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Treatment of Castration Resistant Prostate Cancer Using Multi-Targeted Recombinant Ad5 PSA/MUC1/Brachyury Based Immunotherapy Vaccines

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03481816
Recruitment Status : Active, not recruiting
First Posted : March 29, 2018
Last Update Posted : January 29, 2020
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Tracking Information
First Submitted Date  ICMJE March 28, 2018
First Posted Date  ICMJE March 29, 2018
Last Update Posted Date January 29, 2020
Actual Study Start Date  ICMJE July 24, 2018
Estimated Primary Completion Date May 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 28, 2018)
overall safety and recommended phase 2 dose [ Time Frame: 1 year ]
Percentage of subjects that achieve an objective confirmed complete or partial overall tumor response using RECIST Version 1.1 will be evaluated by dose cohort and overall.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 28, 2018)
  • objective response rate (ORR) [ Time Frame: end of treatment ]
    percentage of subjects who experience partial or complete response at any time point during treatment period.
  • Disease control rate (DCR) [ Time Frame: 6 months post treatment ]
    percentage of subjects who experience partial response, complete response, or stable disease lasting for at least 6 months
  • Duration of Response [ Time Frame: time of progression ]
    the time from when measurement criteria for PR or CR are met until disease recurrence or progression per dose cohort and overall
  • Progression-free survival (PFS) [ Time Frame: time of progression or death ]
    the time from the date of first treatment to the date of disease progression or death (any cause) whichever occurs first per dose cohort
  • Overall Survival [ Time Frame: time of death ]
    the time from the date of first treatment to the date of death (any cause) per dose cohort and overall
  • PSA doubling time (PSADT) [ Time Frame: week 14 and end of study treatment ]
    week 14 and at the end of study treatment in subjects with advanced cancer treated with the ETBX-071, ETBX-061, and ETBX-051 vaccines
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Treatment of Castration Resistant Prostate Cancer Using Multi-Targeted Recombinant Ad5 PSA/MUC1/Brachyury Based Immunotherapy Vaccines
Official Title  ICMJE Treatment of Patients With Castration Resistant Prostate Cancer Using a Multi-Targeted Recombinant Ad5 PSA/MUC1/Brachyury Based Immunotherapy Vaccine
Brief Summary

Background:

Metastatic castration resistant prostate cancer (mCRPC) keeps growing even when the amount of testosterone in the body is reduced to very low levels. mCRPC is incurable. Researchers want to develop vaccines to teach the immune system to target and kill cancer cells. They want to test three of these vaccines (ETBX-071, ETBX-061, and ETBX-051) against mCRPC.

Objective:

To test the safety of combination ETBX-071, ETBX-061, and ETBX-051 and to study their effects on the immune system.

Eligibility:

People ages 18 and older with mCRPC that has not responded to standard therapies

Design:

Participants will be screened with:

Medical history

Physical exam

Blood, urine, and heart tests

CT or MRI scans

Bone scan

Participants will get the vaccines as shots under the skin every 3 weeks for 3 doses. They may then have the shots every 8 weeks for up to 1 year.

Participants will keep a diary to record any symptoms from the vaccines.

Participants will have blood tests each time they get the vaccines. They will also have scans and other tests to measure the effect the vaccines have on their tumors.

Participants will have a visit within 28 days after their last treatment. This includes a physical exam and blood and urine tests.

Participants will then be contacted by phone every 3 months for the first year, every 6 months for the next 2 years, and every 12 months for another 2 years.

Participants will be asked to join a long-term follow up study.

Detailed Description

Background:

  • The overall goal of the current project is to expand our immunotherapeutic approach for the treatment of prostate cancer employing a multi-targeted approach.
  • Therapeutic cancer vaccines targeting overexpressed proteins offer a potential method to activate T cells against tumors.
  • A novel adenovirus based vaccines targeting three (3) human tumor associated antigens (TAA), PSA, MUC1, and brachyury, respectively have demonstrated anti-tumor cytolytic T cell responses in pre-clinical animal models of cancer.

Objectives:

-To determine the overall safety and recommended phase 2 dose of a combination of three immunotherapeutic vaccines (ETBX-071, ETBX-061, and ETBX-051) when administered subcutaneously (SC) to subjects with metastatic castration resistant prostate cancer

Eligibility:

  • Subjects age 18 and older with cytologically or histologically confirmed prostate cancer for which no curative standard approved therapy is available.
  • Metastatic Castration Resistant Prostate Cancer (mCRPC) patients with rising PSA or progressive disease despite castration levels of testosterone.
  • Prior treatment with immunotherapy hormonal therapy, radiotherapy, chemotherapy, and/or other experimental therapy is allowed.
  • ECOG performance status less than or equal to 1
  • Adequate organ and bone marrow function
  • Subjects with a history of autoimmune disease (active or past) and subjects requiring systemic steroids are not eligible (physiologic doses of steroids for steroid replacement as well as nasal, topical and inhaled steroids are allowed). Autoimmune-related thyroid disease, type I diabetes and vitiligo are permitted if the condition is well controlled.

Design:

  • This is a Phase I trial in subjects with mCRPC. A combination of three therapeutic vaccines (ETBX-071, ETBX-061, and ETBX-051) which use the same modified Adenovirus vector backbone, separately encoding three well studied TAA,PSA, MUC1, and brachyury, respectively) will be assessed. The vaccines will be tested at standard dose levels, with a dose de-escalation (if required) design employed. The dose level of each vaccine tested will be 5x10 to the eleventh power VP. This dose has been found in a prior phase 1 testing of a similar vaccine Ad5 [E1-, E2b-]-CEA(6D) (ETBX-011) to be well tolerated (with no DLT s or related SAE s), and be optimal for induction of immune responses.
  • Up to six patients will be enrolled at dose level 1. If less than or equal to 1 of 6 patients experience a DLT, an initiation of the dose expansion phase will occur. If more than or equal to 2 of 6 experience DLT at dose level 1, then dose de-escalation will occur. Up to six patients will be enrolled at the lower dose level (-1) (1x10 to the eleventh power VP). If less than or equal to 1 of 6 patients experience a DLT, then the maximum tolerated (MTD) will be declared at this dose, and initiation of the dose expansion phase will occur. If more than or equal to 2 of 6 experience DLT at dose level -1, then a further dose de-escalation will occur. Up to six patients will be enrolled at the lower dose level (-2) (5x10 to the tenth power VP). If less than or equal to 1 of 6 patients experience a DLT, then the maximum tolerated (MTD) will be declared at this dose, and initiation of the dose expansion phase will occur. If more than or equal to 2 of 6 experience DLT at dose level -2, then the study will be stopped.
  • A dose expansion phase of study will be enrolled after the MTD of the vaccines have been determined. An additional 12 subjects will be enrolled in the dose expansion component of the trial, for a total of 18 subjects at the MTD.
  • The ETBX-051, ETBX-61 and ETBX-71 vaccines will be administered subcutaneously (SC) at separate injection sites (proximal limb, preferably the thigh), will be administered SC every 3 weeks for 3 doses (dose de-escalation cohorts) followed by boosts every 8 weeks for 1 year (only patients enrolled in dose expansion cohort).
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Prostatic Neoplasms
  • Prostatic Cancer
Intervention  ICMJE
  • Biological: ETBX-071; adenoviral PSA vaccine
    5 x 10 to the eleventh power VP (standard dose), 1 x 10 to the eleventh power VP (DL-1), or 5 x 10 to the tenth power VP (DL-2) subcutaneous injection every 3 weeks for 3 immunizations.
  • Biological: ETBX-061; adenoviral MUC1 vaccine
    5 x 10 to the eleventh power VP (standard dose), 1 x 10 to the eleventh power VP (DL-1), or 5 x 10 to the tenth power VP (DL-2) subcutaneous injection every 3 weeks for 3 immunizations.
  • Biological: ETBX-051; adenoviral brachyury vaccine
    5 x 10 to the eleventh power VP (standard dose), 1 x 10 to the eleventh power VP (DL-1), or 5 x 10 to the tenth power VP (DL-2) subcutaneous injection every 3 weeks for 3 immunizations.
Study Arms  ICMJE
  • Experimental: 1/Dose De-Escalation
    Subjects enrolled to dose de-escalation cohorts
    Interventions:
    • Biological: ETBX-071; adenoviral PSA vaccine
    • Biological: ETBX-061; adenoviral MUC1 vaccine
    • Biological: ETBX-051; adenoviral brachyury vaccine
  • Experimental: 2/Dose expansion
    Subjects enrolled at the MTD after the MTD is established
    Interventions:
    • Biological: ETBX-071; adenoviral PSA vaccine
    • Biological: ETBX-061; adenoviral MUC1 vaccine
    • Biological: ETBX-051; adenoviral brachyury vaccine
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: October 3, 2019)
5
Original Estimated Enrollment  ICMJE
 (submitted: March 28, 2018)
30
Estimated Study Completion Date  ICMJE June 1, 2021
Estimated Primary Completion Date May 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • INCLUSION CRITERIA:
  • Age more than or equal to 18 years (male).
  • Ability to understand and provide signed informed consent that fulfills Institutional Review Board (IRB) s guidelines.
  • Cytologically or histologically confirmed prostate cancer for which no curative standard approved therapy is available by either the Laboratory of Pathology at the NIH Clinical Center or Walter Reed National Military Medical Center at Bethesda prior to starting this study. If no pathologic specimen is available, patients may enroll with a pathologist s report showing a histological diagnosis of prostate cancer and a clinical course consistent with the disease.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
  • Subjects who have received prior PSA, MUC1, and/or brachyury-targeted immunotherapy (e.g. vaccine) are eligible for this trial if this treatment was discontinued at least 3 months prior to enrollment.
  • Resolution of all toxic side effects of prior chemotherapy, radiotherapy, or surgical procedures to NCI CTCAE Grade less than or equal to1.
  • Adequate hematologic function at screening, as follows:
  • Absolute neutrophil conunt (ANC) greater than or equal to x 10 to the ninth power/L
  • Hemoglobin more than or equa to 9 g/dL
  • Platelets more than or equal to 75,000/microliter.
  • Prothrombin (PT)-international normalized ratio (INR) < 1.5.
  • Partial thromboplastin time (PTT) < 1.5 x upper limit of normal (ULN).
  • Adequate renal and hepatic function at screening, as follows:

    --Serum creatine less than or equal to 1.5x upper limit of normal (ULN) OR creatinine clearance (CrCl) more than or equal to 40mL/min (if using the Cockcroft-Gault formula below):

    1. Female CrCl = [(140 - age in years) x weight in kg x 0.85] / [72 x serum creatinine in mg/dL]
    2. Male CrCl = [(140 - age in years) x weight in kg x1.00] / [72 x serum creatinine in mg/dL]
  • Total bilirubin less than or equal to 1.5 x ULN OR in subjects with Gilbert s syndrome, a total bilirubin less than or equal to x ULN
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to 2.5 x ULN, unless liver metastes are present, then values must be less than or equal to 5 x ULN)
  • The effects of ETBX-051, ETBX-061 and ETBX-071 vaccines on the developing human fetus are unknown. For this reason subjects must agree to use a condom and acceptable contraceptive method with their partner during the study and for one month after the last dose of vaccines.
  • Ability to attend required study visits and return for adequate follow up, as required by this protocol.
  • Castrate testosterone level (<50ng/dl or 1.7nmol /L)
  • Metastatic disease documented by at least one of the following:
  • Metastatic bone disease on an imaging study, or
  • Soft tissue disease documented by CT/MRI
  • Progressive disease at study entry defined as one or more of the following criteria occurring in the setting of castrate levels of testosterone:
  • Radiographic progression defined as any new or enlarging bone lesions or growing lymph node disease, consistent with prostate cancer

OR

  • PSA progression defined by sequence of rising values separated by >1 week (2 separate increasing values over a minimum of 2ng/ml (PCWG2 PSA eligibility criteria). If patients had been on flutamide, PSA 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. The requirement for a 4-6 week withdrawal period following discontinuation of flutamide, nilutamide or bicalutamide only applies to patients who have been on these drugs for at least the prior 6 months. For all other patients, they must stop bicalutamide, nilutamide or flutamide the day prior to enrollment.
  • Patients must agree to continue to continuation of androgen deprivation therapy (ADT) with a gonadotropin-releasing hormone analogue/antagonist or bilateral orchiectomy
  • Prior treatment with immunotherapy, hormonal therapy, radium 223, chemotherapy and/or other experimental therapy is allowed.

EXCLUSION CRITERIA:

  • Treatment with an investigational drug study within 28 days of before starting on study treatment.
  • Subjects with concurrent cytotoxic chemotherapy or radiation therapy. There must be at least 28 days between any other prior chemotherapy (or radiotherapy) and study treatment. Prior antibody therapy must be discontinued 8 weeks prior to start of study treatment. Prior hormonal therapy can be discontinued 24 hours prior to start of study treatment.
  • Any prior PSA, MUC1, and/or brachyury-targeted immunotherapy (e.g., vaccine) must have been discontinued at least 12 weeks before initiation of study treatment. Subjects must have recovered from all acute toxicities from prior treatment prior to screening for this study.
  • Prior treatment with Adenovirus-Based vectors immunotherapy
  • Known active brain or central nervous system metastasis, or seizures requiring anticonvulsant treatment, cerebrovascular accident, or transient ischemic attack (< 6 months prior to enrollment).
  • Subjects with a history of autoimmune disease (active or past), such as but not restricted to inflammatory bowel disease, systemic lupus erythematosus, ankylosing spondylitis, scleroderma, or multiple sclerosis. Autoimmune-related thyroid disease, type I diabetes and vitiligo are permitted if the condition is well controlled.
  • Subjects with serious intercurrent chronic or acute illness, such as cardiac or pulmonary disease, hepatic disease, or other illness considered by the Investigator as high risk for investigational drug treatment.
  • Subjects with a history of heart disease, such as congestive heart failure (class II, III, or IV defined by the New York Heart Association functional classification), history of unstable or poorly controlled angina, or history (< 1 year prior to enrollment) of ventricular arrhythmia.
  • Subjects with a medical or psychological impediment that would impair the ability of the subject to receive therapy per protocol or impact ability to comply with the protocol or protocol-required visits and procedures.
  • Presence of a known active acute or chronic infection, including human immunodeficiency virus (HIV, as determined by enzyme-linked immunosorbent assay [ELISA] and confirmed by western blot) and hepatitis B and hepatitis C virus (HBV/HCV, as determined by HBsAg and hepatitis C serology).
  • Subjects on systemic intravenous or oral steroid therapy (or other immunosuppressive, such as azathioprine or cyclosporin A) are excluded on the basis of potential immune suppression. Subjects must have had at least 6 weeks of discontinuation of any steroid therapy (except that used as premedication for chemotherapy or contrast-enhanced studies) prior to enrollment. Physiologic (replacement) doses of steroids as well as nasal, topical or inhaled steroids are allowed.
  • Subjects with known allergy or hypersensitivity to any component of the investigational product will be excluded.
  • Subjects with acute or chronic skin disorders that will interfere with injection into the skin of the extremities or subsequent assessment of potential skin reactions will be excluded.
  • Subjects vaccinated with a live (attenuated) vaccine (e.g., FluMist ) or a killed (inactivated)/subunit vaccine (e.g., PNEUMOVAX , Fluzone ) within 28 days or 14 days, respectively, of the first planned dose of ETBX vaccine.
  • Patients with second malignancy within 3 years of enrollment; Patients curatively treated non-melanoma skin cancers or carcinoma in situ of the bladder, are not excluded.
  • Use of herbal products that may decrease PSA levels (e.g. saw palmetto)
  • Patients who have received radiation therapy, radionuclide therapy or undergone surgery within certain duration (4 weeks) of enrollment
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years to 99 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03481816
Other Study ID Numbers  ICMJE 180073
18-C-0073
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Marijo Bilusic, M.D. National Cancer Institute (NCI)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date January 27, 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP