Clinical trial NCT01553188: AMG 386 and Abiraterone for Advanced Prostate Cancer
Official title: A Phase II Multicenter Study of AMG 386 and Abiraterone in Metastatic Castration Resistant Prostate Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Prostatic Neoplasms
Prostate Cancer
Neoplasm, Prostate
Neoplasm,Prostatic
Keywords: Anti-Angiogenesis
Ang 1
Ang 2
Peptide-Fc fusion protein
Small Molecule
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2012-03-14
Enrollment: 36
Sex: MALE
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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. Trebananib (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.

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 Immunoglobulin gamma-1 heavy chain constant region, partial (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 Cytochrome P450 17A1 (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 vascular endothelial growth factor (VEGF), fibroblast growth factor (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 castration-resistant prostate cancer (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 maximum tolerated dose (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 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 prostatic specific antigen (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 National Cancer Institute (NCI) or Walter Reed National Military Medical Center prior to entering this study. Patients enrolled at participating sites may have histopathological confirmation at the enrolling 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 computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam.
* Patients participating in the study must have Metastatic Castration-Resistant Prostate Cancer (mCRPC).
* Patients who have received docetaxel plus androgen deprivation therapy (ADT) for metastatic castrate sensitive prostate cancer are eligible for the study. (Patients may enroll as long as they did not have progressive disease while on docetaxel and are 6 months removed from treatment, with all treatment related toxicities resolving to at least grade 1.)
* Patients may not have had more than 7 days of treatment with ketoconazole by mouth in the past 6 months.
* Males greater than or equal 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.
* Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2 for run-in phase; ECOG less than or equal to 1 for randomized phase.
* Life expectancy of \> 3 months for the run in phase and \> 6 months for the randomized phase.
* Adequate bone marrow, hepatic, and renal function with:

  * Leukocytes greater than or equal to 3000/mu L
  * Absolute neutrophil count (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
  * Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase(SGOT)/alanine aminotransferase (ALT) serum glutamic pyruvic transaminase(SGPT) less than or equal to 2.5 times institutional upper limits of normal
  * Partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) less than or equal to 1.5 times upper limits of normal (ULN) per institutional laboratory range and international normalized ratio (INR) less than or 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

  ---Creatinine clearance (CrCl) (mL/min) = (((140-age) times actual body weight (kg))/(72 x serum creatinine (mg/dL)))\*(x 0.85 for females)
* Urinary protein less than or equal to 30 mg/dL in urinalysis or less than or equal 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 Common Terminology Criteria in Adverse Events (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 reason and 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 use adequate contraception prior to the study, for the duration of study participation, and 6 months after completion of AMG 386 administration.

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

EXCLUSION CRITERIA:

* Patients who have had chemotherapy for metastatic castration-resistant prostate cancer.
* 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.
* 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.
* Human immunodeficiency virus (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.
* Have had treatment with docetaxel for the treatment of metastatic castrate-sensitive prostate cancer within 6 months before the first dose of study enrollment.
* Have had progression of prostate cancer on prior docetaxel treatment for castrate sensitive disease.

Primary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: Median potential follow-up of 50.3 months
Secondary outcomes:
measure: Radiographic Progression Free Survival
timeFrame: Median potential follow-up of 50.3 months
measure: Overall Survival
timeFrame: Time between the first day of treatment to the day of death, approximately 50.3 months.
measure: Count of Participants With Serious and Non-serious Adverse Events
timeFrame: Date treatment consent signed to date off study, approximately 65 months and 7 days
Other outcomes:
measure: Maximum Tolerated Dose (MTD)
timeFrame: First 28 days of treatment
measure: Dose Limiting Toxicity (DLT)
timeFrame: First 28 days of treatment
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
Study officials:
affiliation: National Cancer Institute (NCI)
name: Ravi A Madan, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Goktas S, Crawford ED. Optimal hormonal therapy for advanced prostatic carcinoma. Semin Oncol. 1999 Apr;26(2):162-73.
citation: Gulley J, Dahut WL. Chemotherapy for prostate cancer: finally an advance! Am J Ther. 2004 Jul-Aug;11(4):288-94. doi: 10.1097/01.mjt.0000133582.68709.e3.
citation: Berthold DR, Sternberg CN, Tannock IF. Management of advanced prostate cancer after first-line chemotherapy. J Clin Oncol. 2005 Nov 10;23(32):8247-52. doi: 10.1200/JCO.2005.03.1435.