Clinical Trials - Trovagene

Focusing on Indications with the Greatest Need for New Cancer Treatment Options

Onvansertib, in combination with already approved therapies, may provide new treatment options for patients across a wide array of cancers

Latest Update on Clinical Trials: Phase 1b/2 Acute Myeloid Leukemia (AML) and Phase 2 metastatic Castration-Resistant Prostate Cancer (mCRPC)

Currently, we have three active clinical trials:

Phase 1b/2 open-label trial of onvansertib in combination with either low-dose cytarabine (LDAC) or decitabine for the treatment of Acute Myeloid Leukemia (AML) – (NCT03303339);

Phase 2 open-label trial of onvansertib in combination with Zytiga® (abiraterone acetate)/prednisone for the treatment of metastatic Castration-Resistant Prostate Cancer (mCRPC) – (NCT03414034);

Phase 1b/2 open-label trial of onvansertib in combination with FOLFIRI + Avastin® for second-line treatment of metastatic Colorectal Cancer (mCRC) with a KRAS mutation – (NCT03829410).

 

Phase 1b/2 Clinical Trial in Acute Myeloid Leukemia (AML)

Improving clinical response in patients with AML who have relapsed/refractory disease

Acute Myeloid Leukemia (AML) is a type of cancer in which the bone marrow makes abnormal myeloblasts (a type of white blood cell), red blood cells, or platelets. There are approximately 20,000 new cases and 10,400 deaths each year, with a five-year survival of 25%.

Phase 1b/2 Open-Label Trial of Onvansertib in Combination with Either Low-Dose Cytarabine or Decitabine in Patients with AML

Onvansertib is a first-in-class, 3rd generation, oral and highly-selective Polo-like Kinase 1 (PLK1) inhibitor with best-in-class attributes. We are conducting a Phase 1b/2 multi-center, open-label trial of onvansertib in combination with either low-dose cytarabine (LDAC) or decitabine in patients who have relapsed/refractory disease (NCT03303339).

In the Phase 1b dose-escalation segment of the trial, the primary objective is to determine the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D), using a traditional 3+3 design. In Phase 2 the MTD or RP2D will be administered to 32 patients to evaluate preliminary anti-tumor 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 at Yale School of Medicine, Hematology expert at Yale Cancer Center. The trial is being conducted at nine sites in the U.S.

Phase 2:

Efficacy Endpoint

Rate of complete response (CR + CRi) defined as morphologic leukemia-free state (MLF)

Safety Endpoint

Assess the safety and tolerability of the combination regimen

Exploratory Endpoint

Evaluate pharmacodynamic and correlative biomarkers

Phase 2 Clinical Trial in metastatic Castration-Resistant Prostate Cancer (mCRPC)

Extending the duration of response to Zytiga® in patients with mCRPC

Metastatic Castration-Resistant Prostate Cancer (mCRPC) affects approximately 25,000 men annually and has a five-year survival rate of 37%. Current treatment is with hormonal therapy, specifically androgen inhibitors, such as Zytiga® (abiraterone acetate). Most patients will develop resistance within 9-15 months of starting treatment and do not generally respond well to subsequent therapies. Thus, there is an ongoing need to increase the duration of response to treatment.

Preclinical studies have demonstrated synergy when onvansertib and Zytiga® are given together and PLK1 inhibition by onvansertib appears to improve Zytiga® efficacy by repressing the androgen signaling pathway.

Trovagene has entered into an exclusive patent license agreement with the Massachusetts Institute of Technology (MIT) to develop combination therapies that include anti-androgen or androgen antagonist and a Polo-like Kinase (PLK) Inhibitor for the treatment of cancer. The unique synergy between anti-androgen and PLK inhibitor combination therapies for inducing tumor cell death may represent a new treatment paradigm. The combination therapies can be used to improve the initial efficacy of one or the other of the active agents, or to re-sensitize cells that have become resistant to one of the active agents when administered alone.

Phase 2 Open-Label Trial of Onvansertib in Combination with Zytiga® and Prednisone in Patients with mCRPC

In our ongoing Phase 2 open-label trial (NCT03414034) of onvansertib in combination with Zytiga®, the primary efficacy endpoint is the proportion of patients who achieve disease control following 12-weeks of treatment, as defined by the lack of prostate specific antigen (PSA) progression.

This trial is being conducted at Beth Israel Deaconess Medical Center (BIDMC), Dana Farber Cancer Institute (DFCI) and Massachusetts General Hospital (MGH), under principal investigator, David Einstein, MD, Genitourinary Oncology Program at BIDMC.

Dosing and Schedule
Arm A
Dosing Regimen
Onvansertib 24 mg/m2
Days 1-5 (21-Day Cycle)
+ Abiraterone daily

Duration
4 Cycles = 12 Weeks

Efficacy Endpoint
Disease Control
PSA Stabilization or Decline

Arm B
Dosing Regimen
Onvansertib 24 mg/m2
Days 1-5 (14-Day Cycle)
+ Abiraterone daily

Duration
6 Cycles = 12 Weeks

Efficacy Endpoint
Disease Control
PSA Stabilization or Decline

Efficacy Endpoint

Effect of onvansertib in combination with Zytiga®/prednisone on disease control assessed by prostate-specific antigen (PSA) decline or stabilization pre- and post-treatment

Safety Endpoint

Safety of onvansertib in combination with Zytiga®/prednisone

Exploratory Endpoint

Target inhibition of PLK1, evaluation of relevant biomarkers that correlate with patient response

Phase 1b/2 Clinical Trial in metastatic Colorectal Cancer (mCRC)

Providing a new treatment option, in the second-line setting, for patients with KRAS-mutated mCRC

There are approximately 140,000 new cases of CRC each year with a 64.5% 5-year survival rate; approximately 51,000 deaths each year are from mCRC.

Tumor biomarkers drive therapy decisions for 1st line mCRC treatment; approximately 50% of mCRC is RAS mutant (KRAS) and targeted therapies exclude patients with RAS mutations. Thus, there is a large unmet need to provide new treatment options for these patients. Standard-of-care is chemotherapy (FOLFOX/FOLFIRI). Second-line therapies have only about a 5% response rate in metastatic colorectal cancer (mCRC).

Colorectal Cancer Image

Image: “Location and appearance of two examples of colorectal tumors” by Blausen Medical Communications, Inc. License: CC BY 3.0

Preclinical studies have demonstrated synergy when onvansertib and irinotecan are given together and the combination significantly reduces tumor growth compared to either drug administered alone. In three independent tumor models tested, onvansertib induced maximal tumor regression of ~84% compared to vehicle.

The KRAS mutation is a biomarker for onvansertib sensitivity. KRAS-mutated NIH3T3 cells showed higher sensitivity to onvansertib compared to KRAS wild-type (WT) cells.

Phase 1b/2 Open-Label Trial of Onvansertib in Combination with FOLFIRI + Avastin® for Second-Line Treatment of Patients with mCRC with a KRAS Mutation

In our Phase 1b/2 open-label trial (NCT03829410) of onvansertib in combination with FOLFIRI + Avastin® (bevacizumab), up to 44 patients will be treated. The primary objective of the Phase 1b component is to determine the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D), using a traditional 3+3 design. In Phase 2 the RP2D will be administered to evaluate preliminary anti-tumor activity and to continue to evaluate the safety and tolerability of the combination regimen.

This trial is being conducted at the Mayo Clinic and USC Norris Comprehensive Cancer Center.

crc p2 dose escalation graph image

Phase 2:

Access safety and preliminary antitumor activity

Efficacy Primary Endpoint

Objective response rate (ORR) in patients who receive at least 1 cycle (2 courses) of Onvansertib in combination with FOLFIRI and bevacizumab

Efficacy Secondary Endpoint

Preliminary efficacy defined as complete response (CR) plus partial response (PR) plus stable disease (SD)