A Phase II Evaluation of Maintenance Therapy Combination Mirvetuximab Soravtansine and Olaparib in Recurrent Platinum Sensitive Ovarian, Peritoneal, and Fallopian Tube Cancer

The Principal Investigator hypothesizes the combination of MIRV and Olaparib is an effective, and tolerable, maintenance therapy strategy in platinum sensitive recurrent ovarian cancer.

开始日期2023-10-03

申办/合作机构

University of Colorado Denver

[+1]

NCT05271318 / Recruiting临床1期

A Two-part, Phase I/Ib, Open-Label, Dose-escalation Trial of Tumor Necrosis Factor Alpha and Interleukin-2 Coding Oncolytic Adenovirus (TILT-123) in Combination With Pembrolizumab (Phase I Part) and Pembrolizumab and Pegylated Liposomal Doxorubicin (Phase Ib Part) in Patients With Platinum Resistant or Refractory Ovarian Cancer.

This is an open-label, phase 1, dose-escalation, multicenter and multinational trial evaluating the safety of oncolytic adenovirus TILT-123 in combination with Pembrolizumab, or Pembrolizumab and Pegylated Liposomal Doxorubicin in patients with platinum resistant or refractory ovarian cancer.

开始日期2022-05-17

申办/合作机构

TILT Biotherapeutics Oy

[+1]

EUCTR2021-003592-34-DE / Unknown status临床2期

PICCOLO: A Phase 2, Single Arm Study of Mirvetuximab Soravtansine in Recurrent Platinum-Sensitive, High-Grade Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancers with High Folate Receptor-Alpha Expression

开始日期2022-05-06

申办/合作机构

ImmunoGen, Inc.

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项与铂敏感性输卵管癌相关的文献（医药）

2021-12-01·JAMA Oncology1区 · 医学

Preexisting TP53-Variant Clonal Hematopoiesis and Risk of Secondary Myeloid Neoplasms in Patients With High-grade Ovarian Cancer Treated With Rucaparib

1区 · 医学

Article

作者: Oaknin, Ana ; Oza, Amit M. ; Dean, Andrew ; Coleman, Robert L. ; Weberpals, Johanne ; Severson, Eric ; Vo, Lan-Thanh ; Harding, Thomas ; Colombo, Nicoletta ; Maloney, Lara ; Tinker, Anna V. ; Lin, Kevin K. ; Ledermann, Jonathan A. ; Ray-Coquard, Isabelle ; Lorusso, Domenica ; McNeish, Iain A. ; Goble, Sandra ; Aghajanian, Carol ; Kwan, Tanya T. ; Kaufmann, Scott H. ; Swisher, Elizabeth M.

IMPORTANCEA total of 1% to 3% of patients treated with a poly(adenosine diphosphate-ribose) polymerase inhibitor for high-grade ovarian cancer (HGOC) develop therapy-related myeloid neoplasms (t-MNs), which are rare but often fatal conditions. Although the cause of these t-MNs is unknown, clonal hematopoiesis of indeterminate potential (CHIP) variants can increase the risk of primary myeloid malignant neoplasms and are more frequent among patients with solid tumors.OBJECTIVESTo examine whether preexisting CHIP variants are associated with the development of t-MNs after rucaparib treatment and how these CHIP variants are affected by treatment.DESIGN, SETTING, AND PARTICIPANTSThis retrospective genetic association study used peripheral blood cell (PBC) samples collected before rucaparib treatment from patients in the multicenter, single-arm ARIEL2 (Study of Rucaparib in Patients With Platinum-Sensitive, Relapsed, High-Grade Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer) (n = 491; between October 30, 2013, and August 9, 2016) and the multicenter, placebo-controlled, double-blind ARIEL3 (Study of Rucaparib as Switch Maintenance Following Platinum-Based Chemotherapy in Patients With Platinum-Sensitive, High-Grade Serous or Endometrioid Epithelial Ovarian, Primary Peritoneal or Fallopian Tube Cancer) (n = 561; between April 7, 2014, and July 19, 2016), which tested rucaparib as HGOC therapy in the treatment and maintenance settings, respectively. The follow-up data cutoff date was September 1, 2019. Of 1052 patients in ARIEL2 and ARIEL3, PBC samples from 20 patients who developed t-MNs (cases) and 44 randomly selected patients who did not (controls) were analyzed for the presence of CHIP variants using targeted next-generation sequencing. Additional longitudinal analysis was performed on available ARIEL2 samples collected during treatment and at the end of treatment.MAIN OUTCOMES AND MEASURESEnrichment analysis of preexisting variants in 10 predefined CHIP-associated genes in cases relative to controls; association with clinical correlates.RESULTSAmong 1052 patients (mean [SE] age, 61.7 [0.3] years) enrolled and dosed in ARIEL2 and ARIEL3, 22 (2.1%) developed t-MNs. The t-MNs were associated with longer overall exposure to prior platinum therapies (13.2 vs 9.0 months in ARIEL2, P = .04; 12.4 vs 9.6 months in ARIEL3, P = .003). The presence of homologous recombination repair gene variants in the tumor, either germline or somatic, was associated with increased prevalence of t-MNs (15 [4.1%] of 369 patients with HGOC associated with an HRR gene variant vs 7 [1.0%] of 683 patients with wild-type HGOC, P = .002). The prevalence of preexisting CHIP variants in TP53 but not other CHIP-associated genes at a variant allele frequency of 1% or greater was significantly higher in PBCs from cases vs controls (9 [45.0%] of 20 cases vs 6 [13.6%] of 44 controls, P = .009). TP53 CHIP was associated with longer prior exposure to platinum (mean 14.0 months of 15 TP53 CHIP cases vs 11.1 months of 49 non-TP53 CHIP cases; P = .02). Longitudinal analysis showed that preexisting TP53 CHIP variants expanded in patients who developed t-MNs.CONCLUSIONS AND RELEVANCEThe findings of this genetic association study suggest that preexisting TP53 CHIP variants may be associated with t-MNs after rucaparib treatment.

2020-05-01·The Lancet Oncology1区 · 医学

Rucaparib for patients with platinum-sensitive, recurrent ovarian carcinoma (ARIEL3): post-progression outcomes and updated safety results from a randomised, placebo-controlled, phase 3 trial

1区 · 医学

Article

作者: Jesus García-Donas ; Lara Maloney ; Carol Aghajanian ; Domenica Lorusso ; Elizabeth M Swisher ; Margarita Amenedo Gancedo ; Johanne I Weberpals ; Ana Oaknin ; Susana Banerjee ; Sandra Goble ; Robert L Coleman ; Jeffrey C Goh ; David M O'Malley ; Robert W Holloway ; Jonathan A Ledermann ; Giovanni Scambia ; Andrew R Clamp ; Nicoletta Colombo ; Deborah K Armstrong ; Andrew Dean ; Alexandra Leary ; Amit M Oza ; Peter C Fong ; Terri Cameron

BACKGROUNDIn ARIEL3, rucaparib maintenance treatment significantly improved progression-free survival versus placebo. Here, we report prespecified, investigator-assessed, exploratory post-progression endpoints and updated safety data.METHODSIn this ongoing (enrolment complete) randomised, placebo-controlled, phase 3 trial, patients aged 18 years or older who had platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 who had received at least two previous platinum-based chemotherapy regimens and responded to their last platinum-based regimen were randomly assigned (2:1) to oral rucaparib (600 mg twice daily) or placebo in 28-day cycles using a computer-generated sequence (block size of six with stratification based on homologous recombination repair gene mutation status, progression-free interval following penultimate platinum-based regimen, and best response to most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary endpoint of investigator-assessed progression-free survival has been previously reported. Prespecified, exploratory outcomes of chemotherapy-free interval (CFI), time to start of first subsequent therapy (TFST), time to disease progression on subsequent therapy or death (PFS2), and time to start of second subsequent therapy (TSST) and updated safety were analysed (visit cutoff Dec 31, 2017). Efficacy analyses were done in all patients randomised to three nested cohorts: patients with BRCA mutations, patients with homologous recombination deficiencies, and the intention-to-treat population. Safety analyses included all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT01968213.FINDINGSBetween April 7, 2014, and July 19, 2016, 564 patients were enrolled and randomly assigned to rucaparib (n=375) or placebo (n=189). Median follow-up was 28·1 months (IQR 22·0-33·6). In the intention-to-treat population, median CFI was 14·3 months (95% CI 13·0-17·4) in the rucaparib group versus 8·8 months (8·0-10·3) in the placebo group (hazard ratio [HR] 0·43 [95% CI 0·35-0·53]; p<0·0001), median TFST was 12·4 months (11·1-15·2) versus 7·2 months (6·4-8·6; HR 0·43 [0·35-0·52]; p<0·0001), median PFS2 was 21·0 months (18·9-23·6) versus 16·5 months (15·2-18·4; HR 0·66 [0·53-0·82]; p=0·0002), and median TSST was 22·4 months (19·1-24·5) versus 17·3 months (14·9-19·4; HR 0·68 [0·54-0·85]; p=0·0007). CFI, TFST, PFS2, and TSST were also significantly longer with rucaparib than placebo in the BRCA-mutant and homologous recombination-deficient cohorts. The most frequent treatment-emergent adverse event of grade 3 or higher was anaemia or decreased haemoglobin (80 [22%] patients in the rucaparib group vs one [1%] patient in the placebo group). Serious treatment-emergent adverse events were reported in 83 (22%) patients in the rucaparib group and 20 (11%) patients in the placebo group. Two treatment-related deaths have been previously reported in this trial; there were no new treatment-related deaths.INTERPRETATIONIn these exploratory analyses over a median follow-up of more than 2 years, rucaparib maintenance treatment led to a clinically meaningful delay in starting subsequent therapy and provided lasting clinical benefits versus placebo in all three analysis cohorts. Updated safety data were consistent with previous reports.FUNDINGClovis Oncology.

2019-11-14·New England Journal of Medicine1区 · 医学

Secondary Surgical Cytoreduction for Recurrent Ovarian Cancer

1区 · 医学

Article

作者: Kim, Byoung-Gie ; Enserro, Danielle ; Huang, Helen Q ; DiSilvestro, Paul ; Cohn, David E ; Spirtos, Nick M ; Coleman, Robert L ; Mannel, Robert S ; Kim, Jae-Weon ; Armstrong, Deborah K ; Alvarez Secord, Angeles ; Basen-Engquist, Karen ; Park, Sang-Yoon ; Walker, Joan L ; Davidson, Susan A ; Rubin, Steve ; Fujiwara, Keiichi ; Chan, John K ; Tewari, Krishnansu S ; Brady, Mark F ; Nam, Joo-Hyun ; Herzog, Thomas J ; Sabbatini, Paul ; Casey, Ann C

BACKGROUNDSecondary surgical cytoreduction in women with platinum-sensitive, recurrent epithelial ovarian, primary peritoneal, or fallopian-tube ("ovarian") cancer is widely practiced but has not been evaluated in phase 3 investigation.METHODSWe randomly assigned patients with recurrent ovarian cancer who had received one previous therapy, had an interval during which no platinum-based chemotherapy was used (platinum-free interval) of 6 months or more, and had investigator-determined resectable disease (to no macroscopic residual disease) to undergo secondary surgical cytoreduction and then receive platinum-based chemotherapy or to receive platinum-based chemotherapy alone. Adjuvant chemotherapy (paclitaxel-carboplatin or gemcitabine-carboplatin) and use of bevacizumab were at the discretion of the investigator. The primary end point was overall survival.RESULTSA total of 485 patients underwent randomization, 240 to secondary cytoreduction before chemotherapy and 245 to chemotherapy alone. The median follow-up was 48.1 months. Complete gross resection was achieved in 67% of the patients assigned to surgery who underwent the procedure. Platinum-based chemotherapy with bevacizumab followed by bevacizumab maintenance was administered to 84% of the patients overall and was equally distributed between the two groups. The hazard ratio for death (surgery vs. no surgery) was 1.29 (95% confidence interval [CI], 0.97 to 1.72; P = 0.08), which corresponded to a median overall survival of 50.6 months and 64.7 months, respectively. Adjustment for platinum-free interval and chemotherapy choice did not alter the effect. The hazard ratio for disease progression or death (surgery vs. no surgery) was 0.82 (95% CI, 0.66 to 1.01; median progression-free survival, 18.9 months and 16.2 months, respectively). Surgical morbidity at 30 days was 9%; 1 patient (0.4%) died from postoperative complications. Patient-reported quality of life decreased significantly after surgery but did not differ significantly between the two groups after recovery.CONCLUSIONSIn this trial involving patients with platinum-sensitive, recurrent ovarian cancer, secondary surgical cytoreduction followed by chemotherapy did not result in longer overall survival than chemotherapy alone. (Funded by the National Cancer Institute and others; GOG-0213 ClinicalTrials.gov number, NCT00565851.).

项与铂敏感性输卵管癌相关的新闻（医药）

2023-11-21

·PMLiVE

EC approves pharmaand’s Rubraca as advanced ovarian cancer maintenance treatment

The European Commission (EC) has approved pharmaand’s (pharma&) Rubraca (rucaparib) as a first-line maintenance treatment for advanced ovarian cancer in patients who have responded to first-line platinum-based chemotherapy. The PARP inhibitor, which has been authorised for use in all advanced ovarian cancer patients regardless of their BRCA mutation status, was previously approved for the maintenance treatment of adults with platinum-sensitive relapsed high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who have a complete or partial response to platinum-based chemotherapy. The EC’s latest decision on the drug follows a recent recommendation from the European Medicines Agency’s human medicines committee and was supported by positive results from the late-stage ATHENAMONO trial. Results showed that, as a first-line maintenance treatment, Rubraca significantly improved investigator- assessed progression-free survival compared with placebo in advanced ovarian cancer patients, regardless of BRCA mutation status. The safety profile observed in the ATHENAMONO trial was also consistent with both the current US and European labels for Rubraca, the company said. An estimated 66,000 people in Europe are diagnosed with ovarian cancer each year and, despite recent advances in newly diagnosed ovarian cancer, advanced cases of the disease are still considered incurable for the majority of patients. Frank Rotmann, founder and managing director of pharma&, said the approval "will help to ensure that healthcare providers and eligible patients, regardless of their BRCA mutation status, have access to and may benefit from [Rubraca] earlier in their treatment journey". Elmar Zagler, also founder and managing director of pharma&, added that the company looks forward to “broadening access to the potential benefits of [Rubraca] to a wider group of eligible patients living with advanced ovarian cancer in Europe”. The approval comes just months after pharma& acquired Rubraca from Clovis Oncology as part of an auction associated with Clovis' bankruptcy proceedings. pharma& paid $70m upfront for the rights to the drug, according to a regulatory filing at the time, which also outlined that the company could pay another $65m if certain regulatory and sales milestones are met.