Conclusions: Aflibercept can be safely administered at 6 mg/kg with docetaxel repeatedly in this population of recurrent ovarian cancer patients. Preliminary efficacy supports phase II study, which is ongoing. No significant financial relationships to disclose.

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