Metastatic Castration-resistant Prostate Cancer, Metastatic Castration-sensitive Prostate Cancer, Metastatic Prostate Cancer
Conditions
Keywords
Prostate, Metastatic, Cancer
Brief summary
The purpose of this study is to investigate the safety and efficacy of a new formulation of an existing drug product called TAVT-45 in patients with metastatic prostate cancer.
Detailed description
This is a Phase 3 randomized, open-label study to evaluate the pharmacodynamic effect and safety profile of TAVT-45 compared to Zytiga (reference abiraterone acetate formulation, hereafter referred to as R-AA) in patients with high-risk metastatic castrate sensitive prostate cancer (mCSPC) and metastatic castrate resistant prostate cancer (mCRPC). Randomization was stratified by prostate cancer population (CSPC vs CRPC) and baseline testosterone (\<10 vs ≥ 10 ng/dL). Patients were treated for 84 days and randomized into one of two groups in a 1:1 ratio: * TAVT-45: Administered twice daily as 1 x sachet containing TAVT-45 (250 mg abiraterone acetate), reconstituted in water or specified fruit juice (orange juice), + Prednisone (5 mg once or twice daily, depending on prostate cancer population) * R-AA: Administered once daily as (2 x 500 mg Zytiga tablets) + Prednisone (5 mg once or twice daily, depending on prostate cancer population)
Interventions
DRUGTAVT-45
250 mg abiraterone acetate granules for oral suspension in a sachet, reconstituted in water or specified fruit juice (orange juice), administered twice daily.
DRUGZytiga
500 mg tablet, two tablets administered once daily
DRUGPrednisone
mCSPC patients received 5 mg orally once daily. mCRPC patients received 5 mg orally twice daily.
Sponsors
Tavanta Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Written informed consent obtained prior to any study-related procedure being performed 2. Male patients at least 18 years of age or older at time of consent 3. Pathologically confirmed adenocarcinoma of the prostate 4. Ongoing therapy with a gonadotropin releasing hormone (GnRH) agonist or antagonist (unless patient has already had a bilateral orchiectomy) AND serum testosterone level \<50 ng/dL at screening 5. Have either metastatic CSPC or metastatic CRPC (per protocol definitions). 6. The following prior treatments and/or surgery for prostate cancer are allowed: 1. CSPC: * Up to 90 days of androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) agonists/antagonists or orchiectomy with or without concurrent anti-androgens prior to patients' randomization is permitted * Patients may have one course of palliative radiation or surgical therapy to treat symptoms resulting from metastatic disease (e.g., impending cord compression or obstructive symptoms) if administered prior to randomization * Radiation or surgical therapy that was not initiated 4 weeks after the start of ADT or orchiectomy 2. CRPC: * Previous chemotherapy with docetaxel for metastatic disease with treatment completed at least 1 year prior to screening 7. Discontinuation of flutamide or nilutamide, and other anti-androgens prior to the start of study medication; discontinuation of bicalutamide prior to start of study medication 8. Discontinuation of strong cytochrome P450 3A4 (CYP3A4) inducers at least 4 weeks prior to start of study medication 9. Discontinuation of radiotherapy prior to start of study medication 10. Discontinuation of herbal supplements at least 4 weeks prior to the first dose of study medication and for the duration of the trial. 11. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 at screening 12. Normal organ function with acceptable initial laboratory values within the screening period: * Absolute neutrophil count (ANC): ≥ 1,500/μl * Albumin: ≥ 3.0g/dL * Hemoglobin: ≥ 9g/dL * Platelet count: ≥ 100,000/μl * Serum Creatinine: ≤ 3.0 x the institutional upper limit of normal (ULN) * Potassium: ≥ 3.5 mmol/L (within institutional normal range) * Bilirubin: ≤ 1.5 ULN (unless documented Gilbert's disease) * Aspartate aminotransferase (AST): ≤ 2.5 x ULN * Alanine aminotransferase (ALT): ≤ 2.5 x ULN 13. Life expectancy of at least 6 months at screening 14. Patients engaged in sex with women of child-bearing potential agree to use a condom plus another effective contraception method. Patients agree to use a condom when engaged in any sexual activity, including sex with a pregnant woman. These restrictions will apply from the time informed consent is provided until 3 weeks after the last dose of study medication is taken. 15. Patient is willing and able to comply with all protocol requirements
Exclusion criteria
1. For mCSPC patients: any prior pharmacotherapy, radiation therapy, or surgery for metastatic prostate cancer not specified as allowable treatment in Inclusion Criterion 6. For example, prior therapy with apalutamide or enzalutamide is prohibited as well as therapy with an investigational agent as described in Exclusion Criterion 16. 2. For mCRPC patients: * Prior treatment with abiraterone or enzalutamide is prohibited * Previous chemotherapy is prohibited with exception of docetaxel treatment as specified in the inclusion criteria 6. 3. Initiation of bisphosphonate or denosumab therapy within 4 weeks prior to the start of study drug/reference product. Patients who are on a stable dose of these medications for at least 4 weeks at the time of starting study drug/reference product will be eligible. 4. Therapy with estrogen within 4 weeks prior to the start of study drug 5. Use of systemic glucocorticoids equivalent to \>10 mg prednisone daily. Patients who have discontinued or reduced dosing to the equivalent of ≤ 10 mg prednisone daily within 14 days prior to the start of study drug are eligible 6. Known, symptomatic metastases to the brain or central nervous system involvement (patients with asymptomatic and neurologically stable disease for the past 4 weeks will be permitted) 7. History of adrenal gland dysfunction defined as requiring treatment for adrenal insufficiency 8. History of other malignancy within the previous 2 years (no longer being actively treated), with the exceptions of basal cell carcinoma, nonmuscle invasive bladder cancer that has been treated and is under surveillance, or other in-situ cancers with a low likelihood of recurrence 9. Major surgery within 4 weeks prior to the start of study drug 10. Known gastrointestinal disease or condition that could impair absorption inclusive of gastrocolic fistula, gastroenterostomy, biliary obstruction, cirrhosis, chronic pancreatitis or pancreatic cancer, cystic fibrosis, lactate deficiency, amyloidosis, celiac disease, Crohn's disease, radiation enteritis, intestinal resection, and history of bariatric surgery 11. Known history of human immunodeficiency virus or seropositive test for hepatitis C virus (HCV) or hepatitis B surface antigen (HBsAg) (note: HCV patients with undetectable viral load will be eligible) 12. Poorly controlled diabetes, defined as hemoglobin A1c (HbA1c) \> 8% within the past 12 months 13. Uncontrolled hypertension at screening 14. History of New York Heart Association class III or IV heart failure 15. Serious concurrent illness, including psychiatric illness, that could interfere with study participation 16. Receipt of another investigational agent within 4 weeks or 5 x the treatment half-life, whichever is longer, of treatment start. 17. Known hypersensitivity or allergy to abiraterone acetate, prednisone or any excipients in the study drugs 18. In the opinion of the investigator, participation in the trial would prevent the patient from receiving local standard-of-care treatment for metastatic prostate cancer, if clinically indicated, after completion of the trial 19. Other condition which, in the opinion of the Investigator, would preclude participation in this trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Serum Testosterone (ng/dL) Days 9 and 10 Average (Rounded-up), CR-ITT | Average over Day 9 and Day 10 | The primary endpoint was the between group comparison of serum testosterone levels for the average of levels on Days 9 and 10 (rounded-up) for mCRPC patients. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Serum Testosterone (ng/dL) Days 9 and 10 Average (Rounded-up), CS-ITT | Average over Day 9 and Day 10 | This was a supplementary analysis of equivalence, with a between group comparison of serum testosterone for the Days 9 and10 average (rounded-up) values for mCSPC patients treated with either TAVT-45 or R-AA. |
| Serum Testosterone (ng/dL) Days 9 and 10 Average (Rounded-up), mITT | Average over Day 9 and Day 10 | Supplementary analysis of equivalence of TAVT-45 and R-AA on Days 9 and 10 average (rounded-up) values in the mITT population (including mCRPC and mCSPC patients). |
| Percent of Subjects With PSA-50 Response, mITT | Response at any time over the 84-day post-treatment period. | The PSA-50 response is defined as a decrease of ≥ 50% in prostate-specific antigen (PSA) levels from baseline. |
Countries
France, Hungary, Poland, Puerto Rico, Spain, Sweden, United Kingdom, United States
Participant flow
Pre-assignment details
In total, 107 patients were randomized, and 103 patients received at least 1 dose of study medication (4 patients randomized to the R-AA arm were discontinued before receiving any study medication due to adverse event \[n=1\], lab result \[n=1\] and subject withdrawal \[n=2\]).
Participants by arm
| Arm | Count |
|---|---|
| TAVT-45 TAVT-45 administered twice daily as a 1 x sachet containing TAVT-45 (250 mg abiraterone acetate) + Prednisone (5mg once or twice daily, depending on prostate cancer population). TAVT-45 administered approximately every 12 hours without respect to food. Patients treated for 84 days.
TAVT-45: 250 mg abiraterone acetate granules for oral suspension in a sachet, administered twice daily.
Prednisone: mCSPC patients received 5 mg orally once daily. mCRPC patients received 5 mg orally twice daily. | 54 |
| Reference Abiraterone Acetate (Zytiga®) - R-AA Zytiga (reference abiraterone acetate formulation, hereafter referred to as R-AA) administered once daily as (2 x 500mg Zytiga tablets) + Prednisone (5mg once or twice daily, depending on prostate cancer population). R-AA administered once daily either ≥ 1 hour before or ≥ 2 hours after a meal. Patients treated for 84 days.
Zytiga: 500 mg tablet, administered twice daily.
Prednisone: mCSPC patients received 5 mg orally once daily. mCRPC patients received 5 mg orally twice daily. | 49 |
| Total | 103 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 3 |
| Overall Study | Death | 1 | 1 |
| Overall Study | Other - Not Reported | 1 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 3 |
Baseline characteristics
| Characteristic | TAVT-45 | Reference Abiraterone Acetate (Zytiga®) - R-AA | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 47 Participants | 43 Participants | 90 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 6 Participants | 13 Participants |
| Age, Continuous | 74.5 years STANDARD_DEVIATION 8.45 | 74.9 years STANDARD_DEVIATION 8.4 | 74.7 years STANDARD_DEVIATION 8.39 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 50 Participants | 45 Participants | 95 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 3 Participants | 6 Participants |
| Gleason score High (8-10) | 38 Participants | 35 Participants | 73 Participants |
| Gleason score Low (<7) | 3 Participants | 7 Participants | 10 Participants |
| Gleason score Medium (7) | 10 Participants | 7 Participants | 17 Participants |
| Gleason score Missing | 3 Participants | 0 Participants | 3 Participants |
| Prostate Cancer Type metastatic castrate resistant prostate cancer (mCRPC) | 33 participants | 30 participants | 63 participants |
| Prostate Cancer Type metastatic castrate sensitive prostate cancer (mCSPC) | 21 participants | 19 participants | 40 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 51 Participants | 44 Participants | 95 Participants |
| Region of Enrollment France | 2 participants | 2 participants | 4 participants |
| Region of Enrollment Hungary | 5 participants | 4 participants | 9 participants |
| Region of Enrollment Poland | 5 participants | 2 participants | 7 participants |
| Region of Enrollment Spain | 19 participants | 19 participants | 38 participants |
| Region of Enrollment Sweden | 5 participants | 0 participants | 5 participants |
| Region of Enrollment United Kingdom | 10 participants | 6 participants | 16 participants |
| Region of Enrollment United States | 8 participants | 16 participants | 24 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 54 Participants | 49 Participants | 103 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 54 | 1 / 49 |
| other Total, other adverse events | 38 / 54 | 36 / 49 |
| serious Total, serious adverse events | 5 / 54 | 3 / 49 |
Outcome results
Primary
Serum Testosterone (ng/dL) Days 9 and 10 Average (Rounded-up), CR-ITT
The primary endpoint was the between group comparison of serum testosterone levels for the average of levels on Days 9 and 10 (rounded-up) for mCRPC patients.
Time frame: Average over Day 9 and Day 10
Population: The mCRPC ITT (CR-ITT) population was a subset of the mITT population (all randomized patients who received at least one dose of study medication) and included mCRPC patients only.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| TAVT-45 CR-ITT | Serum Testosterone (ng/dL) Days 9 and 10 Average (Rounded-up), CR-ITT | 1.0000 ng/dL |
| R-AA CR-ITT | Serum Testosterone (ng/dL) Days 9 and 10 Average (Rounded-up), CR-ITT | 1.0000 ng/dL |
Comparison: Primary analysis of equivalence of TAVT 45 and R AA based on average serum testosterone (ng/dL) (rounded up values of Days 9 and 10).
Secondary
Percent of Subjects With PSA-50 Response, mITT
The PSA-50 response is defined as a decrease of ≥ 50% in prostate-specific antigen (PSA) levels from baseline.
Time frame: Response at any time over the 84-day post-treatment period.
Population: mITT population: all randomized patients who received at least one dose of study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TAVT-45 CR-ITT | Percent of Subjects With PSA-50 Response, mITT | 47 Participants |
| R-AA CR-ITT | Percent of Subjects With PSA-50 Response, mITT | 39 Participants |
p-value: 0.340895% CI: [0.574, 4.979]Regression, Logistic
Secondary
Serum Testosterone (ng/dL) Days 9 and 10 Average (Rounded-up), CS-ITT
This was a supplementary analysis of equivalence, with a between group comparison of serum testosterone for the Days 9 and10 average (rounded-up) values for mCSPC patients treated with either TAVT-45 or R-AA.
Time frame: Average over Day 9 and Day 10
Population: The mCSPC ITT (CS-ITT) population was a subset of the mITT population and included mCSPC patients only.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| TAVT-45 CR-ITT | Serum Testosterone (ng/dL) Days 9 and 10 Average (Rounded-up), CS-ITT | 1.01179 ng/dL |
| R-AA CR-ITT | Serum Testosterone (ng/dL) Days 9 and 10 Average (Rounded-up), CS-ITT | 1.03758 ng/dL |
Comparison: Supplementary analysis of equivalence of TAVT-45 and R-AA based on average serum testosterone (ng/dL) (rounded up values of Days 9 and 10) in the CS-ITT population.90% CI: [0.944, 1.007]
Secondary
Serum Testosterone (ng/dL) Days 9 and 10 Average (Rounded-up), mITT
Supplementary analysis of equivalence of TAVT-45 and R-AA on Days 9 and 10 average (rounded-up) values in the mITT population (including mCRPC and mCSPC patients).
Time frame: Average over Day 9 and Day 10
Population: mITT population: all randomized patients who received at least one dose of study medication.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| TAVT-45 CR-ITT | Serum Testosterone (ng/dL) Days 9 and 10 Average (Rounded-up), mITT | 1.00410 ng/dL |
| R-AA CR-ITT | Serum Testosterone (ng/dL) Days 9 and 10 Average (Rounded-up), mITT | 1.01469 ng/dL |
Comparison: Supplementary analysis of equivalence of TAVT-45 and R-AA based on average serum testosterone (ng/dL) (rounded up values of Days 9 and 10) in the mITT population.90% CI: [0.978, 1.002]