A phase I trial of the proteosome inhibitor PS-341 in combination with carboplatin in platinum and taxane resistant ovarian cancer patinets

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5558-5558
Author(s):  
C. N. Landen ◽  
R. Coleman ◽  
M. R. Milam ◽  
T. Johnston ◽  
R. Iyer ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase I ◽  
Stable Disease ◽  
Performance Status ◽  
Single Agent ◽  
Optimal Dose ◽  
Recurrent Ovarian Cancer ◽  
Cytotoxic Agents ◽  
Pharmacokinetic Data ◽  
Resistant Disease

5558 Background. PS-341 (Millenium Pharmaceuticals, Inc.), a proteosome inhibitor, affects p53, NFκB, cell adhesion molecules, and sensitivity to cytotoxic agents to promote apoptosis and inhibit metastasis in cancer cells. PS-341 alone rarely causes myelosupression or renal toxicity, and therefore is an attractive agent to use in combination with cytotoxic chemotherapy. This phase I study evaluates the safety, dose-limiting toxicities (DLTs), and optimal dose of PS-341 when combined with carboplatin in ovarian cancer patients with recurrent, platinum- and taxane-resistant disease. Methods: After IRB approval, patients with recurrent ovarian cancer, platinum and taxane resistant (progression on platinum and/or taxane therapy or recurrence within 6 months of completing platinum and/or taxane therapy), measurable disease, and performance status 0–2 were eligible and enrolled after giving informed consent. As guided by toxicity and pharmacokinetic data from single-agent phase I trials, PS-341 was administered on days 1, 4, 8, and 11 by IV push every 28 days with carboplatin (AUC 5) on day 1. Four dose levels were evaluated: 0.8, 1.0, 1.3, and 1.5 mg/m2. Dose was escalated if 0 of 3 or 1 of 6 patients had a DLT. The MTD was defined as 2 or more patients out of 6 with a DLT. Results: 21 women (median age 63, range 43–83), were treated with carboplatin and PS-341 at 0.8mg/ m2 (n=6), 1.0 mg/m2 (n=3), 1.3 mg/m2 (n=6), or 1.5 mg/m2. (n=6). At each level, respectively, there were 1, 0, 1, and 3 DLT’s attributable to PS- 341; all were grade 3, consisting of fatigue (n=3), nausea/vomiting/dehydration (n=1), and anorexia/dehydration/syncope (n=1). There were no Grade 4 toxicities. Common grade 2 toxicities included fatigue (n=12), nausea (n=10), anorexia, anemia, and dyspnea (n=7 each). 18 patients evaluable for response had stable disease (SD) or progression of disease (PD): at 0.8 mg/m2, SD=2, PD=3; at 1.0 mg/m2, PD=3; at 1.3 mg/m2, SD=3, PD=3; at 1.5 mg/m2, SD=3, PD=1. Median duration of stable disease was 4 months (range 3–10). Conclusions: The recommended dose of PS-341 in combination is 1.3 mg/m2. Treatment was well-tolerated with reversible side effects and no grade 4 toxicities, and at the optimal dose, there was a 50% rate of stable disease. No significant financial relationships to disclose.

Phase I/II study of the combination of sorafenib and temsirolimus in patients with metastatic melanoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 9026-9026 ◽  
Author(s):  
K. B. Kim ◽  
M. A. Davies ◽  
N. E. Papadopoulos ◽  
A. Y. Bedikian ◽  
W. Hwu ◽  
...  
Keyword(s):  
Phase I ◽  
Performance Status ◽  
Single Agent ◽  
Stage Iv ◽  
Pharmacokinetic Data ◽  
Advanced Cancer Patients ◽  
Ecog Performance Status ◽  
Multikinase Inhibitor ◽  
Taste Alteration

9026 Background: Inhibition of Signal transduction pathways at multiple levels may be a more effective therapeutic cancer strategy for advanced cancer patients. Sorafenib, a multikinase inhibitor and temsirolimus, an inhibitor of critical survival pathways, are targeted compounds with single agent anti-tumor activity in several solid tumors. Inhibition of mutant B-Raf and the AKT signaling pathway has been effective in vitro with melanoma cell lines. Therefore, we designed a phase I/II study of the combination of sorafenib and temsirolimus to inhibit multiple pathways for greater clinical efficacy.Methods: Patients (pts) with stage IV or unresectable or recurrent stage III melanoma and ECOG performance status of 0 to 1 were eligible. Pts with treated brain metastases were eligible if they had not progressed for 3 months. Sorafenib was given orally twice daily and temsirolimus was given intravenously once a week, both starting on day 1, with a 4-week cycle. Responses were assessed every 2 cycles per RECIST. Results: To date, 22 pts have been enrolled and treated. Median age was 56.5, and 17 were male. Median ECOG PS was 1. The MTD doses were sorafenib 400 mg in AM / 200 mg in PM daily and temsirolimus 25 mg IV weekly. The dose-limiting toxicity (DLT) included thrombocytopenia, hand-foot syndrome (HFS), serum transaminase elevation and hypertriglyceridemia. Other common adverse events were dry skin, fatigue, taste alteration, anorexia, flatulence, diarrhea, skin rash, insomnia, neuropathy, myalgia, and headaches, anemia, hypercholesterolemia, hyperglycemia and hypophosphatemia. There were 9 pts with stable disease among 21 evaluable pts for response. Conclusions: Sorafenib and temsirolimus can be administered concomitantly although with significant toxicity at higher dose levels. Currently, pts are enrolled in a dose expansion cohort. Pharmacokinetic data will be presented. Supported in part by NCI grant UO1 CA062461 and N01 CM17003. [Table: see text] No significant financial relationships to disclose.

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.

Azacitidine (AZA) Combined with Idarubicin in Untreated Patients with High Risk MDS – Results of a Phase I/II Study of the Groupe Francophone Des Myelodysplasies

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1720-1720 ◽  
Author(s):  
Lionel Ades ◽  
Benoit de Renzis ◽  
Ramzi Jeddi ◽  
Jacques Delaunay ◽  
Thorsten Braun ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
Disease Progression ◽  
Stable Disease ◽  
Overall Response Rate ◽  
Response Rate ◽  
Conflicts Of Interest ◽  
Performance Status ◽  
Single Agent ◽  
Overall Response

Abstract Abstract 1720 Background: hypomethylating agents, especially AZA, have become the reference treatment of higher risk MDS, but the median survival of about 2 years obtained with AZA remains modest, and must be further improved. In addition, if it is able to increase overall survival in MDS, AZA yields only about 30% of marrow response (including CR+PR+ mCR), Idarubicin given at conventional dose (12 mg/m2/d during 3 days) is the anthracycline of choice in the intensive chemotherapy given with cytarabine in patients with high risk MDS and, given as a single agent, induces up to 30% of complete remission (CR) in elderly AML patients. Thus, we designed a phase I/II study evaluating the safety and efficacy of 2 doses of Idarubicin combined with Azacitidine in high risk MDS patients (clinical trial NCT01305135). Methods: For this trial Azacitidine was combined with increasing doses of Idarubicin. Main Inclusion criteria were: (1) IPSS int 2 or high MDS, or CMML with WBC < 13,000/mm3 and marrow blasts > 10% or AML with 20–30% marrow blasts (corresponding to EU label for AZA) (2) Age 3 18 years (3) Performance Status (PS) <=2 (4) no prior treatment except ESAs. Patients received Azacytidine 75 mg/m2/d SC during 7 days every 4 weeks combined on day 8 of each cycle to Idarubicin 5 mg/m2 (administered by 1 hour IV infusion) in the first cohort of 10 patients, escalated to Idarubicin 10 mg/m2 IV in the second cohort of 10 patients after review of toxicity (especially hematological) of the 1st cohort by the independent DSMB r. The primary endpoint of the study was response after 6 cycles according to IWG criteria. Data were analyzed at the reference date of June, 1St 2012. Results: The 20 study patients (from 8 centers) were enrolled between Dec 2010 and Feb 2012, including 7 women and 13 men with a median age of 75 years. At inclusion, WHO classification was RCMD in 1 pt, CMML in 1 pt, RAEB-1 in 6 pts, RAEB-2 in 7 pts, AML in 3 pts and unclassified in 2 pt. Median marrow blasts were 6.5% (0–26) Karyotype (IPSS) was favorable in 7 pts, int in 3 pts and unfav in 8 pts (2 pts had cytogenetic failure). IPSS was high in all patients. PS was 0 in 28% pts, 1 in 50% and 2 in 22%. A total of 92 cycles of treatment had been administrated with a median number of 5 cycles/patient and 10 pts had received 6 or more cycles. 14 patients had terminated the study due to side effects (severe febrile pancytopenia, n=2), disease progression (n=5, after 2–10 cycles), death (disease progression, severe septic shock after Cycle 2, and unrelated coma), stable disease after 6 cycles (n=3), and patient decision (n=1). Overall 7 pt had died. 18 SAEs were reported observed in 9 patients, including 10 episodes of febrile neutropenia, 3 episodes of bleeding and 5 unrelated SAE. Of the 20 patients enrolled in the study, 19 were evaluable for response after 3 cycles, including 10/10 in the First cohort and 9/10 in the second cohort. One patient achieved CR, 2 PR, 1 mCR and 2 additional patients achieved stable disease with HI, leading to an Overall response rate of 6/19 (32%). Two patients were still on study but did not reached cycle 6. Thus, after 6 cycles, 17 patients, only could be evaluated. Among them 9/17 (53%) patients were still on study, 2 pts had died, 3 progressed, 2 had experienced sides effects and had terminated the study and 1 pt had withdrawn consent. Two patients achieved CR (including 1 already in CR at cycle 3), 2 PR and 2 additional patients achieved stable disease with HI leading to an Overall response rate of 6/17 (35%). At the time of the present analysis, none of the responder had relapsed. Conclusion: The phase I/II results presented here show that Idarubicin can be combined to Azacitidine with acceptable toxicity. Whether the azacitidine- Idarubicin combination can improve the outcome of higher risk MDS patients will be evaluated in a phase II randomized trial comparing this combination (and other combinations of azacitidine with other drugs) to azacitdine alone alone. Data of the present phase I/II trial will be updated at the meeting. Disclosures: No relevant conflicts of interest to declare.

A pharmacodynamic study of JI-101, an orally active inhibitor of VEGF-2, PDGF-β, and EphB4 receptors, in patients with refractory/recurrent ovarian cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13548-e13548
Author(s):  
Theresa Louise Werner ◽  
Aaron Lynn Luebke ◽  
Mark Wade ◽  
Nuggehally R Srinivas ◽  
Dhiraj J. Abhyankar ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Mechanism Of Action ◽  
Stable Disease ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Single Agent ◽  
Recurrent Ovarian Cancer ◽  
Active Inhibitor ◽  
Common Grade ◽  
Grade 3

e13548 Background: JI-101 is an oral multi-kinase inhibitor, which targets VEGFR-2, PDGF-β, and EphB4. By targeting multiple angiogenesis signaling pathways, JI-101 has the potential advantage of inhibiting all vital stages of tumor angiogenesis, reducing tumor resistance, and enhancing anti-tumor efficacy. None of the currently approved angiogenesis inhibitors have any appreciable inhibition of EphB4, and therefore, this represents a novel mechanism of action. JI-101 has preclinical activity in various tumor models and has been well tolerated in phase 1 trials. Methods: Eleven women with refractory/recurrent ovarian cancer were enrolled with a median age of 54 yrs (range 52-76). All patients had adequate organ function and ECOG performance status ≤ 2. Each patient received single agent JI-101 at 200mg BID for 28 day treatment cycles. Toxicity and response were evaluated at two month intervals. Results: Eight of 11 patients were evaluable for response (3 were unevaluable due to inability to complete two cycles). A median of 3 cycles (range 2-6) was given. No grade 4 adverse events (AEs) were seen. The most common grade 2/3 hematological AEs were grade 2 anemia (1) and lymphopenia (1). The most common grade 2/3 non-hematological AEs were grade 3 hypertension (7), grade 3 bowel obstruction (2), grade 3 transaminitis (2), and abdominal pain (2). Six patients had stable disease (SD) at two months and two had progressive disease. Best response was SD at four months. Two-month progression free survival was 71% (90% CI 52-99%). Conclusions: JI-101 is well tolerated in refractory/recurrent ovarian cancer patients with the majority of patients with stable disease at two months. The most common toxicity was hypertension, which was easily controlled with anti-hypertensives. The novel mechanism of action of JI-101 is promising in ovarian cancer treatment and further prospective studies of this agent could be pursued in a less refractory patient population.

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.

Single agent vanucizumab (RO5520985) for platinum (Pt)-resistant recurrent ovarian cancer (OC): Results from a single arm extension phase of the phase I FIH study.

2015 ◽  
Vol 33 (15_suppl) ◽  
pp. 5549-5549 ◽  
Author(s):  
Ana Oaknin ◽  
Anne Floquet ◽  
Christophe Le Tourneau ◽  
Isabelle Laure Ray-Coquard ◽  
Florence Joly ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase I ◽  
Single Agent ◽  
Recurrent Ovarian Cancer ◽  
Extension Phase

Phase I Trial of Oral Vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) in Combination with Bortezomib in Patients with Advanced Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1172-1172 ◽  
Author(s):  
Donna M. Weber ◽  
Sundar Jagannath ◽  
Amitabha Mazumder ◽  
Ronald Sobecks ◽  
Gary J. Schiller ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Phase I ◽  
Stable Disease ◽  
Phase I Trial ◽  
Performance Status ◽  
Single Agent ◽  
Primary Objective ◽  
Combination Regimen ◽  
Ecog Performance Status

Abstract Background: Vorinostat is a histone deacetylase inhibitor that has demonstrated antiproliferative and proapoptotic activity alone and in combination with the proteasome inhibitor bortezomib in preclinical multiple myeloma (MM) models. In a Phase I study, vorinostat also demonstrated modest single agent activity in patients (pts) with relapsed or refractory MM. Patients and Methods: We conducted a Phase I trial of oral vorinostat (200 mg bid or 400 mg daily × 14 days (d1–14) in combination with bortezomib 0.7 or 0.9 mg/m2 i.v. on d 4, 8, 11 and 15 or 0.9, 1.1, or 1.3 mg/m2 i.v. on d 1, 4, 8 and 11. Cycles were repeated every 21 d for a maximum of 8 cycles until progressive disease (PD) or intolerable toxicity. Pts with active relapsed or refractory MM who had not received bortezomib in the preceding 3 months and with adequate hematologic, hepatic, and renal function, and ECOG performance status of 0–2 were eligible. The primary objective was to determine the maximum tolerated dose (MTD). Activity (utilizing EBMT criteria) and safety of the combination regimen were also assessed. Results: Twenty pts have been enrolled: median age, 61 years (range 52–76), median number prior systemic therapies, 3 (range 1–14), prior therapy with bortezomib (4 pts). Eighteen pts have received ≥ 1 dose and were evaluable for safety as of 7/1/07. One pt (cohort 3) experienced a dose-limiting toxicity (DLT, Table). The MTD has not been reached. The most common drug-related toxicities of any grade were nausea (56%), thrombocytopenia (50%), diarrhea (39%), vomiting (39%), fatigue (39%), and anemia (22%). Grade ≥ 3 drug-related adverse events were thrombocytopenia (33%, none associated with bleeding), peripheral neuropathy (11%), neutropenia (11%, none associated with fever), diarrhea (6%), diverticulitis (6%), fatigue (6%), increased AST (6%), memory changes (6%), nausea (6%), vomiting (6%), and upper respiratory infection (6%). Eight pts discontinued treatment, 3 due to PD and 5 due to adverse experiences [fatigue (2), nausea (2), diverticulitis (1)]. Of 17 evaluable pts for efficacy, all had measurable response or stable disease; 4 had a partial response, 2 had a minimal response, and 11 stable disease. Among 3 evaluable pts previously treated with bortezomib, 1 achieved a partial response and 1, minimal response. Pts at the highest dose level were not yet evaluable for response. Conclusion: Although accrual continues to determine the MTD, the combination of vorinostat and bortezomib is well tolerated and effective in this group of heavily pretreated pts with refractory/relapsed MM. Table Cohort Vorinostat Dose (mg) Bortezomib Dose (mg/m2) N # of Cycles DLTs Best Response MR = minimal response; NE = not evaluable; PR = partial response; SD = stable disease. *Days 4, 8, 11 and 15. †Days 1, 4, 8 and 11. ‡Treatment cycle in progress. 1 200 0.7* 3 3, 3, 14 - SD (2), PR 2 200 0.9* 3 4, 5, 6 - SD (2), PR 3 400 0.9† 6 2, 3, 5, 6, 6, 6 Transient AST elevation SD (3), MR, PR (2) 4 400 1.1† 5 3, 3, 4, 5, 11 - SD (4), MR 5 400 1.3† 3 1‡, 1‡, 2 - NE (3)

A multi-institutional evaluation of the safety and efficacy of bevacizumab for recurrent, platinum-resistant ovarian cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 5019-5019 ◽  
Author(s):  
J. D. Wright ◽  
A. Alvarezsecord ◽  
T. M. Numnum ◽  
R. P. Rocconi ◽  
M. A. Powell ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stable Disease ◽  
Bowel Perforation ◽  
Single Agent ◽  
Recurrent Ovarian Cancer ◽  
Significant Activity ◽  
Recent Trial ◽  
Platinum Resistant ◽  
Heavily Pretreated ◽  
Grade 3

5019 Background: Bevacizumab has shown activity in recurrent ovarian cancer with an acceptable adverse event profile. However, the incidence of bowel perforation in a recent trial of heavily pretreated ovarian cancer patients was higher than expected from prior experience with bevacizumab. Whether the difference in the rate of bowel perforation was due to refractory disease, treatment history, disease burden, or location of tumor is uncertain. We sought to review our multi-institutional experience with bevacizumab in patients with recurrent ovarian cancer. Methods: A retrospective review of patients with recurrent ovarian cancer treated with single agent or combination bevacizumab therapy was undertaken. Toxicity was assessed using standard criteria. Response was determined radiographically and through serial CA125 measurements. Statistical analysis to determine factors associated with toxicity and response was performed. Results: Sixty-two eligible patients were identified. All had failed prior platinum-based therapy and had received a median of 5 prior chemotherapy regimens and 2 prior platinum-containing regimens. Single agent bevacizumab was administered to 12 (19%) women, while 50 (81%) received the drug in combination with a cytotoxic agent. The most common toxicities were myelosuppression (60%), proteinuria (19%) and hypertension (16%). Grade 3–5 toxicities occurred in 15 (24%) patients, including grade 3–4 hypertension in 4 (7%). Gastrointestinal perforations were identified in 4 (7%) subjects. Nine (15%) patients discontinued therapy due to toxicity. Fifty-eight patients were assessable for response. The overall response rate was 36% (4 CR, 17 PR) with stable disease in 40%. Clinical benefit (CR, PR, stable disease) was seen in 83% of patients treated with single agent therapy and 74% of those treated with bevacizumab-combination regimens. Conclusions: Bevacizumab demonstrates significant activity for recurrent, platinum-resistant ovarian cancer. Life threatening bowel perforations were noted in 7% of our subjects. The frequency of perforations in our cohort suggests that this complication is more likely to occur in heavily pretreated patients. No significant financial relationships to disclose.

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.

Oxaliplatin plus continuous infusion topotecan: First stage of an ongoing phase II study for recurrent ovarian cancer: A New York Cancer Consortium study (#N01-CM62204)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5556-5556
Author(s):  
N. LaNatra ◽  
H. Hochster ◽  
F. Muggia ◽  
S. V. Blank ◽  
J. Curtin ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
New York ◽  
Phase I ◽  
Continuous Infusion ◽  
Stable Disease ◽  
Response Duration ◽  
Recurrent Ovarian Cancer ◽  
Good Tolerability ◽  
Median Response ◽  
Grade 3

5556 Background: Topoisomerase-1 inhibitors and platinums are active in ovarian cancer. Our prior series described infusional topotecan as less myelosuppressive than bolus and more easily combined with oxaliplatin than cisplatin. An NYU phase I study of the combination in previously treated ovarian cancer patients (pts) showed promising activity and good tolerability (Hochster H, Gynecol Oncol 2008). Methods: Ovarian cancer pts treated with 1–2 prior regimens (1 platinum/taxane regimen, no topotecan) were treated with oxaliplatin 85 mg/m2 day 1, 15 and topotecan (0.4 mg/m2/day) continuous infusion x 14 days every 4 weeks (wks). Platinum resistant (stratum I = 10) and sensitive (stratum II = 17) pts are included in this two-stage trial (n = 52) to evaluate overall response rate (ORR) and toxicities. Results: From January 2006 to November 2008, 27 pts entered. Median age was 61 (37–79). Fifteen pts had 1 prior regimen and 12 pts had 2. Five pts discontinued before 2 cycles (3 for predefined toxicity, 2 by pt/physician choice). 102 cycles of chemotherapy were given (median 4, [1–6]). Grade 3/4 toxicities included thrombocytopenia (37% grade 3, 19% grade 4), neutropenia (37% grade 3, 11% grade 4), anemia (15% grade 3), neuropathy (7% grade 3), diarrhea (4% grade 3), transaminitis (4% grade 3), and fatigue (7% grade 3). Twenty-one pts had day 15 oxaliplatin held, 10 pts required dose reductions, and 21 pts had treatment delays mainly from thrombocytopenia. No pts had neutropenic fever. Twenty-one pts are now evaluable. Stratum I had 1 complete and no partial responses, 5 pts with stable disease and 2 with progressive disease. Stratum II had 3 complete and 6 partial responses, 4 pts with stable disease and none progressed. Median response duration is 41 wks (17–62); median duration of stable disease is 17 wks (4–70). Conclusions: Excluding thrombocytopenia, tolerance to this regimen confirms phase I results. In pts with creatinine clearances (CrCl) < 60 ml/min, the incidence of grade 3/4 thrombocytopenia was 75% versus 35 % for pts with CrCl > 60 ml/min. Pts with CrCl of 40–60 ml/min will now start topotecan 0.3 mg/m2/day x 14 days. Reaching our predefined ORR of at least 30% for stratum II and 20% for stratum I, the second stage of accrual has begun. [Table: see text]

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