A Study of Dovitinib With Androgen Deprivation Therapy (ADT) in Patients With Metastatic Prostate Cancer Receiving Primary ADT

January 15, 2015 updated by: Oscar Goodman, Jr.

A Randomized Open-label Phase II Study of Oral Dovitinib in Combination With Androgen Deprivation Therapy to Delay the Onset of Castration-resistant Disease in Patients With Metastatic Prostate Cancer Undergoing Primary Androgen Deprivation Therapy

This study will evaluate if adding the investigational drug Dovitinib to standard androgen ablation therapy (ADT) is beneficial in prolonging the time to disease progression in patients with metastatic prostate cancer who are receiving ADT for the first time.

Dovitinib belongs to the class of drugs known as tyrosine kinase receptor inhibitors. Tyrosine kinase receptor inhibitors have been shown to have anti-tumor effects and inhibit new blood vessel formation. New blood vessel development is necessary for the growth and spread of certain tumors, such as prostate cancer. It is thought that by inhibiting new blood vessel formation, any existing or new tumors may be unable to grow. Dovitinib targets existing cancer cells and also works to stop the formation of new blood vessels.

Patients will be randomly assigned to received ADT alone or ADT plus Dovitinib. ADT will be administered per standard of care. Dovitinib will be taken by mouth once daily for 5 continuous days, followed by 2 days with no Dovitinib. This schedule will repeat and continue until disease progression or removal from treatment for other reasons. Participants may start ADT prior to entering the study; however, treatment with Dovitinib must begin no later than 120 days from the start of ADT.

Participants will be asked to donate blood samples for research purposes; this is an optional part of the study. Research on blood samples will study circulating tumor cells and certain biomarkers (proteins on cells) to increase the understanding of prostate cancer and explore if certain biomarkers can help predict how tumors will react to treatment. Samples of existing tumor tissue will also be examined for research purposes.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Detailed Description

In 2010, an estimated 217,730 new cases of prostate cancer occurred with 32,050 deaths in the United States of America. Prostate cancer exhibits a unique natural history that is a function of therapies rendered. Initially, the disease is treated with androgen deprivation therapy (ADT) with substantial regression of disease in the vast majority of patients. However, the response is short-lived, on the order of 18-24 months, with subsequent resumption of cancer growth manifesting as an increasing PSA, radiographic disease progression, and progressive symptoms related to the increasing disease burden, so called metastatic castration-resistant prostate cancer (CRPC). Almost all prostate cancer deaths occur in men with metastatic castration-resistant disease (CRPC).

An appropriate therapeutic strategy would be to utilize agents in combination with ADT that could serve to extend the sensitivity of the disease to primary ADT. The hormonal sensitive state, when the tumor burden is dramatically lowered due to therapeutic response, could represent the optimal context to introduce novel agents, leading to cytoreduction and/or maintenance of the hormone-sensitive state.

It has been demonstrated that the proangiogenic factor FGF-2 appears to play a central role in angiogenesis in hormone sensitive prostate cancer (HSPC). Thus targeting FGF-2 in conjunction with primary ADT may represent a novel therapeutic strategy in the initial treatment of metastatic HSPC.

Dovitinib is a broad-targeted-profiled RTK inhibitor active against VEGF, FGF and PDGF. Anti-tumor effects for this agent may, therefore, be secondary to anti-angiogenesis, anti-proliferative activity against tumor cells, and anti-stromal activity.

The study will enroll patients with metastatic prostate disease receiving initial ADT. Participants will be randomized to receive ADT alone, or in combination with Dovitinib. Participants will be stratified based on ECOG PS, Prior ADT > or < 30 days, and disease location (bone only vs. other).

ADT will be administered per standard of care on both treatment arms. Patients randomized to the combination arm will receive ADT plus Dovitinib at a dose of 500 mg/day given on a five-days-on-two-days-off schedule. One cycle equals 28 days. Dovitinib cycles will repeat continuously until disease progression, or removal from study for other reasons. Patients must begin Dovitinib within 120 days after the start of ADT. Thereafter, patients will be allowed to remain on the study until unacceptable side effect(s) occur, or until there is disease progression to castration-resistance status.

Quality of life will be assessed during the course of the study utilizing the Functional Assessment of Cancer Therapy-Prostate (self administered FACT-P).

Blood samples obtained at specified time points will be collected for research purposes from participants who provide consent to do so. Biomarkers pertinent to the hypothesized mechanism of action will be evaluated. Circulating tumor cells (CTC) will be enumerated at baseline (CellSearch™), and every 3 months thereafter. An additional citrate tube of blood will be collected for CTC-based ex-vivo culture analysis with each CTC draw. Samples of archival prostate biopsy specimens will also be analyzed for specific proteins related to Dovitinib's mechanism of action.

Study Type

Interventional

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Nevada
      • Las Vegas, Nevada, United States, 89148
        • Comprehensive Cancer Centers of Nevada

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

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:

  • Men with metastatic hormone-sensitive metastatic prostate cancer
  • ECOG (WHO) performance status 0-2
  • Age ≥ 18 years old
  • PSA > 4.0

  • Patients must have the following laboratory values:

    • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
    • Platelets ≥ 100 x 109/L
    • Hemoglobin (Hgb) > 9 g/dL
    • Serum total bilirubin: ≤ 1.5 x ULN
    • ALT and AST ≤ 3.0 x ULN (for patients with or without liver metastases)
    • Serum creatinine ≤ 1.5 x ULN or serum creatinine > 1.5 - 3 x ULN if calculated creatinine clearance (CrCl) is ≥ 30 mL/min using the Cockroft-Gault equation
    • Urine dipstick reading negative for proteinuria, or if 1+, then total urinary protein must be less than 500 mg and measured creatinine cleaners ≥ 50 mL/min/1.73m2 from a 24 hour urine collection
  • Histologically or cytologically confirmed prostate cancer.
  • Urine dipstick reading negative for proteinuria, or, if documentation of +1 results for protein on dipstick reading, then total urinary protein ≤ 500 mg and measured creatinine clearance ≥ 50 mL/min/1.73m2 from a 24 hour urine collection.
  • Patients may have begun hormonal therapy, but must have done so within 120 days of study treatment.
  • Patients must have metastatic disease (extensive or limited).
  • Scans (CT chest, abdomen, and pelvis) and bone scan must be obtained within 4 weeks of treatment.
  • Written informed consent obtained according to local guidelines

Exclusion Criteria:

  • Patients with brain metastases
  • Patients with another primary malignancy within 3 years prior to starting study drug, with the exception of adequately treated in-situ carcinoma of the uterine cervix, or skin cancer (such as basal cell carcinoma, squamous cell carcinoma, or non-melanomatous skin cancer)
  • Patients who have received prior cytotoxic chemotherapy within 3 years of starting study drug.
  • Patients who have received targeted therapy (e.g., sunitinib, sorafenib, pazopanib) ≤ 4 weeks prior to starting study drug, or who have not recovered from the side effects of such therapy.
  • Patients who have had radiotherapy ≤ 4 weeks prior to starting study drug, or ≤ 2 weeks prior to starting study drug in the case of localized radiotherapy (e.g., for analgesic purpose or for lytic lesions at risk of fracture), or who have not recovered from radiotherapy toxicities.
  • Patients who have undergone major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic), open biopsy or significant traumatic injury ≤ 4 weeks prior to starting study drug, or patients who have had minor procedures, percutaneous biopsies or placement of vascular access device ≤ 1 week prior to starting study drug, or who have not recovered from side effects of such procedure or injury.

  • Patients with any of the following concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study:

    • Impaired cardiac function or clinically significant cardiac diseases
    • Neurological compromise or dysfunction due to metastases
    • Ureteral or bladder outlet obstruction due to metastases or local invasion
    • Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of dovitinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
    • Cirrhosis, chronic active hepatitis or chronic persistent hepatitis
    • Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory)
    • Patients who are currently receiving anticoagulation treatment with therapeutic doses of warfarin
    • Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active or uncontrolled infection, uncontrolled diabetes) that could cause unacceptable safety risks or compromise compliance with the protocol
  • Rising PSA meeting criteria for progression to CRPC
  • Patients unwilling or unable to comply with the protocol

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: ADT alone
Standard androgen deprivation therapy (LHRH analogue or orchiectomy)
Drug: Standard ADT
Standard androgen deprivation therapy with either continually dosed LHRH agonist or antagonist, or achieved via bilateral orchiectomy.
Experimental: ADT plus Dovitinib

Standard androgen deprivation therapy (LHRH analogue or orchiectomy)

Dovitinib 500 mg/day given on a five-days-on-two-days-off schedule. One cycle equals 28 days. Cycles will repeat continuously until disease progression, or removal from study for other reasons.
Drug: Standard ADT
Standard androgen deprivation therapy with either continually dosed LHRH agonist or antagonist, or achieved via bilateral orchiectomy.
Drug: Dovitinib
Dovitinib 500 mg/day given on a five-days-on-two-days-off schedule. One cycle equals 28 days. Cycles will repeat continuously until disease progression, or removal from study for other reasons.
Other Names:
  • TKI258

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Time to onset of castration resistant prostate cancer (CRPC)
Time Frame: Every 12 weeks from the start of treatment until the date of first documented progression, up to 24 months.
CRPC defined as documented presence of two of the following criteria: PSA progression, radiographic progression, and/or symptomatic deterioration due to prostate cancer.
Every 12 weeks from the start of treatment until the date of first documented progression, up to 24 months.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Effect on predictive PSA benchmarks
Time Frame: PSA measured at baseline and every 12 weeks until the date of first documented progression, up to 24 months.
Comparison of PSA at baseline to PSA at 7 months following initiation of ADT, and time to PSA nadir.
PSA measured at baseline and every 12 weeks until the date of first documented progression, up to 24 months.
Overall survival
Time Frame: From date of randomization until date of death, or patient lost to follow up. Survival will be assessed at least every 4 weeks during treatment and every 6 months after disease progression up to 5 years.
Time from first study treatment to date of death. After removal from study patients will be contacted by phone every 6 months.
From date of randomization until date of death, or patient lost to follow up. Survival will be assessed at least every 4 weeks during treatment and every 6 months after disease progression up to 5 years.
Radiographic response rate and progression free survival in patients with measurable disease.
Time Frame: Radiographic evaluations occur at baseline and every 12 weeks while on study until date of first documented disease progression, up to 24 months.
Radiographic progression documented by CT, MRI, and/or Bone scan. For non-target osseous disease, progressive disease defined as appearance of two or more new lesions that are confirmed by confirmatory scan 6-12 weeks later.
Radiographic evaluations occur at baseline and every 12 weeks while on study until date of first documented disease progression, up to 24 months.
Adverse event frequency
Time Frame: Assessed every 2 weeks for first 8 weeks, then every 4 weeks while on study and at 30 days following last dose of dovitinib, up to 24 months.
Appearance of (or worsening of any pre-existing) undesirable sign(s), symptoms(s), or medical conditions(s); assessed according to CTCAE v4.0.
Assessed every 2 weeks for first 8 weeks, then every 4 weeks while on study and at 30 days following last dose of dovitinib, up to 24 months.
Changes in circulating tumor cell counts
Time Frame: Baseline and every 3 months while on study until date of first documented progression, up to 24 months.
CTC enumeration and comparison among sequential samples.
Baseline and every 3 months while on study until date of first documented progression, up to 24 months.
Quality of life
Time Frame: Assessed at baseline, once every cycle during treatment, and at end of treatment (when treatment stopped for disease progression or any other reason), up to 24 months.
Assessed using Functional Assessment of Cancer Therapy-Prostate (self administered FACT-P)
Assessed at baseline, once every cycle during treatment, and at end of treatment (when treatment stopped for disease progression or any other reason), up to 24 months.

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Exploratory: Pharmacodynamic effect on plasma biomarkers
Time Frame: Baseline and every 3 months while on study until date of first documented progression, up to 24 months.
Assessed by measuring concentrations of circulating growth factors and soluble receptors (e.g. bFGF, VEGF, PLGF, sVEGFR1 and 2, collagen IV, FGF23)
Baseline and every 3 months while on study until date of first documented progression, up to 24 months.
Exploratory: Archival tissue expression of biomarkers and mutations related to dovitinib mechanism of action and correlation with clinical outcome
Time Frame: Baseline one-time.
Expression of biomarkers (e.g. bFGF, VEGF, PLGF, sVEGFR1 and 2, collagen IV, FGF23) and somatic mutations and correlation with clinical outcome.
Baseline one-time.
Exploratory: Circulating Tumor Cell expression of biomarkers and mutations related to dovitinib mechanism of action and correlation with clinical outcome
Time Frame: Baseline and every 3 months while on study until date of first documented progression, up to 24 months.
Assessed by measuring CTC expression of NEP, FGF-2, VEGF-R and time to onset of CRPC.
Baseline and every 3 months while on study until date of first documented progression, up to 24 months.
Exploratory: Serum levels of biomarkers related to dovitinib mechanism of action and correlation with clinical outcome
Time Frame: Baseline and every 3 months while on study until date of first documented progression, up to 24 months.
Assessed by measuring serum concentrations of growth factors and soluble receptors (e.g. bFGF, VEGF, PLGF, sVEGFR1 and 2, collagen IV, FGF23)
Baseline and every 3 months while on study until date of first documented progression, up to 24 months.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Oscar Goodman, Jr.

Collaborators

Comprehensive Cancer Centers of Nevada

Investigators

  • Principal Investigator: Oscar B Goodman, Jr., MD, PhD, Comprehensive Cancer Centers of Nevada

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Primary Completion (Actual)

August 1, 2014

Study Registration Dates

First Submitted

February 3, 2014

First Submitted That Met QC Criteria

February 13, 2014

First Posted (Estimate)

February 19, 2014

Study Record Updates

Last Update Posted (Estimate)

January 19, 2015

Last Update Submitted That Met QC Criteria

January 15, 2015

Last Verified

January 1, 2015

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CCCN-PC1301
  • CTKI258AUS18T (Other Identifier: Novartis)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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