A Phase II Study of Androgen Deprivation Therapy With or Without Palbociclib in RB-Positive Metastatic Prostate Cancer

A Randomized Phase II Study of Androgen Deprivation Therapy With or Without Palbociclib in RB-Positive Metastatic Hormone-Sensitive Prostate Cancer

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.

Study Overview

• Status: Completed
• Conditions: Prostate Cancer
• Intervention / Treatment: Drug: Bicalutamide; Drug: Zoladex; Drug: Lupron Depot; Drug: Ibrance

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.

• Study Type: Interventional
• Enrollment (Actual): 72
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope Cancer Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University in St. Louis
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt-Ingram Cancer Center
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute, University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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 .

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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).	Drug: Bicalutamide; Other Names: Casodex; Drug: Zoladex; Other Names: Goserelin acetate implant; Drug: Lupron Depot; Other Names: Leuprolide
Experimental: 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).	Drug: Bicalutamide; Other Names: Casodex; Drug: Zoladex; Other Names: Goserelin acetate implant; Drug: Lupron Depot; Other Names: Leuprolide; Drug: Ibrance; Other Names: PD 0332991; Palbociclib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	28 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Up to 54 months
Duration of Therapy	Duration of therapy will be reported to describe tolerability within each arm.	Up to 54 months
Proportion of Patients Who Achieve Undetectable PSA (<0.2ng/mL)		Up to 54 months
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.	Up to 54 months
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.	Up to 54 months
Frequency of Dose Modification	Dose modifications will be reported to describe tolerability for arm 2 only (Ibrance®)	Up to 54 months
Frequency of Treatment Delay	Treatment delays will be reported to describe tolerability within each arm.	Up to 54 months

Collaborators and Investigators

• Sponsor: University of Michigan Rogel Cancer Center
• Collaborators: Johns Hopkins University; Washington University School of Medicine; Northwestern University; University of Utah; Thomas Jefferson University; Vanderbilt-Ingram Cancer Center; City of Hope Comprehensive Cancer Center
• Investigators: Principal Investigator: Maha Hussain, MD, FACP, FASCO, University of Michigan Comprehensive Cancer Center and Northwestern University

Publications and helpful links

General Publications

• Palmbos PL, Daignault-Newton S, Tomlins SA, Agarwal N, Twardowski P, Morgans AK, Kelly WK, Arora VK, Antonarakis ES, Siddiqui J, Jacobson JA, Davenport MS, Robinson DR, Chinnaiyan AM, Knudsen KE, Hussain M. A Randomized Phase II Study of Androgen Deprivation Therapy with or without Palbociclib in RB-positive Metastatic Hormone-Sensitive Prostate Cancer. Clin Cancer Res. 2021 Jun 1;27(11):3017-3027. doi: 10.1158/1078-0432.CCR-21-0024. Epub 2021 Mar 16.

Study record dates

Study Major Dates

• Study Start: June 1, 2014
• Primary Completion (Actual): September 9, 2017
• Study Completion (Actual): June 4, 2019

Study Registration Dates

• First Submitted: February 7, 2014
• First Submitted That Met QC Criteria: February 10, 2014
• First Posted (Estimate): February 11, 2014

Study Record Updates

• Last Update Posted (Actual): September 16, 2020
• Last Update Submitted That Met QC Criteria: August 28, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protein Kinase Inhibitors; Hormone Antagonists; Reproductive Control Agents; Fertility Agents, Female; Fertility Agents; Androgen Antagonists; Palbociclib; Leuprolide; Goserelin; Bicalutamide
• Other Study ID Numbers: UMCC 2013.117; HUM00082715 (Other Identifier: University of Michigan)