Trovagene announced the filing of its protocol for a Phase 2 clinical trial of PCM-075 in combination with abiraterone acetate (Zytiga - Johnson & Johnson), for metastatic Castration-Resistant Prostate Cancer (mCRPC) has been submitted to the U.S. Food and Drug Administration (FDA) for review.
In this multi-center, open-label, Phase 2 trial, PCM-075 in combination with the standard dose of abiraterone and prednisone, all administered orally, will be evaluated for safety and efficacy. The primary efficacy endpoint is the proportion of patients achieving disease control after 12 weeks of study treatment, as defined by lack of Prostate Specific Antigen (PSA) progression in patients who are showing signs of early progressive disease (rise in PSA but minimally symptomatic or asymptomatic) while currently receiving androgen deprivation therapy (ADT) plus abiraterone and prednisone.
As submitted, the Phase 2 clinical trial will enroll 25 patients with metastatic Castration-Resistant Prostate Cancer showing signs of disease progression demonstrated by two rising PSA values separated by at least one week, while on abiraterone/prednisone therapy. The follow-up of patients will occur approximately every six weeks until disease progression in patients with stable disease or better at the end of treatment assessments.
The Phase 2 trial also includes the following secondary observation endpoints:
The effects of PCM-075 in combination with abiraterone and prednisone on time to PSA progression in subjects with mCRPC;
The effects of PCM-075 in combination with abiraterone and prednisone on time to radiographic progression, based on the Prostate Cancer Working Group 3 (PCWG3) guidelines; and
The effects of PCM-075 in combination with abiraterone and prednisone on radiographic response in subjects with mCRPC and measurable disease.
"We are encouraged by our preclinical data demonstrating that the combination of PCM-075 and Zytiga appears to enhance the PCM-075 mechanism of action of arresting cells during mitosis with subsequent tumor cell death," said Bill Welch, Chief Executive Officer of Trovagene. "Filing our Phase 2 clinical trial protocol with the FDA is an important milestone towards addressing the medical need to extend the benefit of response to Zytiga in patients with mCRPC. We are looking forward to a decision from FDA permitting our study to proceed and initiating our mCRPC clinical trial with leading investigators in prostate cancer in 2018."
PCM-075 is a highly-selective adenosine triphosphate (ATP) competitive inhibitor of the serine/threonine polo-like-kinase 1 (PLK 1) enzyme, which is over-expressed in multiple hematologic and solid tumor cancers. Studies have shown that inhibition of polo-like-kinases can lead to tumor cell death, including a Phase 2 study in Acute Myeloid Leukemia (AML) where response rates up to 31% were observed when used in conjunction with a standard therapy for AML (low-dose cytarabine-LDAC) versus treatment with LDAC alone with a 13.3% response rate. A Phase 1 open-label, dose escalation safety study of PCM-075 has been completed in patients with advanced metastatic solid tumor cancers, and published in Investigational New Drugs.
PCM-075 has been granted Orphan Drug Designation by the FDA for the treatment of patients with AML.
PCM-075 only targets PLK1 isoform (not PLK2 or PLK3), is oral, has a 24-hour drug half-life with reversible on-target hematologic toxicities. Trovagene believes that targeting only PLK1 with reversible on-target activity and an improved dose/scheduling protocol can significantly improve on the long-term outcome observed in previous studies with a PLK inhibitor in AML.
PCM-075 has demonstrated synergy in preclinical studies with over 10 chemotherapeutic and target agents used in hematologic and solid tumor cancers, including FLT3 and HDAC inhibitors, taxanes, and cytotoxins. Trovagene believes the combination of its targeted PLK-1 inhibitor, PCM-075, with other compounds has the potential for improved clinical efficacy in Acute Myeloid Leukemia (AML), Castration-Resistant Prostate Cancer (CRPC), Non-Hodgkin Lymphoma (NHL), Triple Negative Breast Cancer (TNBC) and Adrenocortical Carcinoma (ACC).
Castration-Resistant Prostate Cancer (CRPC) is defined by disease progression despite androgen-deprivation therapy (ADT) and may present as one or any combination of a continuous rise in serum levels of prostate-specific antigen (PSA), progression of pre-existing disease, or appearance of new metastases. Prognosis is associated with several factors, including performance status, presence of bone pain, extent of disease on bone scan, and serum levels of alkaline phosphatase. Bone metastases occur in 90% of men with CPRC and can produce significant morbidity, including pain, pathologic fractures, spinal cord compression, and bone marrow failure. Paraneoplastic effects are also common, including anemia, weight loss, fatigue, hypercoagulability, and increased susceptibility to infection. Institution of treatment and the choice of systemic or local therapy depend on a number of factors.