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

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

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.

Study Overview

• Status: Completed
• Conditions: Stage II Prostate Adenocarcinoma; Stage III Prostate Adenocarcinoma; Stage I Prostate Adenocarcinoma
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Radiation: Radiation Therapy; Drug: Antiandrogen Therapy; Drug: Multitargeted Tyrosine Kinase Inhibitor PLX3397

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Wayne State University/Karmanos Cancer Institute
    • Petoskey, Michigan, United States, 49770
      • Karmanos Cancer Institute at McLaren Northern Michigan - Petoskey Radiation Oncology
    • Petoskey, Michigan, United States, 49770
      • Karmanos Cancer Institute at McLaren Northern Michigan- Petoskey Medical Oncology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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.)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (PLX3397, radiation therapy, ADT); Patients receive multitargeted tyrosine kinase inhibitor PLX3397 PO 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.

Other: Laboratory Biomarker Analysis; Correlative studies; Radiation: Radiation Therapy; Undergo radiation therapy; Other Names: Cancer Radiotherapy; Irradiate; Irradiated; Irradiation; Radiotherapeutics; Radiotherapy; RT; Therapy, Radiation; RADIATION; Drug: Antiandrogen Therapy; Undergo ADT with leuprolide acetate, goserelin acetate, or degarelix; Other Names: ADT; Androgen Deprivation Therapy; Anti-androgen Therapy; Anti-androgen Treatment; Antiandrogen Treatment; Hormone Deprivation Therapy; Hormone-Deprivation Therapy; Drug: Multitargeted Tyrosine Kinase Inhibitor PLX3397; Given PO; Other Names: PLX3397

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
MTD of multitargeted tyrosine kinase inhibitor PLX3397, determined according to incidence of DLT		4 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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

Collaborators and Investigators

• Sponsor: Barbara Ann Karmanos Cancer Institute
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Elisabeth I. Heath, M.D., Barbara Ann Karmanos Cancer Institute

Study record dates

Study Major Dates

• Study Start: June 1, 2015
• Primary Completion (Actual): August 5, 2019
• Study Completion (Actual): August 5, 2019

Study Registration Dates

• First Submitted: June 11, 2015
• First Submitted That Met QC Criteria: June 11, 2015
• First Posted (Estimate): June 15, 2015

Study Record Updates

• Last Update Posted (Actual): October 6, 2020
• Last Update Submitted That Met QC Criteria: October 4, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms; Adenocarcinoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protective Agents; Estrogens; Micronutrients; Hormone Antagonists; Vitamins; Antioxidants; Anabolic Agents; Hormones; Ascorbic Acid; Androgens; Methyltestosterone; Estrogens, Conjugated (USP); Androgen Antagonists
• Other Study ID Numbers: 2014-075 (Other Identifier: Wayne State University/Karmanos Cancer Institute); P30CA022453 (U.S. NIH Grant/Contract); NCI-2015-00742 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); 1501013723