Metastatic Castration-resistant Prostate Cancer
Conditions
Keywords
carfilzomib, prostate cancer, PSA (prostate-specific antigen), CRPC (castration-resistant prostate cancer)
Brief summary
This study will test how effective the drug, Carfilzomib, reduces progression of prostate cancer in patients who have previously received chemotherapy and androgen inhibitors. Carfilzomib is approved for multiple myeloma but is not approved for prostate cancer. Therefore, it is considered investigational. Other approved methods of treatment for metastatic prostate cancer have demonstrated only modest benefits. Novel and tolerable agents are necessary to make further gains and extend overall survival.
Detailed description
First-line chemotherapy for metastatic castration-resistant prostate cancer (CRPC) combined with androgen inhibitors modestly extends overall survival. Carfilzomib is anticipated to enhance progression-free survival (PFS) as well as reduce pain and toxicities. Proteasome inhibitors are promising agents used in the therapy of prostate cancer. Carfilzomib is a more potent and irreversible proteasome inhibitor than the frequently used proteasome inhibitor, Bortezomib. In Phase I trials Carfilzomib demonstrated substantial antitumor activity while exhibiting tolerable side effects. Carfilzomib has been approved by the FDA for patients with multiple myeloma. The drug, however, is not approved for the use with CRPC patients. This trial will evaluate the tolerance and effectiveness of Carfilzomib in men with metastatic progressive CRPC following chemotherapy and androgen inhibitors.
Interventions
DRUGCarfilzomib
Carfilzomib will be administered on days 1, 2, 8, 9, 15, 16 within each 4 week cycle.
DRUGDexamethasone
Administered prior to administration of Study drug
DRUGAcyclovir
Administered orally twice daily
Sponsors
Amgen
University of Alabama at Birmingham
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
19 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically proven adenocarcinoma of the prostate * Metastatic disease * Progressive disease (PSA, radiologic, symptomatic) following abiraterone acetate and/or Enzalutamide (prior sipuleucel-T and chemotherapy are allowed); PSA progression is defined as baseline increase followed by any PSA increase ≥1 week apart. * Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care. * Patients, even if surgically sterilized (i.e., status post-vasectomy) must agree to one of the following: practice effective barrier contraception during the entire study treatment period and through a minimum of 30 days after the last dose of study drug, or completely abstain from heterosexual intercourse if female partner of childbearing age. * An elevated PSA level of \>2ng/mL for patients progressing by PSA criteria is required (last confirmatory sample must be \>2ng/mL) * Currently on androgen ablation hormone therapy (a luteinizing hormone- releasing hormone (LHRH) agonist/antagonist or orchiectomy) with testosterone level \<50ng/dL) * Has an Eastern Cooperative Oncology Group (ECOG) Performance status of 0 - 2 * Left ventricular ejection fraction (LVEF) ≥40% on 2-D transthoracic echocardiogram (ECHO); Multi-gated Acquisition Scan (MUGA) is acceptable if ECHO is not available. * ≥19 years of age * Resolution of all acute toxic effects of prior chemotherapy or surgical procedures to NCI CTCAE Version 4.03 Grade \<1, in the opinion of the treating physician. * Ability to understand and the willingness to sign a written informed consent document
Exclusion criteria
* Patient has a platelet count of \<100,000/mm3, or absolute neutrophil count of \<1500/mm3 or Hemoglobin \<8.0gm/dL * Patient has a calculated or measured creatinine clearance of \<30 milliliters (mL)/minute * Patient has total bilirubin \>2 x upper limit of normal (ULN), or aspartate aminotransferase (AST), alanine aminotransferase (ALT) \>3.5 x ULN * Patient has ≥ Grade 2 peripheral neuropathy within 14 days before enrollment * Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Before study entry, any ECG abnormality at screening has to be documented by the investigator as not medically relevant. * Participation in clinical trials with other investigational agents not included in this trial, within 14 days of the start of this trial and throughout the duration of this trial. * Serious medical or psychiatric illness likely to interfere with participation in this clinical study. * Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the breast; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder or benign tumors of the adrenal or pancreas. * Known HIV, hepatitis B and hepatitis C infection * Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to randomization * Prior treatment with bortezomib * Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize Carfilzomib) * Has received prior radiation to \>50% of the bone marrow * Has had significant bleeding/thrombosis in previous 4 weeks * Has received treatment with radiation therapy, surgery, chemotherapy, or an investigational agent within 4 weeks prior to registration, (6 weeks for radiation therapy, radionuclides, nitrosoureas, or Mitomycin C) or who have not recovered from adverse events due to agents administered more than 4 weeks earlier * Has evidence of uncontrolled Central Nervous System (CNS) involvement (previous radiation and off steroids is acceptable) * Patients may not be receiving any other investigational agents * Has a serious uncontrolled intercurrent medical or psychiatric illness, including serious infection * Is unable to comply with study requirements * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | Baseline through 6 months for evaluating all patients | The study will measure patient survival at 6 months but will continue to monitor overall survival as a secondary objective. The Kaplan-Meier method will be used. |
| Overall Survival | From baseline through 36 months. | Outcome measure was completed by using a count of participants. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Prostate-Specific Antigen (PSA) Changes | Baseline through 36 months | PSA levels were collected at each visit on the day of treatment. Linear regression with PSA as the dependent variable and time as the dependent variable was performed. |
| Number of Participants With Circulating Tumor Cell (CTC) Decline Over Three Time Points (Before Study Initiation, Day 1 of Cycles 2 and 4 | Baseline through 36 months | The CTC marker will be used to evaluate efficacy of response to treatment. CTC changes will include changes from unfavorable (less than or equal to 5/7.5 ml) to favorable and declines by \>30%. Three collections: before study initiation, Day 1 of Cycles 2 and 4 |
| Assessment of Toxicities | Baseline through 36 months | Hematologic and non-hematologic toxicities will be graded. The new international criteria proposed by the Response Evaluation Criteria In Solid Tumors (RECIST) will serve as the guideline. On Day 1 of each cycle (4 weeks) for the duration of treatment and then 30 days following the last treatment |
Countries
United States
Participant flow
Recruitment details
Protocol Open to Accrual: April 2014, Primary Completion Date: June 2017 and Study Completion Date: July 14, 2017. Recruitment location: University of Alabama at Birmingham (UAB) Comprehensive Cancer Center, Birmingham; Tulane University, New Orleans; Medical Center of Central Georgia, Macon, Georgia, Dana Farber Cancer Institute, Boston.
Participants by arm
| Arm | Count |
|---|---|
| Carfilzomib Carfilzomib is administered twice-weekly on consecutive days (days 1, 2, 8, 9, 15, 16) as a 30-minute intravenous infusion for 3 weeks every 4 weeks (1 cycle) with dexamethasone given as pre-medication. The dose of carfilzomib is 20 mg/m2 on days 1 and 2 of cycle 1 and is then escalated in succeeding weeks and cycles to 56 mg/m2 if no dose limiting toxicities occur. Acyclovir is given orally at 400 mg twice daily during therapy but may be discontinued at some point. Therapy will continue until side effects become unacceptable, the disease progresses, or the doctor withdraws the patient.
Carfilzomib: Carfilzomib will be administered on days 1, 2, 8, 9, 15, 16 within each 4 week cycle.
Dexamethasone: Administered prior to administration of Study drug
Acyclovir: Administered orally twice daily | 28 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 8 |
Baseline characteristics
| Characteristic | Carfilzomib |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 15 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 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 | 0 Participants |
| Race (NIH/OMB) White | 22 Participants |
| Region of Enrollment United States | 28 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 6 / 28 |
| other Total, other adverse events | 0 / 28 |
| serious Total, serious adverse events | 5 / 28 |
Outcome results
Primary
Overall Survival
Outcome measure was completed by using a count of participants.
Time frame: From baseline through 36 months.
Population: 8 patients did not complete treatment and were lost to follow up
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Carfilzomib | Overall Survival | 11 Participants |
Primary
Progression-free Survival (PFS)
The study will measure patient survival at 6 months but will continue to monitor overall survival as a secondary objective. The Kaplan-Meier method will be used.
Time frame: Baseline through 6 months for evaluating all patients
Population: 8 patients did not complete treatment and were not included in the analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Carfilzomib | Progression-free Survival (PFS) | 1 Participants |
Secondary
Assessment of Toxicities
Hematologic and non-hematologic toxicities will be graded. The new international criteria proposed by the Response Evaluation Criteria In Solid Tumors (RECIST) will serve as the guideline. On Day 1 of each cycle (4 weeks) for the duration of treatment and then 30 days following the last treatment
Time frame: Baseline through 36 months
Population: All serious adverse events and \> grade 3 toxicities were reported for patients who received treatment with Carfilzomib
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Carfilzomib | Assessment of Toxicities | Hypertension (>= Grade 3 or 4) | 2 Participants |
| Carfilzomib | Assessment of Toxicities | Anemia (>= Grade 3 or 4) | 3 Participants |
Secondary
Number of Participants With Circulating Tumor Cell (CTC) Decline Over Three Time Points (Before Study Initiation, Day 1 of Cycles 2 and 4
The CTC marker will be used to evaluate efficacy of response to treatment. CTC changes will include changes from unfavorable (less than or equal to 5/7.5 ml) to favorable and declines by \>30%. Three collections: before study initiation, Day 1 of Cycles 2 and 4
Time frame: Baseline through 36 months
Population: 1 patient did not have blood draw. 27 patients had blood draws for CTC enumeration across baseline, Cycle 2 day 1 and cycle 4 day 1.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Carfilzomib | Number of Participants With Circulating Tumor Cell (CTC) Decline Over Three Time Points (Before Study Initiation, Day 1 of Cycles 2 and 4 | CTC decline | 3 Participants |
| Carfilzomib | Number of Participants With Circulating Tumor Cell (CTC) Decline Over Three Time Points (Before Study Initiation, Day 1 of Cycles 2 and 4 | CTC increased or No change/decline in CTC levels | 24 Participants |
Secondary
Number of Participants With Prostate-Specific Antigen (PSA) Changes
PSA levels were collected at each visit on the day of treatment. Linear regression with PSA as the dependent variable and time as the dependent variable was performed.
Time frame: Baseline through 36 months
Population: We were unable to collect blood specimen for PSA analysis for 1 patient.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Carfilzomib | Number of Participants With Prostate-Specific Antigen (PSA) Changes | 3 Participants |