OVARIO phase II trial of combination niraparib plus bevacizumab maintenance therapy in advanced ovarian cancer following first-line platinum-based chemotherapy with bevacizumab.

OBJECTIVE: To assess safety and efficacy of niraparib + bevacizumab as a first-line maintenance therapy for patients with newly diagnosed advanced ovarian cancer. METHODS: This multicenter, phase II, single-arm, open-label study enrolled adult patients with stage IIIB to IV ovarian, fallopian tube, or primary peritoneal cancer (NCT03326193). Patients were required to have an attempt at debulking surgery and have a complete response, partial response, or no evidence of disease following first-line, platinum-based chemotherapy with ≥3 cycles of bevacizumab. The primary endpoint was the progression-free survival (PFS) rate at 18 months. Secondary endpoints included PFS, overall survival, and safety. RESULTS: Among the 105 evaluable patients, the PFS rate at 18 months was 62% (95% CI 52-71%) in the overall population and 76% (95% CI 61-87) in the homologous recombination deficient (HRd), 47% (95% CI 31-64%) in the HR proficient (HRp), and 56% (95% CI 31-79%) in the HR not determined (HRnd) subgroups (December 24, 2020, cutoff). After a median follow-up time of 28.7 months (IQR, 23.9-32.5 months), median PFS was 19.6 months (95% CI 16.5-25.1) in the overall population (N = 105) and 28.3 months (95% CI 19.9-NE), 14.2 months (95% CI 8.6-16.8), and 12.1 months (95% CI 8.0-NE) in the HRd, HRp, and HRnd subgroups, respectively (June 16, 2021, cutoff). The most common any-grade treatment-related adverse events (related to niraparib and/or bevacizumab) were thrombocytopenia (74/105), fatigue (60/105), and anemia (55/105; December 24, 2020, cutoff). CONCLUSION: Niraparib + bevacizumab first-line maintenance therapy displayed promising PFS results. Safety was consistent with the known safety profiles of niraparib and bevacizumab as monotherapy.

Phase II study of Vigil® DNA engineered immunotherapy as maintenance in advanced stage ovarian cancer.

OBJECTIVES: The majority of women with Stage III/IV ovarian cancer who achieve clinical complete response with frontline standard of care will relapse within 2years. Vigil immunotherapy, a GMCSF/bi-shRNA furin DNA engineered autologous tumor cell (EATC) product, demonstrated safety and induction of circulating activated T-cells against autologous tumor in Phase I trial Senzer et al. (2012, 2013) . Our objectives for this study include evaluation of safety, immune response and recurrence free survival (RFS). METHODS: This is a Phase II crossover trial of Vigil (1.0×107 cells/intradermal injection/month for 4 to 12 doses) in Stage III/IV ovarian cancer patients achieving cCR (normal imaging, CA-125≤35units/ml, physical exam, and no symptoms suggestive of the presence of active disease) following primary surgical debulking and carboplatin/paclitaxel adjuvant or neoadjuvant chemotherapy. Patients received Vigil or standard of care during the maintenance period. RESULTS: Forty-two patients were entered into trial, 31 received Vigil and 11 received standard of care. No≥Grade 3 toxicity related to product was observed. A marked induction of circulating activated T-cell population was observed against individual, pre-processed autologous tumor in the Vigil arm as compared to pre-Vigil baseline using IFNγ ELISPOT response (30/31 negative ELISPOT pre Vigil to 31/31 positive ELISPOT post Vigil, median 134 spots). Moreover, in correlation with ELISPOT response, RFS from time of procurement was improved (mean 826days/median 604days in the Vigil arm from mean 481days/median 377days in the control arm, p=0.033). CONCLUSION: In conjunction with the demonstrated safety, the high rate of induction of T-cell activation and correlation with improvement in RFS justify further Phase II/III assessment of Vigil.

The changing role of thoracotomy in gestational trophoblastic neoplasia at the New England Trophoblastic Disease Center.

OBJECTIVE: To review our experience with thoracotomy in gestational trophoblastic neoplasia (GTN). STUDY DESIGN: Nineteen thoracotomy patients from our database were identified. Thoracotomy was performed for therapeutic reasons in 11 patients and to clarify the diagnosis in eight. RESULTS: Among the 11 patients with chemotherapy-resistant pulmonary tumors, 10 of 11 (90.9%) achieved remission with thoracotomy. Thoracotomy was more likely to be done to clarify diagnosis before 1980 (83%) than after 1980 (23%) (p = 0.04), when it became more likely to be done for therapeutic indications. Ten patients had solitary lung lesions and 9 had multiple lesions. Four patients died (21%), with an average survival after thoracotomy of 149 days; patients had bilateral or multiple lung lesions, median preoperative hCG was 58,000 mIU/mL and all were stage IV. Survivors had lower stage disease, were more likely to have solitary lesions and had lower preoperative hCG levels. CONCLUSION: There have been several temporal changes in the indications for thoracotomy for GTN. In general, the optimal patient to achieve remission with thoracotomy will have stage III disease, a preoperative hCG of < 1,500 mIU/mL, and a solitary lung nodule resistant to chemotherapy. Likelihood of remission after thoracotomy is high in properly selected patients.

Overexpression of CEACAM6 in borderline and invasive mucinous ovarian neoplasms.

OBJECTIVE: Identifying markers specific for mucinous ovarian neoplasms (MON) is important for cancer diagnosis and surveillance, and will help improve our general understanding of the pathobiology of these tumors. CEACAM6 overexpression appears to be an early molecular event with prognostic significance in gastrointestinal carcinomas. Microarray analysis previously demonstrated high CEACAM6 overexpression in MON's and this study sought to validate this finding. METHODS: Western blot compared CEACAM6 expression in normal human ovarian surface epithelium (HOSE) and ovarian cancer cell lines. Quantitative RT-PCR (qRT-PCR) was performed on 75 laser-microdissected HOSE and ovarian cancer tissue samples. Immunohistochemistry (IHC) was performed and slides were analyzed in a semi-quantitative manner. RESULTS: CEACAM6 was expressed in 2 of 3 mucinous cancer cell lines. Expression was absent in all 2 HOSE, 7 serous cancer, and 2 clear cell cancer cell lines. 100-fold CEACAM6 overexpression (qRT-PCR) was demonstrated in 13/16 (81%) borderline, low-grade, and high-grade invasive MON's, compared to 5/50 (10%) serous and 1/5 (20%) benign mucinous samples. CEACAM6 expression was not different between borderline and invasive MON's (p=0.55) or across tumor stage (p=0.76). CEACAM6 staining was present in 24/28 (86%) borderline, low-grade, and high-grade invasive MON's; 13/28 (46%) exhibited moderate-strong staining. Neither CEACAM6 expression (p=0.36) nor staining intensity (p=0.51) was different between borderline and invasive MON's. None of the serous or benign mucinous tumors exhibited CEACAM6 staining. CONCLUSIONS: CEACAM6 is overexpressed in borderline and invasive MON's.

Elevated body mass index does not increase the risk of palmar-plantar erythrodysesthesia in patients receiving pegylated liposomal doxorubicin.

OBJECTIVES: The dose-limiting toxicity of pegylated liposomal doxorubicin (PLD) is palmar-plantar erythrodysesthesia (PPE). Some physicians are reluctant to use this drug in overweight patients, postulating that larger size increases the likelihood of PPE. We sought to determine whether a correlation exists between body mass index (BMI) and the frequency or severity of skin reactions during PLD chemotherapy. METHODS: The records of all patients receiving PLD chemotherapy for gynecologic malignancy at our institution were reviewed for chemotherapy history, BMI at start of treatment, dose, infusion time, and adverse outcomes. Skin reaction sites, grade, and treatments were recorded. Possible predisposing factors were extracted, as well as the reason for drug discontinuation. RESULTS: Over 7 years, 103 patients were treated with PLD for gynecologic malignancies. 429 cycles were given, and PPE occurred in 36% of patients treated. Of those with PPE, reactions were grades 1, 2, or 3 in 54%, 32%, and 14% of patients, respectively. The BMI of patients with PPE (29.0) was not significantly different from that of patients without PPE (28.8). Analysis using finer subsets of weight also revealed no association. Finally, logistic regression revealed no relationship between BMI and rash grade. CONCLUSIONS: Elevated BMI does not appear to correlate with occurrence of PPE in our population. Of interest, among patients discontinuing PLD due to skin toxicity, 25% had clinical evidence of response. The identification of predisposing risk factors may help guide treatment decisions; however, elevated BMI does not appear to be such a risk factor.