Prostate CancerPhase 1/2NCT02494921
LEE011 (Ribociclib) in Combination With Docetaxel Plus Prednisone in mCRPC
A Phase 1/2 study testing Docetaxel-PNP, Ribociclib and Prednisone in people with Prostate Cancer, run by Rahul Aggarwal at 6 sites in United States.
Trial summary
This is a Phase Ib/II open label clinical trial in patients with metastatic castration resistant prostate cancer. The objective of the phase Ib portion of the study is to establish the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of docetaxel (75 mg/m2 IV q21 days) and prednisone (5mg orally BID) in… Read more about this study
- Who is it for?
- Ages 18 years and older, men only
- Conditions the study is for
- Prostate Cancer
- What is being tested?
- Docetaxel-PNP, Ribociclib and Prednisone
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 43 participants
- Where
- 6 sitesUnited States
- Study dates
- 20 Nov 2015to 30 Jul 2021
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Men only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Histologically confirmed prostate cancer. Small cell/neuroendocrine differentiated allowed but not required for study participation.
- Progressive metastatic prostate cancer (as defined below in Item #5) despite castrate levels of testosterone (< 50 ng/dL).
- Patients may have either non-measurable disease OR measurable disease
- Progressive disease during (or within 4 weeks of completion) with abiraterone, enzalutamide, and/or ARN-509 based on any one of the following:
- For patients with measurable disease, progression by the RECIST criteria.
- PSA evidence for progressive prostate cancer consists of a PSA level of at least 2 ng/ml which has risen on at least 2 successive occasions, at least one week apart. If the confirmatory PSA (#3) value is less (i.e., #3b) than the screening PSA (#2) value, then an additional test for rising PSA (#4) will be required to document progression for the purposes of eligibility.
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- Radionuclide bone scan: At least two new foci consistent with metastatic lesions
- Testosterone < 50 ng/dL. Patients must continue primary androgen deprivation with a luteinizing hormone-releasing hormone (LHRH) analogue if they have not undergone orchiectomy.
- Patients treated with first generation anti-androgen as most recent systemic therapy (bicalutamide, nilutamide) must have at least 4 weeks elapsed from treatment discontinuation to start of protocol therapy with evidence of disease progression by Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria following discontinuation of prior anti-androgen.
- Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1.
- Patient has adequate bone marrow and organ function as defined by the following laboratory values:
- Absolute neutrophil count ≥ 1.5 × 109/L.
- Platelets ≥ 100 × 109/L.
- Hemoglobin ≥ 9 g/dl.
- Potassium, total calcium (corrected for serum albumin) and magnesium within normal limits for the institution or corrected to within normal limits before first dose of study medication.
- International normalized ratio (INR) ≤ 1.5 unless on direct thrombin inhibitor at time of study entry.
- Serum creatinine ≤ 1.5mg/dL or estimated creatinine clearance ≥ 50 ml/min
- In the absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <2.5 x upper limit of normal (ULN). If the patient has liver metastases, ALT and AST <5 x ULN
- Total bilirubin < ULN; or total bilirubin ≤3.0 x ULN or direct bilirubin ≤1.5 x ULN in patients with well-documented Gilbert's Syndrome.
- No other systemic therapies for prostate cancer within 28 days or 5 half-lives, whichever is shorter, prior to day 1 of study therapy.
- Sexually active males must use a condom during intercourse while taking the drug and for 30 days after stopping treatment and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid. Fertile males must use a condom with spermicide (double barrier method).
- Age ≥ 18 years
- Written informed consent must be obtained prior to any screening procedures and according to local guidelines.
Who cannot join
- Patient has a known hypersensitivity to ribociclib or any of its excipients, or prior treatment with cyclin-dependent kinase (CDK) 4/6 inhibitor.
- Prior chemotherapy for metastatic castration-resistant prostate cancer. Chemotherapy administered in the castration-sensitive setting is allowed provided last dose of chemotherapy was greater than 6 months prior to study entry
- Patient has a concurrent malignancy or malignancy within 3 years of randomization, with the exception of adequately treated, basal cell skin cancer, squamous cell carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer.
- Patients with central nervous system (CNS) involvement unless they meet all of the following criteria:
- At least 4 weeks from prior therapy completion (including radiation and/or surgery) to starting the study treatment
- Clinically stable CNS tumor at the time of screening and not receiving steroids and/or enzyme-inducing anti-epileptic medications for brain metastases.
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- Baseline screening for CNS metastases is not required unless presence of signs and/or symptoms of involvement
- Patient is not able to swallow oral medication and/or has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or significant small bowel resection).
- Clinically significant, uncontrolled heart disease and/or recent events including any of the following:
- History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty or stenting) or symptomatic pericarditis within 12 months prior to screening
- History of documented congestive heart failure (New York Heart Association functional classification III-IV)
- Patient has a left ventricular ejection fraction (LVEF) < 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO) obtained during Screening.
- History of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality within 12 months of screening. Patients with rate-controlled atrial fibrillation or flutter are permitted.
- Bradycardia (heart rate < 50 bpm at rest), by ECG or pulse, at screening
- Congenital long QT syndrome or family history of long QT syndrome
- Any of the following abnormalities on screening 12-lead ECG:
- QT interval with Fridericia's correction (QTcF) > 450 msec
- Bradycardia (heart rate < 50 bpm at rest)
- Tachycardia (heart rate > 100 bpm at rest)
- P-R interval > 220msec,
- QRS interval >109 msec
- Documented cardiomyopathy
- Systolic blood pressure >160 mmHg or <90 mmHg at screening
- AST and/or ALT > 1.5 x ULN with concomitant alkaline phosphatase > 2.5 x ULN
- Patient receiving any of the following medications within 7 days of day 1 of study treatment.
- Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit hybrids, pummelos, star-fruit, and Seville oranges
- That have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5.
- That have a known risk to prolong the QT interval or induce Torsades de Pointes.
- Herbal preparations/medications
- Patient is currently receiving or has received systemic corticosteroids ≤2 weeks prior to starting study drug at a dose greater than the equivalent of 10 mg prednisone/day, or who have not fully recovered from the side effects of such treatment
- The following uses of corticosteroids are permitted: short duration (<5 days) of systemic corticosteroids; any duration of topical applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intra-articular).
- Patient is currently receiving warfarin or other coumarin-derived anticoagulant for treatment, prophylaxis or otherwise. Therapy with heparin, direct thrombin inhibitors, low molecular weight heparin (LMWH) or fondaparinux is allowed.
- Participation in a prior investigational study within 30 days prior to enrollment or within 5 half-lives of the investigational product, whichever is longer
- Major surgery within 14 days prior to starting study drug or has not recovered from major side effects (tumor biopsy is not considered as major surgery).
- Patient who has received radiotherapy ≤4 weeks or limited field radiation for palliation ≤2 weeks prior to starting study drug, and who has not recovered to grade 1 or better from related side effects of such therapy (exceptions include alopecia), and/or in whom ≥25% of the bone marrow was irradiated.
- Patient has a known history of HIV infection (testing not required)
- Patient has not recovered from all toxicities related to prior anticancer therapies to NCI-CTCAE version 4.03 to less than or equal to Grade 1 (Exception to this criterion: patients with grade 1 taxane-induced neuropathy, any grade of alopecia, amenorrhea or other toxicities not considered a safety risk for the patient as per investigator's discretion, are allowed to enter the study).
- Patients with chronic liver disease with a Child-Pugh score B or C.
- Patients with serious intercurrent infections, or nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the complications of this therapy.
- Patients with severe psychiatric illness/social situations that would limit compliance with study requirements in the judgment of study investigator.
- History of bleeding diathesis. Patients receiving anti-coagulation must be able safely interrupt treatment for tumor biopsy (Phase 2 only)
- Patient has a history of non-compliance to medical regimen or inability to grant consent
Trial locations and contacts
6 sites in 1 country.
6 sites in 1 country
United States6 sites
University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan, 48109
Northwestern University
Chicago, Illinois, 60611
University of Chicago Comprehensive Cancer Center
Chicago, Illinois, 60637
University of Minnesota Masonic Cancer Center
Minneapolis, Minnesota, 55455
Brown University
Providence, Rhode Island, 02912
University of California, San Francisco
San Francisco, California, 94143
About this study
Official title: A Phase 1b/2 Study of the Oral CDK4/6 Inhibitor LEE011 (Ribociclib) in Combination With Docetaxel Plus Prednisone in Metastatic Castration Resistant Prostate Cancer
This is a Phase Ib/II open label clinical trial in patients with metastatic castration resistant prostate cancer. The objective of the phase Ib portion of the study is to establish the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of docetaxel (75 mg/m2 IV q21 days) and prednisone (5mg orally BID) in combination with ribociclib in escalating oral daily doses in patients with metastatic castrate resistant prostate cancer (mCRPC) with prior resistance to abiraterone and/or enzalutamide who have not undergone prior chemotherapy for metastatic disease. Up to three cohorts will be enrolled to determine the MTD and DLT profile of this combination during Phase 1b. Dose escalation will follow the standard 3+3 design. The dosing schedule is being chosen to allow patients to be exposed to the most efficacious dosing schedule of docetaxel (75 mg/m2 every 3 weeks). If there is excess toxicity observed with the treatment combination at the first dose level (dose level I), an alternative dosing schema may be pursued with weekly docetaxel treatment (35 mg/m2 weekly), which has demonstrated activity in mCRPC and decreased risk of cytopenias compared with every 3 week dosing schedule.
The Phase II portion (N = 29) of the study is a single arm, two stage, open-label study of ribociclib (dosed at the RP2D) in combination with docetaxel and prednisone to determine the efficacy and further define the safety of the treatment combination. Patients will be treated with the combination of ribociclib plus docetaxel + prednisone for up to 9 cycles. If there is no evidence of radiographic or clinical disease progression after 9 cycles of protocol therapy, patients may continue on single agent maintenance ribociclib until the time of disease progression. Patients will have the option of starting maintenance ribociclib after 6 cycles of docetaxel if stable disease or better on re-staging scans. The dose of ribociclib used during maintenance will be the same dose as that immediately preceding cessation of docetaxel treatment.
Read the detailed description
PRIMARY OBJECTIVES:
- To determine the safety profile, maximally tolerated dose (MTD), and recommended phase 2 dose of ribociclib in combination with docetaxel plus prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC). (Phase IB) II. To determine the 6-month radiographic progression-free survival rate with the combination of ribociclib, docetaxel, and prednisone in patients with mCRPC. (Phase 2)
SECONDARY OBJECTIVES:
- To determine the median radiographic progression-free survival with the combination of ribociclib, docetaxel, and prednisone in patients with mCRPC.
II. To determine the objective response rate and median duration of response among patients with measurable disease at baseline.
III. To determine the prostate-specific antigen (PSA) response proportion and time to PSA progression.
IV. To characterize the safety profile of ribociclib in combination with docetaxel.
- To determine if there is evidence of drug-drug interaction between docetaxel + prednisone with ribociclib.
EXPLORATORY OBJECTIVES:
- To determine whether baseline or percent change from baseline in gallium citrate uptake on positron emission tomography (PET) scan is associated with clinical outcomes. (For University of California San Francisco (USCF) Patients Only) II. To determine whether genomic assessment of MYC pathway activation (MYC amplification or overexpression, Rb1 deletion, cyclin D/E and CDK 4/6 overexpression) assessed within metastatic tumor tissue, circulating tumor cells (CTCs), and/or cell-free circulating tumor deoxyribonucleic acid (ctDNA) is predictive of clinical outcomes with the combination of ribociclib plus docetaxel.
III. To determine whether MYC activation score as determined by validated expression signature can distinguish those with and without clinical benefit with ribociclib in combination with docetaxel.
IV. To use an unbiased approach with integration of clinical, genomic, and proteomic data (differential pathway signature correlation; DiPSC) to define a signature associated with response to taxane + CDK4/6 inhibition in mCRPC.
OUTLINE: This is a phase Ib, dose-escalation study of ribociclib followed by a phase II study.
Patients receive docetaxel intravenously (IV) over 1 hour on day 1 or on days 1 and 8, prednisone orally (PO) twice daily (BID) on days 1-21, and ribociclib PO once daily (QD) on days 1-4, and 8-15. Treatment repeats every 21 days for 9 cycles in the absence of disease progression or unacceptable toxicity. Patients achieving stable disease or better on re-staging scans after 6 cycles and patients without radiographic or clinical disease progression after 9 cycles of treatment may continue on single agent maintenance ribociclib PO QD on days 1-14 of every 21 day cycle in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every three months.
- Conditions
- Prostate Cancer
- Being tested
- Docetaxel-PNP, Ribociclib, Prednisone, Filgrastim
- Keywords
- Metastatic, Castration-Resistant
- Medical subject headings
- Prostatic Neoplasms, Neoplasm Metastasis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Docetaxel-PNPDrug
Also called Taxotere, Docetaxel Injection
Given IV
RibociclibDrug
Also called Kisqali
Given Orally
PrednisoneDrug
Also called Prednisone Oral
Given Orally
FilgrastimDrug
Also called Neupogen
Given IV
| Study group | Role | What they receive |
|---|---|---|
| Treatment (Phase 1b) | Experimental | The starting cohort dose level (1) for docetaxel will be 75 mg/m2, administered on day 1 of each cycle. Prednisone will be fixed at 5 mg twice a day. The starting dose level and schedule for ribociclib will begin at 200 mg orally once daily, starting on day 1 of the 21-day cycle. If dose level 1 is not tolerated, then alternative dosing schedules of docetaxel will be evaluated, starting with dose level 1A of 60mg/m2 docetaxel. Receives: Drug: Docetaxel-PNP; Drug: Ribociclib; Drug: Prednisone; Drug: Filgrastim |
| Treatment (Phase 2) | Experimental | Participants in Phase 2 will receive the Recommended Phase 2 Dose for docetaxel and ribociclib Receives: Drug: Docetaxel-PNP; Drug: Ribociclib; Drug: Prednisone; Drug: Filgrastim |
What is being measured
The primary outcome is the main question the study is designed to answer.
Maximally Tolerated Dose (MTD) (Phase 1b)
Maximally tolerated dose (MTD) of ribociclib in combination with docetaxel and prednisone is based upon evaluation of dose-limiting toxicities (DLTs) and adverse events for all participants who received treatment in Phase Ib. If 1 of 3 participants in a cohort experiences a DLT, then the cohort will be expanded to treat an additional 3 participants. If only 1 of 6 participants experiences a DLT, the next cohort of participants will be treated at the next higher dose level. If 2 or more participants in a cohort experience a DLT, then MTD has been exceeded and the previous dose level will be considered the MTD. If more than 1 of 6 patients experience a DLT at dose level IA then the study will be terminated, as the MTD cannot be determined and de-escalation from dose level IA is not planned. Per Investigator discretion the Recommended Phase 2 Dose (RP2D) schedule of ribociclib and docetaxel may be established in the absence of reaching MTD.
Measured: Up to 2 years
RP2D of Docetaxel (Phase 1b)
The RP2D of docetaxel will be reported when used in combination with ribociclib and prednisone based upon evaluation of dose-limiting toxicities (DLTs) and adverse events for all participants in the Phase Ib group. Per Investigator discretion, the RP2D schedule of docetaxel and ribociclib may be established in the absence of reaching MTD, based on the cumulative safety data of the treatment regimen.
Measured: Up to 2 years
Percentage of Participants With Radiographic Progression-free Survival at 6 Months (Phase 1b/2 RP2D)
Radiographic progression-free survival will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The percent of participants has been estimated using the Kaplan-Meier product limit method. Duration will be measured from day 1 of study treatment to first date of radiographic progression or death, whichever occurs first, for all Phase 1b or Phase 2 participants receiving the RP2D. Participants who discontinue study therapy for toxicity, withdrawal from study, or prostate-specific antigen (PSA)-only progression, will be censored at the date of last radiographic tumor assessment for this analysis. Patients who discontinue therapy for evidence of clinical progression/clinical deterioration will be included in this analysis.
Measured: Up to 6 months
Secondary outcomes (9)
Median Radiographic Progression-free Survival (Phase1b/2 RP2D)
Radiographic progression-free survival will be assessed using RECIST version 1.1. Median duration will be Estimated using the Kaplan-Meier product limit method. Duration will be measured from day 1 of study treatment to first date of radiographic progression or death, whichever occurs sooner for participants in Phase 1b and Phase 2 who receive the RP2D. Participants who discontinue study therapy for toxicity, withdrawal from study, or prostate-specific antigen (PSA)-only progression, will be censored at the date of last radiographic tumor assessment for this analysis. Participants who discontinue therapy for evidence of clinical progression/clinical deterioration will be included in this analysis.
Measured: Up to 2 years
Objective Response Rate (ORR) (Phase1b/2 RP2D)
ORR will be assessed using RECIST version 1.1 criteria, and defined as participants who were determined to have demonstrated a complete response (CR) and/or partial response (PR). Participants must have measurable disease at baseline with at least one restaging scan on treatment to be included in the analysis.
Measured: Up to 2 years
Median Duration of Response (Phase1b/2 RP2D)
For participants with both measurable disease at baseline and at least one restaging scan on treatment, duration of response will be defined as the time criteria are met for CR or PR until recurrent or progressive disease is objectively documented.
Measured: Up to 2 years
Prostate-Specific Antigen (PSA) Response Rate (Phase 1b/2 RP2D)
PSA progression occurs when the PSA value has increased 25% or greater above nadir and an absolute increase of 2 ng/mL or more from the nadir is documented. Where no decline is observed, PSA progression similarly occurs when a 25% increase from baseline value along with an increase in absolute value of 2 ng/mL or more per the Prostate Cancer Working Group 2 (PCWG2) Criteria.
Measured: Up to 2 years
Median PSA Progression-Free Survival (Phase 1b/2 RP2D)
The PSA response duration commences on the date of the first 50% decline in PSA. The response duration ends when the PSA value increases by 25% above the nadir, provided that the increase in the absolute-value PSA level is at least 5 ng/mL or back to baseline, whichever is lower. The probability distribution of the median time to PSA progression will be estimated using the Kaplan-Meier product limit method.
Measured: Up to 2 years
Number of Participants With Treatment-Related Adverse Events
The number of participants with reported adverse events related to the treatment regimen will be descriptively reported using the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Analyses will be performed for all patients having received at least one dose of study drug.
Measured: Up to 2 years
Mean Area Under Curve (AUC) 0-24 Hour (Phase 1b)
The estimated AUC for serum concentration of ribociclib for a 24 hour interval after dose will be reported using descriptive statistics for all participants in Phase 1b who received at least one dose of study treatment and completed a serum blood draw.
Measured: Pre-dose on day 1, and 1, 2, 4, and 24 hours post-dose
Mean Maximum Serum Concentration of Ribociclib (Cmax) (Phase 1b)
The maximum concentration (Cmax) is shown to reflect not only the rate but also the extent of absorption. The mean Cmax for serum concentration of ribociclib will be reported using descriptive statistics for all participants in Phase 1b who received at least one dose of study treatment and completed a serum blood draw.
Measured: Pre-dose on day 1, and 1, 2, 4, and 24 hours post-dose
Estimated Steady-state Serum Concentration (Csteady-state) (Phase 1b)
Steady-state serum concentration occurs when the amount of a drug being absorbed is the same amount that is being cleared from the body when the drug is given continuously. Steady-state concentration is the time during which the concentration of the drug in the body stays consistent. The estimated steady state for serum concentration of ribociclib will be reported using descriptive statistics for all participants in Phase 1b who received a steady dosing schedule of study treatment and completed a serum blood draw.
Measured: Up to 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Jul 2015 (estimated)
- Study start20 Nov 2015
- Primary completion30 Jul 2021
- Study completion30 Jul 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Prostate CancerStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 43 participants (actual)
Sponsor and investigators
- Lead sponsor
- Rahul Aggarwal
- Sponsor type
- University, hospital or other
- Collaborators
- Novartis
- Responsible party
- Sponsor-investigator, Rahul Aggarwal, University of California, San Francisco
- Investigators
- Rahul Aggarwal, MD, Principal investigator, University of California, San Francisco
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02494921
- Sponsor's protocol ID
- 145515
- Other IDs
- NCI-2015-01797
- Status last verified
- Aug 2022
- First submitted
- 8 Jul 2015
- Last updated
- 31 Aug 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 31 Aug 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 1b/2 Study of the Oral CDK4/6 Inhibitor LEE011 (Ribociclib) in Combination With Docetaxel Plus Prednisone in Metastatic Castration Resistant Prostate Cancer
- ClinicalTrials.gov ID
- NCT02494921
- Acronym / sponsor ID
- 145515
- Conditions
- Prostate Cancer
- Keywords
- Metastatic, Castration-Resistant
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 43 participants (actual)
- Lead sponsor
- Rahul AggarwalUniversity, hospital or other
- Collaborators
- Novartis
- Study start
- 20 Nov 2015 (actual)
- Primary completion
- 30 Jul 2021 (actual)
- Study completion
- 30 Jul 2021 (actual)
- First posted
- 10 Jul 2015 (estimated)
- Results
- Posted 31 Aug 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This is a Phase Ib/II open label clinical trial in patients with metastatic castration resistant prostate cancer. The objective of the phase Ib portion of the study is to establish the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of docetaxel (75 mg/m2 IV q21 days) and prednisone (5mg orally BID) in combination with ribociclib in escalating oral daily doses in patients with metastatic castrate resistant prostate cancer (mCRPC) with prior resistance to abiraterone and/or enzalutamide who have not undergone prior chemotherapy for metastatic disease. Up to three cohorts will be enrolled to determine the MTD and DLT profile of this combination during Phase 1b. Dose escalation will follow the standard 3+3 design. The dosing schedule is being chosen to allow patients to be exposed to the most efficacious dosing schedule of docetaxel (75 mg/m2 every 3 weeks). If there is excess toxicity observed with the treatment combination at the first dose level (dose level I), an alternative dosing schema may be pursued with weekly docetaxel treatment (35 mg/m2 weekly), which has demonstrated activity in mCRPC and decreased risk of cytopenias compared with every 3 week dosing schedule.
The Phase II portion (N = 29) of the study is a single arm, two stage, open-label study of ribociclib (dosed at the RP2D) in combination with docetaxel and prednisone to determine the efficacy and further define the safety of the treatment combination. Patients will be treated with the combination of ribociclib plus docetaxel + prednisone for up to 9 cycles. If there is no evidence of radiographic or clinical disease progression after 9 cycles of protocol therapy, patients may continue on single agent maintenance ribociclib until the time of disease progression. Patients will have the option of starting maintenance ribociclib after 6 cycles of docetaxel if stable disease or better on re-staging scans. The dose of ribociclib used during maintenance will be the same dose as that immediately preceding cessation of docetaxel treatment.
Detailed description
PRIMARY OBJECTIVES:
- To determine the safety profile, maximally tolerated dose (MTD), and recommended phase 2 dose of ribociclib in combination with docetaxel plus prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC). (Phase IB) II. To determine the 6-month radiographic progression-free survival rate with the combination of ribociclib, docetaxel, and prednisone in patients with mCRPC. (Phase 2)
SECONDARY OBJECTIVES:
- To determine the median radiographic progression-free survival with the combination of ribociclib, docetaxel, and prednisone in patients with mCRPC.
II. To determine the objective response rate and median duration of response among patients with measurable disease at baseline.
III. To determine the prostate-specific antigen (PSA) response proportion and time to PSA progression.
IV. To characterize the safety profile of ribociclib in combination with docetaxel.
- To determine if there is evidence of drug-drug interaction between docetaxel + prednisone with ribociclib.
EXPLORATORY OBJECTIVES:
- To determine whether baseline or percent change from baseline in gallium citrate uptake on positron emission tomography (PET) scan is associated with clinical outcomes. (For University of California San Francisco (USCF) Patients Only) II. To determine whether genomic assessment of MYC pathway activation (MYC amplification or overexpression, Rb1 deletion, cyclin D/E and CDK 4/6 overexpression) assessed within metastatic tumor tissue, circulating tumor cells (CTCs), and/or cell-free circulating tumor deoxyribonucleic acid (ctDNA) is predictive of clinical outcomes with the combination of ribociclib plus docetaxel.
III. To determine whether MYC activation score as determined by validated expression signature can distinguish those with and without clinical benefit with ribociclib in combination with docetaxel.
IV. To use an unbiased approach with integration of clinical, genomic, and proteomic data (differential pathway signature correlation; DiPSC) to define a signature associated with response to taxane + CDK4/6 inhibition in mCRPC.
OUTLINE: This is a phase Ib, dose-escalation study of ribociclib followed by a phase II study.
Patients receive docetaxel intravenously (IV) over 1 hour on day 1 or on days 1 and 8, prednisone orally (PO) twice daily (BID) on days 1-21, and ribociclib PO once daily (QD) on days 1-4, and 8-15. Treatment repeats every 21 days for 9 cycles in the absence of disease progression or unacceptable toxicity. Patients achieving stable disease or better on re-staging scans after 6 cycles and patients without radiographic or clinical disease progression after 9 cycles of treatment may continue on single agent maintenance ribociclib PO QD on days 1-14 of every 21 day cycle in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every three months.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Treatment (Phase 1b) | Experimental | Drug: Docetaxel-PNP, Drug: Ribociclib, Drug: Prednisone, Drug: FilgrastimThe starting cohort dose level (1) for docetaxel will be 75 mg/m2, administered on day 1 of each cycle. Prednisone will be fixed at 5 mg twice a day. The starting dose level and schedule for ribociclib will begin at 200 mg orally once daily, starting on day 1 of the 21-day cycle. If dose level 1 is not tolerated, then alternative dosing schedules of docetaxel will be evaluated, starting with dose level 1A of 60mg/m2 docetaxel. |
| Treatment (Phase 2) | Experimental | Drug: Docetaxel-PNP, Drug: Ribociclib, Drug: Prednisone, Drug: FilgrastimParticipants in Phase 2 will receive the Recommended Phase 2 Dose for docetaxel and ribociclib |
Who may qualify
- Ages
- 18 years and older
- Sex
- Male only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (23 listed)
- Histologically confirmed prostate cancer. Small cell/neuroendocrine differentiated allowed but not required for study participation.
- Progressive metastatic prostate cancer (as defined below in Item #5) despite castrate levels of testosterone (< 50 ng/dL).
- Patients may have either non-measurable disease OR measurable disease
- Progressive disease during (or within 4 weeks of completion) with abiraterone, enzalutamide, and/or ARN-509 based on any one of the following:
- Testosterone < 50 ng/dL. Patients must continue primary androgen deprivation with a luteinizing hormone-releasing hormone (LHRH) analogue if they have not undergone orchiectomy.
Key exclusion criteria (42 listed)
- Patient has a known hypersensitivity to ribociclib or any of its excipients, or prior treatment with cyclin-dependent kinase (CDK) 4/6 inhibitor.
- Prior chemotherapy for metastatic castration-resistant prostate cancer. Chemotherapy administered in the castration-sensitive setting is allowed provided last dose of chemotherapy was greater than 6 months prior to study entry
- Patient has a concurrent malignancy or malignancy within 3 years of randomization, with the exception of adequately treated, basal cell skin cancer, squamous cell carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer.
- Patients with central nervous system (CNS) involvement unless they meet all of the following criteria:
- At least 4 weeks from prior therapy completion (including radiation and/or surgery) to starting the study treatment
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Docetaxel-PNPAlso: Taxotere, Docetaxel InjectionGiven IV | Drug | Treatment (Phase 1b), Treatment (Phase 2) |
| RibociclibAlso: KisqaliGiven Orally | Drug | Treatment (Phase 1b), Treatment (Phase 2) |
| PrednisoneAlso: Prednisone OralGiven Orally | Drug | Treatment (Phase 1b), Treatment (Phase 2) |
| FilgrastimAlso: NeupogenGiven IV | Drug | Treatment (Phase 1b), Treatment (Phase 2) |
Primary outcome
Maximally Tolerated Dose (MTD) (Phase 1b)
Time frame: Up to 2 years
Maximally tolerated dose (MTD) of ribociclib in combination with docetaxel and prednisone is based upon evaluation of dose-limiting toxicities (DLTs) and adverse events for all participants who received treatment in Phase Ib. If 1 of 3 participants in a cohort experiences a DLT, then the cohort will be expanded to treat an additional 3 participants. If only 1 of 6 participants experiences a DLT, the next cohort of participants will be treated at the next higher dose level. If 2 or more participants in a cohort experience a DLT, then MTD has been exceeded and the previous dose level will be considered the MTD. If more than 1 of 6 patients experience a DLT at dose level IA then the study will be terminated, as the MTD cannot be determined and de-escalation from dose level IA is not planned. Per Investigator discretion the Recommended Phase 2 Dose (RP2D) schedule of ribociclib and docetaxel may be established in the absence of reaching MTD.
RP2D of Docetaxel (Phase 1b)
Time frame: Up to 2 years
The RP2D of docetaxel will be reported when used in combination with ribociclib and prednisone based upon evaluation of dose-limiting toxicities (DLTs) and adverse events for all participants in the Phase Ib group. Per Investigator discretion, the RP2D schedule of docetaxel and ribociclib may be established in the absence of reaching MTD, based on the cumulative safety data of the treatment regimen.
Percentage of Participants With Radiographic Progression-free Survival at 6 Months (Phase 1b/2 RP2D)
Time frame: Up to 6 months
Radiographic progression-free survival will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The percent of participants has been estimated using the Kaplan-Meier product limit method. Duration will be measured from day 1 of study treatment to first date of radiographic progression or death, whichever occurs first, for all Phase 1b or Phase 2 participants receiving the RP2D. Participants who discontinue study therapy for toxicity, withdrawal from study, or prostate-specific antigen (PSA)-only progression, will be censored at the date of last radiographic tumor assessment for this analysis. Patients who discontinue therapy for evidence of clinical progression/clinical deterioration will be included in this analysis.
9 secondary outcomes
Median Radiographic Progression-free Survival (Phase1b/2 RP2D)
Time frame: Up to 2 years
Objective Response Rate (ORR) (Phase1b/2 RP2D)
Time frame: Up to 2 years
Median Duration of Response (Phase1b/2 RP2D)
Time frame: Up to 2 years
Prostate-Specific Antigen (PSA) Response Rate (Phase 1b/2 RP2D)
Time frame: Up to 2 years
Median PSA Progression-Free Survival (Phase 1b/2 RP2D)
Time frame: Up to 2 years
Number of Participants With Treatment-Related Adverse Events
Time frame: Up to 2 years
Mean Area Under Curve (AUC) 0-24 Hour (Phase 1b)
Time frame: Pre-dose on day 1, and 1, 2, 4, and 24 hours post-dose
Mean Maximum Serum Concentration of Ribociclib (Cmax) (Phase 1b)
Time frame: Pre-dose on day 1, and 1, 2, 4, and 24 hours post-dose
Estimated Steady-state Serum Concentration (Csteady-state) (Phase 1b)
Time frame: Up to 2 years
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 31 Aug 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Rahul Aggarwal, MD principal investigator
University of California, San Francisco
6 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Docetaxel-PNP, Ribociclib and Prednisone in people with Prostate Cancer, run by Rahul Aggarwal at 6 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 23 inclusion and 42 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 31 Aug 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 6 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 31 Aug 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Maximally Tolerated Dose (MTD) (Phase 1b) (time frame: Up to 2 years). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 Aug 2022.