Treatment of Castration Resistant Prostate Cancer Using Multi-Targeted Recombinant Ad5 PSA/MUC1/Brachyury Based Immunotherapy Vaccines
- Conditions
- Prostatic CancerProstatic Neoplasms
- Interventions
- Biological: ETBX-071; adenoviral PSA vaccineBiological: ETBX-061; adenoviral MUC1 vaccineBiological: ETBX-051; adenoviral brachyury vaccine
- Registration Number
- NCT03481816
- Lead Sponsor
- 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.
- 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), Prostate specific antigen (PSA), Mucin 1 (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.
* Eastern Cooperative Oncology Group (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 \[E1-, E2b-\]-carcinoembryonic antigen (CEA)(6D) (ETBX-011) to be well tolerated (with no dose-limiting toxicities (DLTs) or related serious adverse events(SAEs), 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).
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Male
- Target Recruitment
- 18
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Arm 1/Dose De-Escalation ETBX-061; adenoviral MUC1 vaccine Subjects enrolled to dose de-escalation cohorts. Arm 1/Dose De-Escalation ETBX-071; adenoviral PSA vaccine Subjects enrolled to dose de-escalation cohorts. Arm 1/Dose De-Escalation ETBX-051; adenoviral brachyury vaccine Subjects enrolled to dose de-escalation cohorts. Arm 2/Dose expansion ETBX-071; adenoviral PSA vaccine Subjects enrolled at the maximum tolerated dose (MTD) after the MTD is established. Arm 2/Dose expansion ETBX-061; adenoviral MUC1 vaccine Subjects enrolled at the maximum tolerated dose (MTD) after the MTD is established. Arm 2/Dose expansion ETBX-051; adenoviral brachyury vaccine Subjects enrolled at the maximum tolerated dose (MTD) after the MTD is established.
- Primary Outcome Measures
Name Time Method Recommended Phase 2 Dose 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.
Number of Participants With Dose-Limiting Toxicities 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.
- Secondary Outcome Measures
Name Time Method Percentage of Participants With a Disease Control Rate (DCR) Lasting for at Least 6 Months 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.
Percentage of Participants With an Objective Response 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.
Overall Survival (OS) 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).
Percentage of Overall Survival (OS) Probability at 12 Months and 24 Months 12 and 24 months after first treatment Probability of being alive at 12 Months and 24 Months after first vaccine.
Prostate-Specific Antigen Doubling Time (PSA DT) at Week 14 and End of Study 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.
Progression-free Survival (PFS) 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.
Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0) 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.
Duration of Response 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.
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States