Prostate Cancer Metastatic
Conditions
Keywords
Metastatic Prostate Cancer, Prostate Cancer, Castrate-Resistant, mCRPC, bavdegalutamide
Brief summary
Phase 1b study to assess the combination of ARV-110 (bavdegalutamide) and abiraterone in participants with metastatic prostate cancer with rising PSA values on abiraterone.
Interventions
DRUGBavdegalutamide
Bavdegalutamide oral tablets daily in 28 day cycles.
DRUGAbiraterone
Abiraterone oral tablets daily at the same dose they were on prior to study enrollment with a concomitant corticosteroid of Investigator's choice as per local label/guidelines.
Sponsors
Arvinas Androgen Receptor, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histological, pathological, or cytological confirmed diagnosis of adenocarcinoma of the prostate. 2. Ongoing treatment with stable doses of abiraterone (on an empty stomach) and a concomitant corticosteroid for mCRPC or for metastatic castration sensitive prostate cancer (mCSPC) until Cycle 1, Day 1 (C1D1). 3. Recent Prostate-specific antigen (PSA) values must demonstrate: 1. Rising PSAs at least 16 weeks after initiation of abiraterone 2. At least 2 PSA values that are higher than the PSA nadir on abiraterone, measured at a minimum of 1 week apart . The screening PSA for this study may be used as the 2nd PSA value. 4. No known radiographic evidence of disease progression while receiving abiraterone and clinically benefitting at the time of consent. If there is radiographic disease progression during screening, the participant may be considered eligible if, in the judgement of the investigator, the participant is clinically benefitting from abiraterone. 5. Ongoing androgen deprivation therapy with a gonadotropin-releasing hormone (GnRH) analogue or inhibitor, or orchiectomy (surgical or medical castration). 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Exclusion criteria
1. Previously treated with enzalutamide, apalutamide, darolutamide or experimental therapies (e.g., protein degraders or inhibitors) directed at the androgen receptor. 2. Treatment with any chemotherapy, investigational agents, immunotherapy, or hormonal therapy other than gonadotropin-releasing hormone (GnRH) agonists within 28 days of the start of treatment on protocol. 3. Radiation therapy within 4 weeks of first dose of study drug or prior irradiation to \>25% of the bone marrow. 4. Participants taking agents that are either a) sensitive P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) substrates, or Cytochrome P450 3A4 (CYP3A4) substrates, b) P-gp, BCRP, CYP3A4, or CYP2D6 substrates that have a narrow therapeutic index, c) strong CYP3A4 inhibitors or inducers, or d) any other prohibited and/or restricted medications described in the protocol. 5. Major surgery (as judged by the Investigator) within 4 weeks of first dose of study drug. 6. Untreated brain metastases or brain metastases requiring steroids 7. Any other active malignancy within 3 years prior to enrollment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ. 8. Any of the following in the previous 12 months: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (New York Heart Association class II, III or IV), cerebrovascular accident, transient ischemic attack, symptomatic pulmonary embolism, or other clinically significant episode of thromboembolic disease. 9. Any of the following in the previous 6 months: congenital long QT syndrome, Torsade de Pointes, arrhythmias (including sustained ventricular tachyarrhythmia and ventricular fibrillation), left anterior hemiblock (bifascicular block), or ongoing cardiac dysrhythmias of National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Grade ≥2, atrial fibrillation of any grade (Grade ≥2 in the case of asymptomatic lone atrial fibrillation). 10. Hypertension that cannot be controlled by medications (\>150/90 millimeters of mercury \[mmHg\] despite optimal medical therapy). 11. Active, uncontrolled bacterial, fungal, or viral infection, including hepatitis B virus, hepatitis C virus, known human immunodeficiency virus (HIV), or acquired immunodeficiency syndrome (AIDS)-related illness. 12. Active inflammatory gastrointestinal disease, uncontrolled chronic diarrhea, known diverticular disease, or previous gastric resection or lap band surgery. Gastroesophageal reflux disease is allowed except for if under treatment with proton pump inhibitors. 13. Participants with Child Pugh C. 14. Participants with electrolyte imbalances of hypokalemia, hypomagnesemia, and/or hypocalcemia. 15. Participants with QTcF ≥470 millisecond (msec).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety Lead-in: Number of Participants Experiencing Dose Limiting Toxicities (DLTs) | Baseline (Day 1) up to Day 28 | DLT was defined as: Grade \>=3 hematologic parameters, Grade ≥ 3 neutropenia with infection, Grade 4 neutropenia lasting \> 5 days, Febrile neutropenia, Grade 3 thrombocytopenia with clinically significant bleeding, Grade 4 thrombocytopenia, any toxicity requiring dose interruption for \>=14 days; Grade \>=3 non-hematologic toxicities considered clinically significant and non-clinically significant Grade \>=3 toxicities requiring dose interruption for \>=10 days that determined by the investigator to be clinically relevant. Severity graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. |
| Safety Lead-in: Recommended Phase 2 Dose (RP2D) of Bavdegalutamide | Baseline (Day 1) up to Day 28 | Dose limiting toxicities in first 4 weeks of the study combination treatment assessed to determine the dose of bavdegalutamide associated with acceptable safety and tolerability. |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs and Treatment Related TEAEs | From Day 1 of study treatment in Safety lead-in up to 30 days after end of study treatment (assessed up to approximately 111.57 weeks) | An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study drug, whether or not considered related to the study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. A TEAE is an AE occurring on/after the date of first dose of bavdegalutamide and on-study abiraterone and within 30 days of the last dose of bavdegalutamide and on-study abiraterone. TEAEs included both Serious TEAEs and non-serious TEAEs. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety Lead-in: Area Under the Concentration-Time Curve During a Dosing Interval (AUCtau) of Bavdegalutamide and Abiraterone | Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Cycle 1 Day 21 (each cycle is of 28 days) | AUCtau is defined as area under the concentration-time curve during a dosing interval. |
| Safety Lead-in: Area Under the Concentration-time Curve From Time 0 Through the Last Measurable Concentration (AUClast) of Bavdegalutamide and Abiraterone | Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Cycle 1 Day 21 (each cycle is of 28 days) | AUClast is defined as area under the concentration-time curve from time 0 through the last measurable concentration (AUClast). |
| Safety Lead-in: Maximum Observed Plasma Concentration (Cmax) of Bavdegalutamide and Abiraterone | Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Cycle 1 Day 21 (each cycle is of 28 days) | Cmax is the maximum observed plasma concentration. |
| Safety Lead-in: Minimum Observed Plasma Concentration (Cmin) of Bavdegalutamide and Abiraterone | Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Cycle 1 Day 21 (each cycle is of 28 days) | Cmin is the minimum observed plasma concentration. |
| Safety Lead-in: Time of Maximum Observed Plasma Concentration (Tmax) of Bavdegalutamide and Abiraterone | Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Cycle 1 Day 21 (each cycle is of 28 days) | Tmax is the time of maximum observed plasma concentration. |
| Safety Lead-in: Last Measurable Plasma Concentration (Clast) of Bavdegalutamide and Abiraterone | Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Cycle 1 Day 21 (each cycle is of 28 days) | Clast is the last measurable plasma concentration. |
| Safety Lead-in: Time of Last Measurable Plasma Concentration (Tlast) of Bavdegalutamide and Abiraterone | Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Cycle 1 Day 21 (each cycle is of 28 days) | Tlast is the time of last measurable plasma concentration. |
| Percentage of Participants With Lack of Prostate-Specific Antigen (PSA) Progression | Baseline (Day 1) up to 12 weeks | PSA control rate was defined as the percentage of participants with lack of PSA progression at 12 weeks. PSA progression was defined as a \>=25% increase in PSA and an absolute increase in PSA of \>=2 nanograms per milliliter (ng/mL) above the nadir, which was confirmed by a second consecutive value obtained 3 or more weeks later. |
| PSA30 Response Rate | Baseline up to approximately 152 weeks | A PSA30 response rate was the percentage of participants with a PSA30 response. A PSA30 response was defined as a \>=30% decline in PSA from baseline. This decline must have been confirmed to be sustained by a second PSA performed \>=3 weeks later. Baseline was defined as the last available observation prior to or on the first administration of bavdegalutamide and on study abiraterone. |
| PSA50 Response Rate | Baseline up to approximately 152 weeks | A PSA50 response rate was the percentage of participants with a PSA50 response. A PSA50 response was defined as a \>=50% decline in PSA from baseline. This decline must have been confirmed to be sustained by a second PSA performed \>=3 weeks later. Baseline was defined as the last available observation prior to or on the first administration of bavdegalutamide and on study abiraterone. |
| Duration of PSA30 Response | From the date of the first confirmed PSA30 response up to confirmed PSA progression (assessed up to approximately 152 weeks) | Duration of PSA30 response was the time interval from the date of the first confirmed PSA30 response to the date of confirmed PSA progression. Participants who did not have PSA progression were to be censored on the date of the last PSA assessment before receipt of new subsequent anticancer therapy. A PSA30 response was defined as a \>=30% decline in PSA from baseline. This decline must have been confirmed to be sustained by a second PSA performed \>=3 weeks later. PSA progression was defined as a \>=25% increase in PSA and an absolute increase in PSA of \>=2 ng/mL above the nadir, which was confirmed by a second consecutive value obtained 3 or more weeks later. Baseline was defined as the last available observation prior to or on the first administration of bavdegalutamide and on study abiraterone. Kaplan-Meier estimates were used for analysis. |
| Duration of PSA50 Response | From the date of the first confirmed PSA50 response up to confirmed PSA progression (assessed up to approximately 152 weeks) | Duration of PSA50 response was the time interval from the date of the first confirmed PSA50 response to the date of confirmed PSA progression. Participants who did not have PSA progression were to be censored on the date of the last PSA assessment before receipt of new subsequent anticancer therapy. A PSA50 response was defined as a \>=50% decline in PSA from baseline. This decline must have been confirmed to be sustained by a second PSA performed \>=3 weeks later. PSA progression was defined as a \>=25% increase in PSA and an absolute increase in PSA of \>=2 ng/mL above the nadir, which was confirmed by a second consecutive value obtained 3 or more weeks later. Baseline was defined as the last available observation prior to or on the first administration of bavdegalutamide and on study abiraterone. Kaplan-Meier estimates were used for analysis. |
| Time to PSA Progression | From first dose up to date of PSA progression (assessed up to approximately 152 weeks) | Time to PSA progression was the time interval from the date of the first study dose to the date of PSA progression. The PSA progression date was defined as the date that a \>=25% increase and an absolute increase of \>=2 ng/mL above the nadir was documented, which was confirmed by a second consecutive value obtained \>=3 weeks later. Participants who did not have PSA progression were to be censored on the date of the last PSA assessment before receipt of new anticancer therapy. If a participant did not have a postbaseline PSA, they were to be censored on the date of the first study dose. Kaplan-Meier estimates were used for analysis. |
| Radiographic Progression-Free Survival (rPFS) | From first dose to the date of first progression (assessed up to approximately 152 weeks) | rPFS was defined as the time interval from the date of the first study dose to the date of first progression per modified Response Evaluation Criteria in Solid Tumors 1.1 (RECIST v1.1)/Prostate Cancer Working Group 3 (PCWG3) Criteria, or death from any cause, whichever occurred first. Radiological progression was defined by either soft tissue tumor progression defined by RECIST v1.1, or bone progression defined by PCWG2. Bone progression was defined as a minimum of two new lesions. Progression on bone scans before or at week 8 required a confirmatory scan performed 6 or more weeks later. rPFS was analyzed using Kaplan-Meier methodology. Participants who were alive and whose disease did not progress were to be censored on the date of the last disease assessment before receipt of new anticancer therapy. If the participant was alive and did not have post baseline imaging assessment, participant was to be censored on the date of the first study drug dose. |
| Overall Response Rate (ORR) by Modified RECIST v1.1)/PCWG3 Criteria | From first dose up to approximately 152 weeks | ORR was defined as the percentage of participants whose best overall response was a confirmed complete response (CR) or confirmed partial response (PR), as determined by the investigator according to modified RECIST v1.1/PCWG3. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis \<10 mm) and no new lesions. PR was defined as \>=30% decrease under baseline of the sum of diameters of all target measurable lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease and no new lesions. |
| Duration of Radiographic Response (DOR) | From the date of first documented confirmed response to the date of the first documented tumor progression (assessed up to approximately 152 weeks) | DOR was defined as the time interval from the date of first documented confirmed CR/PR to the date of the first documented tumor progression (per modified RECIST 1.1/PCWG3 criteria), or death, whichever occurred first. CR was defined as complete disappearance of all target lesions and non-target disease and no new lesions. PR was defined as \>=30% decrease under baseline of the sum of diameters of all target measurable lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease and no new lesions. Radiological progression was defined by either soft tissue tumor progression defined by RECIST v1.1, or bone progression defined by PCWG2. Bone progression was defined as a minimum of two new lesions. Progression on bone scans before or at week 8 required a confirmatory scan performed 6 or more weeks later. |
Countries
Canada, France, United Kingdom, United States
Participant flow
Recruitment details
Participants with metastatic prostate cancer enrolled at 13 sites in the United States (US), Canada, United Kingdom (UK), and France.
Pre-assignment details
Total 45 participants were enrolled with an initial safety lead-in of 6 evaluable participants.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 69.2 Years STANDARD_DEVIATION 8.78 |
| Race/Ethnicity, Customized Ethnicity: Hispanic or Latino | 0 Participants |
| Race/Ethnicity, Customized Ethnicity: Missing | 18 Participants |
| Race/Ethnicity, Customized Ethnicity: Not Hispanic or Latino | 24 Participants |
| Race/Ethnicity, Customized Ethnicity: Not reported | 2 Participants |
| Race/Ethnicity, Customized Ethnicity: Unknown | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 20 Participants |
| Race (NIH/OMB) White | 21 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 45 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 45 |
| other Total, other adverse events | 45 / 45 |
| serious Total, serious adverse events | 4 / 45 |
Outcome results
None listed