CA125 Progression Research Articles

Differences in clinical features between CA-125 and RECIST progression in patients with ovarian cancer treated with PARP inhibitors.

e17568 Background: The clinical features of disease progression (PD) based on Response Evaluation Criteria in Solid Tumors (RECIST) and carbohydrate antigen (CA)-125 criteria, and the impact on prognosis in ovarian cancer patients treated with poly (ADP-ribose) polymerase inhibitors (PARPi) were ambiguous. Methods: All ovarian cancer patients included in this retrospective analysis were treated with PARPi monotherapy and regularly assessed with RECIST and CA-125 criteria until disease progression was confirmed by RECIST criteria. According to the presence or absence of CA-125 PD within a 28-day period before and after RECIST PD, patients were categorized into two groups: RECIST PD group (no CA-125 PD within 28 days) and CA-125 PD group (CA-125 PD present within 28 days). Subsequently, the differences in clinical features and progression-free survival (PFS) of subsequent treatment after PARPi resistance between the two groups were analyzed. Results: A total of 139 patients were included, with 71 (51.1%) in RECIST PD group and 68 (48.9%) in CA-125 PD group. Patients in RECIST PD group had a lower proportion of lymph nodes progression (22.5% vs. 52.9%, p=0.000), and multi-sites progression (28.2% vs. 45.6%, p=0.033). Patients in CA-125 PD group had poorer benefit to subsequent chemotherapy after progression of PARPi, with a median PFS of 5.5 and 7.9 months, respectively (HR=1.44, p=0.019). The multivariate analysis showed that PARPi treatment time less than 6 months (HR=2.218, p=0.001) and RECIST PD accompanied by CA-125 PD (HR=1.766, p=0.024) were the main risk factors for PFS of subsequent treatment. Conclusions: Patients with RECIST PD but without CA125 PD have a reduced likelihood of experiencing lymph nodes progression or multi-sites progression. Conversely, patients with RECIST PD and CA125 PD simultaneously demonstrate poorer outcomes in subsequent treatment after PARPi resistance.

Discordance between GCIG CA-125 progression and RECIST progression in the CALYPSO trial of patients with platinum-sensitive recurrent ovarian cancer

BackgroundCA-125 alone is widely used to diagnose progressive disease (PD) in platinum-sensitive recurrent ovarian cancer (PSROC) on chemotherapy. However, there are increasing concerns regarding its accuracy. We assessed concordance between progression defined by CA-125 and RECIST using data from the CALYPSO trial.MethodsWe computed concordance rates for PD by CA-125 and RECIST to determine the positive (PPV) and negative predictive values (NPV).ResultsOf 769 (79%) evaluable participants, 387 had CA-125 PD, where only 276 had concordant RECIST PD (PPV 71%, 95% CI 67–76%). For 382 without CA-125 PD, 255 had RECIST PD but 127 did not (NPV 33%, 95% CI 29–38). There were significant differences in NPV according to baseline CA-125 (≤100 vs >100: 42% vs 25%, P < 0.001); non-measurable vs measurable disease (51% vs 26%, P < 0.001); and platinum-free-interval (>12 vs 6–12 months: 41% vs 14%, P < 0.001). We observed falling CA-125 levels in 78% of patients with RECIST PD and CA-125 non-PD.ConclusionApproximately 2 in 3 women with PSROC have RECIST PD but not CA-125 PD by GCIG criteria. Monitoring CA-125 levels alone is not reliable for detecting PD. Further research is required to investigate the survival impact of local therapy in radiological detected early asymptomatic PD.

Results of TRIO-15, a multicenter, open-label, phase II study of the efficacy and safety of ganitumab in patients with recurrent platinum-sensitive ovarian cancer

BackgroundIGF signaling has been implicated in the pathogenesis and progression of ovarian carcinoma (OC). Single agent activity and safety of ganitumab (AMG 479), a fully human monoclonal antibody against IGF1R that blocks binding of IGF1 and IGF2, were evaluated in patients with platinum-sensitive recurrent OC. MethodsPatients with CA125 progression (GCIG criteria) or measurable disease per RECIST following primary platinum-based therapy received 18 mg/kg of ganitumab q3w. The primary endpoint was objective response rate (ORR) assessed per RECIST 1.1 by an independent radiology review committee (IRC) and/or GCIG CA125 criteria. Secondary endpoints included clinical benefit rate (CBR), progression free survival (PFS) and overall survival (OS). Results61 pts. were accrued. Objective responses were seen in 5/61 patients (ORR 8.2%, 95% CI, 3.1–18.8) with 1 partial response (PR) by RECIST and 2 complete responses (CR) as well as 2 PR by CA125 criteria. CBR was 80.3% (95% CI, 67.8–89.0%). The median PFS according to RECIST by IRC was 2.1 months (95% CI, 2.0–3.1). The median PFS per RECIST IRC and/or CA125 was 2.0 months (95% CI, 1.8–2.2). The median OS was 21 months (95% CI, 19.5-NA). The most common overall adverse events were fatigue (36.1%) and hypertension (34.4%). Grade 1/2 hyperglycemia occurred in 30.4% of patients. Hypertension (11.5%) and hypersensitivity (8.2%) were the most frequent grade 3 adverse events. ConclusionsIGF1R inhibition with ganitumab was well-tolerated, however, our results do not support further study of ganitumab as a single agent in unselected OC patients.

Maintenance therapy of patients with recurrent epithelial ovarian carcinoma with the anti-tumor-associated-mucin-1 antibody gatipotuzumab: results from a double-blind, placebo-controlled, randomized, phase II study

BackgroundGatipotuzumab is a humanized monoclonal antibody recognizing the carbohydrate-induced epitope of the tumor-associated mucin-1 (TA-MUC1). This study aimed to evaluate the efficacy and safety of switch maintenance therapy with gatipotuzumab in patients with TA-MUC1-positive recurrent ovarian, fallopian tube, or primary high-grade serous peritoneal cancer.Patients and methodsIn this double-blind, randomized, placebo-controlled, phase II trial, patients with at least stable disease (SD) following chemotherapy were randomized 2:1 to receive intravenous gatipotuzumab (500 mg followed by 1700 mg 1 week later) or placebo every 3 weeks until tumor progression or unacceptable toxicity occurred. Stratification factors were the number of prior chemotherapy lines (2 versus 3-5), response versus SD after the most recent chemotherapy, and progression-free survival (PFS) <6 versus 6-12 months following the prior therapy. Primary endpoint was PFS according to modified immune-related RECIST 1.1 response criteria. Secondary endpoints were PFS at 6 months, safety, overall response rate, CA-125 progression, overall survival, quality of life, and pharmacokinetics.ResultsOverall, 216 patients were randomized to gatipotuzumab (n = 151) or placebo (n = 65). Median PFS with gatipotuzumab was 3.5 months as compared with 3.5 months with placebo (hazard ratio 0.96, 95% confidence interval 0.69-1.33, P = 0.80). No advantage for gatipotuzumab over placebo was seen in the secondary efficacy endpoints or in any stratified subgroups. Gatipotuzumab was well tolerated, with mild to moderate infusion-related reactions being the most common adverse events.ConclusionsGatipotuzumab switch maintenance therapy does not improve outcome in TA-MUC1-positive ovarian cancer patients.Trial registrationClinicalTrials.govNCT01899599; https://clinicaltrials.gov/ct2/show/NCT01899599

RECIST/CA-125 progression-free survival and the role of CA-125 surveillance in the phase III PAOLA-1/ENGOT-ov25 trial evaluating maintenance olaparib plus bevacizumab in patients with newly diagnosed advanced high-grade ovarian carcinoma

<h3>Objectives:</h3> In the PAOLA-1/ENGOT-ov25 primary analysis (NCT02477644), adding the PARP inhibitor olaparib to maintenance bevacizumab (bev) after first-line platinum-based chemotherapy with bev led to a significant progression-free survival (PFS) benefit vs placebo (pbo) + bev in patients (pts) with advanced high-grade ovarian cancer (HGOC), using modified RECIST v1.1 criteria (HR 0.59; 95% CI 0.49-0.72; <i>P</i><0.001; median PFS 22.1 vs 16.6 months) (Ray-Coquard <i>et al. NEJM</i> 2019). Limited evidence supports use of serum CA-125, a surrogate biomarker for progression, to detect relapse in pts receiving PARP inhibitor maintenance therapy. We evaluated RECIST/CA-125 progression and CA-125 surveillance in PAOLA-1. <h3>Methods:</h3> Pts with newly diagnosed, FIGO stage III-IV HGOC in response after platinum-based chemotherapy plus bev received bev (15 mg/kg q3w for 15 months) + olaparib (300 mg bid for 24 months) or pbo. Scans were performed every 24 weeks, or every 12 weeks if there was evidence of clinical or CA-125 progression. CA-125 levels were assessed every 12 weeks. Time to RECIST or CA-125 progression or death was a secondary endpoint; RECIST/CA-125 progression by biomarker status, response to initial therapy and CA-125 level at baseline were explored. <h3>Results:</h3> 537 pts were randomized to olaparib + bev and 269 to pbo + bev with median follow-up for PFS by RECIST/CA-125 of 24.2 vs 24.7 months (DCO 22 March 2019). In the ITT population, the benefit provided by olaparib + bev vs pbo + bev for PFS by RECIST/CA-125 (HR 0.58; 95% CI 0.48-0.70; <i>P</i><0.0001; median PFS 22.1 vs 15.4 months) was consistent with the primary analysis of PFS by RECIST. Of 462 pts with RECIST progression (ITT), 39% had RECIST progression alone and 45% had CA-125 progression more than 7 days before RECIST progression, with a median 2.4 months between CA-125 and RECIST progression (Table). In subgroup analyses, 49% of t<i>BRCA</i>m pts and 45% of HRD-positive pts had RECIST progression alone compared with only 37% of HRD-negative pts. 42% of pts with NED or CR had RECIST progression alone compared with 33% of pts with PR. 44% of pts with normal baseline CA-125 levels had RECIST progression alone compared with only 17% of pts with abnormal baseline CA-125 levels (<i>P</i><0.001). The rate of PFS events by RECIST/CA-125 was higher for pbo + bev vs olaparib + bev (74% vs 53%) (ITT). Of pts with RECIST progression, a similar proportion in each treatment arm had RECIST progression alone, including in subgroup analyses by biomarker status and response to initial therapy. <h3>Conclusions:</h3> Median PFS and HRs were consistent when progression was assessed by either RECIST or RECIST/CA-125 in PAOLA-1. Scans appear particularly important for detecting progression in HRD-positive pts, t<i>BRCA</i>m pts or pts with normal CA-125 levels at baseline as CA-125 levels did not seem to predict relapse in these pts. Results suggest that CA-125 surveillance alone may be sufficient to detect progression in most pts with abnormal baseline CA-125 levels when starting maintenance therapy.

Concordance between CA-125 and RECIST progression in patients with germline BRCA-mutated platinum-sensitive relapsed ovarian cancer treated in the SOLO2 trial with olaparib as maintenance therapy after response to chemotherapy

BackgroundLimited evidence exists to support CA-125 as a valid surrogate biomarker for progression in patients with ovarian cancer on maintenance PARP inhibitor (PARPi) therapy. We aimed to assess the concordance between CA-125 and Response Evaluation Criteria in Solid Tumours (RECIST) criteria for progression in patients with BRCA mutations on maintenance PARPi or placebo. MethodsWe extracted data on progression as defined by Gynecologic Cancer InterGroup CA-125, investigator- and independent central-assessed RECIST from the SOLO2/ENGOT-ov21(NCT01874353) trial. We excluded those with progression other than by RECIST, progression on date of randomisation, and no repeat CA-125 beyond baseline. We evaluated the concordance between CA-125 progression and RECIST progression, and assessed the negative (NPV) and positive predictive value (PPV). ResultsOf 295 randomised patients, 275 (184 olaparib, 91 placebo) were included. 171 patients had investigator-assessed RECIST progression. Of 80 patients with CA-125 progression, 77 had concordant RECIST progression (PPV 96%, 95% confidence interval 90–99%). Of 195 patients without CA-125 progression, 94 had RECIST progression (NPV 52%, 45–59%). Within treatment arms, PPV was similar (olaparib: 95% [84–99%], placebo: 97% [87–100%]) but NPV was lower in patients on placebo (olaparib: 60% [52–68%], placebo: 30% [20–44%]). Of 94 patients with RECIST but without CA-125 progression, 64 (68%) had CA-125 that remained within normal range. We observed similar findings using independent-assessed RECIST. ConclusionsAlmost half the patients without CA-125 progression had RECIST progression, and most of these had CA-125 within the normal range. Regular computed tomography imaging should be considered as part of surveillance in patients treated with or without maintenance olaparib rather than relying on CA-125 alone.

Concordance between CA-125 and RECIST progression (PD) in patients with germline BRCA-mutated platinum-sensitive, relapsed ovarian cancer treated with a PARP inhibitor (PARPi) as maintenance therapy after response to chemotherapy.

6014 Background: There are no data to support CA-125 as a surrogate biomarker for ovarian cancer PD in patients on maintenance therapy with a PARPi. We aimed to assess the concordance of PD by CA-125 with RECIST PD in patients treated with maintenance PARPi. Methods: We extracted data on PD as defined by GCIG CA-125 and investigator-assessed RECIST from the SOLO2/ENGOT-Ov21 (NCT01874353) trial. Patients were categorized into: (i) CA-125 and RECIST non-PD concordant; (ii) CA-125 and RECIST PD concordant; and (iii) CA-125 and RECIST discordant. We excluded those with PD other than by RECIST, PD on date of randomization, and no repeat CA-125 beyond baseline. To assess the concordance of CA-125 PD with RECIST PD and CA-125 non-PD with RECIST non-PD, we computed the positive predictive value (PPV), i.e. the probability that patients with CA-125 PD also had RECIST PD, and negative predictive value (NPV), i.e. probability that patients with no CA-125 PD also did not have RECIST PD, respectively. Results: Of 295 randomised patients, 275 (184 olaparib, 91 placebo) were included in the primary analysis. 80 (29%) had CA-125 PD and 77 had concordant RECIST PD, resulting in a PPV of 96% (95% CI 90%-99%). Of 195 patients without CA-125 PD, 101 also did not have RECIST PD, resulting in a NPV of 52% (95% CI 45%-59%; Table). Among those with RECIST PD (n = 171), a greater proportion of patients with RECIST-only PD had a normal baseline CA-125 than those with both CA-125 and RECIST PD (94% vs 69%; p&lt; 0.001). Of 94 patients without CA-125 PD but had RECIST PD, 65 (69%) had CA-125 that remained within normal range, while 27 (29%) had rising and elevated CA-125 that did not meet the criteria for GCIG CA125-PD. Discordance between RECIST PD and CA-125 non-PD was similar in early (≤12 weeks) and late ( &gt; 12 weeks) PD (56% vs 55%, respectively; p= 0.96). Conclusions: Almost half the patients with RECIST PD did not have CA-125 PD and most had CA-125 still within the normal range. Regular imaging should be considered as part of surveillance in patients on maintenance olaparib rather than relying on CA-125 alone. [Table: see text]

995PD - Time to second progression (PFS2) and second subsequent therapy (TSST) for patients (pts) with newly diagnosed, advanced ovarian cancer (OC) and a BRCA mutation (BRCAm) treated with maintenance (mt) olaparib (ola): Phase III SOLO1 trial

995PD - Time to second progression (PFS2) and second subsequent therapy (TSST) for patients (pts) with newly diagnosed, advanced ovarian cancer (OC) and a BRCA mutation (BRCAm) treated with maintenance (mt) olaparib (ola): Phase III SOLO1 trial

A multicenter open-label phase II study of the efficacy and safety of ganitumab (AMG 479), a fully human monoclonal antibody against insulin-like growth factor type 1 receptor (IGF-1R) as second-line therapy in patients with recurrent platinum-sensitive ovarian cancer.

5515 Background: IGF signaling has been implicated in the pathogenesis and progression of ovarian cancer (OC). Single agent activity and safety of ganitumab (AMG 479), a fully human monoclonal antibody against IGF-1R that blocks binding of IGF1 and IGF2, were evaluated in asymptomatic patients with platinum-sensitive recurrent OC. Differential expression of IGF-1R pathway genes in OC underscores the potential of developing predictive biomarkers for patient selection. Methods: Pts with CA125 progression (GCIG criteria) and/or measurable disease per RECIST failing primary platinum-based therapy received 18 mg/kg of ganitumab q3w. Objective response rate per RECIST or CA125 criteria was the primary end point (complete response, CR; partial response, PR). Secondary end points included, progression-free survival (PFS) and safety. Tumor tissue was collected for gene expression profiling (Nanostring) and sequencing. Results: From 02/2009 to 05/2010, 61 pts were accrued from 20 centers. Pt characteristics were: Serous (77%), median platinum-free interval (11 months), measurable disease (74%), and ECOG performance status 0 (67%). According to CA125 criteria median PFS was 6.8 months (95%CI, 2.8-10.8); 2 CR (3.4%) 2 PR (3.4%), and 38 stable disease (SD, 64%) were observed. When using RECIST criteria, median PFS was 2.1 months (95%CI, 2.0-2.8), 2 PR (3.4%) and 22 SD (38%) were observed. Toxicity has been mild; grade 2 hyperglycemia was seen in 5 pts (8.2%). Grade 3 related events included hearing loss (1), nausea (1), asthenia (2), fatigue (1), and hypersensitivity (5). There were no grade 4 or 5 treatment-related events. Efficacy is being correlated with gene expression profiles and mutational data. Conclusions: IGF-1R inhibition with ganitumab was well tolerated and demonstrated modest single-agent activity in unselected patients with platinum-sensitive recurrent OC. However, encouraging activity was seen in a subset of patients. Ongoing predictive biomarker analyses may facilitate patient selection. Clinical trial information: NCT00719212.

How to approach patients in relapse

How to approach patients in relapse

Optimal assessment of response in ovarian cancer

Objective tumor response and progression, measured by standard criteria such as RECIST 1.1, are important measures of change in tumor size that are utilized as endpoints in phase II and III clinical trials. In ovarian cancer, RECIST criteria, which are based on anatomical tumor size, have been supplemented by CA125 response and progression criteria developed by the Gynecologic Cancer InterGroup. CA125 progression has been integrated with objective criteria into a composite definition of progression often used in the front-line setting, whereas response criteria are generally intended for use in recurrent disease trials. In terms of the performance of these endpoints in clinical trials, objective response, when used to assess the activity of new drugs in phase II trials in recurrent ovarian cancer, has proven to be helpful in identifying agents that have subsequently been shown to improve overall or progression-free survival in randomized trials. Thus, objective response has utility as an endpoint for new drug screening trials. Progression-free survival is often used as the primary (or co-primary) efficacy endpoint in studies of first-line therapy in ovarian cancer. Data from historical studies of platinum-based chemotherapy regimens indicate that improvements in progression-free survival generally translate into overall survival gains, indicating it may qualify as a surrogate endpoint for overall survival. It is not yet clear if this relationship will hold true in randomized trials of targeted agents, making it important to continue to assess overall survival in such studies. Finally, the routine monitoring of CA125 in patients after completion of front-line treatment as part of the standard of care has come under question with the publication of the results of a large European study; therefore, the use of CA125 progression as an endpoint in clinical trials will also likely be debated in the coming years.

Correlation between CA-125 serum level and response by RECIST in a phase III recurrent ovarian cancer study

Objectives To evaluate in a large phase III recurrent ovarian cancer trial (OVA-301): 1) the concordance between CA-125 level vs. best overall response (OR) and progression-free survival (PFS) determined by radiological assessment 2) the impact of early CA-125 changes over the subsequent radiological response, and 3) the prognostic value of CA-125 response and CA-125 PFS to predict radiological response and PFS. Methods Assessment of response in the entire randomized population was performed by the Response Evaluation Criteria in Solid Tumors 1.0 (RECIST) and modified Rustin criteria for CA-125 determination. Results Most CA-125 decreases were observed in RECIST responders (82% of patients treated with the combination and 74% in the PLD alone). CA-125 progression preceded RECIST progression in 35% of patients with a median lead time of 8.4 weeks. A high concordance rate between CA-125 PFS status at 4 months (PFS4) and CA-125 response as a predictor of PFS4 (87%) and radiological response (79%) was found in the combination, with high positive predictive value for radiological PFS4 (92%) and high negative predictive value for OR (90%). An early CA-125 decrease was predictive for the ultimate response since it was found in a high rate of RECIST responders. Conclusion Radiological response was preceded by a favorable predictive CA-125 decrease in a high proportion of patients, suggesting that CA-125 evaluation may be an appropriate tool for tumor assessment in patients with ovarian cancer.

Clinical Trials in Recurrent Ovarian Cancer

The 4th Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup was held in Vancouver, Canada, in June 2010. Representatives of 23 cooperative research groups studying gynecologic cancers gathered to establish international consensus on issues critical to the conduct of large randomized trials. Group C, 1 of the 3 discussion groups, examined recurrent ovarian cancer, and we report the consensus reached regarding 4 questions. These included the following: (1) What is the role of cytoreductive surgery for recurrent ovarian cancer? (2) How do we define distinct patient populations in need of specific therapeutic approaches? (3) Should end points for trials with recurrent disease vary from those of first-line trials? (4) Is CA-125 progression alone sufficient for entry/eligibility into clinical trials?

The prognostic and predictive value of CA-125 regression during neoadjuvant chemotherapy for advanced ovarian or primary peritoneal carcinoma

To assess the significance of CA-125 regression as a prognostic indicator and predictor of optimal cytoreduction at interval debulking surgery (IDS) in women with ovarian or primary peritoneal carcinoma receiving neoadjuvant chemotherapy (NAC). 63 women treated between 2004 and 2007 with neoadjuvant platinum-based chemotherapy followed by IDS were studied retrospectively. Pre-operative CA-125 values were used to calculate a regression coefficient (CA-125r) using exponential regression analysis. Outcome endpoints were overall survival (OS), time to CA-125 progression (TTC) by Rustin criteria and time to second-line treatment (TTS). Women with a CA-125 half-life greater than 18 days had a significantly worse OS compared to those with a half-life less than 12 days on univariate testing (HR 3.34, 95% CI 1.25-8.94, p = 0.017). On multivariable analysis, CA-125r was an independent predictor of OS [HR 1.18 (per 0.01 increase in CA-125r), 95% CI 1.01-1.40, p = 0.043]. CA-125r was independently predictive of TTC and TTS (HR 1.17, p ≈ 0.03 for each). CA-125r was also predictive of achieving optimal cytoreduction at IDS (AUC 0.756, p < 0.001). CA-125 regression rate during pre-operative NAC is of independent prognostic value. CA-125 regression rate strongly predicts for optimal cytoreduction.

Phase Ib study of AMG 386 combined with either pegylated liposomal doxorubicin (PLD) or topotecan (T) in patients with advanced ovarian cancer.

5049 Background: AMG 386 is an investigational peptide-Fc fusion protein that inhibits angiogenesis by preventing angiopoietin 1/2 interaction with the Tie2 receptor. We report on an ongoing, open-label study of AMG 386 combined with PLD or T in advanced ovarian cancer. Methods: In part 1 of this 2-part dose de-escalation study, adult patients (pts) with recurrent, epithelial ovarian, fallopian tube, or primary peritoneal cancer and GOG performance 0 or 1, and ≤ 3 prior chemotherapy regimens received, IV, AMG 386 at 10 mg/kg QW plus PLD at 50 mg/m2 Q4W (Arm A, n = 6 planned) or T at 4 mg/m2 QW (3 on/1 off; Arm B, n = 6 planned) until progression or unacceptable toxicity. Dose-limiting toxicities (DLTs) in ≥ 3 pts in either arm triggers dose de-escalation of AMG 386 to 3 mg/kg; 6 pts to be enrolled at lower dose. Cohort expansion with 19 pts is planned for part 2 of the study if ≤ 1 pt in either arm has a DLT at either AMG 386 dose. The primary endpoint is DLT incidence; secondary endpoints are safety, PK and response per RECIST (ORR) or CA-125 (GCIG criteria). Results: 12 pts have been enrolled and received ≥ 1 dose of AMG 386 (Arm A/B, n = 6/6). With ≥ 4 weeks follow-up for each pt, there have been no DLTs and no AMG 386 dose de-escalations. 11 pts (Arm A/B, n = 6/5) had AMG 386-related adverse events (AEs): 5 had grade 3 AEs (n = 4/1). There were no grade 4 or 5 AEs. The most common AMG 386-related AEs were nausea (Arm A/B, n = 3/2; no grade 3), fatigue (n = 3/2; grade 3, n = 2/0), rash (n = 3/0; grade 3, n = 2/0), and anemia (n = 0/2; no grade 3). Other key AMG 386-related AEs included hypertension (n = 5/4, no grade 3) and peripheral edema (n = 0/1, grade 3). With median follow-up of 13/21 weeks (Arm A/B), 8 pts were progression-free (n = 5/3); 3 pts had progressed (n = 1/2) and 1 pt (Arm B) died from disease progression. ORR data are not mature. 6 pts had CA-125 responses (Arm A/B, n = 3/3); 1 pt in Arm A had CA-125 progression. Combining AMG 386 with PLD or T did not appear to affect the PK parameters of either agent. Planned cohort expansion to part 2 is underway. Conclusions: Based on these interim results with short follow-up, AMG 386 combined with PLD or T appears tolerable in pts with advanced ovarian cancer. Updated safety and efficacy data will be presented. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, Nuwan Nanayakkara via Quintiles Amgen, CTI Amgen Amgen, GlaxoSmithKline, Ortho Biotech Amgen

The prognostic and predictive value of CA-125 regression during neoadjuvant chemotherapy for advanced ovarian or primary peritoneal carcinoma.

5070 Background: The selection of patients with ovarian cancer for interval debulking surgery (IDS) following neoadjuvant chemotherapy (NAC) is an important clinical goal. We have examined the significance of CA-125 regression as a prognostic indicator and predictor of optimal cytoreduction at IDS in women with ovarian or primary peritoneal carcinoma receiving NAC. Methods: 63 women treated between 2004 and 2007 with neoadjuvant platinum-based chemotherapy followed by IDS were studied retrospectively. Preoperative CA-125 values were used to calculate a regression coefficient (CA-125r) using exponential regression analysis. Outcome endpoints were overall survival (OS), time to CA-125 progression by Rustin criteria (TTC) and time to second-line treatment (TTS). Results: On multivariable analysis, CA-125r was an independent predictor of OS (HR 1.18 [per 1% change in CA-125r], 95% CI: 1.00-1.38, p = 0.048). CA-125r was independently predictive of TTC and TTS (HR 1.16, p ≂̃F 0.03 for both). CA-125r was also predictive of achieving optimal cytoreduction at IDS (AUC 0.756, p < 0.001). Conclusions: CA-125 regression rate during preoperative NAC is of independent prognostic value. CA-125 regression rate strongly predicts for optimal cytoreduction. No significant financial relationships to disclose.

Doubling time of serum CA125 is an independent prognostic factor for survival in patients with ovarian cancer relapsing after first-line chemotherapy

IntroductionConfirmed doubling of CA125 value is one definition of progression in ovarian cancer patients. If asymptomatic, the management of these patients is unclear. To provide information which may assist in therapeutic decision making, we set out to determine the independent prognostic significance for the rate of rise in CA125 during surveillance in ovarian cancer patients as measured by CA125 doubling time. Patient and methodsClinical information was obtained through a 2-staged chart review of ovarian cancer patients treated in our department from 1994 to 2003. We searched for patients who met criteria for CA125 progression and doubling during surveillance following first-line therapy. ResultsA total of 296 patients were initially identified. During surveillance, the median doubling time of CA125 was 40d and the median survival for patients with a CA125 doubling time of ⩽40d was 10.6months compared to 22.1months for those with doubling time>40d. In a univariate analysis, age, high-grade, suboptimal cytoreduction, short CA125 doubling time, short time to progression and high CA125 at progression were significantly associated with poor survival, but in a multivariate analysis, a short CA125 doubling time of ⩽40d and a short time to disease progression (⩽180d) were the only independent adverse prognostic factors (p=0.001). Second stage review identified 28 new patients who provided a confirmatory set that supported the adverse survival trend for patients with short CA125 doubling time. DiscussionThe rate of rise of CA125 during surveillance carries independent prognostic significance, and should be considered when making therapeutic decisions.

Predictive value of serum CA125 levels in women with persistent or recurrent epithelial ovarian cancer (EOC) or primary peritoneal cancer (PPC) treated with bevacizumab (Bev) on a Gynecologic Oncology Group (GOG) phase II trial

e16505 Background: The clinical utility of serum CA125 in patients (pts) with EOC/PPC treated with biologic agents is unknown. The primary objective of this study was to determine the proportion of pts treated with bevacizumab on a phase II clinical trial with stable disease by RECIST who demonstrated disease progression (pgrn) as assessed by modified GCIG CA125 criteria. Methods: Sixty-two pts with measurable recurrent or persistent EOC/PPC were treated with bevacizumab 15 mg/kg Q 21 days on a phase II clinical trial. Primary endpoints of the clinical trial were progression-free (PF) survival at 6 months and response assessed by RECIST criteria. Pts were removed from therapy/evaluation for disease prgn by RECIST, toxicity, or by subject request. Serum CA125 was collected at entry and prior to each cycle but levels were only used to define a complete response which required CA125 normalization (≤35). Modified GCIG criteria were retrospectively applied to these CA125 values to determine time to progression from date of entry to either the first time CA125&gt;70 for pts whose CA125 normalized on treatment or was greater than 2X the nadir value for pts whose CA125 did not normalize. Censored cases provided time until the date of last CA125 measurement. Results: The median PFS by RECIST was 4.7 mos. Of those patients who had prgn by CA125, the median residual time to prgn by RECIST was 1.4 mos. In all, twenty-five (40.3%) pts survived PF for 6 mos. by RECIST and 16 (25.8%) by CA125. Ten pts who survived PF for at least 6 mos. by RECIST indicated treatment failure before 6 mos. by CA125, or 40% of the 25 positive outcomes. Eight pts continued to receive treatment for at least 4 mos. after prgn by CA125, with one continuing therapy for more than 3 years. Conclusions: Serum CA125 levels were a useful marker of progression in some pts treated on this trial; however, some pts received clinical benefit from continued therapy in spite of indications of disease prgn by CA125. Consideration should be given before discontinuing bevacizumab therapy based on CA125 progression alone. No significant financial relationships to disclose.

A phase 2, randomized, double-blind, placebo-controlled trial of clinical activity and safety of subcutaneous Å6 in women with asymptomatic CA125 progression after first-line chemotherapy of epithelial ovarian cancer

Objectives Å6 is a novel peptide that interferes with single-chain urokinase plasminogen activator activity and has shown anti-angiogenic, anti-migratory, and anti-invasive properties. We evaluated clinical efficacy and safety of subcutaneously administered Å6 in women with epithelial ovarian cancer. Methods Women with epithelial ovarian, fallopian tube, or primary peritoneal cancer in clinical remission after first-line chemotherapy with 2 consecutive increases of CA125 values above normal but with no disease on physical examination or imaging studies were randomly assigned to receive daily subcutaneous injections of placebo, low-dose Å6 (150 mg), or high-dose Å6 (300 mg) until disease progression or end of study participation. Primary endpoints were time to clinical progression of disease and safety of Å6. Secondary endpoints were changes in serum CA125 and biomarkers of the urokinase system. Results Data are available for 24 women (placebo, n = 12; low-dose, n = 8; high-dose n = 4). Å6 therapy was associated with a statistically significant delay in time to clinical progression (log-rank p-value 0.01) with a median of 100 days (95% CI: 64,168) for women who received Å6 compared with 49 days (95% CI: 29,67) for women who received placebo. The treatments appeared to be well tolerated. Treatment was not associated with CA125 response ( p = 0.44). On-treatment values for plasma urokinase plasminogen activator receptor were statistically significantly lower in the Å6 groups compared with placebo ( p = 0.02). Conclusions Å6 therapy increases time to clinical disease progression and appears to be well tolerated in this patient population.

A phase III trial of cisplatin plus topotecan followed by paclitaxel plus carboplatin versus standard carboplatin plus paclitaxel as first-line chemotherapy in women with newly diagnosed advanced epithelial ovarian cancer (EOC) (OV.16). A Gynecologic Cancer Intergroup Study of the NCIC CTG, EORTC GCG, and GEICO

LBA5505 Background: Topotecan was evaluated in a novel combination regimen in comparison to standard therapy in front-line EOC. Methods: Women with newly diagnosed EOC stages IIB-IV, ECOG PS 0–1, age ≤ 75, and were randomized to one of two q 21 day regimens. Arm 1 cycles 1 to 4: cisplatin 50 mg/m2 d1 plus topotecan 0.75 mg/m2 d1–5 IV; cycles 5 to 8: paclitaxel 175 mg/m2 over 3 hrs d1 followed by carboplatin AUC5 day 1. Arm 2 paclitaxel plus carboplatin as in Arm 1 for 8 cycles. Patients (pts) were stratified for type of primary surgery/residual disease, centre, and age (< 65 vs. > 65 yrs). The primary endpoint was progression free survival (PFS). Progression was defined as the earlier of objective or CA125 progression (GCIG definition) or death. Secondary endpoints were response (in pts with measurable disease), CA125 normalization at 3 mo, overall survival, toxicity and Quality of Life. The sample size required 800 pts and 631 progression events to demonstrate an increase in PFS from 16 to 20 months with a power of 80% and alpha (2-sided) <0.05. Results: 819 pts (409 Arm 1, 410 Arm 2) were entered from Aug 2001 to June 2005. All randomized patients were included in the analysis. 650 pts have had a progression event and 406 have died. Pt characteristics were well balanced. Median age was 57 yrs (range: 28–78); 80% had debulking surgery: of these 55% had < 1 cm residual disease; 8.5% pts were stage II, 66% stage III, 25.5% stage IV. Arm 1 vs Arm 2 pts had more hematological toxicity (gr 3/4 febrile neutropenia 9.9% vs. 2.7%) and hospitalizations (11.3% cycles vs. 7.1% cycles). Conclusions: Topotecan/cisplatin followed by carboplatin/paclitaxel was more toxic and did not show any evidence of improved efficacy compared to standard therapy. Carboplatin plus paclitaxel remains the standard of care for advanced EOC. * stratified log rank; ** stratified Cochran-Mantel-Haenszel No. Pts Arm 1 Arm 2 Hazard Ratio Odds Ratio p value PFS median (mo) 819 14.6 16.2 1.10 (0.94-1.28) 0.25* CR + PR (%) 389 67.9 77.2 0.63 0.04** CA125 normal < 3 mo (%) 819 57.5 66.3 0.63 0.006** Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GlaxoSmithKline