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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
Results First Posted : December 22, 2020
Last Update Posted : December 22, 2020
Sponsor:
Information provided by (Responsible Party):
Marijo Bilusic, M.D., National Cancer Institute (NCI)

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

Computed tomography (CT) or magnetic resonance imaging (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.


Condition or disease Intervention/treatment Phase
Prostatic Neoplasms Prostatic Cancer Biological: ETBX-071; adenoviral PSA vaccine Biological: ETBX-061; adenoviral MUC1 vaccine Biological: ETBX-051; adenoviral brachyury vaccine Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 18 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Treatment of Patients With Castration Resistant Prostate Cancer Using a Multi-Targeted Recombinant Ad5 PSA/MUC1/Brachyury Based Immunotherapy Vaccines
Actual Study Start Date : July 24, 2018
Actual Primary Completion Date : January 15, 2020
Estimated Study Completion Date : January 1, 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Prostate Cancer

Arm Intervention/treatment
Experimental: Arm 1/Dose De-Escalation
Subjects enrolled to dose de-escalation cohorts.
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.

Experimental: Arm 2/Dose expansion
Subjects enrolled at the maximum tolerated dose (MTD) after the MTD is established.
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.




Primary Outcome Measures :
  1. Number of Participants With Dose-Limiting Toxicities [ Time Frame: 4 weeks after receiving the first vaccine dose ]
    A dose-limiting toxicity is defined as occurring within 28 days after the first vaccine administration and meeting on of these criteria: Any Grade 3 or greater toxicity or any Grade 2 or higher autoimmune reaction as defined by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0; or generalized erythroderma or macular or papular rash.

  2. Recommended Phase 2 Dose [ Time Frame: Within the first 4 weeks after drug is administered. ]
    RP2D is the maximum tolerated dose declared after ≤1 of 6 participants experience a dose-limiting toxicity within the first 4 weeks.


Secondary Outcome Measures :
  1. Percentage of Participants With an Objective Response [ Time Frame: Objective response at any time point during treatment on study up to 1 year ]
    ORR is the percentage of subjects who experience partial response (PR) or complete response (CR) measured by the Response Evaluation Criteria in Solid Tumors (RECIST) at any time point during the treatment period. PR is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. CR is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.

  2. Percentage of Participants With a Disease Control Rate (DCR) Lasting for at Least 6 Months [ Time Frame: 6 months post treatment ]
    DCR is the percentage of subjects who experience partial response (PR), complete response (CR), or stable disease (SD) lasting for at least 6 months. Response was measured by the Response Evaluation Criteria in Solid Tumors (RECIST)v1. PR is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. CR is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum of diameters while on study. Progressive disease is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The appearance of one or more new lesions is also considered progressions.

  3. Duration of Response [ Time Frame: Time from recorded partial response until development of progressive disease. This was accessed every 3 weeks for the first 3 doses and then every 8 weeks up to 1 year (Arm 2) ]
    Duration of response is the time from when measurement criteria for Partial Response (PR) or Complete Response (CR) are met until disease recurrence or progression per dose cohort. Response was measured by the Response Evaluation Criteria in Solid Tumors (RECIST)v1. PR is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. CR is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Progression is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progressions.

  4. Progression-free Survival (PFS) [ Time Frame: This was accessed every 3 weeks for the first 3 doses, then every 8 weeks up to 1 year (Arm 2). ]
    PFS is the time from the date of first treatment to the date of disease progression or death (any cause) whichever occurs first per dose cohort. Progression was measured by the Response Evaluation Criteria in Solid Tumors (RECIST)v1. Progression is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progressions.

  5. Overall Survival (OS) [ Time Frame: Every 3 weeks for the first 3 doses, then every 8 weeks up to 1 year then every 3 months for 12 months and then approximately every 6 months every 6 months for 24 months and then every 12 months thereafter for another 24 months. ]
    OS is the time from the date of first treatment to the date of death (any cause).

  6. Percentage of Overall Survival (OS) Probability at 12 Months and 24 Months [ Time Frame: 12 and 24 months after first treatment ]
    Probability of being alive at 12 Months and 24 Months after first vaccine.

  7. Prostate-Specific Antigen Doubling Time (PSA DT) at Week 14 and End of Study [ Time Frame: PSA DT was done once at week 14 and the second time at the end of study (any time point within a year while on study when they met criteria for progression) ]
    PSA DT in participants with advanced cancer treated with the ETBX-071, ETBX-061, and ETBX-051 vaccines were determined using a nomogram to find detectable PSA.

  8. Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0) [ Time Frame: Date treatment consent signed to date off study, approximately 8 months and 30 days for the Arm 1/Dose De-Escalation group, and 10 months and 25 days for the Arm 2/Dose Expansion group. ]
    Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.



Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria
  • 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 National Institutes of Health (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 pathologists 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 prostate specific antigen (PSA), mucin1 (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 National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade less than or equal to1.
  • Adequate hematologic function at screening, as follows:
  • Absolute neutrophil count (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 Gilberts 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 metastasis 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 computed tomography (CT)/magnetic resonance imaging (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 (Prostrate Cancer Working Group 2 (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 Hepatitis B surface antigen (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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03481816


Locations
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United States, Maryland
National Institutes of Health Clinical Center
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Marijo Bilusic, M.D. National Cancer Institute (NCI)
  Study Documents (Full-Text)

Documents provided by Marijo Bilusic, M.D., National Cancer Institute (NCI):
Informed Consent Form  [PDF] October 10, 2018

Additional Information:
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Responsible Party: Marijo Bilusic, M.D., Principal Investigator, National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03481816    
Other Study ID Numbers: 180073
18-C-0073
First Posted: March 29, 2018    Key Record Dates
Results First Posted: December 22, 2020
Last Update Posted: December 22, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Marijo Bilusic, M.D., National Cancer Institute (NCI):
mCRPC
Therapeutic Cancer Vaccines
ETBX-071
ETBX-061
ETBX-051
Additional relevant MeSH terms:
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Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Prostatic Diseases
Vaccines
Immunologic Factors
Physiological Effects of Drugs