A phase I study of pemetrexed (P) plus gemcitabine (G) in relapsed ovarian cancer (OC): Dosing results and evidence of activity

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 5083-5083 ◽  
Author(s):  
M. L. Hensley ◽  
F. Derosa ◽  
S. R. Gerst ◽  
P. Sabbatini ◽  
J. Dupont ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Objective Response ◽  
Median Number ◽  
Vitamin Supplementation ◽  
Ovarian Cancer Cells ◽  
Resistant Disease ◽  
Platinum Resistant ◽  
Best Response ◽  
Adequate Organ Function ◽  
Q 14

5083 Background: High expression of folate receptors on ovarian cancer cells may provide excellent targets for P. Preclinical data support synergism with G. Optimal doses of q 14 day P+G with vitamin support in pre-treated OC pts are not known. We sought to determine the maximally tolerated doses (MTD) and to assess for toxicity and activity in relapsed OC. Methods: Pts with relapsed OC, no prior P or G, KPS ≥ 70, and adequate organ function were eligible. Pts were enrolled in cohorts of 3, expanding to 6 if dose-limiting toxicity (DLT) was observed during the first 4 cycles. Pts received P at 300 (cohort 1) or 400 (cohort 2) or 500 (cohort 3) or 600 (cohort 4) mg/m2 followed by G 1500 mg/m2 q 14 d without GCSF. B12 and folic acid were given 1 week prior and continued throughout. DLT was defined as grade (gr) 4 neutropenia (ANC) lasting >7d or neutropenic fever (NF); gr 4 thrombocytopenia or gr 3 with bleeding; ≥gr 3 nonhematologic toxicity, except ALT, AST, alopecia, fatigue; treatment delay ≥1 week due to any unresolved toxicity. Response assessed by RECIST. Results: 16 pts (median age 55, range 43–75; median number prior cytotoxic regimens 2, range 1–4) have enrolled in 4 cohorts. 15 are evaluable for response (1 treated after resection of recurrence); 13 of these15 had a platinum-free interval <6 months. 1 pt in cohort 1 had global deterioration during cycle 1 and was replaced, with best response counted as progressive disease (PD). 1 pt in cohort 3 had dose delay ≥1 week, meeting DLT criteria. Cohort 3 was expanded to 6 pts with no further DLT. 3 pts enrolled in cohort 4 with no DLTs observed. Toxicities per cycle (n = 108): gr 3 ANC 31%; gr 4 ANC 27%; gr 3 dehydration 0.9%; gr 3 platelets 0.9%; 0 pts had NF. Median # cycles/pt was 6, range 1–16, median cycle length 14 d. Objective response was observed in 27% (4/15 pts: 4 PR; 7 SD; 4 PD). All 4 responses were among pts with platinum resistant disease. >50% decrease in CA125 for more than two measurements was observed in 9/15 (60%) pts with evaluable CA125s. Median time to progression is 15 wks (95% confidence interval 10–32 wks). Conclusions: MTD is not yet reached. P 500 mg/m2 + G 1500 mg/m2 with vitamin supplementation is safe in pts with previously treated OC. 27% of patients with platinum-resistant disease had objective responses. [Table: see text]

scholarly journals PARP Inhibitor in Platinum-Resistant Ovarian Cancer: Single-Center Real-World Experience

2021 ◽  
pp. 506-511
Author(s):  
Amit Agarwal ◽  
Saphalta Baghmar ◽  
Chandragouda Dodagoudar ◽  
Suhail Qureshi ◽  
Aseem Khurana ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Partial Response ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Progression Free Survival ◽  
Complete Response ◽  
Median Number ◽  
Platinum Sensitive ◽  
Platinum Resistant ◽  
Proven Efficacy

PURPOSE Poly (ADP-ribose) polymerase inhibitors (PARPi) have proven efficacy in treatment of BReast CAncer ( BRCA) gene mutation-positive platinum-sensitive ovarian cancers. There is paucity of data for their role in platinum-resistant ovarian cancer (PROC). We report here retrospective analysis of outcome of PARPi treatment in a group of patients including those of PROC. PATIENTS AND METHODS We analyzed all consecutive patients who received PARPi. The efficacy of PARPi monotherapy was assessed in patients with relapsed high-grade serous ovarian carcinoma with g BRCAm. The drug was procured through compassionate program. Drugs (olaparib and talazoparib) were provided in capsule form. RESULTS Between July 1, 2015, and June 30, 2019, 28 patients with ovarian cancer received PARPi. At the time of data censoring (September 30, 2019), four (14.3%) patients are still on treatment. Median age was 54.5 years (range, 39-75 years). Median number of previous lines of chemotherapy received was three (range, 1-6). Eleven platinum-sensitive patients received the drug as maintenance (five in complete response and six in partial response after chemotherapy), whereas 17 (60.7%) had platinum-resistant progressive disease while starting the drug. In PROC, objective response rate (complete response plus partial response) was 47%, median progression-free survival was 8.2 months (5.3-11.3), and overall survival was 14.9 months (11.2-18.5). No new side effects were observed. CONCLUSION This is the first study from India evaluating PARPi in platinum-resistant ovarian cancer. This study suggests that PARPi is a viable treatment option in patients with PROC with gBRCAm. This should be further evaluated in randomized clinical trial.

Phase 1/2 study of cirmtuzumab and ibrutinib in mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7556-7556
Author(s):  
Hun Ju Lee ◽  
Michael Y. Choi ◽  
Tanya Siddiqi ◽  
Jacqueline Claudia Barrientos ◽  
William G. Wierda ◽  
...  
Keyword(s):  
Phase 1 ◽  
Single Agent ◽  
Objective Response ◽  
Median Number ◽  
Lymphocytic Leukemia ◽  
Synergistic Activity ◽  
Best Response ◽  
Car T ◽  
Treatment Naïve

7556 Background: Cirmtuzumab (Cirm) is a humanized monoclonal antibody that inhibits the tumor promoting activity of ROR1 and had demonstrated additive/synergistic activity with many anti-cancer agents including ibrutinib (Ibr). Methods: Patients (Pts) with relapsed or refractory (RR) MCL or treatment naïve (TN) or RR CLL were enrolled. In Part 1 (Dose Escalation), doses of Cirm IV q2wks x5 then q4wks of 2-16 mg/kg and 300 or 600 mg were examined. Safety of Cirm alone was assessed during the first 28 days, then Ibr was started at approved doses for each indication. Cirm 600 mg IV q2wks x3 then q4wks in combination with Ibr starting day 0 was chosen as the recommended dosing regimen for use in Part 2 (Expansion) and Part 3 (CLL only, Cirm/Ibr vs. Ibr alone). Results: Twelve evaluable MCL pts were enrolled into Part 1, and 5 into Part 2. Median number of prior regimens was 2 (1-5), including pts relapsing after Ibr (4), auto-SCT (3), auto-SCT/ allo-SCT (1), auto-SCT/CAR-T (1). In CLL, 34 evaluable pts (12 TN and 22 RR) enrolled into Part 1 (18) or Part 2 (16). At least 74% of CLL pts in Parts 1 and 2 were high risk as determined by unmutated IGHV, del17p, and/or del11q. In Part 3, 22 evaluable pts received Cirm/Ibr (15) or Ibr (7). As of the 30OCT2020 safety cut-off for MCL and CLL, common TEAEs (all grades) included diarrhea (41%), contusion (39%), fatigue (39%), URI (31%), hypertension (25%) arthralgia (23%). Grade ≥3 neutropenia was 13% and thrombocytopenia 1%. There were no Cirm dose reductions or discontinuations for toxicity. Overall, Cirm did not appear to negatively impact the safety of Ibr. Efficacy (MCL): As of the 02FEB2021 efficacy cutoff, the best response of 17 evaluable pts in Parts 1 and 2 included an objective response rate (ORR) of 82%, 41% CR/CMR, 41% PR, 12% SD, and 6% PD. CR/CMR remain durable from 8-28+ mos. Most responses occurred rapidly after ̃3 mos of Cirm/Ibr. Notably, responses were achieved in all pts who received prior SCT+/- CAR-T (4CR, 1PR) or prior Ibr (2CR, 2PR). At a median follow-up of 14.6 mos, the median PFS (mPFS) had not been reached (NR) (95% CI: 17.5, NA). Efficacy (CLL): The best response of 34 evaluable pts in Parts 1 and 2 included 91% ORR, 3% CR, 88% PR/PR-L, 9% SD, 0% PD. In Part 3, both arms achieved 100% ORR (all PRs). At a median follow-up of 20.2 mos, the mPFS was NR (95% CI: NA, NA), and the PFS estimate at 24 months was 95% for R/R, and 87% for TN, respectively, for evaluable CLL pts receiving Cirm/Ibr. Conclusions: Cirm/Ibr is a well-tolerated, active regimen in both MCL and CLL. For MCL, the mPFS of NR (95% CI: 17.5, NA) and CRR (41%), with all CRs remaining without PD, compare favorably to mPFS of 12.8 mos (95% CI 8.5-16.6) and CRR (20%) reported for single agent Ibr (Rule 2017). For CLL, the high ORR and PFS are encouraging, particularly for RR CLL. The study is ongoing, with MCL enrollment expanded to study Cirm + Ibr in pts who have had a suboptimal response to an Ibr regimen, or who have failed other approved BTKi agents. Clinical trial information: NCT03088878.

Clinical trial in progress: Pivotal study of VB-111 combined with paclitaxel versus paclitaxel for treatment of platinum-resistant ovarian cancer (OVAL, VB-111-701/GOG-3018).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS5599-TPS5599
Author(s):  
Rebecca Christian Arend ◽  
Bradley J. Monk ◽  
Thomas J. Herzog ◽  
Jonathan A. Ledermann ◽  
Kathleen N. Moore ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Trial ◽  
Antiangiogenic Therapy ◽  
Objective Response ◽  
Phase Iii ◽  
Weekly Paclitaxel ◽  
Ca 125 ◽  
Recist 1.1 ◽  
Platinum Resistant ◽  
Phase Iii Study

TPS5599 Background: Ofranergene obadenovec (VB-111) is a targeted anti-cancer gene therapy with a dual mechanism of action that includes a broad antiangiogenic effect and induction of a tumor directed immune response. A phase II trial in patients with platinum resistant ovarian cancer showed that VB-111 in combination with weekly paclitaxel was well tolerated and associated with a CA-125 Objective Response Rate (ORR) of 58% with a trend for improved survival. The favorable outcomes were associated with induction of an immunotherapeutic effect of tumor infiltration with CD-8 T cells. Based on these observations, a phase III study was initiated in collaboration with the GOG Foundation, Inc. Methods: Study NCT03398655 is an international, randomized, double-blind, placebo-controlled, phase III study. Eligible patients have recurrent platinum-resistant epithelial ovarian cancer with measurable disease (RECIST 1.1), and may have been previously treated with up to 5 prior lines of therapy. Patient are randomized 1:1 to receive VB-111 (1x1013 VPs) with weekly paclitaxel (80mg/m2), or weekly paclitaxel with placebo. Randomization is stratified by number of prior treatment lines, prior antiangiogenic therapy and platinum refractory disease status. The efficacy endpoints are OS, PFS and ORR by RECIST 1.1 and by CA-125 (GCIG criteria). A pre-planned interim analysis was performed by the DSMC in the first 60 patients evaluable for CA-125 response. The analysis met the pre-defined criteria of a CA-125 ORR (GCIG) in the treatment arm at least 10% higher than in the control arm. Study enrolment is ongoing and over 220 patients were enrolled in the US, EU, and Israel. Enrolment of the full sample size of 400 patients is expected to complete by the end of 2021. Clinical trial information: NCT03398655.

scholarly journals Resistance to glucose starvation as metabolic trait of platinum-resistant human epithelial ovarian cancer cells

Oncotarget ◽  
2016 ◽  
Vol 8 (4) ◽  
pp. 6433-6445 ◽  
Author(s):  
Anna Pastò ◽  
Anna Pagotto ◽  
Giorgia Pilotto ◽  
Angela De Paoli ◽  
Gian Luca De Salvo ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Cancer Cells ◽  
Ovarian Cancer Cells ◽  
Glucose Starvation ◽  
Metabolic Trait ◽  
Platinum Resistant

scholarly journals Y15 Enhances the Cytotoxic Profile of Cisplatin, Paclitaxel and Vitamin E in Platinum Resistant Ovarian Cancer Cells

2015 ◽  
Vol 29 (S1) ◽  
Author(s):  
Monique Reboe ◽  
Arkene Levy ◽  
Sivanesan Dhandyuthapani ◽  
Appu Rathinavelu
Keyword(s):  
Ovarian Cancer ◽  
Vitamin E ◽  
Cancer Cells ◽  
Ovarian Cancer Cells ◽  
Platinum Resistant

Phase II study of vinorelbine in patients with pretreated advanced ovarian cancer: activity in platinum-resistant disease.

1996 ◽  
Vol 14 (9) ◽  
pp. 2546-2551 ◽  
Author(s):  
E Bajetta ◽  
A Di Leo ◽  
L Biganzoli ◽  
L Mariani ◽  
F Cappuzzo ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Confidence Interval ◽  
Cancer Patients ◽  
Response Rate ◽  
Advanced Ovarian Cancer ◽  
Dose Intensity ◽  
Ca 125 ◽  
Resistant Disease ◽  
Platinum Resistant ◽  
Exact Confidence Interval

PURPOSE The aim of the study was to evaluate the activity of vinorelbine (VNLB) in a population of advanced ovarian cancer patients, with particular attention to defining its role in platinum-resistant disease. PATIENTS AND METHODS Thirty-three patients were recruited and treated with VNLB 25 mg/m2 intravenously (IV) weekly. the median age was 53 years, performance status 0 to 2, and number of previous chemotherapy regimens two (range, one to five). Twenty-four patients were platinum-resistant; the remaining nine either were platinum-sensitive (four cases) or had undetermined sensitivity (five cases). RESULTS The mean delivered dose-intensity of VNLB was 67% of the planned level, because 60% of the cycles were delayed due to neutropenia or anemia. Four partial responses (PRs) and one complete response (CR) were observed, for an overall response rate of 15% (95% exact confidence interval, 5.1% to 31.9%). All the responses occurred in the subgroup of 24 platinum-resistant cases, in whom the response rate was 21% (95% exact confidence interval, 7.1% to 42.1%). Seven patients became stabilized on VNLB, and 27% of the cases showed a reduction in serum cancer antigen 125 (CA 125) levels. G3/G4 side effects consisted of neutropenia, anemia, and worsening of preexisting peripheral neuropathy. No treatment-related deaths occurred. CONCLUSION VNLB led to a 21% response rate in the population of heavily pretreated and platinum-resistant ovarian cancer patients. Further studies of VNLB alone or in combination with taxanes are warranted in patients with less pretreatment.

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