Prostate Cancer
Conditions
Brief summary
This study will look at the effect of adding the drug Palbociclib to CAD (Combined Androgen Deprivation) therapy in patients with RB (Retinoblastoma Protein) positive hormone sensitive prostate cancer. The investigators hypothesize that the addition of Palbociclib to initial ADT (Androgen Deprivation Therapy) in patients with newly metastatic RB-positive prostate cancer may significantly increase the efficacy of ADT.
Detailed description
Patients will undergo exams, tests, and procedures to determine if they are eligible to participate. Subjects will be randomized to one of two groups. Patients randomized to Arm 1 - Patients will receive the LHRH agonist every 3 months. Patients will also take 50 mg. of bicalutamide by mouth every day. Bicalutamide comes in tablet form. This arm is broken down into periods of time called cycles, starting with cycle 1 then cycle 2, and so on.Each cycle is 28 days long. If randomized to Arm 2 - Patients will receive the LHRH agonist every 3 months. Patients will also take 50 mg. of bicalutamide by mouth every day. Patients will also take 125 mg. of Ibrance® daily for 21 days, and then will stop taking Ibrance® for 7 days. Patients will then begin taking Ibrance® again after 7 days off. Patients will keep repeating this cycle every 28 days. When the patient starts the first 28 day cycle that will be cycle 1, then cycle 2, and so on. During each cycle the patient will come in for routine and research tests and procedures for patient safety, to see how patients are doing, and for research purposes. The researchers will ask patients to complete a drug diary to track bicalutamide and Ibrance® administration. The total time of study participation depends on how a patient responds to the study medications. Patients may be on the study for a short period of time, such as a week, or for a longer period of time, such as a few years. Patients may continue on study treatment until one of the following: cancer progresses (gets worse); another illness or condition develops that prevents study participation; unacceptable side effects occur; drug is delayed more than 4 weeks; patient withdraws consent; the study doctor thinks the patient should stop; the patient does not follow researcher's instructions; the study is cancelled.
Interventions
Sponsors
University of Utah
Vanderbilt-Ingram Cancer Center
Johns Hopkins University
Thomas Jefferson University
Washington University School of Medicine
Northwestern University
City of Hope Comprehensive Cancer Center
University of Michigan Rogel Cancer Center
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
* Have pathologic diagnosis of prostate cancer. * Have hormone-sensitive metastatic disease (M1) as evidenced by soft tissue and/or bony metastases. * Patients may either be untreated for their newly diagnosed metastatic disease (preferred as much as possible) or have started androgen deprivation therapy. Patients who have started androgen deprivation therapy for the treatment of their newly diagnosed metastatic disease are eligible as long as the duration of treatment is less than or equal to 2 weeks (14days) prior to registration. The start date of androgen deprivation is considered the day the patient first received an injection of a LHRH agonist/antagonist (or orchiectomy), not the date when an oral antiandrogen started. * Patients must have a minimum PSA (Prostate-Specific Antigen) ≥ 5 ng/mL within 60 days of registration or prior to the initiation of androgen deprivation for patients who have started androgen deprivation therapy. * Agree to undergo a biopsy of at least one metastatic site for RB (Retinoblastoma Protein) status evaluation. Adequate metastatic tissue from prior biopsy/resection can be used if available in lieu of a biopsy. * ECOG performance status of 0-2 (Eastern Cooperative Oncology Group scoring system used to quantify general well-being and activities of daily life; scores range from 0 to 5 where 0 represents perfect health and 5 represents death). * Patients may have received prior neoadjuvant and/or adjuvant hormonal therapy, for non-metastatic disease but it must not have lasted for more than 36 months. At least 12 months must have elapsed since completion of androgen deprivation therapy in the neoadjuvant and/or adjuvant setting. * Within 14 days prior to registration patients must have adequate organ and marrow function: White Blood Cell (WBC) count ≥ 3,000/μl, Absolute Neutrophil Count (ANC) ≥ 1,500/μl, Platelet Count ≥ 100,000/μl, Serum Creatinine ≥1.5 x the institutional upper limits of normal or corrected creatinine clearance of ≥ 50 mg/ml/hr/1.73 m2 BSA (Body Surface Area), Bilirubin within the institutional limits of normal, AST (Aspartate Aminotransferase) ≤ 2 x upper limits of normal, ALT (Alanine Aminotransferase) ≤ 2 x upper limits of normal. * Patients must be able to take oral medication without crushing, dissolving or chewing tablets. * Patients may have received prior radiation therapy or surgery. However, at least 14 days must have elapsed since completion of radiation therapy or surgery and patient must have only grade 2 or less adverse effects at the time of registration. * Patients must agree to use highly effective contraception during treatment and for a period of 90 days after ending treatment with PD 0332991. * Ability to understand and the willingness to sign a written informed consent document that is approved by an institutional review board.
Exclusion criteria
* Patients who have received androgen deprivation therapy for greater than 14 days (LHRH-agonist or antagonist) for the treatment of their newly diagnosed metastatic disease prior to enrollment are not eligible for this study. * Patients who are currently being treated with strong CYP3A4 inhibitors (e.g., amprenavir, fosamprenavir, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, miconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, voriconazole, and grapefruit) or strong inducers (e.g., carbamazepine, felbamate, nevirapine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine and St. John's wort) must either discontinue these drugs or are ineligible. * Patients must refrain from the use of proton pump inhibitors. If needed, alternative antacid therapies may be used including H2-receptor antagonists, and locally acting antacids. * Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure (New York Heart Association Class III and IV heart failure), unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * Patients with a currently active second malignancy other than non-melanoma skin cancers are not eligible. Patients are not considered to have a currently active malignancy if they have completed all therapy and are now considered without evidence of disease for 1 year. * HIV-positive patients on combination antiretroviral therapy are ineligible .
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Who Achieve a PSA ≤ 4ng/mL After Seven Months of Protocol Treatment in Each Arm | 28 weeks | The primary analysis will be assessment of the proportion of patients who achieve a (Prostate-specific antigen) PSA \< 4ng/mL after seven months of protocol treatment in each arm. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Therapy | Up to 54 months | Duration of therapy will be reported to describe tolerability within each arm. |
| Proportion of Patients Who Achieve Undetectable PSA (<0.2ng/mL) | Up to 54 months | — |
| Biochemical Progression-free Survival Rate | Up to 54 months | 12-month biochemical progression-free survival rate will begin from treatment start until the event of biochemical (PSA) progression or death, whichever occurs first. Described by arm using Kaplan-Meier methods. |
| Number of Participants With Grade >=3 Adverse Events That Are Possibly, Probably or Definitely Related to Study Treatment | Up to 54 months | Grade \>=3 adverse events that are possibly, probably or definitely related to study treatment, reported by number of participants affected in each arm |
| Frequency of Dose Modification | Up to 54 months | Dose modifications will be reported to describe tolerability for arm 2 only (Ibrance®) |
| Frequency of Treatment Delay | Up to 54 months | Treatment delays will be reported to describe tolerability within each arm. |
| Clinical Progression-free Survival Rate | Up to 54 months | 12-month clinical progression-free survival rate will begin from treatment start until the event of biochemical (PSA) progression or death, whichever occurs first. Described by arm using Kaplan-Meier methods. |
Countries
United States
Participant flow
Pre-assignment details
72 patients were enrolled to the trial. Seven patients did not have adequate tissue for testing retinoblastoma status. Two patients tested negative for retinoblastoma and one patient was found to have small cell metastasis and not adenocarcinoma. 62 patients were randomized.
Participants by arm
| Arm | Count |
|---|---|
| ADT Alone Androgen Deprivation Therapy (ADT): Bicalutamide (an active non-steroidal antiandrogen; 50mg taken daily by mouth) and Zoladex (LHRH agonist administered by injection), or Lupron Depot (LHRH agonist, administered by injection). | 20 |
| ADT + Ibrance® Ibrance® (125mg taken daily by mouth days 1-21 of a 28 day cycle) in addition to Androgen Deprivation Therapy (ADT): Bicalutamide (an active non-steroidal antiandrogen; 50mg taken daily by mouth) and Zoladex (LHRH agonist administered by injection), or Lupron Depot (LHRH agonist, administered by injection). | 42 |
| Total | 62 |
Baseline characteristics
| Characteristic | ADT Alone | ADT + Ibrance® | Total |
|---|---|---|---|
| Age, Continuous | 67.5 years | 67.5 years | 67.5 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 2 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 39 Participants | 55 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 20 Participants | 42 Participants | 62 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 1 / 40 |
| other Total, other adverse events | 20 / 20 | 40 / 40 |
| serious Total, serious adverse events | 5 / 20 | 7 / 40 |
Outcome results
Primary
Number of Patients Who Achieve a PSA ≤ 4ng/mL After Seven Months of Protocol Treatment in Each Arm
The primary analysis will be assessment of the proportion of patients who achieve a (Prostate-specific antigen) PSA \< 4ng/mL after seven months of protocol treatment in each arm.
Time frame: 28 weeks
Population: 72 patients were enrolled to the trial. Seven patients did not have adequate tissue for testing retinoblastoma status. Two patients tested negative for retinoblastoma and one patient was found to have small cell metastasis and not adenocarcinoma. 62 patients were randomized. 60 randomized patients initiated therapy on trial.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ADT Alone | Number of Patients Who Achieve a PSA ≤ 4ng/mL After Seven Months of Protocol Treatment in Each Arm | 16 Participants |
| ADT + Ibrance® | Number of Patients Who Achieve a PSA ≤ 4ng/mL After Seven Months of Protocol Treatment in Each Arm | 32 Participants |
Comparison: With 20 patients treated with ADT and 40 treated with ADT + palbociclib there is a 64.2% power to detect a 20% difference in proportions with a one-sided type I error of 0.10 using the mid p-value method of the Fisher's exact test.p-value: 0.87Fisher Exact
Secondary
Biochemical Progression-free Survival Rate
12-month biochemical progression-free survival rate will begin from treatment start until the event of biochemical (PSA) progression or death, whichever occurs first. Described by arm using Kaplan-Meier methods.
Time frame: Up to 54 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ADT Alone | Biochemical Progression-free Survival Rate | 12-month | 74.7 percentage of participants |
| ADT Alone | Biochemical Progression-free Survival Rate | 26-month (time of last event in Arm 1) | 45.8 percentage of participants |
| ADT Alone | Biochemical Progression-free Survival Rate | 43-month (time of last event in Arm 2) | 45.8 percentage of participants |
| ADT + Ibrance® | Biochemical Progression-free Survival Rate | 12-month | 76.5 percentage of participants |
| ADT + Ibrance® | Biochemical Progression-free Survival Rate | 26-month (time of last event in Arm 1) | 59.4 percentage of participants |
| ADT + Ibrance® | Biochemical Progression-free Survival Rate | 43-month (time of last event in Arm 2) | 33.9 percentage of participants |
p-value: 0.72Log Rank
Secondary
Clinical Progression-free Survival Rate
12-month clinical progression-free survival rate will begin from treatment start until the event of biochemical (PSA) progression or death, whichever occurs first. Described by arm using Kaplan-Meier methods.
Time frame: Up to 54 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ADT Alone | Clinical Progression-free Survival Rate | 12-month | 77.7 percentage of participants |
| ADT Alone | Clinical Progression-free Survival Rate | 22-month (time of last event in Arm 1) | 64.8 percentage of participants |
| ADT Alone | Clinical Progression-free Survival Rate | 32-month (time of last event in Arm 2) | 64.8 percentage of participants |
| ADT + Ibrance® | Clinical Progression-free Survival Rate | 12-month | 83.8 percentage of participants |
| ADT + Ibrance® | Clinical Progression-free Survival Rate | 22-month (time of last event in Arm 1) | 77.7 percentage of participants |
| ADT + Ibrance® | Clinical Progression-free Survival Rate | 32-month (time of last event in Arm 2) | 58.5 percentage of participants |
p-value: 0.76Log Rank
Secondary
Duration of Therapy
Duration of therapy will be reported to describe tolerability within each arm.
Time frame: Up to 54 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ADT Alone | Duration of Therapy | 22.4 months | Standard Deviation 13.1 |
| ADT + Ibrance® | Duration of Therapy | 22.0 months | Standard Deviation 13.8 |
p-value: 0.92t-test, 2 sided
Secondary
Frequency of Dose Modification
Dose modifications will be reported to describe tolerability for arm 2 only (Ibrance®)
Time frame: Up to 54 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ADT Alone | Frequency of Dose Modification | No Dose Reduction (Palbociclib 125mg/day) | 28 participants |
| ADT Alone | Frequency of Dose Modification | 1 Dose Reduction, to Palbociclib 100mg/day | 5 participants |
| ADT Alone | Frequency of Dose Modification | 2 Dose Reductions, to Palbociclib 75mg/day | 7 participants |
Secondary
Frequency of Treatment Delay
Treatment delays will be reported to describe tolerability within each arm.
Time frame: Up to 54 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ADT Alone | Frequency of Treatment Delay | No Treatment delay of Bicalutamide | 19 participants |
| ADT Alone | Frequency of Treatment Delay | No Treatment Delay of Palbociclib | 0 participants |
| ADT Alone | Frequency of Treatment Delay | Treatment Delay of Palbociclib | 0 participants |
| ADT Alone | Frequency of Treatment Delay | Treatment Delay of Bicalutamide | 1 participants |
| ADT + Ibrance® | Frequency of Treatment Delay | Treatment Delay of Palbociclib | 19 participants |
| ADT + Ibrance® | Frequency of Treatment Delay | No Treatment delay of Bicalutamide | 35 participants |
| ADT + Ibrance® | Frequency of Treatment Delay | Treatment Delay of Bicalutamide | 5 participants |
| ADT + Ibrance® | Frequency of Treatment Delay | No Treatment Delay of Palbociclib | 21 participants |
Secondary
Number of Participants With Grade >=3 Adverse Events That Are Possibly, Probably or Definitely Related to Study Treatment
Grade \>=3 adverse events that are possibly, probably or definitely related to study treatment, reported by number of participants affected in each arm
Time frame: Up to 54 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ADT Alone | Number of Participants With Grade >=3 Adverse Events That Are Possibly, Probably or Definitely Related to Study Treatment | 0 participants |
| ADT + Ibrance® | Number of Participants With Grade >=3 Adverse Events That Are Possibly, Probably or Definitely Related to Study Treatment | 23 participants |
Secondary
Proportion of Patients Who Achieve Undetectable PSA (<0.2ng/mL)
Time frame: Up to 54 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ADT Alone | Proportion of Patients Who Achieve Undetectable PSA (<0.2ng/mL) | 13 Participants |
| ADT + Ibrance® | Proportion of Patients Who Achieve Undetectable PSA (<0.2ng/mL) | 22 Participants |
p-value: 0.5Fisher Exact