A randomized phase II study evaluating the combination of carboplatin-based chemotherapy with pertuzumab versus carboplatin-based therapy alone in patients with relapsed,platinum-sensitive ovarian cancer

BackgroundPertuzumab, a humanized monoclonal antibody targeting human epidermal growth factor receptor (HER)-mediated signalling, has shown activity in ovarian cancer in preclinical models and in the clinic. This randomized phase II study evaluated efficacy and safety of pertuzumab in combination with carboplatin-based chemotherapy in patients with platinum-sensitive, recurrent advanced ovarian cancer.Patients and methodsPatients were randomized to receive six cycles of chemotherapy (carboplatin and either paclitaxel (Taxol) or gemcitabine) with or without pertuzumab. The primary end point was progression-free survival (PFS) as determined by Response Evaluation Criteria in Solid Tumors and/or by CA 125 measurements. Secondary end points evaluated the response rate, safety profile, duration of response, time to progression and overall survival for both treatment arms.ResultsA total of 149 patients received either chemotherapy with pertuzumab (arm A, n = 74) or chemotherapy alone (arm B, n = 75). There was no significant difference either in median PFS or in the secondary end points between the two arms. No differences were seen in an exploratory biomarker analysis of HER3 mRNA expression between the two arms. Pertuzumab was well tolerated, with no increase in cardiac adverse events compared with chemotherapy alone.ConclusionsThe addition of pertuzumab to carboplatin-based chemotherapy did not substantially prolong PFS in unselected patients with platinum-sensitive ovarian cancer.     

Comparisons of survival outcomes between bevacizumab and olaparib in BRCA-mutated,platinum-sensitive relapsed ovarian cancer: a Korean Gynecologic Oncology Group study (KGOG 3052)

ObjectiveTo compare survival outcomes between bevacizumab (BEV) and olaparib (OLA) maintenance therapy in BRCA-mutated, platinum-sensitive relapsed (PSR) high-grade serous ovarian carcinoma (HGSOC).MethodsFrom 10 institutions, we identified HGSOC patients with germline and/or somatic BRCA1/2 mutations, who experienced platinum-sensitive recurrence between 2013 and 2019, and received second-line platinum-based chemotherapy. Patients were divided into BEV (n=29), OLA (n=83), and non-BEV/non-OLA users (n=36). The OLA and non-BEV/non-OLA users were grouped as the OLA intent group. We conducted 1:2 nearest neighbor-matching between the BEV and OLA intent groups, setting the proportion of OLA users in the OLA intent group from 65% to 100% at 5% intervals, and compared survival outcomes among the matched groups.ResultsOverall, OLA users showed significantly better progression-free survival (PFS) than BEV users (median, 23.8 vs. 17.4 months; p=0.004). Before matching, PFS improved in the OLA intent group but marginal statistical significance (p=0.057). After matching, multivariate analyses adjusting confounders identified intention-to-treat OLA as an independent favorable prognostic factor for PFS in the OLA 65P (adjusted hazard ratio [aHR]=0.505; 95% confidence interval [CI]=0.280−0.911; p=0.023) to OLA 100P (aHR=0.348; 95% CI=0.184−0.658; p=0.001) datasets. The aHR of intention-to-treat OLA for recurrence decreased with increasing proportions of OLA users. No differences in overall survival were observed between the BEV and OLA intent groups, and between the BEV and OLA users.ConclusionCompared to BEV, intention-to-treat OLA and actual use of OLA maintenance therapy were significantly associated with decreased disease recurrence risk in patients with BRCA-mutated, PSR HGSOC.     

A randomized,double-blind phase II study evaluating cediranib versus cediranib and saracatinib in patients with relapsed metastatic clear-cell renal cancer (COSAK)

BackgroundPreclinical work suggests SRC proteins have a role in the development of resistance to vascular endothelial growth factor (VEGF) targeted therapy in metastatic clear-cell renal cancer (mRCC). This hypothesis was tested in this trial using the SRC inhibitor saracatinib and the VEGF inhibitor cediranib.Patients and methodsPatients with disease progression after ≥1 VEGF-targeted therapy were eligible to participate in this double-blind, randomized (1:1) phase II study. The study compared the combination cediranib 30 mg once daily (o.d.) and saracatinib 175 mg o.d. (CS) (n = 69) or cediranib 45 mg o.d. and placebo o.d. (C) (n = 69). Archived tissue was used for biomarker analysis [SRC, focal adhesion kinase (FAK), von Hippel–Lindau, protein tyrosine phosphatase 1b and hypoxia-inducible factor 2α: n = 86]. The primary end point was progression-free survival (PFS) by RECIST v1.1.ResultsBetween 2010 and 2012, 138 patients were randomized across 16 UK sites. The characteristics of the two groups were well balanced. Partial responses were seen in 13.0% for C and 14.5% for CS (P > 0.05). There was no significant difference in PFS [5.4 months (3.6–7.3 months) for C and 3.9 (2.4–5.3 months) for CS; hazard ratio (HR) 1.18 (0.94–1.48)] or overall survival (OS) [14.2 months (11.2–16.8 months) for C and 10.0 (6.7–13.2 months) for CS; HR 1.28 (1.00–1.63)]. There was no significant difference in the frequency of key adverse events, dose reductions or drug discontinuations. None of the biomarkers were prognostic for PFS or OS. FAK overexpression correlated with an OS benefit [HR 2.29 (1.09–4.82), P > 0.05], but not PFS, for CS.ConclusionsSaracatinib did not increase the efficacy of a VEGF-targeted therapy (cediranib) in this setting. Biomarker analysis did not identify consistent predictive biomarkers.ClinicalTrials.govNCT00942877.     

A phase II study of a paclitaxel and oxaliplatin combination in platinum-sensitive recurrent advanced ovarian cancer patients.

PURPOSE: A multicentric, phase II study to evaluate the efficacy and safety of the combination paclitaxel and oxaliplatin in patients with platinum-sensitive recurrent ovarian cancer. PATIENTS AND METHODS: Patients received 175 mg/m(2) paclitaxel (over 3 h) followed by 130 mg/m(2) oxaliplatin (over 2 h) every 21 days for up to nine cycles without hydration or primary granulocyte colony-stimulating factor prophylaxis. Patients had to have an Eastern Cooperative Oncology Group performance status of 0-2 and to have received no more than one prior cisplatin- and/or carboplatin-containing chemotherapy regimen with a platinum-progression-free interval > or =6 months. RESULTS: Of the 105 patients enrolled and treated, 98 were eligible. An overall response rate of 81% (79 of 98 patients) (95% confidence interval 71% to 88%) was observed according to RECIST criteria (third party reviewed), and 88% (86 of 98) when this was complemented with CA-125 response. With a median follow up of 43.6 months (range 30.2-64.2) the median progression-free survival was 10.2 months (range 0.3-21.4) and the overall survival 32.4 months. Seven hundred and eight cycles were administered (median seven per patient; range one to nine). A total of 67% of patients experienced National Cancer Institute Common Toxicity Criteria grade 3-4 neutropenia, including 8% with concomitant febrile episode, without treatment-related deaths. Ninety-three per cent of patients experienced neuropathy of grade 1 or more, including 25% with cumulative reversible peripheral neuropathy of grade 3-4. Oxaliplatin doses were reduced in 30 patients due to neurotoxicity. CONCLUSIONS: The oxaliplatin/paclitaxel combination can be administered in an outpatient setting every 3 weeks without specific measures. The high level of activity and its duration observed warrants further evaluation of this combination in pretreated platinum-sensitive advanced ovarian cancer patients.     

Sunitinib in pancreatic neuroendocrine tumors: updated progression-free survival and final overall survival from a phase III randomized study

BackgroundIn a phase III trial in patients with advanced, well-differentiated, progressive pancreatic neuroendocrine tumors, sunitinib 37.5 mg/day improved investigator-assessed progression-free survival (PFS) versus placebo (11.4 versus 5.5 months; HR, 0.42; P < 0.001). Here, we present PFS using retrospective blinded independent central review (BICR) and final median overall survival (OS), including an assessment highlighting the impact of patient crossover from placebo to sunitinib.Patients and methodsIn this randomized, double-blind, placebo-controlled study, cross-sectional imaging from patients was evaluated retrospectively by blinded third-party radiologists using a two-reader, two-time-point lock, followed by a sequential locked-read, batch-mode paradigm. OS was summarized using the Kaplan–Meier method and Cox proportional hazards model. Crossover-adjusted OS effect was derived using rank-preserving structural failure time (RPSFT) analyses.ResultsOf 171 randomized patients (sunitinib, n = 86; placebo, n = 85), 160 (94%) had complete scan sets/time points. By BICR, median (95% confidence interval [CI]) PFS was 12.6 (11.1–20.6) months for sunitinib and 5.8 (3.8–7.2) months for placebo (HR, 0.32; 95% CI 0.18–0.55; P = 0.000015). Five years after study closure, median (95% CI) OS was 38.6 (25.6–56.4) months for sunitinib and 29.1 (16.4–36.8) months for placebo (HR, 0.73; 95% CI 0.50–1.06; P = 0.094), with 69% of placebo patients having crossed over to sunitinib. RPSFT analysis confirmed an OS benefit for sunitinib.ConclusionsBICR confirmed the doubling of PFS with sunitinib compared with placebo. Although the observed median OS improved by nearly 10 months, the effect estimate did not reach statistical significance, potentially due to crossover from placebo to sunitinib.Trial registration numberNCT00428597.     

Initial toxicity assessment of ICON6: a randomised trial of cediranib plus chemotherapy in platinum-sensitive relapsed ovarian cancer

Background:

Cediranib is a potent oral vascular endothelial growth factor (VEGF) signalling inhibitor with activity against all three VEGF receptors. The International Collaboration for Ovarian Neoplasia 6 (ICON6) trial was initiated based on evidence of single-agent activity in ovarian cancer with acceptable toxicity.

Methods:

The ICON6 trial is a 3-arm, 3-stage, double-blind, placebo-controlled randomised trial in first relapse of platinum-sensitive ovarian cancer. Patients are randomised (2 : 3 : 3) to receive six cycles of carboplatin (AUC5/6) plus paclitaxel (175 mg m⁻²) with either placebo (reference), cediranib 20 mg per day, followed by placebo (concurrent), or cediranib 20 mg per day, followed by cediranib (concurrent plus maintenance). Cediranib or placebo was continued for 18 months or until disease progression. The primary outcome measure for stage I was safety, and the blinded results are presented here.

Results:

Sixty patients were included in the stage I analysis. A total of 53 patients had received three cycles of chemotherapy and 42 patients had completed six cycles. In all, 19 out of 60 patients discontinued cediranib or placebo during chemotherapy because of adverse events/intercurrent illness (n=9); disease progression (n=1); death (n=3); patient decision (n=1); administrative reasons (n=1); and multiple reasons (n=4). Grade 3 and 4 toxicity was experienced by 30 (50%) and 3 (5%) patients, respectively. No gastrointestinal perforations were observed.

Conclusion:

The addition of cediranib to platinum-based chemotherapy is sufficiently well tolerated to expand the ICON6 trial and progress to stage II.     

Paclitaxel-cisplatin combination in advanced ovarian cancer: a phase II study

Background. To date there have been four large randomized studies in Western countries examining the role of combining cisplatin and paclitaxel as first-line treatment for ovarian cancer. A phase II study of paclitaxel and cisplatin in Japanese patients with advanced ovarian cancer was performed to determine the objective response rate and toxicity of this regimen. Methods. Previously untreated patients with stage III or IV ovarian cancer and a good performance status were eligible. Treatment consisted of paclitaxel 180 mg/m² administered as a 3-h intravenous (i.v.) infusion followed by cisplatin 60 mg/m² i.v. Treatment was repeated every 3 weeks for at least four cycles. Granulocyte colony-stimulating factor (G-CSF) was not routinely used. Results. Among 26 eligible patients, there were 4 complete and 17 partial responses, for an overall response rate of 80.8% (95% confidence interval [CI], 60.6% to 93.4%). One hundred and twenty-nine treatment cycles were administered to the 26 patients. Grade 4 neutropenia was observed in 64 treatment cycles (50%) and in 23 patients (88%). Thrombocytopenia was less common. The most common nonhematologic toxicities included neurotoxicity, fatigue, arthralgia/myalgia, and nausea/emesis. Conclusion. Paclitaxel plus cisplatin is a highly active regimen in patients with advanced ovarian cancer. The toxicities of this regimen are well tolerated. Received: September 1, 1999 / Accepted: January 11, 2000     

A phase II study of lenalidomide in platinum-sensitive recurrent ovarian carcinoma

BackgroundLenalidomide has dual antiangiogenic and immunomodulatory properties and confirmed antitumor activity in hematologic malignancies. A phase II study investigating the safety and efficacy of continuous lenalidomide in recurrent ovarian cancer patients was initiated.Patients and methodsPatients with histologically confirmed epithelial ovarian, fallopian tube or primary peritoneal carcinoma, with asymptomatic recurrence 6 months after prior therapy were treated with continuous oral lenalidomide (20 mg/day). The primary end point was to evaluate efficacy according to the rate of disease control at 4 months. Secondary objectives were progression-free survival (PFS) and safety.ResultsMost of the 45 patients enrolled and treated had serous histology (78%) and a single line of prior chemotherapy (73%). Median platinum-free interval (PFI) was 11.3 months (range 6.9–56.8). Clinical benefit at 4 months was 38% [95% confidence interval (CI) 23% to 53%]. A 59% disease control rate was reported in patients with a PFI >12 months versus 24% with PFI of 6–12 months (P = 0.023). Four patients had RECIST partial responses and 21 had stable disease. CA125 responses were reported in eight patients, including one complete response. Median PFS was 3.4 months (95% CI 2.4–4.4). Most frequent toxicity was hematologic, notably grade 3–4 neutropenia in 29% of patients, along with fatigue (69%), gastrointestinal toxicity (constipation 53%, abdominal pain 49%, diarrhea 38%, nausea/vomiting 36%) and thrombosis (11%). Eight patients withdrew due to related toxicity.ConclusionsLenalidomide shows interesting efficacy in late recurrent ovarian cancer patients. Toxicity was mainly hematologic, gastrointestinal and venous thrombosis. Future studies will evaluate combination of lenalidomide with chemotherapy agents.Clinicaltrials.govNCT01111903.     

Docetaxel and oxaliplatin in the second-line treatment of platinum-sensitive recurrent ovarian cancer: a phase II study.

BACKGROUND: A prospective phase II study was conducted to evaluate the efficacy and toxicity of the combination docetaxel (Taxotere) (DTX) and oxaliplatin (OXA) in ovarian cancer patients recurring after a platinum-free interval (PFI) >12 months. PATIENTS AND METHODS: DTX, 75 mg/m(2), was administered by 60 min i.v. infusion, followed by OXA, 100 mg/m(2), given by a 2 h i.v., on day 1 every 21 days. RESULTS: From October 2003 to June 2006, 43 ovarian cancer patients were enrolled. Median PFI was 26 months. All patients were available for response evaluation: 17 complete responses and 12 partial responses were registered, for an overall response rate of 67.4%. The median response duration was 10 months. Stable disease was documented in 11 patients (median duration = 5.5 months). The median time to progression and overall survival were 14 and 28 months. A total of 259 courses were administered. Grade 3-4 leukopenia was documented in 32.5% of the patients, while no case of severe anemia and thrombocytopenia was observed. Grade 3-4 neurotoxicity and grade 2 alopecia were observed in 9.3% and 34.9% of cases, respectively. CONCLUSION: DTX/OXA combination is an active regimen with a favorable toxicity profile, for treatment of recurrent platinum-sensitive ovarian cancer patients.     

Phase II study of NGR-hTNF in combination with doxorubicin in relapsed ovarian cancer patients

Background:

The NGR-hTNF (asparagine–glycine–arginine–human tumour necrosis factor) is able to promote antitumour immune responses and to improve the intratumoural doxorubicin uptake by selectively damaging tumour blood vessels.

Methods:

Patients progressing after ⩾1 platinum/taxane-based regimen received NGR-hTNF 0.8 μg m⁻² and doxorubicin 60 mg m⁻² every 3 weeks. Primary endpoint was a Response Evaluation Criteria in Solid Tumors-defined response rate with a target of more than 6 out of 37 responding patients.

Results:

A total of 37 patients with platinum-free interval lower than 6 months (PFI<6; n=25), or between 6 and 12 months (PFI=6–12; n=12) were enrolled. Median baseline peripheral blood lymphocyte count (PBLC) was 1.6 per ml (interquartile range, 1.2–2.1). In all, 18 patients (49%) received more than 6 cycles. Febrile neutropaenia was registered in one patient (3%). Among 35 assessable patients, 8 (23% 95% CI 12–39%) had partial response (2 with PFI<6; 6 with PFI=6–12) and 15 (43%) had stable disease (10 with PFI<6; 5 with PFI=6–12). Median progression-free survival (PFS) was 5.0 months for all patients, 3.8 months for patients with PFI<6, and 7.8 months for patients with PFI=6–12. Median overall survival (OS) was 17.0 months. Patients with baseline PBLC higher than the first quartile had improved PFS (P=0.01) and OS (P=0.001).

Conclusion:

Tolerability and activity of this combination warrant further randomised testing in patients with PFI<6. The role of PBLC as a blood-based biomarker deserves further investigation.     

Hyaluronan-Irinotecan improves progression-free survival in 5-fluorouracil refractory patients with metastatic colorectal cancer: a randomized phase II trial

Purpose

The objective of this study was to conduct a randomised phase II study in second-line metastatic colorectal cancer with the purpose of confirming preliminary clinical data indicating that the formulation of irinotecan with the drug carrier, hyaluronan (HA) reduced toxicity of the drug.

Methods

Irinotecan-na?ve patients were randomized to receive either irinotecan (350?mg/m²) or HA-Irinotecan (HA 1,000?mg/m² and irinotecan at 350?mg/m²) every 3?weeks for a maximum of eight cycles.

Results

Seventy-six patients (41 HA-Irinotecan and 35 irinotecan-alone) were enrolled. There was no significant difference in any individual, or overall, grade 3 or 4 toxicity. There was a trend for increased diarrhea in the HA-Irinotecan-treated patients (20 versus 9%; P?=?21), potentially explained by a disproportionate number of baseline toxicity-associated risk factors in this treatment group. The median number of cycles completed was six for HA-Irinotecan patients and two for irinotecan-alone patients (P?=?0.005). When compared to the control arm, HA-Irinotecan patients had a significantly longer median progression-free survival of 5.2 versus 2.4?months (P?=?0.017) and time to treatment failure (4 vs. 1.8?months; P?=?0.007). Median overall survival was 10.1?months for HA-Irinotecan compared to 8.0?months for irinotecan patients (P?=?0.196).

Conclusion

Further studies are required to define the safety of the formulation of irinotecan with HA. While this study was not adequately powered to demonstrate survival differences, these phase II data indicated HA-Irinotecan to be a promising therapy demonstrating improved efficacy compared to irinotecan-alone.     

The safety and efficacy of olaparib therapy in patients with relapsed ovarian cancer

Introduction: PARP inhibition is an exciting new anticancer strategy. Olaparib has recently obtained a first in class license in Europe and the USA for the treatment of relapsed BRCA-mutant ovarian cancer.

Areas covered: We review the key preclinical and clinical data surrounding its use in the maintenance setting.

Expert commentary: We also consider the market profile, regulatory issues surrounding the agent and offer a five year speculative viewpoint of its future development in ovarian cancer.     

Randomized,two-arm,noncomparative phase 2 study of olaparib plus cediranib or durvalumab in HRR-mutated,platinum-resistant ovarian cancer: A substudy of KGOG 3045

Choosing an optimal concomitant drug for combination with poly-ADP ribose polymerase (PARP) inhibitor based on patient-specific biomarker status may help increase to improve treatment efficacy in patients with ovarian cancer. However, the efficacy and safety of different PARP inhibitor-based combinations in patients with homologous recombination repair (HRR) mutations have not been evaluated in ovarian cancer. In this sub-study of Korean Gynecologic Oncology Group (KGOG) 3045, we compared the efficacy and safety of two olaparib-based combinations and biomarkers of patients with platinum-resistant ovarian cancer with HRR gene mutations. Patients were randomized to receive either olaparib (200 mg twice a day) + cediranib (30 mg daily) (Arm 1, n = 16) or olaparib (300 mg) + durvalumab (1,500 mg once every 4 weeks) (Arm 2, n = 14). The objective response rates for Arm 1 and Arm 2 were 50.0% and 42.9%, respectively. Most patients (83.3%) had BRCA mutations, which were similarly distributed between arms. Grade 3 or 4 treatment-related adverse events were observed in 37.5% and 35.7% of the patients, respectively, but all were managed properly. A high vascular endothelial growth factor signature was associated with favorable outcomes in Arm 1, whereas immune markers (PD-L1 expression [CPS ≥10], CD8, neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio) were associated with favorable outcomes in Arm 2. The activation of homologous recombination pathway upon disease progression was associated with poor response to subsequent therapy. Based on comprehensive biomarker profiling, including immunohistochemistry, whole-exome and RNA sequencing and whole blood-based analyses, we identified biomarkers that could help inform which of the two combination strategies is appropriate given a patient's biomarker status. Our findings have the potential to improve treatment outcome for patients with ovarian cancer in the PARP inhibitor era.     

Cost-effectiveness of combination versus sequential docetaxel and carboplatin for the treatment of platinum-sensitive, recurrent ovarian cancer

BACKGROUND:

In a randomized controlled trial (RCT) of patients with recurrent, platinum‐sensitive ovarian cancer, the combination weekly docetaxel and carboplatin was associated a with progression‐free survival (PFS) of 13.7 months compared with 8.4 months for sequential, single‐agent docetaxel followed by carboplatin. The objective of the current study was to construct a cost‐utility model to compare these 2 regimens with the incorporation of prospectively collected quality‐of‐life (QoL) data.

METHODS:

An RCT of concurrent docetaxel and carboplatin (cDC) versus docetaxel followed by carboplatin (sequential docetaxel and carboplatin [sDC]) was the basis for a Markov decision model, and the primary effectiveness outcome was PFS. Costs were estimated using US dollars based on Medicare reimbursements for chemotherapy regimens, bone marrow support, and management of adverse events. QoL data obtained using the Functional Assessment of Cancer Therapy‐General questionnaire were converted to utilities. Costs and incremental cost‐effectiveness ratios (ICERs) were reported in US dollars per quality‐adjusted life year (QALY). Extensive 1‐way sensitivity analyses and a Monte Carlo probabilistic sensitivity analysis were performed.

RESULTS:

The least expensive strategy was sDC, which cost an average of $20,381, compared with cDC, which cost an average of $25,122. cDC had an ICER of $25,239 per QALY compared with sDC. cDC remained cost‐effective, with an ICER <$50,000 per QALY, over a range of costs and estimates. In Monte Carlo sensitivity analysis using a $50,000 per QALY willingness‐to‐pay threshold, cDC was either dominant or cost‐effective with an ICER <$50,000 per QALY in 83% of simulations.

CONCLUSIONS:

Combined weekly cDC appeared to be cost‐effective compared with sDC as treatment strategy for patients with platinum‐sensitive ovarian cancer, even when accounting for slightly lower QoL during treatment. Cancer 2011;. © 2011 American Cancer Society.     

Hormonal therapy with letrozole for relapsed epithelial ovarian cancer. Long-term results of a phase II study

OBJECTIVE: We conducted a phase II trial to evaluate the activity of oral letrozole in women with relapsed or recurrent epithelial ovarian cancer. METHODS: Twenty-seven patients were treated with letrozole at a dose of 2.5 mg once a day. Patients with measurable or evaluable disease (n = 21) and those with only increasing CA 125 serum levels (n = 6) were eligible. Paraffin-fixed histological sections from tumor specimens resected at the initial laparotomy were assessed for the presence of estrogen, and progesterone receptors. RESULTS: Among the 21 patients with measurable or evaluable disease who were evaluated for response by WHO criteria, we observed one complete and two partial responses for an objective response rate of 15%. Using criteria for CA 125 response we obtained a marker response in 4 of 27 patients (15%), and the marker remained stable in 5 additional patients (18%). Letrozole treatment was generally well tolerated. No correlation was observed between tumor marker response or stabilization and either estrogen or progesterone receptor expression. CONCLUSION: The results of our study suggest that the aromatase inhibitor letrozole is an agent with some activity and limited toxicity for relapsed ovarian cancer. As we could not find any association between response and hormonal receptor expression, the underlying mechanisms of letrozole action have to be elucidated.