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Expert Opinion on Investigational Drugs Feb 2021: Ovarian cancer (OC) represents the leading cause of death among gynecological cancers. Despite novel compound classes like vascular endothelial growth factor (VEGF)... (Review)
Review
: Ovarian cancer (OC) represents the leading cause of death among gynecological cancers. Despite novel compound classes like vascular endothelial growth factor (VEGF) inhibitors or poly-ADP ribose polymerase (PARP) inhibitors are available, which improve significantly efficacy of platinum-based chemotherapy, OC prognosis remains poor and innovative strategies are needed. The induction of tumor specific immune response with a therapeutic intent is a very challenging approach. Oregovomab is a murine monoclonal antibody direct to the tumor-associated antigen CA125 that stimulate a host cytotoxic immune response against tumor cells expressing CA125. : This paper reviews the preclinical and clinical published data underlying the use of oregovomab in advanced OC. A literature search was performed in PubMed for oregovomab, ovarian cancer, anti-CA125, and on ClinicalTrials.gov for currently ongoing trials. : Oregovomab demonstrated a significant improvement in progression-free and overall survival in advanced OC treatment when administered simultaneously with first-line chemotherapy. This promising schedule is currently investigated in a phase III trial. Since oral treatments as PARP-inhibitors have recently been approved in the OC first-line setting, the possible role of oregovomab needs still to be defined, also considering the intravenous route of administration. The easy to manage toxicity profile makes oregovomab an ideal candidate for association strategies.
Topics: Animals; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents, Immunological; CA-125 Antigen; Drugs, Investigational; Female; Humans; Ovarian Neoplasms; Progression-Free Survival; Tumor Microenvironment
PubMed: 33423551
DOI: 10.1080/13543784.2021.1868436 -
Drugs in R&D 2006ViRexx Medical Corp is developing the murine monoclonal antibody oregovomab [OvaRex, MAb B43.13] for the treatment of ovarian cancer. Oregovomab targets the circulating... (Review)
Review
ViRexx Medical Corp is developing the murine monoclonal antibody oregovomab [OvaRex, MAb B43.13] for the treatment of ovarian cancer. Oregovomab targets the circulating tumour-associated antigen CA 125, which is shed from the surface of human ovarian cancer cells; the antibodies induce broad cellular and humoral immune responses against CA 125 via complex formation. Unlike free CA 125, CA 125-oregovomab complexes can prime dendritic cells, leading to downstream activation of T cells. The antibody is undergoing advanced clinical development. AltaRex, the originator of oregovomab, was acquired by, and merged into, ViRexx Medical Corp in December 2004. AltaRex (now ViRexx Medical Corp) has established several strategic corporate alliances for the development and/or commercialisation of oregovomab. Unither Pharmaceuticals, a subsidiary of United Therapeutics Corporation, entered into a licensing agreement with ViRexx in April 2002. The agreement covers most territories worldwide, except Europe and the Middle East, which are covered by other agreements (see below); ViRexx did retain the rights to most member nations of the EU and certain other countries. In August 2003, the agreement was extended, granting United Therapeutics Corporation development rights for Germany. AltaRex and Dompe entered into a distribution agreement for oregovomab in July 2004. Territories included in the agreement are Italy, Spain, Portugal, Hungary, Poland, Czech Republic, Switzerland, Austria and certain other Eastern European countries. Under the terms of the agreement, ViRexx retains responsibility for product development and registration of the antibody, upon commercialisation in the agreed territory. The two companies will work closely to achieve product registration throughout Europe. In June 2001, Dompe entered into a sublicensing agreement with FAES for the commercialisation of oregovomab in Spain and Portugal. ViRexx is also seeking collaboration partners for Northern European markets. Medison Pharma and AltaRex entered into an agreement in April 2002. Under the terms of the agreement, the two companies will establish a joint venture to market oregovomab in Israel and the Middle East. ViRexx also has an agreement with Genesis Pharma covering the commercialisation of the antibody in Greece, Turkey, Cyprus and the Balkans. Unither Pharmaceuticals has completed trial enrollment for its two pivotal phase III trials investigating oregovomab for the treatment of advanced ovarian cancer. In June 2006, Unither reached its enrollment goal of 177 patients for the IMPACT II study, the second of two identical double-blind, placebo-controlled trials. The IMPACT I study achieved its enrollment target in December 2005. Both IMPACT studies are designed to assess the effect of oregovomab on time to disease relapse in patients with advanced ovarian cancer (stage III/IV) who have achieved an optimal response with front-line chemotherapy, and are being conducted at over 60 sites across the US. Data from the studies are intended to support registration of the antibody in the US. ViRexx also plans to utilise results from the IMPACT studies to support regulatory filings in Europe and in other countries. In addition, a phase II trial is being conducted to evaluate two dosing regimens of adjunctive oregovomab plus platinum-based first-line chemotherapy in patients with advanced ovarian cancer. The enrollment target of 40 patients has been achieved; primary study analysis is anticipated to be completed by the end of 2006. Several phase II trials with oregovomab as monotherapy or in combination with other chemotherapeutics have been completed across the US and Canada. Clinical trials have also been conducted in the EU, but ViRexx has suspended such EU studies on the basis of commercial considerations. Oregovomab has orphan drug status for the treatment of ovarian cancer; designation was granted by the US and the EU in 1996 and 2002, respectively. In addition, the US FDA granted fast-track status to the antibody in 1998. AltaRex (now ViRexx Medical Corp) has been awarded the US patent covering the company's technology for administering a low dose of foreign antibody to patients expressing the CA 125 antigen. A second US patent has also been issued for oregovomab covering the technique of photoactivation using ultraviolet light to modify antibodies and enhance specific beneficial immune responses. Furthermore, AltaRex was granted a 'multi-epitopic' patent application covering oregovomab by the European Patent Office (EPO) in October 2003. The patent covers the company's technology of IV administration of a low-dose foreign antibody, such as oregovomab, to patients expressing the target tumour-associated antigen CA 125. The EPO's grant of the patent for the European Union enables intellectual property protection of oregovomab in the great majority of worldwide markets.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; CA-125 Antigen; Clinical Trials as Topic; Female; Humans; Infusions, Intravenous; Mice; Ovarian Neoplasms; Treatment Outcome
PubMed: 17073521
DOI: 10.2165/00126839-200607060-00007 -
Expert Opinion on Biological Therapy Jul 2004Recent advances in the molecular and cellular biology of malignancy and tumour immunology have stimulated significant progress in the application of immunotherapies as... (Review)
Review
Recent advances in the molecular and cellular biology of malignancy and tumour immunology have stimulated significant progress in the application of immunotherapies as adjuvant treatments in cancer. Oregovomab (OvaRex, AltaRex) is a murine monoclonal antibody with high affinity to the ovarian cancer associated antigen CA125. Infusion of low-dose antibody results in formation of circulating immune complexes which can trigger a cellular immune response targeting CA125 and the ovarian cancer. Oregovomab has activity following initial chemotherapy and in recurrent disease settings and is in Phase III trials to establish its efficacy to prolong time to relapse in patients with advanced ovarian cancer and favourable outcomes to their front-line treatment. Additional studies of antigen processing and combination chemo-immunotherapy are ongoing. The treatment shows promise as a potential new addition to the standard care of ovarian cancer.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antibodies, Neoplasm; Antibody Affinity; Antigen-Antibody Complex; Antigens, Neoplasm; Antineoplastic Agents; CA-125 Antigen; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Combined Modality Therapy; Drug Evaluation, Preclinical; Female; Humans; Immunity, Cellular; Immunoglobulin G; Immunotherapy; Mice; Mice, SCID; Ovarian Neoplasms; Recurrence; T-Lymphocyte Subsets; Treatment Outcome
PubMed: 15268682
DOI: 10.1517/14712598.4.7.1159 -
Annals of Surgical Oncology Mar 2023
Topics: Humans; Female; Carcinoma, Ovarian Epithelial; Cytoreduction Surgical Procedures; Ovarian Neoplasms; Antibodies, Monoclonal, Murine-Derived; Neoplasm Staging; Neoadjuvant Therapy
PubMed: 36400892
DOI: 10.1245/s10434-022-12838-w -
Journal of Clinical Oncology : Official... Jan 2009This phase III study tested the hypothesis that the CA-125-specific murine monoclonal antibody, oregovomab, administered as a monoimmunotherapy after front-line therapy... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
This phase III study tested the hypothesis that the CA-125-specific murine monoclonal antibody, oregovomab, administered as a monoimmunotherapy after front-line therapy in a selected ovarian cancer population would prolong time to relapse (TTR) and, ultimately, survival.
PATIENTS AND METHODS
Patients with stage III to IV ovarian cancer with preoperatively elevated CA-125 and objectively defined characteristics were randomly assigned 4 to 12 weeks after front-line carboplatin and paclitaxel chemotherapy to maintenance monoimmunotherapy in a fully blinded protocol. Two mg of oregovomab or placebo was infused over 20 minutes at weeks 0, 4, and 8 and then 12 weeks until recurrence or up to year 5. Patients were evaluated with serial imaging and clinical evaluation for evidence of recurrence at quarterly visits. TTR was the primary end point.
RESULTS
Three hundred seventy-three patients were accrued at more than 60 centers; 251 patients were assigned to oregovomab and 120 patients were assigned to placebo. The treatment arms were well balanced. There were no differences in the clinical outcomes between treatment groups. Median TTR measured from randomization after completion of chemotherapy for the integrated study was 10.3 months (95% CI, 9.7 to 13.0 months) for oregovomab and 12.9 months (95% CI, 10.1 to 17.4 months) for placebo (P = .29, log-rank test). The treatment was well tolerated. Grade 3 to 4 toxicity was reported in 24.6% of patients in the placebo group and 20.1% of patients in the oregovomab group, respectively.
CONCLUSION
Although oregovomab has demonstrated bioactivity, the strategy of monoimmunotherapy is not effective as maintenance therapy after front-line treatment of a favorable subset of patients with advanced ovarian cancer. Future studies of this or other tumor-antigen specific immunization strategies should seek ways to further augment induced immunity.
Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antibodies, Neoplasm; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; CA-125 Antigen; Carboplatin; Female; Humans; Immunotherapy; Middle Aged; Neoplasm Recurrence, Local; Ovarian Neoplasms; Paclitaxel; Treatment Outcome
PubMed: 19075271
DOI: 10.1200/JCO.2008.17.8400 -
Taiwanese Journal of Obstetrics &... Jan 2024In the Part I, we have discussed the background of CA125 and the development of anti-CA125 monoclonal antibody (MAb) to highlight the potential role of CA125 and... (Review)
Review
In the Part I, we have discussed the background of CA125 and the development of anti-CA125 monoclonal antibody (MAb) to highlight the potential role of CA125 and anti-CA125 MAb in the management of women with advanced stage epithelial ovarian cancer (EOC). Glycosylation change either by N-link or by O-link of CA125 is supposed to play a role in the modification of immunity. Anti-CA125 MAb, which can be classified as OC 125-like Abs, M11-like Abs, and OV197-like Abs, is often used for diagnosing, screening, monitoring and detecting the mesothelin-related diseases of the abdominal cavity, particular for those women with EOC. Additionally, anti-CA125 MAb also plays a therapeutic role, named as OvaRex MAb-B43.13 (oregovomab), which has also been extensively reviewed in the Part I review article. The main mechanisms include (a) forming CA125 immune complexes to activate the antigen-presenting cells; (b) triggering induction of CA125-specific immune responses, including anti-CA125 Abs against various epitopes and CA125-specific B and T cell responses; and (c) triggering CD4 and CD8 T-cell responses specific for B43.13 to produce specific and non-specific immune response. With success in vitro, in vivo and in primitive studies, phase II study was conducted to test the effectiveness of chemoimmunotherapy (CIT) for the management of EOC patients. In the 97 EOC patients after optimal debulking surgery (residual tumor <1 cm or no gross residual tumor), patients treated with CIT had a dramatical and statistically significant improvement of both progression-free survival (PFS) and overall survival (OS) compared to those treated with chemotherapy alone with a median PFS of 41.8 months versus 12.2 months (hazard ratio [HR] 0.46, 95 % confidence interval [CI] 0.28-0.7) and OS not yet been reached (NE) versus 42.3 months (HR 0.35, 95 % CI 0.16-0.74), respectively. The current review as Part II will explore the possibility of using CIT as front-line therapy in the management of advanced-stage EOC patients after maximal cytoreductive surgery based on the evidence by many phase 2 studies.
Topics: Humans; Female; Carcinoma, Ovarian Epithelial; Ovarian Neoplasms; Carboplatin; Neoplasm, Residual; Antibodies, Monoclonal, Murine-Derived; Paclitaxel; CA-125 Antigen; Clinical Trials, Phase II as Topic
PubMed: 38216242
DOI: 10.1016/j.tjog.2023.11.005 -
Cancer Immunology, Immunotherapy : CII Mar 2020The standard-of-care (SOC) first-line therapy for ovarian cancer (OC) patients is plagued with high relapse rates. Several studies indicated the immune system's... (Randomized Controlled Trial)
Randomized Controlled Trial
Translational immune correlates of indirect antibody immunization in a randomized phase II study using scheduled combination therapy with carboplatin/paclitaxel plus oregovomab in ovarian cancer patients.
The standard-of-care (SOC) first-line therapy for ovarian cancer (OC) patients is plagued with high relapse rates. Several studies indicated the immune system's prominent role changing the disease course in OC patients. Chemo-immunotherapy regimens, currently being explored, include oregovomab, which is a monoclonal antibody specific for the OC associated antigen carbohydrate/cancer antigen 125 (CA125) that yielded promising results when administered together with SOC in a previous study. The QPT-ORE-002 multi-site phase II randomized study demonstrated that in patients with advanced OC, oregovomab combined with first-line SOC improved overall and progression-free survival, compared to SOC alone. The study included an Italian cohort in which we demonstrated that adding oregovomab to SOC resulted in increased patient numbers with amplified CA125-specific CD8T lymphocytes/ml peripheral blood counts, which might explain the improved therapeutic effect of SOC + oregovomab over SOC alone. Predictive for oregovomab efficacy was a less suppressive immune environment at baseline as indicated by low numbers of circulating myeloid-derived suppressor cells, subset type 4, and a low neutrophil-and-monocyte to lymphocyte ratio.
Topics: Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Female; Humans; Immunotherapy; Middle Aged; Ovarian Neoplasms; Paclitaxel; Precision Medicine
PubMed: 31897661
DOI: 10.1007/s00262-019-02456-z -
Gynecologic Oncology Mar 2020This randomized phase II study tested the hypothesis that schedule dependent chemo-immunotherapy with oregovomab improves progression free survival (PFS) and overall... (Randomized Controlled Trial)
Randomized Controlled Trial
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.
Topics: Adult; Aged; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Ovarian Epithelial; Combined Modality Therapy; Female; Humans; Immunotherapy; Middle Aged; Neoplasm Grading; Neoplasm Staging; Ovarian Neoplasms; Paclitaxel; Treatment Outcome
PubMed: 31916979
DOI: 10.1016/j.ygyno.2019.12.024 -
Journal of Clinical Oncology : Official... Sep 2004To assess oregovomab as consolidation treatment of advanced ovarian cancer and refine the immunotherapeutic strategy for subsequent study. (Clinical Trial)
Clinical Trial Randomized Controlled Trial
PURPOSE
To assess oregovomab as consolidation treatment of advanced ovarian cancer and refine the immunotherapeutic strategy for subsequent study.
PATIENTS AND METHODS
Patients with stage III/IV ovarian cancer who had a complete clinical response to primary treatment were randomly assigned to oregovomab or placebo administered at weeks 0, 4, and 8, and every 12 weeks up to 2 years or until recurrence. The primary end-point was time to relapse (TTR).
RESULTS
One hundred forty-five patients were treated with oregovomab (n = 73) or placebo (n = 72). For the population overall, median TTR was not different between treatments at 13.3 months for oregovomab and 10.3 months for placebo (P =.71). Immune responses were induced in most actively treated patients. This was associated with prolonged TTR. Quality of life was not adversely impacted by treatment. Adverse events were reported with similar frequency in oregovomab and placebo groups, indicating a benign safety profile. A long-term survival follow-up is ongoing. Cox analysis of relapse data identified significant factors: performance status, CA-125 before third cycle, and baseline CA-125. Further evaluation identified a subpopulation with favorable prognostic indicators designated as the successful front-line therapy (SFLT) population. For the SFLT population, TTR was 24.0 months in the oregovomab group compared with 10.8 months for placebo (unadjusted hazard ratio of 0.543 [95% CI, 0.287 to 1.025]), a hypothesis-generating observation.
CONCLUSION
Consolidation therapy with oregovomab did not significantly improve TTR overall. A set of confirmatory phase III studies has been initiated to determine whether the SFLT population derives benefit from oregovomab treatment.
Topics: Adult; Aged; Antibodies; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; CA-125 Antigen; Disease-Free Survival; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Ovarian Neoplasms; Placebos
PubMed: 15337799
DOI: 10.1200/JCO.2004.09.016 -
American Journal of Clinical Oncology Oct 2019Cancer antigen (CA)-125 influences progression, metastasis, and outcomes in pancreatic cancer. This phase I/II trial (NCT01959672) evaluated the safety, efficacy, and...
Phase I/II Trial of Neoadjuvant Oregovomab-based Chemoimmunotherapy Followed by Stereotactic Body Radiotherapy and Nelfinavir For Locally Advanced Pancreatic Adenocarcinoma.
OBJECTIVE
Cancer antigen (CA)-125 influences progression, metastasis, and outcomes in pancreatic cancer. This phase I/II trial (NCT01959672) evaluated the safety, efficacy, and immunologic correlates of chemoimmunotherapy (CIT) with oregovomab (anti-CA-125), followed by stereotactic body radiotherapy (SBRT) with the radiosensitizer nelfinavir.
MATERIALS AND METHODS
Following imaging, pathologic confirmation, and staging laparoscopy, subjects received three 3-week cycles of CIT (gemcitabine/leucovorin/fluorouracil/oregovomab). Thereafter, nelfinavir was delivered (1250 mg bid) for 5 weeks, with SBRT (40 Gy/5 fractions) occurring during the third week of nelfinavir. Following another cycle of CIT, pancreaticoduodenectomy was performed if resectable. Three more cycles of CIT were then delivered (total 7 cycles). In subjects with high (≥10 U/mL) CA-125, oregovomab (2 mg) was administered for 7 total doses (3 pre-SBRT, 1 between SBRT and resection, and 3 postoperatively). The enzyme-linked immunospot assay evaluated the development of CA-125-specific CD8 T-lymphocytes.
RESULTS
The trial was prematurely closed because gemcitabine/leucovorin/fluorouracil was replaced by FOLFIRINOX and gemcitabine/nab-paclitaxel as the standard of care. Median follow-up was 13 months. Of 11 enrolled patients, 10 had high CA-125; 1 patient suffered an unexpected cardiac-related death, so 9 subjects received oregovomab. Ten received SBRT and 4 underwent resection. Overall, 6/11 patients experienced any grade ≥3 event. The median survival and time to progression were 13 and 8.6 months, respectively. Five patients had samples available for immunospot testing, of whom 2 (40%) developed CA-125-specific CD8 T-lymphocytes.
CONCLUSION
A combined pancreatic cancer multimodality approach using CIT and radiosensitized radiotherapy is feasible and safe; delivery of immunotherapy can lead to T-cell immunity. Re-evaluation with modern systemic paradigms is recommended.
Topics: Adenocarcinoma; Adult; Aged; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; CA-125 Antigen; Camptothecin; Combined Modality Therapy; Disease-Free Survival; Female; Fluorouracil; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Leucovorin; Magnetic Resonance Imaging; Male; Membrane Proteins; Middle Aged; Nelfinavir; Neoadjuvant Therapy; Neoplasm Invasiveness; Organoplatinum Compounds; Pancreatic Neoplasms; Pancreaticoduodenectomy; Proportional Hazards Models; Radiosurgery; Risk Assessment; Survival Analysis; Time Factors; Tomography, X-Ray Computed; Treatment Outcome
PubMed: 31513018
DOI: 10.1097/COC.0000000000000599