NCT02494921

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

Completed Phase 1, PHASE2 Results posted Last updated 31 August 2022

What this trial tests

Phase 1, PHASE2 trial testing Docetaxel-PNP in Prostate Cancer in 43 participants. Completed in 30 July 2021.

Timeline

20 November 2015

Primary endpoint
30 July 2021

30 July 2021

Quick facts

Lead sponsor	Rahul Aggarwal
Phase	Phase 1, PHASE2
Status	Completed
Study type	INTERVENTIONAL
Allocation	non randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	43
Start date	20 November 2015
Primary completion	30 July 2021
Estimated completion	30 July 2021
Sites	6 locations across United States

Drugs / interventions tested

• Docetaxel-PNP — full drug profile →
• Ribociclib (ribociclib) — full drug profile →
• Prednisone (prednisone) — full drug profile →
• Filgrastim — full drug profile →

Conditions studied

• Prostate Cancer — all drugs for Prostate Cancer →

Sponsor

Rahul Aggarwal — full company profile →

Who can join

18 and older, male only, with Prostate Cancer. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Maximally Tolerated Dose (MTD) (Phase 1b) Primary · 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 con

Group	Value	95% CI
Treatment (Phase 1b)	NA

RP2D of Docetaxel (Phase 1b) Primary · 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.

Group	Value	95% CI
Treatment (Phase 1b)	60

Percentage of Participants With Radiographic Progression-free Survival at 6 Months (Phase 1b/2 RP2D) Primary · 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 asses

Group	Value	95% CI
Treatment (Phase 1b/2 RP2D)	65.8	50.6 – 85.5

Median Radiographic Progression-free Survival (Phase1b/2 RP2D) Secondary · Up to 2 years

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 disconti

Group	Value	95% CI
Treatment (Phase 1b/2 RP2D)	8.09	6.89 – 10.03

Objective Response Rate (ORR) (Phase1b/2 RP2D) Secondary · Up to 2 years

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.

Group	Value	95% CI
Treatment (Phase 1b/2 RP2D)	23.1	9.1 – 61.4

Median Duration of Response (Phase1b/2 RP2D) Secondary · Up to 2 years

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.

Group	Value	95% CI
Treatment (Phase 1b/2)	141.5	59 – 259

Prostate-Specific Antigen (PSA) Response Rate (Phase 1b/2 RP2D) Secondary · Up to 2 years

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.

Group	Value	95% CI
Treatment (Phase 1b/2 RP2D)	32	15.0 – 53.5

Median PSA Progression-Free Survival (Phase 1b/2 RP2D) Secondary · Up to 2 years

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.

Group	Value	95% CI
Treatment (Phase 1b/2 RP2D)	7.15	2.86 – 8.45

Number of Participants With Treatment-Related Adverse Events Secondary · Up to 2 years

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.

Group	Value	95% CI
Treatment (Phase 1b, Non-RP2D, Cohort I)	5
Treatment (Phase 1b, Non-RP2D, Cohort IA)	4
Treatment (Phase 1b, Non-RP2D, Cohort IIC)	4
Treatment (Phase 1b, R2PD, Cohort IIIC)	6
Treatment (Phase 2, RP2D)	22

Mean Area Under Curve (AUC) 0-24 Hour (Phase 1b) Secondary · Pre-dose on day 1, and 1, 2, 4, and 24 hours post-dose

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.

200 mg ribociclib

Group	Value	95% CI
Treatment (Phase 1b, Non-RP2D)	2909	1699.7 – 4119.2

300 mg ribociclib

Group	Value	95% CI
Treatment (Phase 1b, Non-RP2D)	3340.3	1825.3 – 6491.1

400 mg ribociclib

Group	Value	95% CI
Treatment (Phase 1b, RP2D)	6531.6	2922.5 – 10140.6

Mean Maximum Serum Concentration of Ribociclib (Cmax) (Phase 1b) Secondary · Pre-dose on day 1, and 1, 2, 4, and 24 hours post-dose

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.

200 mg Ribociclib

Group	Value	95% CI
Treatment (Phase 1b, Non-RP2D)	207.5	135.4 – 279.6

300 mg Ribociclib

Group	Value	95% CI
Treatment (Phase 1b, Non-RP2D)	289.8	92.5 – 672

400 mg Ribociclib

Group	Value	95% CI
Treatment (Phase 1b, RP2D)	393.6	139.5 – 647.6

Adverse events — posted to ClinicalTrials.gov

Time frame: Up to 2 years. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Treatment (Phase 1b, Non-RP2D, Cohort I)

Serious: 4/5 (80%)

Deaths: 4/5

Treatment (Phase 1b, Non-RP2D, Cohort IA)

Serious: 2/4 (50%)

Deaths: 1/4

Treatment (Phase 1b, Non-RP2D, Cohort IIC)

Serious: 0/4 (0%)

Deaths: 3/4

Treatment (Phase 1b, RP2D, Cohort IIIC)

Serious: 3/6 (50%)

Deaths: 3/6

Treatment (Phase 2, RP2D)

Serious: 5/24 (21%)

Deaths: 11/24

Serious adverse events (19 terms)

Reaction	System	Treatment (Phase 1b, Non-R…	Treatment (Phase 1b, Non-R…	Treatment (Phase 1b, Non-R…	Treatment (Phase 1b, RP2D,…	Treatment (Phase 2, RP2D)
Febrile neutropenia	Blood and lymphatic system disorders	—	—	—	—	—
Thromboembolic event	Vascular disorders	—	—	—	—	—
Back Pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Cardiac Arrest	Cardiac disorders	—	—	—	—	—
Fatigue	General disorders	—	—	—	—	—
Intracranial hemorrhage	Nervous system disorders	—	—	—	—	—
Seizure	Nervous system disorders	—	—	—	—	—
Headache	Nervous system disorders	—	—	—	—	—
Hyponatremia	Metabolism and nutrition disorders	—	—	—	—	—
Muscle weakness lower limb	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Pneumonitis	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Right lower visual field cut	Eye disorders	—	—	—	—	—
Transient ischemic attacks	Nervous system disorders	—	—	—	—	—
Aortic valve replacement	Surgical and medical procedures	—	—	—	—	—
Pain	General disorders	—	—	—	—	—
Hypocalcemia	Metabolism and nutrition disorders	—	—	—	—	—
Lung infection	Infections and infestations	—	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—	—
Pulmonary edema	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—

Other adverse events (97 terms — click to expand)

Reaction	System	Treatment (Phase 1b, Non-R…	Treatment (Phase 1b, Non-R…	Treatment (Phase 1b, Non-R…	Treatment (Phase 1b, RP2D,…	Treatment (Phase 2, RP2D)
Fatigue	General disorders	—	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—	—
Neutrophil count decreased	Investigations	—	—	—	—	—
Peripheral Neuropathy	Nervous system disorders	—	—	—	—	—
Alopecia	Skin and subcutaneous tissue disorders	—	—	—	—	—
Diarrhea	Gastrointestinal disorders	—	—	—	—	—
Dysgeusia	Nervous system disorders	—	—	—	—	—
Anemia	Blood and lymphatic system disorders	—	—	—	—	—
Musculoskeletal and connective tissue disorder - Other	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Edema Limbs	General disorders	—	—	—	—	—
Hypoalbuminemia	Metabolism and nutrition disorders	—	—	—	—	—
Decreased Appetite	Metabolism and nutrition disorders	—	—	—	—	—
Bone pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Musculoskeletal and connective tissue disorders, Other	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—	—
Mucositis oral	Gastrointestinal disorders	—	—	—	—	—
Lymphocyte count decreased	Investigations	—	—	—	—	—
Weight loss	Investigations	—	—	—	—	—
Anorexia	Metabolism and nutrition disorders	—	—	—	—	—
Hypokalemia	Metabolism and nutrition disorders	—	—	—	—	—
Hypomagnesemia	Metabolism and nutrition disorders	—	—	—	—	—
Hyponatremia	Metabolism and nutrition disorders	—	—	—	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Dizziness	Nervous system disorders	—	—	—	—	—
Ecchymosis	Skin and subcutaneous tissue disorders	—	—	—	—	—
Rash	Skin and subcutaneous tissue disorders	—	—	—	—	—
Hypotension	Vascular disorders	—	—	—	—	—
Epiphoria	Eye disorders	—	—	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—	—	—
Dry mouth	Gastrointestinal disorders	—	—	—	—	—
Dyspepsia	Gastrointestinal disorders	—	—	—	—	—
Fever	General disorders	—	—	—	—	—
Infusion related reaction	General disorders	—	—	—	—	—
Localized edema	General disorders	—	—	—	—	—
Non-cardiac chest pain	General disorders	—	—	—	—	—
Upper respiratory infection	Infections and infestations	—	—	—	—	—
Fall	Injury, poisoning and procedural complications	—	—	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—	—	—
Aspartate aminotransferase increased	Investigations	—	—	—	—	—

Most-reported serious reactions: Febrile neutropenia, Thromboembolic event, Back Pain, Cardiac Arrest, Fatigue, Intracranial hemorrhage, Seizure, Headache.

Data from ClinicalTrials.gov NCT02494921 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Cyclin D1, cancer progression, and opportunities in cancer treatment.
   Qie S, Diehl JA. · · 2016 · cited 527× · PMID 27695879 · DOI 10.1007/s00109-016-1475-3
2. Polymeric Nanoparticles for Drug Delivery.
   Beach MA, Nayanathara U, Gao Y, Zhang C, et al · · 2024 · cited 476× · PMID 38626459 · DOI 10.1021/acs.chemrev.3c00705
3. CDK4/6 Inhibitors: The Mechanism of Action May Not Be as Simple as Once Thought.
   Klein ME, Kovatcheva M, Davis LE, Tap WD, et al · · 2018 · cited 308× · PMID 29731395 · DOI 10.1016/j.ccell.2018.03.023
4. The Strange Case of CDK4/6 Inhibitors: Mechanisms, Resistance, and Combination Strategies.
   Knudsen ES, Witkiewicz AK. · · 2017 · cited 218× · PMID 28303264 · DOI 10.1016/j.trecan.2016.11.006
5. Targeting signaling pathways in prostate cancer: mechanisms and clinical trials.
   He Y, Xu W, Xiao YT, Huang H, et al · · 2022 · cited 192× · PMID 35750683 · DOI 10.1038/s41392-022-01042-7
6. PARP-1 regulates DNA repair factor availability.
   Schiewer MJ, Mandigo AC, Gordon N, Huang F, et al · · 2018 · cited 64× · PMID 30467127 · DOI 10.15252/emmm.201708816
7. Translational and clinical implications of the genetic landscape of prostate cancer.
   Spratt DE, Zumsteg ZS, Feng FY, Tomlins SA. · · 2016 · cited 58× · PMID 27245282 · DOI 10.1038/nrclinonc.2016.76
8. Chemotherapy and CDK4/6 Inhibitors: Unexpected Bedfellows.
   Roberts PJ, Kumarasamy V, Witkiewicz AK, Knudsen ES. · · 2020 · cited 48× · PMID 32546660 · DOI 10.1158/1535-7163.mct-18-1161