A Canadian cancer trials group phase IB study of durvalumab (anti-PD-L1) plus tremelimumab (anti-CTLA-4) given concurrently or sequentially in patients with advanced, incurable solid malignancies.

Background The IND.226 study was a phase Ib study to determine the recommended phase II dose of durvalumab + tremelimumab in combination with standard platinum-doublet chemotherapy. Sequential administration of multiple agents increases total chair time adding costs overall and inconvenience for patients. This cohort of the IND.226 study evaluated the safety and tolerability of durvalumab + tremelimumab given either sequentially (SEQ) or concurrently (CON). Methods Patients with advanced solid tumours were enrolled and randomised to either SEQ tremelimumab 75 mg IV over 1 h followed by durvalumab 1500 mg IV over 1 h q4wks on the same day, or CON administration over 1 h. The serum pharmacokinetic profile of SEQ versus CON of durvalumab and tremelimumab administration was also evaluated. Results 14 patients either received SEQ (n = 7pts) or CON (n = 7 pts). There were no infusion related reactions. Drug related adverse events (AEs) were mainly low grade and manageable, and comparable in frequency between SEQ/CON- fatigue (43%/57%), rash (43%/43%), pruritus (43%/29%) and nausea (14%/29%). One patient in each cohort discontinued treatment due to toxicity. The PK profiles of durvalumab and tremelimumab were similar between CON and SEQ, and to historical reference data. Conclusions Concurrent administration of durvalumab and tremelimumab over 1 h is safe with a comparable PK profile to sequential administration.

18F FDG positron-emission tomography findings of gliomatosis peritonei: A case report and review of the literature.

•Gliomatosis peritonei (GP) is a rare benign complication of ovarian teratomas that does not impact overall survival.•GP exhibits high 18-F FDG uptake unlike other non-malignant forms of mature teratoma.•The specific characteristics of GP on functional imaging may be used to follow it with active surveillance in select cases.

Elevated CDCP1 predicts poor patient outcome and mediates ovarian clear cell carcinoma by promoting tumor spheroid formation, cell migration and chemoresistance.

Hematogenous metastases are rarely present at diagnosis of ovarian clear cell carcinoma (OCC). Instead dissemination of these tumors is characteristically via direct extension of the primary tumor into nearby organs and the spread of exfoliated tumor cells throughout the peritoneum, initially via the peritoneal fluid, and later via ascites that accumulates as a result of disruption of the lymphatic system. The molecular mechanisms orchestrating these processes are uncertain. In particular, the signaling pathways used by malignant cells to survive the stresses of anchorage-free growth in peritoneal fluid and ascites, and to colonize remote sites, are poorly defined. We demonstrate that the transmembrane glycoprotein CUB-domain-containing protein 1 (CDCP1) has important and inhibitable roles in these processes. In vitro assays indicate that CDCP1 mediates formation and survival of OCC spheroids, as well as cell migration and chemoresistance. Disruption of CDCP1 via silencing and antibody-mediated inhibition markedly reduce the ability of TOV21G OCC cells to form intraperitoneal tumors and induce accumulation of ascites in mice. Mechanistically our data suggest that CDCP1 effects are mediated via a novel mechanism of protein kinase B (Akt) activation. Immunohistochemical analysis also suggested that CDCP1 is functionally important in OCC, with its expression elevated in 90% of 198 OCC tumors and increased CDCP1 expression correlating with poor patient disease-free and overall survival. This analysis also showed that CDCP1 is largely restricted to the surface of malignant cells where it is accessible to therapeutic antibodies. Importantly, antibody-mediated blockade of CDCP1 in vivo significantly increased the anti-tumor efficacy of carboplatin, the chemotherapy most commonly used to treat OCC. In summary, our data indicate that CDCP1 is important in the progression of OCC and that targeting pathways mediated by this protein may be useful for the management of OCC, potentially in combination with chemotherapies and agents targeting the Akt pathway.

Dose-dense paclitaxel in advanced ovarian cancer.

Carboplatin and paclitaxel, delivered on a 3-weekly basis, is the historical standard for the management of advanced epithelial ovarian cancers (EOC). Increased dose intensity, the inclusion of additional active cytotoxic agents and lengthening treatment duration have failed to improve the outcomes seen with standard doses of carboplatin and paclitaxel in the treatment of EOC. Dose-dense (i.e. weekly) delivery of paclitaxel may exploit anticancer mechanisms such as anti-angiogenesis and the induction of apoptosis. Tumour regrowth may be more effectively impaired by the dose-dense delivery of paclitaxel. Non-randomised studies of dose-dense chemotherapy in EOC have been promising, particularly in heavily pretreated and platinum-resistant disease, with reported response rates as high as 60%. Dose-dense paclitaxel also seems to be well tolerated. These observations led to a number of comparative trials of dose-dense paclitaxel chemotherapy, three have been reported and four are ongoing. This review explores the rationale behind dose-dense delivery of paclitaxel and evaluates the results of completed phase III trials.

Phase II study of temsirolimus (CCI-779) in women with recurrent, unresectable, locally advanced or metastatic carcinoma of the cervix. A trial of the NCIC Clinical Trials Group (NCIC CTG IND 199).

OBJECTIVE: HPV infection has been associated with deregulation of the PI3K-Akt-mTOR pathway in invasive cervical carcinomas. This 2-stage phase II study assessed the activity of the mTOR inhibitor, temsirolimus, in patients with measurable metastatic and/or locally advanced, recurrent carcinoma of the cervix. METHODS: Temsirolimus 25mg i.v. was administered weekly in 4 week cycles. One response among the first 18 patients was required to proceed to the second stage of accrual. Correlative molecular studies were performed on archival tumor tissue. RESULTS: Thirty-eight patients were enrolled. Thirty-seven patients were evaluable for toxicity and 33 for response. One patient experienced a partial response (3.0%). Nineteen patients had stable disease (57.6%) [median duration 6.5 months (range 2.4-12.0mo)]. The 6-month progression free survival rate was 28% (95% CI: 14-43%). The median progression free survival was 3.52 months [95% CI (1.81-4.70)]. Adverse effects were mild-moderate in most cases and similar to other temsirolimus studies. No toxicity>grade 3 was observed. Assessment of PTEN and PIK3CA by IHC, copy number analyses and PTEN promoter methylation status did not reveal subsets associated with disease stability. CONCLUSION: Single agent temsirolimus has modest activity in cervical carcinoma with about two-thirds of patients exhibiting stable disease. Molecular markers for treatment benefit remain to be identified.

Impact of a reduced dose intensity of adjuvant anthracycline based chemotherapy in a population-based cohort of stage I-II breast cancers.

BACKGROUND: Reductions in the dose intensity (DI) of adjuvant anthracycline-based chemotherapy in early stage breast cancer are frequently required due to treatment toxicity or poor tolerance, but the implications of a minimal reduction in DI on clinical outcome remain uncertain. PATIENTS AND METHODS: Women with stage I-II breast cancer treated with adjuvant adriamycin and cyclophosphamide (AC) from 1990-95 were identified in a provincial breast cancer database. Cases were classified into four cohorts: (1) all cycles delivered at full dose and on time; (2) one single dose reduction or dose delay; (3) >1 dose reduction or dose delay; (4) <2 cycles of chemotherapy delivered. RESULTS: 484 eligible cases were identified (cohort (1): n = 268; (2): n= 88; (3): n= 89; (4) n= 39). Slight imbalances in lymph node status (p=0.05) and adjuvant hormonal therapy (p=0.05) were observed between the cohorts. Fifty-five per cent (267/484) of the patients had node-positive disease and 33% (158/484) were ER+. 45% of cases had a reduction in DI. With a median follow-up of 9.6 years, there were no significant differences in relapse-free survival (p=0.94), breast cancer-specific survival (p=0.87) or overall survival (p=0.86) between the four cohorts. Outcomes were independent of hormone receptor status. CONCLUSIONS: Although toxicity related reductions in the DI of adjuvant AC chemotherapy for early stage breast cancer are common, they did not appear to significantly impact on clinical outcomes in this population-based cohort of women with stage I-II breast cancers.

Phase II trial of weekly docetaxel for patients with relapsed ovarian cancer who have previously received paclitaxel--ANZGOG 02-01.

OBJECTIVE: To determine the response rate of weekly docetaxel in women with relapsed epithelial ovarian cancer previously treated with paclitaxel and at least one line of platinum-based chemotherapy. METHODS: In this multi-center phase II trial, 37 patients with relapsed disease were enrolled and treated with weekly docetaxel at 35 mg/m for 5 out of 6 consecutive weeks. Two patient cohorts were considered, those who progressed or relapsed within 4 months (N=7) or at greater than 4 months (N=30) from the time of completing their last course of paclitaxel. RESULTS: Patients in both cohorts received a median of 2 cycles of treatment (range; 1-4). In evaluable patients, the combined overall response rate, using both CA125 and RECIST response criteria was 18.9% (7/37; 95% CI; 10-34%). The combined overall progression-free survival was 3.1 months (95% CI; 2.5-3.8), and the combined overall survival was 12.3 months (95% CI; 8.2-16.4). Treatment was generally well tolerated with the only grade 4 toxicity being skin toxicity (3%). The most common grade 3 toxicities were fatigue (14%) and watery eyes (8%) with grade 3 neutropenia observed in only 5% of patients. CONCLUSION: Weekly docetaxel is well tolerated and has activity in patients with relapsed ovarian cancer previously treated with platinum and paclitaxel.

Carboplatin and paclitaxel for advanced and recurrent cervical carcinoma: the British Columbia Cancer Agency experience.

BACKGROUND: One of the most active chemotherapy combinations in advanced or recurrent cervical cancer is cisplatin-paclitaxel. However, this palliative regimen is associated with significant toxicity. Carboplatin-paclitaxel is thus an attractive option. METHODS: Patients with advanced or recurrent carcinoma of the cervix treated with carboplatin-paclitaxel from April 2000 were included in the study. Starting doses of carboplatin-paclitaxel were: AUC 5-6 and 155-175 mg/m(2), respectively, repeated every 28 days. RESULTS: Twenty-five women treated with this combination were identified. Twenty-three women (92%) had prior treatment with pelvic radiotherapy and 14 (56%) had had concurrent radio-sensitizing cisplatin. There was a 20% PR and a 20% CR rate (10/25). The median progression-free survival for the entire group was 3 months. Responders had a median PFS of 16 months. Fourteen patients (56%) had died of disease progression. The median overall survival (OS) was 21 months. Common toxicities included: grade 1 or 2 anemia, 68%; grade 3 or 4 anemia, 32%; grade 3 or 4 neutropenia, 32%; and grade 1 or 2 peripheral neuropathy, 24%. ECOG PS did not change significantly while on treatment. Eighty-four percent of treatments were delivered on time, and 96% at full dose. CONCLUSIONS: Carboplatin-paclitaxel is an active combination in advanced and recurrent cervical cancer. In this predominantly pre-irradiated group, the combination was deliverable, well tolerated, and the most commonly observed toxicity was anemia.

Induction of XIST expression from the human active X chromosome in mouse/human somatic cell hybrids by DNA demethylation.

X chromosome inactivation occurs early in mammalian development to transcriptionally silence one of the pair of X chromosomes in females. The XIST RNA, a large untranslated RNA that is expressed solely from the inactive X chromosome, is implicated in the process of inactivation. As previous studies have shown that the XIST gene is methylated on the active X chromosome, we have treated a mouse/human somatic cell hybrid retaining an active human X chromosome with demethylating agents to determine whether expression of the human XIST gene could be induced. Stable expression of XIST was observed after several rounds of demethylation and stability of XIST expression correlated with the loss of methylation at the three sites analysed. We conclude that methylation is sufficient to inhibit expression of the XIST gene in somatic cell hybrids. No loss of expression was detected for eight other X-linked genes from the active X chromosome that was expressing XIST , suggesting that additional developmental or species-specific factors are required for the inactivation process.