A Study of Abemaciclib in Combination With Sunitinib in Metastatic Renal Cell Carcinoma

NCT03905889 | Terminated Phase 1 DMC FDA Drug

• 1 other identifier: BrUOG 411
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to determine the safety, tolerability, and maximal tolerated dose (MTD) of the combination of Abemaciclib and Sunitinib administered orally in patients with advanced and metastatic renal cell carcinoma. This study consists of two parts: Dose Escalation and Dose Expansion. During the dose escalation phase, participants will be sequentially enrolled in a standard 3 x 3 dose escalation study design to receive oral Abemaciclib in Combination with Sunitinib. The purpose of this dose escalation is to determine the maximal tolerated dose based on assessment of any dose limiting toxicity. The Dose Expansion Phase will enroll additional participants at the established maximal tolerated dose to further evaluate safety, tolerability, as well as the pharmacokinetics and pharmacodynamics of this combination drug regimen.

Conditions

Renal Cell Carcinoma Metastatic

Keywords

Renal cell carcinoma; Abemaciclib; Sunitinib

Outcome Measures

Primary Outcomes (3)

• Maximum tolerated dose (MTD)

  A standard 3+3 trial design will be used to determine the safest maximal tolerated dose of the combination of Abemaciclib with Sunitinib. Doses of each medication will be increased or decreased based on upon tolerability and assessment of any dose limiting toxicity(ies) that may occur in study subjects. Safety and toxicity will be evaluated using the NCI Common Toxicity Criteria.

  At the end of Cycle 1 (each cycle is 21 days)

• Continued Toxicity assessment of the maximum tolerated dose (i.e the recommended Phase II dose) of Abemaciclib and Sunitinib as determined from the from dose escalation phase.

  Continued safety assessment of the combination of Abemaciclib and Sunitinib when administered at the maximal tolerated dose (i.e. the recommended phase 2 dose)

  44 days after the last dose of study drug

• Pharmacokinetic Assessment of Abemaciclib and Sunitinib trough levels at steady state

  Assessment of steady state trough levels of Abemaciclib and Sunitinib

  Days 8, 15, 21, 28, 35, 42, 56, 63, 77, 84, 98 (at the beginning and weekly during cycles 1 and 2, days 1 and 15 of cycles 3-5; a cycle is 21-days)

Secondary Outcomes (6)

• Disease Control Rate

  54 weeks

• Progression Free Survival

  3 years

• Overall Survival

  3 years

• Median Progression Free Survival

  3 years

• Median Overall Survival

  3 years

Study Arms (1)

Experimental Abemaciclib and Sunitinib

EXPERIMENTAL

For the dose escalation phase, Subjects will receive a 21-day cycle of continuous oral daily Sunitinib in combination with Abemaciclib every 12 hours for 14 days followed by 7 days off. Using a traditional 3 x 3 study design assessing dose limiting toxicity, if the initial prescribed dosing of these 2 medications (Dose Level 1) is tolerated by the first 3 subjects, the study will pause for a 30 day time period between cohorts to assess toxicity. If no dose limiting toxicity is identified, the next cohort of 3 new subjects will be treated at the next higher dose level (Dose Level 2). If the original cohort treated at Dose Level 1 do not tolerate the combination of medications, the medication regimen will be modified to a lower dose (Dose Level - 1). A dose expansion phase is included which will evaluate the combination of Abemaciclib in combination with Sunitinib when given at the maximum tolerated dose as determined from the from dose escalation phase.

Drug: Abemaciclib; Drug: Sunitinib

Interventions

Abemaciclib DRUG

Subjects will by given oral Abemaciclib every 12 hours for 14 days followed by 7 days off (i.e. a 21 day cycle). The initial dose will be 100 mg (Dose level 1) followed by 150 mg (Dose Level 2) depending on tolerability and toxicity assessment of the combination of medications. If at Dose Level 1 subjects cannot tolerate the combination of medications, the Abemaciclib would not be increased, and the dose will remain stable at 100 mg (Dose Level -1).

Also known as: Verzenio

Experimental Abemaciclib and Sunitinib

Sunitinib DRUG

Subjects will take oral Sunitinib daily for the 21-day cycle. Dosing will be at 50 mg for both Dose Levels 1 and 2. If the combination of the 2 medications is not tolerated by Subjects at Dose Levels 1 a lower dose of Sunitinib (37.5 mg) will be given (Dose Level -1).

Also known as: Sutent

Experimental Abemaciclib and Sunitinib

Eligibility Criteria

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

You may qualify if:

• Has histologic or cytologic evidence of metastatic renal cell carcinoma with histology predominantly (\>50%) clear cell renal cell carcinoma solid neoplasm.
• Has evidence of metastatic disease. Intermediate and poor risk patients according to International Metastatic Renal Cell Carcinoma Database criteria (IMDC) must have received prior combination ipilimumab and nivolumab therapy and subsequently experienced disease progression, or been offered ipilimumab and nivolumab combination therapy and refused, or be ineligible for combination ipilimumab and nivolumab therapy. Patients with favorable risk disease have no eligibility requirement for prior use of ipilimumab and nivolumab immunotherapy.
• Intermediate and poor risk patients (according to IMDC criteria) must also have received prior cabozantinib therapy and subsequently experienced disease progression, or been offered cabozantinib therapy and refused, or be ineligible for cabozantinib therapy. Patients with favorable risk disease have no eligibility requirement for prior use of cabozantinib. Cytoreductive nephrectomy is allowed but not mandatory.
• Has in the opinion of the investigator, a predicted life expectancy of more than 3 months.
• Has presence of at least 1 lesion that is measurable or evaluable using RECIST v1.1. This is defined in at least one dimension as ≥20 mm with conventional techniques or as ≥10 mm with spiral CT, MRI or calipers by clinical exam
• Has either archival tissue for analysis or will require confirmation of disease with fresh biopsy. Tissue will not be required pre/post treatment for biomarker analysis.
• Has an Eastern Cooperative Oncology Group (ECOG) performance score of 0, 1, or 2.
• Patients with central nervous system metastases must have received surgical and/or radiation treatment, the metastases must be neurologically stable, and patients must be off corticosteroids or receiving a stable low-dose regimen of corticosteroids (i.e., a daily dose of 10 mg or less of prednisone or equivalent) for at least 4 weeks prior to the first dose of study drug.
• Has completed any prior anticancer treatment and must have recovered from any acute toxicities. The period between the last dose of prior treatment and the first dose of study drug treatment must be at least 1 week for radiotherapy, at least 3-4 weeks from prior VEGFR/mTOR/ or immunotherapy or any other tyrosine kinase inhibitor (TKI) therapy, and at least 4 weeks for treatment with investigational drugs
• Must be able to swallow capsules and tablets.
• Has adequate organ function (i.e. lung, liver, kidney, bone marrow), as evidenced by multiple laboratory value results within specific parameters.
• Women of childbearing potential (WOCP) as defined as not surgically sterile or not postmenopausal) must have a negative result for a serum pregnancy test before study drug administration on cycle 1 day 1. WOCP must use a medically accepted method of contraception and must agree to continue use this method for the duration of the study and for 30 days after discontinuation of study drug.
• If male, is surgically sterile, or, if capable of producing offspring, is currently using an approved method of birth control and agrees to continued use of this method for the duration of the study (and for 30 days after taking the last dose of study drug because of the possible effects on spermatogenesis).

You may not qualify if:

• Predominately non-clear cell renal cell carcinoma histology (i.e. \>50%)
• Has had chemotherapy within 4 weeks or radiotherapy within 1 week prior to first dose of study drug or those who have not recovered from toxicities due to agents administered more than 4 weeks earlier.
• Has ongoing or active infection requiring parenteral antibiotics.
• Has uncontrolled hypertension despite adequate therapy (i.e., systolic blood pressure higher than 150 mm Hg or diastolic blood pressure higher than 90 mm Hg found on 2 separate occasions separated by 1 week).
• Has diabetes mellitus with occurrence of more than 2 episodes of ketoacidosis in the 12 months prior to the first dose of study drug.
• Has an active second malignancy other than curatively resected basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in situ carcinoma of the cervix, or other cancers for which they are treated with curative intent, and no known active disease in the 3 years prior to enrollment.
• Has a primary brain tumor or has brain metastases from a non-renal cell cancer.
• Has a QTcF interval greater than 470 msec, has a known history of QTcF prolongation, or has a history of torsade de pointes.
• Has a known history of human immunodeficiency virus (HIV), hepatitis B or hepatitis C.
• Has a known history of pulmonary fibrosis or any other restrictive lung disorder.
• Has any other concurrent conditions including a medical, psychiatric, or social condition that, in the opinion of the investigator, could preclude the patient's participation in the study, pose an undue medical hazard, or interfere with the interpretation of the study results, including, but not limited to, patients with congestive heart failure (New York Heart Association \[NYHA\] Class III or IV), cardiac arrhythmia, or acute coronary syndromes within 6 months of enrollment.
• Has used an investigational drug within 4 weeks prior to first dose of study drug or is currently participating in another investigational study.
• Has any disorder that may interfere with drug absorption, distribution, metabolism, or excretion (including gastrointestinal surgery or bariatric surgery).
• Has a history of allergic reactions attributed to compounds of similar chemical or biologic composition to Abemaciclib or Sunitinib.
• Has previous use of a CDK4/6 kinase inhibitor (eg. ribociclib, palbociclib)

Sponsors & Collaborators

• Brown University: lead
• Eli Lilly and Company: collaborator

Study Sites (1)

Rhode Island Hospital

Providence, Rhode Island, 02903, United States

Location

MeSH Terms

Conditions

Carcinoma, Renal Cell

Interventions

abemaciclib; Sunitinib

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Pyrroles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Sheldon Holder, MD, PhD

  Lifespan Cancer Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is a single-arm, non-randomized prospective phase Ib study with expansion. The goal is to determine the maximal tolerated dose by assessing dose limiting toxicities. A classic "3+3" design is used. There are a total of 3 dose levels (level -1, 1, and 2) with dose level 1 as the starting dose. Once the maximum tolerated dose is established, a cohort of an additional 10 subjects will be enrolled at the established dose.

Study Record Dates

• First Submitted: April 3, 2019
• First Posted: April 5, 2019
• Study Start: June 5, 2019
• Primary Completion: March 8, 2022
• Study Completion: March 8, 2022
• Last Updated: June 25, 2024

Record last verified: 2024-06

Locations

US (1)