17 August 2018 - - US-based oncology therapeutics company Trovagene, Inc. (NASDAQ: TROV) has completed the second dosing cohort of Onvansertib, a first-in-class, 3rd generation, highly-selective oral Polo-like Kinase 1 Inhibitor, in combination with standard-of-care low-dose cytarabine, in its Phase 1b/2 clinical trial in patients with Acute Myeloid Leukemia, the company said.

All three patients in the cohort successfully completed treatment with Onvansertib at 18 mg/m2, administered orally, once daily, on days 1-5 of the treatment cycle, in combination with LDAC and the combination was well tolerated. 

The Safety Review Committee has recommended escalating to the next dose level of Onvansertib at 27 mg/m2 (approximately a 50% increase) in combination with LDAC.

Additionally, two patients in the three-patient cohort of Onvansertib at 18 mg/m2 in combination with decitabine have also successfully completed at least one cycle of treatment and recruitment of the third patient to complete this cohort is in process.

Four of the eleven patients treated to-date remain on treatment, three are currently receiving a second cycle of treatment and one patient is scheduled to start a fifth cycle of treatment.

In the Phase 1b segment of this trial, the Onvansertib dose level will be increased by 50% increments in combination with either LDAC or decitabine in successive cohorts of three patients until a maximum tolerated dose or recommended Phase 2 dose is achieved. 

The MTD or RP2D will be used in the Phase 2 segment of the trial to evaluate antitumor activity and to continue to assess the safety and tolerability of Onvansertib in combination with standard-of-care chemotherapy.

The Phase 1b/2 trial (NCT03303339) is a multi-center, open-label trial to evaluate the safety and efficacy of Onvansertib in combination with standard-of-care chemotherapy in AML patients who are ineligible for intensive induction therapy or whose disease is relapsed or refractory.

In Phase 1b dose-escalation segment of the trial, the primary objective is to determine the maximum tolerated dose or recommended Phase 2 dose, using a traditional 3+3 design.

In Phase 2 the MTD or RP2D will be administered to 32 patients to evaluate preliminary antitumor activity and to continue to evaluate the safety and tolerability of Onvansertib in combination with standard-of-care chemotherapy.

This trial is being led by Jorge Cortes, M.D., Deputy Department chair, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center and Amer Zeidan, MBBS, MHS, Assistant Professor of Medicine, Department of Medicine, and Yale Cancer Center, Yale School of Medicine, Yale University. The trial is being conducted at nine sites in the US.

Onvansertib is a highly-selective adenosine triphosphate competitive inhibitor of the serine/threonine polo-like-kinase 1 (PLK 1) enzyme, which is over-expressed in multiple hematologic and solid tumor cancers.

Separate studies with other PLK inhibitors have shown that inhibition of polo-like-kinases can lead to tumor cell death, including a Phase 2 study in Acute Myeloid Leukemia where response rates of 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 Onvansertib has been completed in patients with advanced metastatic solid tumor cancers, and published in Investigational New Drugs.

The maximum tolerated dose or recommended Phase 2 dose in this trial was 24 mg/m2. Trovagene has an ongoing Phase 1b/2 clinical trial with Onvansertib in AML that was accepted by the National Library of Medicine.

The NCT number assigned by clinicaltrials.gov for this study is NCT03303339. Onvansertib has been granted Orphan Drug Designation by the FDA in the US and by the EMA in the European Union for the treatment of patients with AML.

Onvansertib 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.

Onvansertib has demonstrated synergy in preclinical studies with numerous chemotherapeutic and target agents used in leukemias, lymphomas and solid tumor cancers, including FLT3 and HDAC inhibitors, taxanes, and cytotoxins.

Trovagene believes the combination of its targeted PLK1 inhibitor, Onvansertib, with other compounds has the potential for improved clinical efficacy in Acute Myeloid Leukemia, metastatic Castration-Resistant Prostate Cancer (mCRPC), Non-Hodgkin Lymphoma, Triple Negative Breast Cancer, as well as other leukemias, lymphomas and solid tumor cancers.

Trovagene is a clinical-stage, oncology therapeutics company, using a precision medicine approach to develop drugs that target mitosis (cell division) to treat various types of cancer, including leukemias, lymphomas and solid tumors.

The company has intellectual property and proprietary technology that enables the company to analyze circulating tumor DNA (ctDNA) and clinically actionable markers to identify patients most likely to respond to specific cancer therapies.

Trovagene plans to continue to vertically integrate its tumor genomics technology with the development of targeted cancer therapeutics.