Phase I study combining olaparib and tremelimumab for the treatment of women with BRCA-deficient recurrent ovarian cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e17052-e17052 ◽  
Author(s):  
Sarah Foster Adams ◽  
Olivier Rixe ◽  
Ji-Hyun Lee ◽  
Dennis J. McCance ◽  
Sheri Westgate ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Adverse Events ◽  
Phase I ◽  
Phase Ii ◽  
Immune Checkpoint ◽  
Phase I Study ◽  
Immune Therapy ◽  
Recurrent Ovarian Cancer ◽  
Parp Inhibition ◽  
Phase Ii Trials

e17052 Background: With evidence that BRCA dysfunction is associated with increased T cell recruitment to tumor sites, and that PARP-inhibition may increase the immunogenicity of tumor cells, we evaluated the combination of a PARP-inhibitor and CTLA4 immune checkpoint antibody in BRCA1- ovarian cancer models. Our results demonstrated significant therapeutic synergy and durable treatment responses in preclinical studies. Based on this, a Phase I study was conducted to assess the tolerability of this regimen in women with BRCA mutation-associated recurrent ovarian cancer. Methods: Eligibility criteria included a documented BRCA1 or BRCA2 germline mutations and a diagnosis of recurrent ovarian, tubal, or primary peritoneal cancer with measurable disease. Both platinum-sensitive and platinum resistant patients were eligible. Patients with prior exposure to PARP-inhibitors or to immune therapy with the exception of CTLA4 antibodies were also eligible. Exclusion criteria included current use of anti-inflammatory agents or a prior history of autoimmune disease. Treatment consisted of Olaparib at 300mg twice daily, as well as monthly infusions of Tremelimumab at a dose of 10mg/kg, with plans for a dose reduction if toxicity was encountered. Patients completing two full treatment cycles were evaluated for evidence of toxicity, particularly immune-related adverse events, to define a dose for Phase II testing. Results: Three women were treated at the starting dose of 300mg BID of Olaparib and 10mg/kg monthly of Tremelimumab for two cycles without evidence of any dose-limiting toxicities or grade 3 adverse events. All patients experienced grade 1 and 2 toxicities, including immune related toxicities consistent with prior studies of immune checkpoint inhibitors. All three patients showed evidence of treatment response by cycle 3 based on CA125 levels and a decrease in tumor size on CT scans. Conclusions: The combination of PARP-inhibition and CTLA-4 blockade is tolerable in heavily pre-treated women with recurrent BRCA-associated ovarian cancer. Preliminary results also demonstrate evidence of therapeutic effect, supporting ongoing evaluation of this regimen in Phase II trials. Clinical trial information: NCT02571725.

Responses to second-line cisplatin-based intraperitoneal therapy in ovarian cancer: influence of a prior response to intravenous cisplatin.

1991 ◽  
Vol 9 (10) ◽  
pp. 1801-1805 ◽  
Author(s):  
M Markman ◽  
B Reichman ◽  
T Hakes ◽  
W Jones ◽  
J L Lewis ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase Ii ◽  
Small Volume ◽  
Recurrent Ovarian Cancer ◽  
Second Line ◽  
Front Line ◽  
Phase Ii Trials ◽  
Two Phase ◽  
Overall Response ◽  
Intraperitoneal Therapy

Phase II trials of second-line intraperitoneal (IP) cisplatin-based therapy in patients with ovarian cancer have demonstrated the ability of this approach to produce objective antitumor responses, including surgically defined complete responses (CRs), in individuals with persistent small-volume disease after front-line cisplatin-based intravenous (IV) treatment. To examine the influence of a prior response to systemic cisplatin on the activity of second-line IP cisplatin, we retrospectively analyzed two phase II trials of cisplatin-based IP therapy in persistent/recurrent ovarian cancer conducted at our institution. Of the 89 assessable patients on the two trials, 52 (58%) had previously responded to IV cisplatin. The overall response and CR rates to second-line IP cisplatin-based therapy in this previously responding population were 56% and 33%, respectively, compared with overall response and CR rates in the 37 nonresponders to IV cisplatin of 11% and 3%, respectively (P less than .001; chi 2, 1 df). In the 36 patients responding to systemic cisplatin and whose largest tumor mass measured less than 1 cm at IP cisplatin initiation, a 42% CR rate was observed, compared with a 7% CR rate in the 14 patients with the same bulk of disease who had previously failed to respond to systemic cisplatin (P less than .025). We conclude that a prior response to systemic cisplatin strongly influences the antineoplastic activity of second-line IP cisplatin in ovarian cancer.

A phase I study of EP-100, a luteinizing hormone releasing hormone (LHRH) ligand conjugated to a synthetic cytolytic peptide in patients with advanced refractory LHRH- receptor (R)-expressing tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3060-3060
Author(s):  
Ramesh K. Ramanathan ◽  
Manpreet Chadha ◽  
John Sarantopoulos ◽  
Donald W. Northfelt ◽  
Glen J. Weiss ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase I ◽  
Phase Ii ◽  
Antibody Production ◽  
Phase I Study ◽  
Standard Dose ◽  
Pharmacokinetic Profile ◽  
Best Response ◽  
Expression Rate ◽  
Tumor Expression

3060 Background: EP-100 is a synthetic 28 amino acid LHRH peptide conjugated to an 18 aa cytolytic peptide. Selective targeting in LHRH-R expressing cells occurs via direct binding to the extracellular membrane receptor followed by disruption of the membrane by the cytolytic peptide portion. A first in human, phase I study was performed. Methods: Eligible pts had adequate organ function and LHRH-R tumor expression, as determined by IHC. EP-100 was given IV (30-60 min) weekly x 3 for cohorts 1- 6 (n=20 at 0.6 - 5.2 mg/m2) and then twice weekly x 3 for cohorts 7- 11 (n=18 at 7.8 - 40 mg/m2) with a week break. The pharmacokinetic profile of EP-100 and antibody production against EP-100 was determined by a validated HPLC/MS and ELISA respectively. Potential activity of EP-100 on the pituitary gonadotropes was determined by plasma LH and FSH. Results: We screened 97 pts, archival tumor tissue obtained from 81 pts; 53 (65%) were positive for LHRH-R, of which 37 were enrolled (female 76%) and treated. The LHRH-R expression rate in breast was 81% (N=21) and in ovarian cancer 56% (n=18). Most pts had breast (n= 16, 42%) ovary (n=7,18%), colon (n=4, 11%) or uterine (n=3, 8%) cancer. Pts were treated in a 3 + 3 standard dose escalation scheme. Doses were escalated 100% in the absence of a grade 2 drug related toxicity. MTD was not reached at the highest dose level of 40 mg/m2. Only one DLT occurred, a grade 2 increase in ALT/AST. The only other drug-related toxicity was a self limited infusion-related skin reaction (grade 1-2) in 10 pts. EP-100 was rapidly cleared from circulation, mean half life ranged from 7.1 ± 3.8 min to 15.9 ± 3.6 min. Best response was stable disease for >12 weeks in 5 pts. In 3 pts rapid, sustained decreases in LH/FSH levels were noted. Antibody production against EP-100 was absent in all pts. Conclusions: The study has completed accrual, the phase II dose is 30-40 mg/m2 twice a week x 3 weeks.EP-100is safe, well tolerated and not antigenic/immunogenic. Preclinical studies indicated synergy with paclitaxel and doxorubicin. A phase II study of EP-100 plus paclitaxel in ovarian cancer is planned.

Biomodulation of capecitabine by weekly paclitaxel and carboplatin in patients with advanced solid tumor malignancies: A dose-escalating phase I study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2569-2569
Author(s):  
M. B. Lustberg ◽  
J. Nuovo ◽  
J. P. Thomas ◽  
P. J. Monk ◽  
S. Kim ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase I Study ◽  
Dihydropyrimidine Dehydrogenase ◽  
Weekly Paclitaxel ◽  
Unknown Primary ◽  
Cancer Tissue ◽  
Phase Ii Trials ◽  
Two Phase ◽  
Phase Ii Studies

2569 Background: A principal determinant of the therapeutic index with capecitabine-based treatment is the grade of thymidine phosphorylase (TP) activity in malignant tissue. The beneficial interactions of paclitaxel and carboplatin in upregulation of TP promise to make capecitabine more tumor specific and to provide the expected synergy. On the basis of the time-dependency and transiency for this upregulation we performed a phase I study of capecitabine in combination with weekly paclitaxel and carboplatin (CTX). Methods: Patients with advanced solid tumors received carboplatin on day 1, paclitaxel on days 1, 8, 15 and capecitabine orally twice a day on days 8–21, every 4 weeks. There were 5 planned dose levels (DL 1–5). Paclitaxel was escalated from 60 mg/m2 to 80 mg/m2 (DL 4) then 100 mg/m2 (DL 5). Capecitabine from 500 mg/m2 bid to 750 mg/2 bid (DL 2) then 1000 mg/m2 bid (DL 3–5). Carboplatin dose was fixed at AUC 6. Paraffin-embedded tissue was evaluated for expression of TP, thymidylate synthase and dihydropyrimidine dehydrogenase by immunohistochemistry. Results: 32 patients from Ohio State University (OSU) were enrolled. 84% had prior therapy. The most common grade 3/4 toxicities were neutropenia (59%), leukopenia (56%), and fatigue (16%). DLTs included neutropenic fever (1), prolonged neutropenia or thrombocytopenia (2) and diarrhea (1). The MTD was at DL 2. There were 10 confirmed responses [4 CR (esophagus, stomach, unknown primary and ampullary); 6 PRs (Pancreas (3), unknown primary, anal and esophagus] and stabilization of disease > 3 months in 12 patients. In normal tissue, there was no difference in expression levels of both TS and TP. On the other hand, in cancer tissue, TP levels seem to correlate with response whereas TS did not. Conclusions: CTX demonstrates acceptable tolerability. The recommended doses for phase II studies are capecitabine 750 mg/m2 bid, paclitaxel 60 mg/m2/week and carboplatin AUC=6. The acceptable toxicity profile in this dose schedule, and the promising antitumor activity observed warrant further evaluation of this regimen. Two phase II trials are already underway at OSU using this regimen for patients with pancreatic cancer and adenocarcinomas of unknown primary, the latter already actively enrolling patients. Pretreatment tumoral TP levels may help predict patients that are more likely to respond to CTX. Correlation of IHC data with responses will be presented at the meeting. [Table: see text]

A phase I study of a p53MVA vaccine in combination with gemcitabine (GEM) in recurrent ovarian cancer (OC).

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. e17040-e17040
Author(s):  
Mihaela C. Cristea ◽  
Nicola Hardwick ◽  
Paul Henry Frankel ◽  
Robert Morgan ◽  
Lucille A. Leong ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase I ◽  
Phase I Study ◽  
Recurrent Ovarian Cancer

Multicenter, Randomized Phase II Trial of Oral CI-1033 for Previously Treated Advanced Ovarian Cancer

2005 ◽  
Vol 23 (24) ◽  
pp. 5597-5604 ◽  
Author(s):  
Susana Campos ◽  
Oday Hamid ◽  
Michael V. Seiden ◽  
Amit Oza ◽  
Marie Plante ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Adverse Events ◽  
Phase Ii ◽  
Survival Rates ◽  
Growth Factor Receptor ◽  
Advanced Ovarian Cancer ◽  
Recurrent Ovarian Cancer ◽  
Median Number ◽  
Open Label ◽  
Heavily Pretreated

Purpose To evaluate the antitumor activity and toxicity of two doses of CI-1033 in patients with platinum-refractory or recurrent ovarian cancer, and to determine baseline expression of epidermal growth factor receptor in tumor cells. Patients and Methods This phase II, open-label clinical trial evaluated CI-1033 in patients with ovarian cancer who failed prior platinum-based therapy. Two oral doses of CI-1033 were evaluated—a 50-mg and a 200-mg oral dose administered daily for 21 days in a 28-day cycle. Patients were evaluated for tumor response and toxicity; in addition, archival baseline tumor samples were analyzed by immunohistochemistry for erbB1 to erbB4 status. Results One hundred five eligible patients were treated. Baseline demographic characteristics were balanced in this heavily pretreated patient population. The median number of prior chemotherapy regimens received was four. The most commonly encountered drug-related adverse events for both dose arms were gastrointestinal (diarrhea, nausea, stomatitis) toxicity, asthenia, and rash. No responses were observed. Stable disease was confirmed in 34% and 26% of patients in the 200-mg and 50-mg arms, respectively, and 1-year survival rates were 38.5% and 37.7%, respectively. Baseline erbB3 and erbB4 revealed the highest frequencies of expression, while erbB2 was the lowest. Conclusion CI-1033 did not show activity in unscreened patients with advanced ovarian cancer. At 50 mg/d, CI-1033 had a more favorable adverse events profile than at 200 mg/d. erbB3 and erbB4 receptors showed the highest expression in tumor samples while erbB2 revealed the least. There appears to be no association between baseline erbB expression and disease stability.

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