Front-line chemo-immunotherapy with carboplatin-paclitaxel using oregovomab indirect immunization in advanced ovarian cancer: A randomized phase II study.

BACKGROUND: This randomized phase II study tested the hypothesis that schedule dependent chemo-immunotherapy with oregovomab improves progression free survival (PFS) and overall survival (OS) in optimally resected, Stage III/IV ovarian cancer. METHODS: Patients from both academic centers and private practice in the US and Italy with Stage III/IV optimally cytoreduced ovarian cancer were randomized to standard six cycle IV carboplatin-paclitaxel chemotherapy (CP) versus CP plus four immunizations with oregovomab (CPO). A translational assessment of a cellular immune response was the primary endpoint; PFS and OS were measured as secondary endpoints. FINDINGS: 97 patients at thirteen centers were accrued to the protocol, 47 to CPO and 50 to CP. Technical issues led to inconsistent performance of the primary CA125 ELISPOT leading to unevaluable results. At a median follow up of 42 months, PFS and OS outcomes revealed an unexpectedly large treatment effect for CPO relative to CP alone, with median PFS of 41.8 months (95% C.I.: 21.8 - N.E.) for CPO and 12.2 months (10.4-18.6) for CP (p = 0.0027, HR 0.46, CI 0.28-0.7). For OS, the median for CPO has not yet been reached (NE) (45.2-NE) and for CP was 43.2 months (31.8-NE) (p = 0.043, HR 0.35, CI 0.16-0.74). The oregovomab treatment resulted in no change in toxicity profile from CP. INTERPRETATION: The previously identified potential clinical benefit of IV CP when administered with oregovomab was further refined in this randomized phase II study. Increases of PFS and OS of statistically and clinically significant magnitude were evident in this study of a front line chemo-immunotherapy treatment of ovarian cancer.

A Randomized Phase II Trial of Epigenetic Priming with Guadecitabine and Carboplatin in Platinum-resistant, Recurrent Ovarian Cancer.

PURPOSE: Platinum resistance in ovarian cancer is associated with epigenetic modifications. Hypomethylating agents (HMA) have been studied as carboplatin resensitizing agents in ovarian cancer. This randomized phase II trial compared guadecitabine, a second-generation HMA, and carboplatin (G+C) against second-line chemotherapy in women with measurable or detectable platinum-resistant ovarian cancer. PATIENTS AND METHODS: Patients received either G+C (guadecitabine 30 mg/m2 s.c. once-daily for 5 days and carboplatin) or treatment of choice (TC; topotecan, pegylated liposomal doxorubicin, paclitaxel, or gemcitabine) in 28-day cycles until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were RECIST v1.1 and CA-125 response rate, 6-month PFS, and overall survival (OS). RESULTS: Of 100 patients treated, 51 received G+C and 49 received TC, of which 27 crossed over to G+C. The study did not meet its primary endpoint as the median PFS was not statistically different between arms (16.3 weeks vs. 9.1 weeks in the G+C and TC groups, respectively; P = 0.07). However, the 6-month PFS rate was significantly higher in the G+C group (37% vs. 11% in TC group; P = 0.003). The incidence of grade 3 or higher toxicity was similar in G+C and TC groups (51% and 49%, respectively), with neutropenia and leukopenia being more frequent in the G+C group. CONCLUSIONS: Although this trial did not show superiority for PFS of G+C versus TC, the 6-month PFS increased in G+C treated patients. Further refinement of this strategy should focus on identification of predictive markers for patient selection.

A phase II study of ramucirumab (IMC-1121B) in the treatment of persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma.

OBJECTIVE: Vascular endothelial growth factor (VEGF) receptor-mediated signaling contributes to ovarian cancer pathogenesis. Elevated VEGF expression is associated with poor clinical outcomes. We investigated ramucirumab, a fully human anti-VEGFR-2 antibody, in patients with persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. Primary endpoints were progression-free survival at 6 months (PFS-6) and confirmed objective response rate (ORR). METHODS: Women who received ≥ 1 platinum-based chemotherapeutic regimen and had a platinum-free interval of <12 months with measurable disease were eligible. Patients received 8 mg/kg ramucirumab intravenously every 2 weeks. RESULTS: Sixty patients were treated; one patient remained on study as of September 2013. The median age was 62 years (range: 27-80), and median number of prior regimens was 3. Forty-five (75%) patients had platinum refractory/resistant disease. Thirty-nine patients (65.0%) had serous tumors. PFS-6 was 25.0% (n=15/60, 95% CI: 14.7-37.9%). Best overall response was: partial response 5.0% (n=3/60), stable disease 56.7% (n=34/60), and progressive disease 33.3% (n=20/60). The most common treatment-emergent adverse events possibly related to study drug were headache (65.0%; 10.0% Grade ≥ 3), fatigue (56.7%; 3.3% Grade ≥ 3), diarrhea (28.3%; 1.7% Grade ≥ 3), hypertension (25.0%; 3.3% Grade ≥ 3), and nausea (20.0%; no Grade ≥ 3). Two patients experienced intestinal perforations (3.3% Grade ≥ 3). Pharmacodynamic analyses revealed changes in several circulating VEGF proteins following initial ramucirumab infusion, including increased VEGF-A, PlGF and decreased sVEGFR-2. CONCLUSIONS: Although antitumor activity was observed, the predetermined efficacy endpoints were not met.

A phase II trial of oxaliplatin, docetaxel, and bevacizumab as first-line therapy of advanced cancer of the ovary, peritoneum, and fallopian tube.

OBJECTIVE: To determine the safety and efficacy of the novel combination of docetaxel, oxaliplatin, and bevacizumab as first-line treatment of advanced cancer of the ovary, peritoneum or fallopian tube after initial debulking surgery. METHODS: Eligible patients (stage IB-IV) were treated with 6 cycles of oxaliplatin (85 mg/m(2)), docetaxel (75 mg/m(2)), and bevacizumab (15 mg/kg) every 3 weeks, followed by single-agent bevacizumab 15 mg/kg every 3 weeks to complete one year of therapy. The primary endpoint was 12-month progression-free survival (PFS). RESULTS: A total of 132 patients (80 with measurable disease at baseline; 52 with non-measurable, evaluable disease at baseline) enrolled and received study treatment. At diagnosis, 76.5% of patients had stage III disease and 20% had stage IV. 62.9% were optimally cytoreduced. The most common grade 3/4 adverse events were neutropenia (42.4%), leukopenia (13.6%), hypertension (8.3%), fatigue (6.1%), and nausea (6.1%). One patient (0.8%) had a fatal gastrointestinal perforation. The best overall confirmed response rate (complete response+partial response [measurable disease subgroup]) was 58.6% (95% CI 49%, 67%). CA-125 response rates for the measurable and non-measurable disease subgroups were 83.0% and 81.5%, respectively. The 12-month PFS rate for the measurable disease subgroup was 65.7% (95% CI 53.4%, 76.7%); median PFS was 16.3 (95% CI 12.6, 19.6) months. Median overall survival was 47.3 (95% CI 34.1, upper limit not applicable) months. CONCLUSIONS: This novel treatment regimen may provide a promising therapeutic approach for women with ovarian, primary peritoneal, or fallopian tube carcinoma. No unanticipated safety concerns were identified.

The Immune adjuvant properties of front-line carboplatin-paclitaxel: a randomized phase 2 study of alternative schedules of intravenous oregovomab chemoimmunotherapy in advanced ovarian cancer.

Oregovomab is a monoclonal antibody that recognizes CA125 and forms circulating immune complexes that can elicit immunity against both tumor antigen and tumor. This study was designed to assess combining this immunotherapy at 2 dosing schedules with front-line chemotherapy in patients with advanced ovarian cancer. Forty patients with stage III/IV carcinomas were randomized to receive a 2 mg oregovomab infusion either the same day [simultaneous infusion (SIM)] or 1 week after [1-week delayed (OWD)] standard carboplatin-paclitaxel chemotherapy at cycles 1, 3, and 5, then quarterly for up to 11 antibody doses. The primary end point was antibody response to oregovomab. Secondary end points included cellular immune response, response rate to front-line treatment, and progression-free survival. A different immune response pattern was observed between the SIM arm and the OWD arm, baseline plasma cytokines were balanced. Humoral immunity occurred more rapidly (P=0.0033) and with greater magnitude in the SIM arm. Absolute lymphocyte counts decreased in the SIM arm at cycles 3 and 5 compared with baseline. Treatment emergent CA125-specific cellular immunity was measured more commonly with SIM (P=0.04) and clinical parameters directionally favored this schedule. The immune responses were stronger than those measured in a previous maintenance monoimmunotherapy protocol. Immunotherapy-associated toxicity was minimal in this study. Front-line chemotherapy with carboplatin-paclitaxel has immune adjuvant properties when combined with oregovomab immunotherapy; however, schedule is important. SIM strategies of carboplatin and paclitaxel should be further studied with oregovomab and other antigen-specific cancer immunotherapy approaches.

A pilot study to evaluate the safety and clinical outcomes of once-weekly epoetin alfa 80,000 u in anemic patients with cancer receiving chemotherapy.

BACKGROUND: Epoetin alfa is indicated for the treatment of chemotherapy-induced anemia at doses of 150 U/kg 3 times weekly or 40,000 U once weekly. Higher starting doses may lead to higher hematologic response rates (RRs), earlier hematologic responses, and earlier identification of nonresponders. The hematologic response and safety of epoetin alfa at a starting dose of 80,000 U once weekly in anemic patients (hemoglobin [Hb] 13 g/dL or increased > 1.3 g/dL in a 2-week period during the 12-week study. The primary efficacy endpoint was major hematologic response (Hb increase >/= 2 g/dL or Hb >/=12 g/dL, independent of transfusion). Secondary endpoints were minor hematologic response (Hb increase >/= 1 g/dL but > 2 g/dL) and incidence of transfusions. RESULTS: Of 69 patients enrolled, 47 (68%) completed the study. A majority of patients (72%) exhibited a major hematologic response with epoetin alfa 80,000 U once weekly. Mean Hb levels increased by 2.2 g/dL from baseline after 12 weeks of therapy. Six patients (8.8%) received packed red blood cell transfusions during the study. The dose of epoetin alfa was reduced, or held then reduced, per protocol in 48 patients (69.6%). Ten patients (14.5%) in the safety population experienced a total of 11 clinically relevant thrombotic vascular events. CONCLUSION: Epoetin alfa at a starting dose of 80,000 U once weekly (with appropriate dose reductions) increased Hb level, was associated with a packed red blood cell transfusion rate > 5% after 4 weeks of therapy, and was safe and generally well tolerated in anemic patients with cancer receiving chemotherapy. The hematologic RR, however, was not markedly improved compared with previous trials with 40,000-60,000 U once weekly, perhaps partly because of the high frequency of dose reductions.

Prevalence of human papillomavirus genotypes in women from three clinical settings.

Prevalence of 27 human papillomavirus (HPV) genotypes was assessed in 1,331 women in three clinical settings: Family planning clinic (low-risk HIV-, n = 202, 21.3% HPV+), colposcopy clinic (high-risk HIV-, n = 854, 34.3% HPV+), and HIV outpatient clinic (HIV+, n = 275, 48.7% HPV+). Compared to women from both family planning and colposcopy clinics, HIV+ women revealed significantly higher prevalence of infection with oncogenic, non-oncogenic, and multiple HPV types. HPV types 52 and 51 were most prevalent in the low-risk HIV- women, whereas in the high-risk HIV- women, HPV types 16, 52, 58, and 35 were most prevalent. Interestingly, in the HIV+ women, less characterized types 83, 53, and 54 were most prevalent. The distinct profiles of genotype prevalence persisted after stratification by Pap smear status. After adjustment for concurrent infections with other types, HPV type 51 in the low-risk HIV- women, and types 16, 35, 39, 45, 52, and 58 in the high-risk HIV- women were significantly associated with cytologic abnormalities (exact P < 0.05). In HIV+ women across CD4 cell count strata, HPV types 42, 16, and 82 revealed significant decreasing trends with increasing CD4 counts (exact P for trend < 0.05). These data suggest distinct genotypic prevalence profiles in women at diverse risk for cervical cancer. The association of several genotypes with cytologic abnormalities underscores the need for vaccines targeting a wide range of HPV types.

Distribution of human papillomavirus type 16 variants in human immunodeficiency virus type 1-positive and -negative women.

The prevalence of human papillomavirus type 16 E6 variant lineages was characterized in a cross-sectional study of 24 human immunodeficiency virus type 1 (HIV)-positive and 33 HIV-negative women in New Orleans. The European prototype was the predominant variant in the HIV-negative women (39.4 %), while in the HIV-positive women the European 350G variant was predominant (29.1 %). In exact logistic regression models, HIV-positive women were significantly more likely to harbour any variant with a nucleotide G-350 mutation compared with HIV-negative women [58.3 % vs 21.1 %; adjusted odds ratio (AOR)=6.28, 95 % confidence interval (CI)=1.19-46.54]. Models also revealed a trend towards increased prevalence of Asian-American lineage in HIV-positive women compared with HIV-negative women (25.0 % vs 6.0 %; AOR=6.35, 95 % CI=0.77-84.97). No association was observed between any variant and cytology or CD4 cell counts or HIV-1 viral loads. These observations reflect a difference in the distribution of HPV-16 variants among HIV-positive and -negative women, indicating that HIV-positive status may lead to increased prevalence of a subset of variants.

ZYC101a for treatment of high-grade cervical intraepithelial neoplasia: a randomized controlled trial.

OBJECTIVE: The objective of this study was to assess the safety and efficacy of a novel therapeutic, ZYC101a, for the treatment of women with histologically confirmed cervical intraepithelial neoplasia (CIN) 2/3. ZYC101a contains plasmid-DNA-encoding fragments derived from the E6 and E7 proteins of human papillomavirus (HPV) 16 and 18, and is formulated within small biodegradable microparticles. METHODS: A multicenter, double-blind, randomized, placebo-controlled trial was conducted in a group of women with biopsy-confirmed CIN 2/3. Subjects were randomized to 3 intramuscular doses of either placebo or ZYC101a (100 or 200 microg). Six months after the first injection, subjects underwent cervical conization. The primary endpoint for this study was histologically confirmed resolution of CIN 2/3. A total of 161 subjects were randomized, dosed, and evaluated for safety. After central pathology review, 127 subjects were evaluable for efficacy. RESULTS: The most common adverse events were related to the injection site, were mild to moderate, and did not worsen at later treatments. The proportion of subjects who resolved was higher in the ZYC101a groups compared to placebo (43% versus 27%), but the difference was not statistically significant (P =.12). In a prospectively defined population of women younger than 25 years (n = 43), resolution was significantly higher in the combined ZYC101a groups compared to placebo (70% versus 23%; P =.007). ZYC101a activity was not restricted to HPV-16-or HPV-18-positive lesions. CONCLUSIONS: ZYC101a was shown to be well tolerated in all patients and to promote the resolution of CIN 2/3 in women younger than 25 years. LEVEL OF EVIDENCE: I

Combined intraperitoneal and intravenous chemotherapy for women with optimally debulked ovarian cancer: results from an intergroup phase II trial.

PURPOSE: The median survival time for women with optimally debulked adenocarcinoma of the ovary treated with intravenous (IV) chemotherapy is 41 to 52 months, and the 2-year survival rate is 65% to 70%. Recent studies evaluating intraperitoneal (IP) chemotherapy have reported a median survival time of 49 to 63 months and 2-year survival rates of 70% to 80%. This phase II trial was undertaken to evaluate the feasibility of and 2-year survival rate achieved by the combination of IP paclitaxel, IP cisplatin, and IV paclitaxel in women with optimally debulked, stage III ovarian cancer. PATIENTS AND METHODS: Treatment consisted of paclitaxel 135 mg/m(2) IV over 24 hours on days 1 to 2, cisplatin 100 mg/m(2) IP on day 2, and paclitaxel 60 mg/m(2) IP on day 8 administered every 21 days for six cycles. RESULTS: In 68 assessable women with optimal stage III ovarian cancer, the 2-year survival rate was 91%, and the median survival time was 51 months. The 2-year disease-free survival rate was 66%, and median disease-free survival time was 33 months. Ninety-six percent of all patients experienced at least one grade 3 to 4 adverse event during therapy, with the most common events being neutropenia (79%), nausea (50%), vomiting (34%), and fatigue/malaise/lethargy (24%). Seventy-one percent of patients completed all six cycles of IV/IP therapy as planned. CONCLUSION: Combined IV and IP chemotherapy with cisplatin and paclitaxel is associated with a very promising 2-year survival rate in women with optimally debulked ovarian cancer. The ultimate impact of this approach on overall survival requires further evaluation in a randomized trial setting.