LEE011 (Ribociclib) in Combination With Docetaxel Plus Prednisone in mCRPC

NCT02494921 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: 145515NCI-2015-01797
• Study Type: interventional
• Target: 43
• Locations: 1 country
• Sites: 6

Brief 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 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.

Conditions

Prostate Cancer

Keywords

Metastatic; Castration-Resistant

Outcome Measures

Primary Outcomes (3)

• 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.

  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.

  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.

  Up to 6 months

Secondary Outcomes (9)

• Median Radiographic Progression-free Survival (Phase1b/2 RP2D)

  Up to 2 years

• Objective Response Rate (ORR) (Phase1b/2 RP2D)

  Up to 2 years

• Median Duration of Response (Phase1b/2 RP2D)

  Up to 2 years

• Prostate-Specific Antigen (PSA) Response Rate (Phase 1b/2 RP2D)

  Up to 2 years

• Median PSA Progression-Free Survival (Phase 1b/2 RP2D)

  Up to 2 years

Study Arms (2)

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.

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

Drug: Docetaxel-PNP; Drug: Ribociclib; Drug: Prednisone; Drug: Filgrastim

Interventions

Docetaxel-PNP DRUG

Given IV

Also known as: Taxotere, Docetaxel Injection

Treatment (Phase 1b); Treatment (Phase 2)

Ribociclib DRUG

Given Orally

Also known as: Kisqali

Treatment (Phase 1b); Treatment (Phase 2)

Prednisone DRUG

Given Orally

Also known as: Prednisone Oral

Treatment (Phase 1b); Treatment (Phase 2)

Filgrastim DRUG

Given IV

Also known as: Neupogen

Treatment (Phase 1b); Treatment (Phase 2)

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.
• 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

Sponsors & Collaborators

• Rahul Aggarwal: lead
• Novartis: collaborator

Study Sites (6)

University of California, San Francisco

San Francisco, California, 94143, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

University of Chicago Comprehensive Cancer Center

Chicago, Illinois, 60637, United States

Location

University of Michigan Comprehensive Cancer Center

Ann Arbor, Michigan, 48109, United States

Location

University of Minnesota Masonic Cancer Center

Minneapolis, Minnesota, 55455, United States

Location

Brown University

Providence, Rhode Island, 02912, United States

Location

MeSH Terms

Conditions

Prostatic Neoplasms; Neoplasm Metastasis

Interventions

Docetaxel; ribociclib; Prednisone; Filgrastim

Condition Hierarchy (Ancestors)

Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Granulocyte Colony-Stimulating Factor; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Limitations and Caveats

Participants assigned to the Phase 1b RP2D cohort were included in a combined Phase 1b/2 RP2D group for some of the analyses.

Results Point of Contact

• Title: Dr. Rahul Aggarwal, MD
• Organization: University of California, San Francisco

Rahul.Aggarwal@ucsf.edu

(415) 353-9278

Study Officials

• Rahul Aggarwal, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Clinical Professor

Study Record Dates

• First Submitted: July 8, 2015
• First Posted: July 10, 2015
• Study Start: November 20, 2015
• Primary Completion: July 30, 2021
• Study Completion: July 30, 2021
• Last Updated: August 31, 2022
• Results First Posted: August 31, 2022

Record last verified: 2022-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (6)