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AMG 386 and Abiraterone for Advanced Prostate Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT01553188
First received: March 10, 2012
Last updated: October 25, 2014
Last verified: October 2014
  Purpose

Background:

  • Advanced prostate cancer is treated with surgery or drugs that lower the levels of androgens (male hormones) in the body. However, some cancers become resistant to this treatment. These types of cancers are known as castration-resistant prostate cancers.
  • Interfering with the growth of blood vessels that feed tumors can slow prostate cancer growth. AMG 386, a new anticancer drug, targets the blood vessels that feed tumors. It has been tested for different types of cancer, but not for prostate cancer. Researchers want to see if AMG 386 can slow disease progression in men with castration-resistant prostate cancer. AMG 386 will be given with abiraterone and prednisone, two drugs that are also used to treat advanced prostate cancer.

Objectives:

- To test the safety and effectiveness of AMG 386 with abiraterone for castration-resistant prostate cancer.

Eligibility:

- Men at least 18 years of age with castration-resistant prostate cancer.

Design:

  • Participants will be screened with a physical exam, medical history, and imaging studies. Blood and urine samples will also be collected.
  • Participants will be separated into two groups.
  • The first group will have AMG 386 once per week for a total of four doses during a 28-day cycle. They will also take abiraterone once a day and prednisone twice a day, every day of the cycle.
  • The second group will not have AMG 386. They will take abiraterone once a day and prednisone twice a day, every day of the 28-day cycle.
  • Treatment will be monitored with frequent blood tests and imaging studies.
  • Participants will continue to take the study drugs as long as the disease does not progress and there are no severe side effects.

Condition Intervention Phase
Prostatic Neoplams
Prostate Cancer
Neoplasm, Prostate
Neoplasm,Prostatic
Drug: AMG 386
Drug: Abiraterone
Drug: Prednisone
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Multicenter Study of AMG 386 and Abiraterone in Metastatic Castration Resistant Prostate Cancer

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Progression Free Survival [ Time Frame: Disease Progression ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Radiographic Progression Free Survival [ Time Frame: Disease Progression ] [ Designated as safety issue: No ]
  • Overall Survival [ Time Frame: Patient's Death ] [ Designated as safety issue: No ]
  • Determine whether changes occur to AR signaling status of CTCs before and after treatment [ Time Frame: Treatment completion ] [ Designated as safety issue: No ]
  • Compare change in molecular markers prior to and after treatment [ Time Frame: Treatment completion ] [ Designated as safety issue: No ]
  • Correlate change in genetic markers with efficacy [ Time Frame: Treatment completion ] [ Designated as safety issue: No ]

Estimated Enrollment: 88
Study Start Date: February 2012
Estimated Study Completion Date: February 2015
Estimated Primary Completion Date: February 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: B
Abiraterone and prednisone will be given with MTD of AMG
Drug: AMG 386
AMG 386 dose will be calculated using the subject s actual body weight (Kg). Supplied in 240 mg v will be administered as an IV infusion using an intravenous infusion pump given over a 60-minute
Drug: Abiraterone
A 1,000 mg dose of abiraterone should be taken orally once daily
Drug: Prednisone
Prednisone should be taken orally either, at 5mg twice a day for each dose or 10 mg once a day a patient s preference.
Active Comparator: A
Abiraterone and prednisone only
Drug: Abiraterone
A 1,000 mg dose of abiraterone should be taken orally once daily
Drug: Prednisone
Prednisone should be taken orally either, at 5mg twice a day for each dose or 10 mg once a day a patient s preference.
Run in
Dose escalation phase to determine MTD of AMG
Drug: AMG 386
AMG 386 dose will be calculated using the subject s actual body weight (Kg). Supplied in 240 mg v will be administered as an IV infusion using an intravenous infusion pump given over a 60-minute
Drug: Abiraterone
A 1,000 mg dose of abiraterone should be taken orally once daily

Detailed Description:

Background:

  • Inhibition of angiogenesis, either as a stand-alone approach or in combination with chemotherapy, has demonstrable antitumor efficacy against castration-resistant prostate cancer (CRPC) and there are several antiangiogenic agents that are now in clinical trials in this population of patients.
  • AMG 386 is a novel peptide-Fc fusion protein. The molecule is a non-glycosylated homodimer engineered by fusing an IgG1 Fc domain to 4 copies of an anti-angiopoietin 2 (Ang2) peptide. AMG 386 sequesters Ang1 and Ang2, thereby preventing their interaction with Tie2 and inhibiting tumor endothelial cell (EC) proliferation and tumor growth.
  • Abiraterone acetate is a small molecule that irreversibly inhibits CYP17, a rate-limiting enzyme in androgen biosynthesis, to block residual androgen synthesis in the adrenal gland and tumor cells.
  • Previous studies have demonstrated that in vivo alterations of testosterone levels regulate the expression of VEGF, FGF, and angiopoietin family members. Dual targeting of the androgen and angiogenic axis represents a novel approach as a potential targeted therapy for patients with metastatic CRPC.

Objectives:

-To estimate the treatment effect as measured by progression free survival (PFS) in patients treated with AMG 386 plus abiraterone/prednisone relative to abiraterone/prednisone alone.

Eligibility:

-Patients with progressive, metastatic CRPC with radiographic evidence of progression after primary therapy (surgery or radiotherapy) and adequate androgen deprivation therapy.

Design:

  • This is an open-label, randomized, phase II multicenter trial with a two-part design and a planned accrual of 88 patients.
  • An initial run-in phase of AMG 386 will be conducted with 15mg/kg weekly escalating to 30mg/kg weekly to establish the MTD. The decision on declaration of a safe and tolerable dose during this run-in phase will lead to the second part of the study consisting of a randomized comparison of abiraterone/prednisone plus AMG 386 (at the established MTD) vs. abiraterone/prednisone alone.
  • AMG 386 will be administered intravenously every week, on days 1, 8, 15 and 22 of each 28-day cycle. Abiraterone acetate will be self-administered once daily by mouth and prednisone will be self-administered by mouth either twice per day at 5 mg per dose or once per day at 10 mg per dose as the patient prefers.
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:
  • Must have metastatic, progressive, castrate-resistant prostate cancer (CRPC) with radiographic evidence of disease that has continued to progress radiographically or biochemically (rising PSA levels on successive measurements) despite adequate androgen-deprivation therapy. If patients had been on flutamide, disease progression is documented 4 weeks or more after withdrawal. For patients on bicalutamide or nilutamide disease progression is documented 6 or more weeks after withdrawal. Flutamide, nilutamide and bicalutamide disease progression requirements only apply to patients who have been on these drugs for at least the prior 6 months.
  • Histopathological confirmation of prostate cancer by the Laboratory of Pathology of the NCI or Walter Reed National Military Medical Center prior to entering this study. Patients enrolled at Fox Chase Cancer Center may have histopathological confirmation at Fox Chase Cancer Center prior to entering the study. Patients whose pathology specimens are no longer available may be enrolled if the patient has a clinical course that is consistent with prostate cancer and available documentation from an outside pathology laboratory of the diagnosis. All efforts should be made to have the material forwarded to the research team for use in correlative studies in cases where original tissue blocks or archival biopsy material is available.
  • Patients must have metastatic disease, defined as at least one lesion on bone scan or at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as > 20 mm with conventional techniques or as > 10 mm with spiral CT scan, MRI, or calipers by clinical exam.
  • Patients participating in the study after the run-in phase must not have had prior chemotherapy for metastic disease; patients participating in the run-in phase may be either pre- or postchemotherapy.
  • Patients may not have had more than 7 days of treatment with ketoconazole by mouth in the past 6 months.
  • Males greater than or eqaul to 18 years of age. Because no dosing or adverse event data are currently available on the use AMG 386 in combination with abiraterone in patients < 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
  • ECOG performance status less than or equal to 2.
  • Life expectancy of > 3 months.
  • Adequate bone marrow, hepatic, and renal function with:

Leukocytes greater than or equal to 3000/mu L

ANC greater than or equal to 1500/mu L

Platelets greater than or equal to 100000/mu L

Total bilirubin less than or equal to 1.5 times institutional upper limits of normal

AST (SGOT)/ALT (SGPT) less than or equal to 2.5 times institutional upper limits of normal

PTT or aPTT less than or equal to 1.5 times ULN per institutional laboratory range and INR less thanor equal to 5

Creatinine less than or equal to 1.5 times institutional upper limits of normal

OR

Creatinine clearance of > 40 mL/min per 24 h urine collection or calculated according to the Cockcroft-Gault formula

CrCl (mL/min) = (140-age) times actual body weight (kg) (times 0.85 for females)

72 times serum creatinine (mg/dL)

Urinary protein less thanor equal to 30 mg/dL in urinalysis or less than or equall to1+ on dipstick, unless quantitative protein is < 1000 mg in a 24h urine sample

  • Generally well-controlled blood pressure with systolic blood pressure less than or equal to 140 mmHg AND diastolic blood pressure less than or equal to 90 mmHg prior to enrollment. The use of antihypertensive medications to control hypertension is permitted.
  • Must have recovered from any acute toxicity related to prior therapy, including surgery. Toxicity should be less than or equal to grade 1 CTCAE version 4 or has returned to baseline. Alopecia > grade 1 is permitted.
  • The effects of AMG 386 on the developing human fetus are unknown. For this reasonand because inhibitors of angiogenesis as well as other therapeutic agents used in this trial are known to be teratogenic, men must agree to use adequate contraception

(hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while her partner is participating in this study, she should inform her treating

physician immediately. Men treated or enrolled on this protocol must agree to useadequate contraception prior to the study, for the duration of study participation, and 6months after completion of AMG 386 administration.

-Must have the ability to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

  • History or presence of known central nervous system metastases.
  • History of venous or arterial thromboembolism within 12 months prior to enrollment/randomization.
  • History of clinically significant bleeding within 6 months of enrollment/randomization.
  • Currently or previously treated with AMG 386, or other molecules that primarily inhibit the angiopoietins or Tie2 receptor.
  • Clinically significant cardiovascular disease within 12 months prior to enrollment/randomization, including myocardial infarction, unstable angina, grade 2 or greater peripheral vascular disease, cerebrovascular accident, transient ischemic attack, congestive heart failure, or arrhythmias not controlled by outpatient medication or placement of percutaneous transluminal coronary angioplasty/stent.
  • Major surgery within 28 days prior to enrollment or still recovering from prior surgery.
  • Minor surgical procedures, placement of tunneled central venous access device within 3 days prior to randomization/enrollment.
  • Treatment within 30 days prior to enrollment with the following: cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil, methotrexate, azathioprine, rapamycin, and targeted immune modulators such as abatacept (CTLA-4-Ig), adalimumab,

alefacept, anakinra, belatacept (LEA29Y), efalizumab, etanercept, infliximab, or rituximab.

  • Patients who have had large field radiotherapy must wait 2 weeks prior to entering the study.
  • Non-healing wound, ulcer (including gastrointestinal), or fracture.
  • Contraindication to steroid use or history of allergic reactions attributable to the study compounds.
  • History of allergic reactions to bacterially-produced proteins.
  • Have had chemotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study.
  • Previously diagnosed with another malignancy, within the past two years with the exception of non-melanoma skin cancers or non-invasive bladder cancer.
  • Patients who have not yet completed at least 28 days (30 days for prior monoclonal antibody therapy) since receiving other investigational drugs.
  • Inability to absorb abiraterone after oral administration (i.e., previous major gastrointestinal surgery or gastrointestinal disease resulting in malabsorption).
  • Use of ketoconazole, itraconazole, ritonavir, cyclosporine, carbamazepine, phenytoin, phenobarbital within 2 weeks prior to and while on study therapy.
  • HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with the study agents. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive

therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.

-Uncontrolled intercurrent illness or infections, unstable angina pectoris, cardiac arrythmias, renal dysfunction, or psychiatric illness/social situations that would limit compliance with study requirements.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01553188

Contacts
Contact: Guinevere Chun, R.N. (301) 443-4147 gchun@mail.nih.gov
Contact: William L Dahut, M.D. (301) 496-4251 dahutw@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    (888) NCI-1937      
United States, Pennsylvania
Fox Chase Cancer Center Recruiting
Philadelphia, Pennsylvania, United States, 19111
Sponsors and Collaborators
Investigators
Principal Investigator: William L Dahut, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier: NCT01553188     History of Changes
Other Study ID Numbers: 120079, 12-C-0079
Study First Received: March 10, 2012
Last Updated: October 25, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Anti-Angiogenesis
Ang 1
Ang 2
Peptide-Fc fusion protein
Small Molecule

Additional relevant MeSH terms:
Neoplasms
Prostatic Neoplasms
Genital Diseases, Male
Genital Neoplasms, Male
Neoplasms by Site
Prostatic Diseases
Urogenital Neoplasms
Prednisone
Anti-Inflammatory Agents
Antineoplastic Agents
Antineoplastic Agents, Hormonal
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on November 20, 2014