PLX3397, Radiation Therapy, and Antihormone Therapy in Treating Patients With Intermediate- or High-Risk Prostate Cancer

Stage II Prostate Adenocarcinoma Clinical Trial

Official title:

Targeting the Prostatic Tumor Microenvironment With PLX3397, a Tumor-Associated Macrophage Inhibitor in Men With Unfavorable Risk Prostate Cancer Undergoing Radiation Therapy and Androgen Deprivation Therapy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02472275
• Other study ID #: 2014-075
• Secondary ID: NCI-2015-0074215
• Status: Completed
• Phase: Phase 1
• Start date: June 2015
• Est. completion date: August 5, 2019

Study information

• Verified date: October 2020
• Source: Barbara Ann Karmanos Cancer Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase I trial studies the side effects and best dose of multitargeted tyrosine kinase inhibitor PLX3397 (PLX3397) when given together with radiation therapy and antihormone therapy in treating patients with prostate cancer that is at intermediate or high risk of spreading. Multitargeted tyrosine kinase inhibitor PLX3397 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth, and may also help the radiation therapy work better. Radiation therapy uses high-energy x-rays to kill tumor cells. Androgens can cause the growth of prostate cancer cells. Antihormone therapy, such as leuprolide acetate, goserelin acetate, or degarelix, may lessen the amount of androgens made by the body. Giving multitargeted tyrosine kinase inhibitor PLX3397 with radiation therapy and antihormone therapy may be a better treatment for prostate cancer.

Description:

PRIMARY OBJECTIVES:

I. To conduct a phase I, dose escalation trial with a primary objective of establishing the maximum tolerated dose (MTD) and the dose limiting toxicity (DLT).

SECONDARY OBJECTIVES:

I. To assess the effects of radiation therapy (RT), androgen deprivation therapy (ADT), and PLX3397 (at its MTD) on tumor-associated macrophages (TAMs) in the prostate biopsy after treatment.

OUTLINE: This is a dose-escalation study of multitargeted tyrosine kinase inhibitor PLX3397.

Patients receive multitargeted tyrosine kinase inhibitor PLX3397 orally (PO) twice daily (BID) for 6 months, undergo radiation therapy for 2 months daily (Monday-Friday) beginning at month 3, and undergo ADT with leuprolide acetate, goserelin acetate, or degarelix injections in any month.

After completion of study treatment, patients are followed up at 20-30 days and then every 12 weeks thereafter.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 8
• Est. completion date: August 5, 2019
• Est. primary completion date: August 5, 2019
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Pathologically confirmed diagnosis of prostate adenocarcinoma

• Must have confirmed viable archival prostate biopsy tissue available as per Section 8.1 (this will be collected for patients going on study after the MTD has been reached

• Intermediate or high risk prostate cancer patients who are candidates for radiation therapy:

• Gleason >7 or

• Clinical or pathological > T2b disease or

• PSA > 10 ng/mL

• No evidence of metastatic disease by clinical and radiological staging

• Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1

• No standard contraindications to radiation therapy including prior significant radiation therapy, inflammatory bowel disease, irritable bowel syndrome or collagen vascular disease

• Prior history of up to 8 weeks of androgen deprivation therapy defined as lutenizing-hormone releasing hormone (LHRH) or other medical castration therapy prior to registration is acceptable. This will be in addition to the 6 months of ADT on study.

• Life expectancy of at least 3 months

• Adequate hematologic, hepatic, and renal function as defined by:

• Absolute neutrophil count = 1.5 × 109/L

• Hemoglobin > 10 g/dL

• Platelet count = 100 × 109/L

• AST and ALT = upper limit of normal (ULN)

• TBil and DBil = ULN with an exception of patients with confirmed Gilbert's syndrome. For patients with confirmed Gilbert's syndrome, the TBil should be = 1.5 × ULN

• Serum creatinine = 1.5 × ULN

• Must have ability to take oral medication

• Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures

• Ability to understand and willingness to sign a written informed consent document

• Willingness to be treated with radiation therapy and androgen deprivation Therapy

Exclusion Criteria:

• Investigational drug use within 28 days of the first dose of PLX3397 or concurrently

• At Screening QTcF =450 msec

• Patients with serious illnesses, uncontrolled infection, medical conditions, or other medical history including abnormal laboratory results, which in the investigator's opinion would be likely to interfere with a patient's participation in the study, or with the interpretation of the results

• Refractory nausea and vomiting, malabsorption, biliary shunt, or significant bowel resection that would preclude adequate absorption of study drug

• Known active or chronic human immunodeficiency virus (HIV) or hepatitis C virus (HCV) infection, or positive hepatitis B (Hep B) surface antigen. Prior hepatitis infection that has been treated with highly effective therapy with no evidence of residual infection and with normal liver function (ALT, AST, total and direct bilirubin = ULN) is allowed.

• Hepatobiliary diseases including biliary tract diseases, autoimmune hepatitis, inflammation, fibrosis, cirrhosis of liver caused by viral, alcohol, or genetic reasons. Gilbert's disease is allowed if TBil is = 1.5 × ULN.

• Active cancer (either concurrent or within the last 3 years) that requires nonsurgical therapy (e.g. chemotherapy or radiation therapy), with the exception of surgically treated basal or squamous cell carcinoma of the skin, or melanoma insitu.

• AST/ALT > 2.5X ULN or >5X ULN in the presence of liver metastases.

• Current treatment with anti-androgen is allowed for a maximum of one month to prevent flare response with ADT

• Concomitant use of acid reducing agents (e.g., proton pump inhibitors, H2 receptor antagonists, antacids)

• Concomitant use of strong and moderate CYP3A4 inhibitors and inducers

• Patients currently receiving anticancer therapies or who have received anticancer therapies within 4 weeks of the start of the study drug (including chemotherapy, radiation therapy, antibody based therapy, etc.)

Related Conditions & MeSH terms

• Adenocarcinoma
• Prostatic Neoplasms
• Stage I Prostate Adenocarcinoma
• Stage II Prostate Adenocarcinoma
• Stage III Prostate Adenocarcinoma

Intervention

Drug:
• Antiandrogen Therapy
Undergo ADT with leuprolide acetate, goserelin acetate, or degarelix

Other:
• Laboratory Biomarker Analysis
Correlative studies

Drug:
• Multitargeted Tyrosine Kinase Inhibitor PLX3397
Given PO

Radiation:
• Radiation Therapy
Undergo radiation therapy

Locations

Country	Name	City	State
United States	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan
United States	Karmanos Cancer Institute at McLaren Northern Michigan - Petoskey Radiation Oncology	Petoskey	Michigan
United States	Karmanos Cancer Institute at McLaren Northern Michigan- Petoskey Medical Oncology	Petoskey	Michigan

Sponsors (2)

Lead Sponsor	Collaborator
Barbara Ann Karmanos Cancer Institute	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Grade of specific types of toxicity	Frequency distributions will be generated by dose level, and overall.	Up to 30 days after end of study treatment
Primary	MTD of multitargeted tyrosine kinase inhibitor PLX3397, determined according to incidence of DLT		4 months
Secondary	Change in metabolic syndrome parameters	Descriptive statistics will be used to summarize the 7 metabolic syndrome parameters), and changes in them. These statistics will be calculated only for patients treated at the MTD, where the correlatives are measured, and will be generated for all 12 MTD patients combined, and separately by MTD randomization arm.	Baseline to month 7
Secondary	Change in PSA levels	PSA levels (and their change) will be tabulated for individual patients, regardless of dose level. Descriptive statistics will be used to summarize PSA, and changes in it. Serial PSA levels will be displayed using spaghetti plots, and changes in PSA using waterfall plots.	Baseline to up to month 7
Secondary	Change TAM levels as measured by immunohistochemistry	Frequency distributions will be generated for patients treated at the MTD. Descriptive statistics will be used to summarize all markers, and changes in them.	Baseline to month 2