TP53 mutations in cell-free DNA as early markers of therapeutic response in platinum-resistant relapsed ovarian cancer (PROC): a prospective translational analysis of the phase II GANNET53 clinical trial

5518 Background: Platinum resistant ovarian cancer (OC) remains a therapeutic challenge. High grade serous OC (HGSOC) harbors TP53 mutations leading to increased dependency on S- and G2-phase checkpoints. Wee1 inhibition with Adavosertib (AZD 1775) (A) induces G2 checkpoint escape. Gemcitabine (G) is an antimetabolite therapy and blocks the progression of cells through the G1/S phase. We hypothesized that combining G+A would be synergistic and overcome resistance. Methods: We conducted a multicentre double-blind 2:1 randomized phase 2 trial to assess the progression free survival (PFS) in women with recurrent platinum-resistant/refractory HGSOC receiving G+A or G+placebo (P) (NCT02151292). Eligibility required measurable disease and feasibility of paired tumor biopsies; no limitation in prior lines of therapy. Non HGSOC histologic subtypes were enrolled in a separate non-randomized exploratory cohort. A/P was given orally at 175mg QD on D1-2, D8-9 and D15-16 with G 1000mg/m² IV D1, D8 and D15 in a 28-day cycle until progression or unacceptable AE. Tumor staging was scheduled every 8 weeks. TP53 mutations were analyzed on archival tissue with Sanger sequencing, TAm-Seq and IHC. TP53 mutation will be also assessed in circulating tumor DNA (ctDNA). Whole exome and RNA sequencing were performed on paired tumor tissues. Results: 124 patients (pts) with median of 3 prior lines of therapy (range 1-10) from 12 centres across Canada and US were enrolled between Sep 2014 to May 2018, with 99 pts randomized (65 in Arm G+A and 34 in G+P). 5 pts were ineligible; 64 pts have died. The median follow-up was 14.3 months. Main related AE was hematologic toxicity (Anemia G≥3: 31% in G+A vs 18% in G+P; Thrombocytopenia G≥3: 31% vs 6%; Neutropenia G≥3: 62% vs 30%). PFS was significantly improved from 3.0 to 4.6 months (HR 0.56 (95%CI: 0.35-0.90, p=0.015 Log rank). There was a significant improvement in overall survival (OS) from 7.2 to 11.5 months (HR 0.56 (95%CI: 0.34-0.92, P=0.022). Partial response by RECIST 1.1 was observed in 13 (21%) and 1 (3%) pts for Arms G+A and G+P, respectively (p=0.02). From the 25 pts in the exploratory cohort, 3 (12%) partial responses were observed. Final results will be reported at the meeting. Conclusion: Addition of adavosertib to gemcitabine in women with platinum resistant/refractory OC improved response rate, PFS and OS with manageable toxicity. Clinical trial information: NCT02151292.

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Clinical activity of imatinib mesylate in combination with docetaxel in patients with advanced, platinum-resistant ovarian cancer—Hoosier Oncology Group GYN03–62

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.5091 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 5091-5091 ◽

Cited By ~ 2

Author(s):

D. Matei ◽

R. E. Emerson ◽

N. Menning ◽

J. Schilder ◽

J. McClean ◽

...

Keyword(s):

Ovarian Cancer ◽

Clinical Trial ◽

Phase Ii ◽

Response Rate ◽

Advanced Ovarian Cancer ◽

Ovarian Tumors ◽

Phase Ii Clinical Trial ◽

Ovarian Cancer Cells ◽

Clinical Activity ◽

Platinum Resistant

5091 Background: Ovarian tumors harborc-Kit and PDGF receptors. We showed in an in-vitro model that Imatinib (G) inhibits the growth of ovarian cancer cells. We hypothesized that G in combination with chemotherapy inhibits the growth of ovarian tumors. Data from a phase II clinical trial utilizing G in combination with Docetaxel (D) in patients with advanced ovarian cancer (OC) are presented. Methods: This was an open label, one stage, multi-center phase II clinical trial. Planned sample size was 23. Patients with relapsed, platinum-resistant or refractory OC expressing PDGFR or c-kit were eligible. PDGFR and c-kit expression was assessed prior to enrollment by IHC using archival tumor tissue. G was administered at 600mg/d continuously and D was given weekly (30mg/m2) for 4 weeks, with 2 weeks break. Each cycle was 6 weeks, with a maximum of 6 cycles allowed. Tumor assessments were obtained after 2, 4 and 6 cycles. Response rate by RECIST was the primary endpoint. Results: 34 patients were screened. 17 tumors were c-kit + and 25 were PDGFRα +. 23 patients were enrolled. Of those, 4 patients had c-kit+/PDGFR- tumors, 12 were PDGFR+/c-kit- and 7 were c-kit+/PDGFR+. Median age was 55 (range 33–76) and median PS was 0 (range 0–2). Median number of prior treatments was 3 (range 1–9). Efficacy and toxicity data are available for 20 and 14 patients, respectively. Based on RECIST, there were 3 patients with PR and 3 patients with SD lasting at least 12 weeks. Of these 6 patients, 2 pts were c-kit+, 2 were PDGFR+ and 2 were PDGFR and c-kit+. All 6 patients had carboplatin and taxane resistant disease. Grade 3–4 toxicities were: neutropenia (2), thrombocytopenia (1), fatigue (1), dehydration (1), constipation (1), cardiac ischemia (1), nausea/vomiting (2), urinary frequency (1). Other G1–2 toxicities were: N/V (9), diarrhea (7), fatigue (8), mucositis (4), anemia (4), hypocalcemia (5), rash (6), anorexia (7), edema (5), hemolysis (1), non-neutropenic infections (7). Additional data will be available in May 2006. Conclusions: The combination G+D is tolerated well. Clinical activity consisted of 3 PRs (15% response rate) and 3 SD > 3 months in pts with heavily pre-treated, platinum resistant OC expressing c-kit or PDGFRα. [Table: see text]

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Health-related quality of life (QoL) in platinum-resistant ovarian cancer patients treated with olaparib and pegylated liposomal doxorubicin (PLD), a multicenter single-arm phase II clinical trial (ROLANDO, GEICO-1601).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.5549 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 5549-5549

Author(s):

José Alejandro Perez-Fidalgo ◽

Alfonso Cortés Salgado ◽

Yolanda García ◽

María Iglesias ◽

Uriel Bohn Sarmiento ◽

...

Keyword(s):

Ovarian Cancer ◽

Clinical Trial ◽

Phase Ii ◽

Liposomal Doxorubicin ◽

Symptom Control ◽

Pegylated Liposomal Doxorubicin ◽

European Organization ◽

Platinum Resistant ◽

Symptom Intensity ◽

The Impact

5549 Background: The prognosis for patients with platinum-resistant/refractory ovarian cancer (PROC) is poor, and the aim of treatment is focused primarily on symptom control and maintenance of QoL. The objective of this study was to assess the impact on QoL of the combination of pegylated liposomal doxorubicin (PLD) with olaparib (OLA) in PROC patients (pts). Methods: ROLANDO is a single arm phase II trial that enrolled pts with high-grade serous or endometrioid and at least one previous PROC recurrence (between 28 days - 6 months after last platinum). Up to 4 previous lines (up to 5 in BRCA-mut) were allowed. Pts received 6 cycles of PLD 40 mg/m2 intravenously every 28 days + OLA 300 mg b.i.d. followed by OLA 300 mg b.i.d. monotherapy until progression or unacceptable toxicity. QoL was measured by European Organization for Research and Treatment of Cancer QLQ C30 questionnaire evaluating functional status, and symptom intensity and QLQ OV-28 ovarian cancer specific module, both filled out by pts every 4 months (mo) regardless of disease progression. Questionnaire compliance was reported as percentage of the initial number of pts. Changes between baseline and subsequent visits (Wilcoxon rank test) were evaluated. P values < 0.05 were considered significant. Results: From 2017 to 2020, 31 pts were recruited. Median age was 57 y.o., ECOG 0/1: 32.3%/67.7%. Median of prior lines was 2 (range 1-5) and pts were on study treatment for a median of 5 mo (range 1.4-19.5) for OLA and 5 cycles (range 2 - 6) for PLD. QoL information was available at baseline for 30 (97%) pts and decayed to 22 (71%), 13 (42%), 6 (19%) and 4 (13%) pts at 4, 8, 12, and 16 mo respectively. Global health status measured by QLQ C30 and QLQ OV-28 scores was maintained throughout all time points with no significant differences. Significant transient improvement was seen in social functioning after 12 mo (p = 0.013). Nausea-vomiting (p = 0.02), hair loss (p = 0.012) and constipation (p = 0.037) showed a significant increase at 4 mo overlapping with PLD administration, and returned to baseline levels afterwards. This was in line with the reported adverse reactions frequency of nausea (58.1%) and vomiting (45.2%). Dyspnea showed a transient significant increase at 12 mo (p = 0.012), whereas insomnia (p = 0.038) and attitude towards disease (p = 0.007) improved at 16 mo. Symptoms such as appetite and constipation did not change after 12 mo. Most functional scales (physical, role, emotional, cognitive, body, sexuality) and symptom scales (fatigue, pain, appetite loss, diarrhoea, neurologic, hormonal and economic burden) had no statistically significant changes. Conclusions: Pts treated with OLA+PLD combination reported no signs of clinically relevant deterioration of QoL while on treatment. All QoL items changes were transient in no more than 1 time-point. Clinical trial information: NCT03161132.

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832P GEICO1601-ROLANDO trial: A multicentric single arm phase II clinical trial to evaluate the combination of olaparib and pegylated liposomal doxorubicin for platinum-resistant ovarian cancer

Annals of Oncology ◽

10.1016/j.annonc.2020.08.971 ◽

2020 ◽

Vol 31 ◽

pp. S626

Author(s):

J.A. Perez Fidalgo ◽

A. Cortés ◽

Y. García ◽

M. Iglesias ◽

U. Bohn Sarmiento ◽

...

Keyword(s):

Ovarian Cancer ◽

Clinical Trial ◽

Phase Ii ◽

Liposomal Doxorubicin ◽

Pegylated Liposomal Doxorubicin ◽

Phase Ii Clinical Trial ◽

Platinum Resistant

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Targeting VEGFRi resistance through HIF-1á suppression: Phase II clinical trial evaluating CRLX101 as monotherapy and in combination with bevacizumab in recurrent platinum resistant ovarian cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.15_suppl.tps5614 ◽

2015 ◽

Vol 33 (15_suppl) ◽

pp. TPS5614-TPS5614

Author(s):

Carolyn N. Krasner ◽

Michael J. Birrer ◽

Suzanne T. Berlin ◽

Mary K. Buss ◽

Scott Eliasof ◽

...

Keyword(s):

Ovarian Cancer ◽

Clinical Trial ◽

Phase Ii ◽

Phase Ii Clinical Trial ◽

Suppression Phase ◽

Platinum Resistant

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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).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.tps6097 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. TPS6097-TPS6097

Author(s):

Rebecca Christian Arend ◽

Bradley J. Monk ◽

Robert Allen Burger ◽

Thomas J. Herzog ◽

Jonathan A. Ledermann ◽

...

Keyword(s):

Ovarian Cancer ◽

Clinical Trial ◽

Phase Ii ◽

Antiangiogenic Therapy ◽

Sample Size Calculation ◽

Phase Iii ◽

Weekly Paclitaxel ◽

Ca 125 ◽

Recist 1.1 ◽

Platinum Resistant

TPS6097 Background: Ofranergene obadenovec (VB-111) is a targeted anti-cancer gene therapy with a dual mechanism: a broad antiangiogenic effect and induction of a tumor directed viral immune response. In a phase II trial in platinum resistant ovarian cancer VB-111 in combination with weekly paclitaxel showed a CA-125 response rate (RR) of 58% and median overall survival (OS) of 498 days compared to 172.5 days in the sub-therapeutic dose (p = 0.028). The combination treatment was well tolerated. 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 randomized controlled trial, VB-111-701/GOG-3018 (OVAL) was initiated in collaboration with the GOG Foundation, Inc. Methods: The OVAL study, NCT03398655, is an international, randomized, double-blind, placebo-controlled, phase III study. Patients with recurrent platinum-resistant epithelial ovarian cancer, who have measurable disease (RECIST 1.1) and were previously treated with up to 5 lines 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. Treatment beyond asymptomatic RECIST progression may continue until progression is confirmed by follow up imaging. The primary endpoints are OS, safety and tolerability. Secondary endpoints include progression free survival, and objective RR by CA-125 (per GCIG criteria) and RECIST 1.1. The sample size calculation of 400 patients (event driven) provides 92% power to detect a difference in survival at the two-sided 5% significance level using the logrank test. A pre-planned interim analysis will take place in Q1 2020 to assess whether the CA-125 RR per GCIG criteria in the treatment arm is sufficiently larger than in the control arm and is comparable to the positive results of the phase II study. Study enrolment is ongoing and over 80 patients were enrolled in the US and Israel. Enrollment expansion to Europe is planned in 2020. Clinical trial information: NCT03398655.

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