Cancer, Prostate Cancer
Conditions
Brief summary
A Phase 1/2 multicenter, dose determining, open-label study of ADXS31-142 monotherapy and a combination of ADXS31-142 and pembrolizumab (MK-3475) in participants with metastatic castration-resistant prostate cancer. Part A will be dose-determining part of ADXS31-142 monotherapy. Part B will be dose-determining part of ADXS31-142 and pembrolizumab (MK-3475) in combination. Part B expansion will treat additional participants with the recommended dose from Part B.
Detailed description
Part A of the study will be an open-label, Phase 1, multicenter, non-randomized, dose-determining trial of ADXS31-142 monotherapy in participants with mCRPC. The dose determining phase is intended to select a recommended Phase 2 dose (RP2D) for Part B. Part B of the study will be an open-label, Phase 1-2, multicenter, non-randomized dose-determining trial of ADXS31-142 in combination with pembrolizumab (MK-3475) in participants with mCRPC. Part B will consist of a dose-determination phase followed by an expansion cohort phase. The dose-determining phase is intended to select an RP2D for the combination. Dose escalation/de-escalation for this study will be explored by applying the modified toxicity probability interval design.
Interventions
DRUGADXS31-142
ADXS31-142 IV infusion
DRUGPembrolizumab
Pembrolizumab IV infusion
Sponsors
Merck Sharp & Dohme LLC
Advaxis, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Have progressive mCRPC, on androgen deprivation therapy, based on at least one of the following criteria: 1. Prostate-specific antigen (PSA) progression, defined as 25% increase over baseline value with an increase in the absolute value of at least 2 ng/mL that is confirmed by another PSA level with a minimum of a 1 week interval with a minimum PSA of 2 ng/mL. 2. Progression of bi-dimensionally measurable soft tissue (nodal metastasis) assessed within 1 month prior to registration by computed tomography (CT) scan or magnetic resonance imaging (MRI) of the abdomen and pelvis. 3. Progression of bone disease (evaluable disease) (new bone lesion\[s\]) by bone scan. 2. Has discontinued antiandrogens (bicalutamide, nilutamide) \>6 weeks and enzalutamide \>4 weeks prior to Day 1 of trial treatment 3. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale.
Exclusion criteria
1. Received more than 3 prior systemic treatment regimens with chemotherapy, hormonal, or immunotherapy in the metastatic setting or received more than 1 prior chemotherapeutic regimen in the metastatic setting 2. Has a diagnosis of immunodeficiency or is receiving any systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to Day 1 of trial treatment. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor. 3. Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e., Grade ≤1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier. 4. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., Grade ≤1 or at baseline) from adverse events due to a previously administered agent. 5. Has received prior therapy with an anti-programmed cell death protein-1 (PD-1), anti-programmed death-ligand-1 (PD-L1), or anti-Programmed death-ligand-2 (PD-L2) agent or if the participant has previously participated in a Merck MK-3475 clinical trial. 6. Has a contraindication to administration of ampicillin or trimethoprim/ sulfamethoxazole. 7. Has implanted medical device(s) that pose a high risk for colonization and/or cannot be easily removed (e.g., prosthetic joints, artificial heart valves, pacemakers, orthopedic screw(s), metal plate(s), bone graft(s), or other exogenous implant(s)). NOTE: More common devices and prosthetics which include arterial and venous stents, dental and breast implants, and venous access devices (e.g., Port-a-Cath or Mediport) are permitted. Sponsor must be contacted prior to consenting any subject who has any other device and/or implant.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events | From first dose up to 30 days after last dose (maximum duration: 108 weeks) | An adverse event (AE) was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Adverse events with onset dates on or after the first dose of study medication and within 30 days following the last dose of study medication were considered treatment emergent. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | From screening until progression or death (maximum duration: 104 weeks) | The objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 was defined as the number of participants with objective evidence of radiologic complete response (CR: disappearance of all target lesions) and partial response (PR: at least a 30% decrease in the sum of the longest diameters of target lesions compared with baseline, in absence of new lesions or unequivocal progression of non-target lesions) as determined from investigator response assessments. Disease Control Rates are based upon confirmed events only. |
| Objective Response Rate According to Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) | From screening until progression or death (maximum duration: 104 weeks) | The ORR according to irRECIST was defined as the number of participants with objective evidence of radiologic immune-related CR (irCR: Disappearance of all target lesions) and immune-related PR (irPR: At least 30% decrease in tumor burden compared with baseline) as determined from investigator response assessments. |
| Progression-free Survival, Assessed by RECIST Version 1.1 | From screening until progression or death (maximum duration: 104 weeks) | Progression-free survival (PFS) was defined as the time from randomization until objective tumor progression based on response evaluation criteria in solid tumors (RECIST) version 1.1 or death. The progressive disease is defined at least a 20% increase in the sum of the longest diameter of target lesions. Participants who had not experienced disease progression or who were still alive at the time of evaluation were censored for the analysis. The PFS was estimated using Kaplan-Meier method. |
| Overall Survival | From screening until progression or death (maximum duration: 104 weeks) | Overall survival is defined as the time from the date of start of study treatment until death due to any cause. Any participant not died at the time of analysis was censored based on the last recorded date on which the participant was known to be alive. The OS was estimated using Kaplan-Meier method. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Part A: ADXS31-142 1×10^9 CFU Participants received ADXS31-142 1 × 10\^9 CFU intravenously (IV) every 3 weeks (Q3W) in a 12-week cycle for up to 24 months or until disease progression or discontinuation. | 10 |
| Part A: ADXS31-142 5×10^9 CFU Participants received ADXS31-142 5 × 10\^9 CFU intravenously (IV) every 3 weeks (Q3W) in a 12-week cycle for up to 24 months or until disease progression or discontinuation. | 1 |
| Part A: ADXS31-142 1×10^10 CFU Participants received ADXS31-142 1 × 10\^10 CFU intravenously (IV) every 3 weeks (Q3W) in a 12-week cycle for up to 24 months or until disease progression or discontinuation. | 2 |
| Part B: ADXS31-142 + Pembrolizumab Participants received ADXS31-142 1 × 10\^9 CFU IV Q3W (in a 12-week cycle) in combination with 200 mg pembrolizumab IV Q3W for three times, with a fourth pembrolizumab dose 3 weeks later (in 12 week-cycles) for up to 24 months or until disease progression or discontinuation. | 37 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 5 | 1 | 1 | 16 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 1 |
| Overall Study | Other | 0 | 0 | 0 | 5 |
| Overall Study | Progressive disease | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 0 | 0 | 15 |
Baseline characteristics
| Characteristic | Part A: ADXS31-142 1×10^9 CFU | Part A: ADXS31-142 5×10^9 CFU | Part A: ADXS31-142 1×10^10 CFU | Part B: ADXS31-142 + Pembrolizumab | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 7 Participants | 1 Participants | 2 Participants | 26 Participants | 36 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 0 Participants | 0 Participants | 11 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 1 Participants | 2 Participants | 36 Participants | 49 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 7 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 1 Participants | 2 Participants | 30 Participants | 42 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 10 Participants | 1 Participants | 2 Participants | 37 Participants | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 10 | 1 / 1 | 1 / 2 | 16 / 37 |
| other Total, other adverse events | 10 / 10 | 1 / 1 | 2 / 2 | 37 / 37 |
| serious Total, serious adverse events | 4 / 10 | 1 / 1 | 1 / 2 | 22 / 37 |
Outcome results
Primary
Number of Participants With Treatment-Emergent Adverse Events
An adverse event (AE) was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Adverse events with onset dates on or after the first dose of study medication and within 30 days following the last dose of study medication were considered treatment emergent.
Time frame: From first dose up to 30 days after last dose (maximum duration: 108 weeks)
Population: The All Treated Population included all participants who received at least one dose of ADXS31-142 or pembrolizumab.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: ADXS31-142 1×10^9 CFU | Number of Participants With Treatment-Emergent Adverse Events | 10 Participants |
| Part A: ADXS31-142 5×10^9 CFU | Number of Participants With Treatment-Emergent Adverse Events | 1 Participants |
| ADXS31-142 1×10^10 CFU | Number of Participants With Treatment-Emergent Adverse Events | 2 Participants |
| Part B: ADXS31-142 + Pembrolizumab | Number of Participants With Treatment-Emergent Adverse Events | 37 Participants |
Secondary
Objective Response Rate According to Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST)
The ORR according to irRECIST was defined as the number of participants with objective evidence of radiologic immune-related CR (irCR: Disappearance of all target lesions) and immune-related PR (irPR: At least 30% decrease in tumor burden compared with baseline) as determined from investigator response assessments.
Time frame: From screening until progression or death (maximum duration: 104 weeks)
Population: Participants in the ORR Evaluable Population were analyzed. The ORR Evaluable Population included all participants who received at least one dose of ADXS31-142 or pembrolizumab and who had at least one post-baseline radiologic tumor response assessment (CR, PR, stable disease \[SD\], or progressive disease \[PD\]) with evaluable results.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: ADXS31-142 1×10^9 CFU | Objective Response Rate According to Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) | 0 participants |
| Part A: ADXS31-142 5×10^9 CFU | Objective Response Rate According to Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) | 0 participants |
| Part B: ADXS31-142 + Pembrolizumab | Objective Response Rate According to Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) | 0 participants |
Secondary
Objective Response Rate (ORR)
The objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 was defined as the number of participants with objective evidence of radiologic complete response (CR: disappearance of all target lesions) and partial response (PR: at least a 30% decrease in the sum of the longest diameters of target lesions compared with baseline, in absence of new lesions or unequivocal progression of non-target lesions) as determined from investigator response assessments. Disease Control Rates are based upon confirmed events only.
Time frame: From screening until progression or death (maximum duration: 104 weeks)
Population: The ORR Evaluable Population included all participants who received at least one dose of ADXS31-142 or pembrolizumab and who had at least one post-baseline radiologic tumor response assessment (CR, PR, stable disease \[SD\], or progressive disease \[PD\]) with evaluable results.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: ADXS31-142 1×10^9 CFU | Objective Response Rate (ORR) | 0 participants |
| Part A: ADXS31-142 5×10^9 CFU | Objective Response Rate (ORR) | 0 participants |
| Part B: ADXS31-142 + Pembrolizumab | Objective Response Rate (ORR) | 0 participants |
Secondary
Overall Survival
Overall survival is defined as the time from the date of start of study treatment until death due to any cause. Any participant not died at the time of analysis was censored based on the last recorded date on which the participant was known to be alive. The OS was estimated using Kaplan-Meier method.
Time frame: From screening until progression or death (maximum duration: 104 weeks)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: ADXS31-142 1×10^9 CFU | Overall Survival | 7.8 Months |
| Part A: ADXS31-142 5×10^9 CFU | Overall Survival | 18.5 Months |
| ADXS31-142 1×10^10 CFU | Overall Survival | 7.8 Months |
| Part B: ADXS31-142 + Pembrolizumab | Overall Survival | 33.7 Months |
Secondary
Progression-free Survival, Assessed by RECIST Version 1.1
Progression-free survival (PFS) was defined as the time from randomization until objective tumor progression based on response evaluation criteria in solid tumors (RECIST) version 1.1 or death. The progressive disease is defined at least a 20% increase in the sum of the longest diameter of target lesions. Participants who had not experienced disease progression or who were still alive at the time of evaluation were censored for the analysis. The PFS was estimated using Kaplan-Meier method.
Time frame: From screening until progression or death (maximum duration: 104 weeks)
Population: All treated patients population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: ADXS31-142 1×10^9 CFU | Progression-free Survival, Assessed by RECIST Version 1.1 | 2.2 Months |
| Part A: ADXS31-142 5×10^9 CFU | Progression-free Survival, Assessed by RECIST Version 1.1 | NA Months |
| ADXS31-142 1×10^10 CFU | Progression-free Survival, Assessed by RECIST Version 1.1 | NA Months |
| Part B: ADXS31-142 + Pembrolizumab | Progression-free Survival, Assessed by RECIST Version 1.1 | 5.3 Months |