Clinical Trials /

ABEMA Alone or in COMBO With MK-6482

NCT04627064

Description:

This research study will assess whether abemaciclib alone or in combination with MK-6482 are safe and effective in slowing down the growth of clear cell renal cell carcinoma (ccRCC). The names of the study drugs in this investigational combination are: - Abemaciclib - MK-6482

Related Conditions:
  • Clear Cell Renal Cell Carcinoma
  • Sarcomatoid Renal Cell Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: ABEMA Alone or in COMBO With MK-6482
  • Official Title: A Phase I/IB Trial of Abemaciclib Alone or in Combination With MK-6482 in Advanced Renal Cell Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: 20-284
  • NCT ID: NCT04627064

Conditions

  • Clear Cell Renal Cell Carcinoma

Interventions

DrugSynonymsArms
AbemaciclibVerzenioAbemaciclib and MK-6482-Arm 2
MK-6482HIF-2α inhibitorAbemaciclib and MK-6482-Arm 2

Purpose

This research study will assess whether abemaciclib alone or in combination with MK-6482 are safe and effective in slowing down the growth of clear cell renal cell carcinoma (ccRCC). The names of the study drugs in this investigational combination are: - Abemaciclib - MK-6482

Detailed Description

      This a two-arm, non-randomized phase 1/1B trial aiming at assessing the safety and activity
      of abemaciclib alone (arm 1), and abemaciclib plus MK-6482 (arm 2) in patients with advanced
      refractory clear-cell renal cell carcinoma (croc).

      A Phase I clinical trial tests the safety of an investigational drug or drug combination and
      also tries to define the appropriate dose of the investigational drug or drug combination to
      use for further studies. "Investigational" means that the drug is being studied.The U.S. Food
      and Drug Administration (FDA) has not approved either abemaciclib or MK-6482 for renal
      (kidney) cancer but abemaciclib has been approved to treat other forms of cancer.

      Abemaciclib is in a class of drugs known as CDK4 & 6 inhibitors. These proteins control how
      fast cells grow and divide and are found on both normal and cancer cells. They become
      overactive in cancer cells causing cells to grow and divide uncontrollably. Abemaciclib
      blocks these proteins just as the cells start to grow and divide and in other cancers has
      been shown to slow down cancer cell growth and division, causing cancer cells to become
      inactive or even die.

      MK-6482 is an oral, first-in-class selective small-molecule inhibitor that targets
      hypoxia-inducible factor (HIF)-2a, which promotes the growth of new vessels that fuel kidney
      cancer.

      This study is looking at two different treatments:

        -  Arm 1 - abemaciclib alone:

             -  To determine the response rate of abemaciclib alone in patients with advanced ccRCC

        -  Arm 2 - combination therapy of abemaciclib and MK-6482

             -  To determine the maximum dose of abemaciclib and MK-6482 in combination.

             -  To determine the response rate of abemaciclib and MK-6482 in patients with advanced
                ccRCC.

      The research study procedures include screening for eligibility, study treatment, participant
      evaluations and safety follow-up visits, in addition to general health status follow-up after
      study treatment. It is estimated that participants will receive 12 to 18 months of study
      treatment and 3 months of safety follow-up, totaling about 15 to 21 months from the start of
      study treatment. After the safety follow-up visits, the study doctor may request that
      participants return to clinic for additional tumor assessments or his/her staff will contact
      participants about every 6 months to follow their health status and find out about any
      anticancer treatments participants may have begun after study treatment.

      It is expected that about 40 people will take part in this research study.

      The pharmaceutical company Eli Lilly is supporting this research study by providing funding
      for the research study, tests required for research purposes only, and the study drugs. The
      pharmaceutical company Merck is supporting this research study by providing study drug.
    

Trial Arms

NameTypeDescriptionInterventions
Abemaciclib-Arm 1ExperimentalArm 1 Abemaciclib will be taken at a standard recommended starting dose 2X daily during 28 day study cycles and will be taken until radiographic progression, unacceptable toxicity or withdrawal. Imaging assessments will be performed every 8 weeks during the first six months of the study, then every 12 weeks, in both Arm 1 and Arm 2.
  • Abemaciclib
Abemaciclib and MK-6482-Arm 2ExperimentalArm 2 Arm 2 will start enrolling only after there is experience with Arm 1 to see what abemaciclib effects are when given alone, Dose escalation will occur following a 3+3 design. Abemaciclib will be taken 2X daily uring 28 day study cycle MK-6482 will be taken 1x daily during 28 day study cycle Imaging assessments will be performed every 8 weeks during the first six months of the study, then every 12 weeks, in both arms.
  • Abemaciclib
  • MK-6482

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically or cytologically confirmed unresectable advanced or metastatic renal
             cell carcinoma with clear cell component. Patient with extensive sarcomatoid histology
             are accepted.

          -  Participants must have failed at least 1 prior anti-VEGFR systemic therapy and 1
             immune checkpoint inhibitor for metastatic RCC. No limit on the number of prior lines
             of therapies.

          -  Measurable disease as per RECIST 1.1. See section 12 for the evaluation of measurable
             disease.

          -  Age ≥ 18 years

          -  ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)

          -  Participants must undergo fresh tumor biopsy unless medically unsafe or not feasible.

          -  Normal organ and marrow function as defined below:

               -  Absolute neutrophil count ≥1,500/mcL

               -  Platelets ≥100,000/mcL

               -  Hemoglobin ≥10g/dL (transfusions allowed)

                    -  Total bilirubin ≤2.0 x institutional upper limit of normal with the
                       following exception: patients with known Gilbert disease should have a serum
                       bilirubin ≤ 3 x ULN

                    -  AST(SGOT)/ALT(SGPT)≤3.0 × institutional upper limit of normal with the
                       following exception: patients with known liver metastases should have AST
                       and ALT

                       ≤ 5 x ULN

                    -  Creatinine clearance ≥30 mL/min/1.73 m2 according to the Cockcroft-Gault
                       equation. (APPENDIX F)

                    -  Urine protein/creatinine ratio (UPC ratio) ≤2

          -  Women of child-bearing potential and men must agree to use adequate contraception
             (intrauterine device or barrier method of birth control; abstinence) prior to study
             entry, for the duration of study participation and 6 months after completion
             abemaciclib plus MK- 6482 and at least 3 weeks after the completion of abemaciclib
             administration. If condoms are used as a barrier method, a spermicidal agent should be
             added as a double barrier protection. A negative pregnancy serum test should be
             obtained within 7 days of therapy initiation. Should a woman become pregnant or
             suspect she is pregnant while she or her partner is participating in this study, she
             must discontinue treatment immediately. Data on fetal outcome and breast-feeding are
             to be collected for regulatory reporting and drug safety evaluation.. Men treated or
             enrolled on this protocol must also agree to use adequate contraception prior to the
             study, for the duration of study participation, and 6 months after completion
             abemaciclib plus MK-6482 and at least 3 weeks after the completion of abemaciclib
             administration.

          -  Ability to swallow oral medications

          -  Ability to understand and willingness to sign a written informed consent document.

        Exclusion Criteria:

        A patient will be excluded from the study if he or she meets any of the following criteria:

          -  Patients receiving any other investigational agents.

          -  Patients who received prior CDK4/6 inhibitors.

          -  For Arm 2 only, patients who have received prior HIF-2α inhibitor.

          -  Participants who have received any continuous or intermittent small molecule
             therapeutics (excluding monoclonal antibodies) ≤ 4 effective half-lives prior to
             starting study drug or who have not recovered from side effects of such therapy to
             grade 1 or less (except for non-clinically significant laboratory abnormalities).

          -  Patients must have discontinued all biologic therapy including therapeutic antibodies
             at least 28 days before C1D1.

          -  Participants who have received wide field radiotherapy ≤ 4 weeks or limited field
             radiation for palliation ≤ 2 weeks prior to starting study drug or who have not
             recovered from side effects of such therapy to at least grade 1.

          -  Participants with untreated brain metastases are excluded. However, participants with
             metastatic ccRCC to the brain may participate in this trial, if the participant is ≥ 4
             weeks from therapy completion (incl. radiation and/or surgery), is clinically stable
             at the time of study entry and is not receiving corticosteroid therapy >10 mg/day
             prednisone or equivalent. A repeat MRI or CT Brain to show stability is required

          -  O2 saturation <92% by arterial blood gas analysis or pulse oximetry on room air

          -  Untreated deep vein thrombosis or pulmonary embolism, or event of deep vein thrombosis
             or pulmonary embolism within 2 weeks of treatment start. Patient should be on at least
             1 week of anticoagulation before C1D1.

          -  The patient has serious and/or uncontrolled preexisting medical condition(s) that, in
             the judgment of the investigator, would preclude participation in this study (for
             example, interstitial lung disease, severe dyspnea at rest or requiring oxygen
             therapy, severe renal impairment [e.g. estimated creatinine clearance <30ml/min],
             history of major surgical resection involving the stomach or small bowel, or
             preexisting Crohn's disease or ulcerative colitis or a preexisting chronic condition
             resulting in baseline Grade 2 or higher diarrhea)."

          -  Patient with active systemic bacterial infection (requiring IV antibiotics at the time
             of initiating study treatment), fungal infection, or detectable viral infection.
             Patients with known viral infection (such as HIV) are excluded given the potential for
             interactions between antiretroviral agents and abemaciclib, and the potential for
             increased risk of lifethreatening infection with therapy that is myelosuppressive. If
             you are not known to have HIV, a HIV test is required.

          -  Patients with known Hepatitis B or Hepatitis C infection are excluded only if there is
             evidence of active infection (detectable Hepatitis B surface antigen, detectable
             Hepatitis C RNA).

          -  Prior allogenic stem cell or solid organ transplant.

          -  Impairment of gastrointestinal function or gastrointestinal disease that may
             significantly alter the absorption of oral drugs (e.g., ulcerative diseases,
             uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel
             resection).

          -  Participants who have undergone major surgery ≤ 4 weeks (28 days) prior to starting
             study drug(s) or who have not recovered from side effects of such therapy.

          -  Participants who are currently taking therapeutic doses of warfarin sodium or any
             other coumadin-derivative anticoagulant.

          -  Other malignancy diagnosed within 2 years of first study treatment unless negligible
             risk of metastases or death according to the investigator (included but not limited to
             carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized
             prostate cancer, ductal carcinoma in situ of the breast, non-muscle invasive
             urothelial carcinoma, or other malignancy not deemed to impact patients 5-year life
             expectancy).

          -  Has a personal history of any of the following conditions: syncope of cardiovascular
             etiology, ventricular arrhythmia of pathological origin (including, but not limited
             to, ventricular tachycardia and ventricular fibrillation), sudden cardiac arrest.

          -  Has had any major cardiovascular event within 6 months prior to study drug
             administration iincluding but not limited to: myocardial infarction, unstable angina,
             cerebrovascular accident, transient ischemic event or New York Heart Association Class
             III or IV heart failure. Patients with history of DVT or PE are eligible provided DVT
             or PE occurred at least 2 weeks prior to C1D1 and anticoagulation has been initiated
             at least 1 week before C1D1.

          -  History of symptomatic respiratory condition considered clinically significant by the
             investigator. History of asymptomatic radiation pneumonitis within a previous
             radiation field is permitted.

          -  Participants with a known hypersensitivity to the study compounds or to its
             excipients.

          -  Participant is unable or unwilling to abide by the study protocol or cooperate fully
             with the investigator

          -  Females that are pregnant or lactating

          -  Participants who have taken herbal medications and certain fruits within 7 days prior
             to starting study drug. Herbal medications include, but are not limited to St. John's
             wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe,
             saw palmetto, and ginseng. Fruits include the CYP3A inhibitors Seville oranges,
             grapefruit, pommelos.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate (ORR) Abemaciclib/Arm 1
Time Frame:start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started up to 21 Months
Safety Issue:
Description:Percentage of patients with partial (PR) or complete response (CR) as best overall response according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 by central review.

Secondary Outcome Measures

Measure:Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE 5- Abemaciclib and MK-6482/Arm 2
Time Frame:Baseline, day 1 of every cycle (every 4 weeks) and End of Treatment up 21 months
Safety Issue:
Description:Graded and analyzed using CTCAE version 5
Measure:Duration of response (DOR) Abemaciclib(Arm 1)
Time Frame:Every 8 weeks during the first six months of the study, then every 12 weeks, in both arms up to 21 months
Safety Issue:
Description:Response and progression will be evaluated in this study using the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1)
Measure:Progression-free survival (PFS) Abemaciclib/Arm 1
Time Frame:Defined as the time from trial treatment start to the earlier of progression or death due to any cause up to 21 months.
Safety Issue:
Description:Response and progression will be evaluated in this study using the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1)
Measure:Overall survival (OS) Abemaciclib/Arm 1
Time Frame:Defined as the time from trial treatment start to death due to any cause, or censored at date last known alive up to 21 months
Safety Issue:
Description:Estimated using the method of Kaplan-Meier, for each treatment arm. Median and event-free rate at selected timepoints along with 95% confidence intervals will be provided.
Measure:Duration of response (DOR) Abemaciclib and MK-6482/Arm 2
Time Frame:Every 8 weeks during the first six months of the study, then every 12 weeks, in both arms up to 21 months
Safety Issue:
Description:Response and progression will be evaluated in this study using the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1)
Measure:Progression-free survival (PFS) Abemaciclib and MK-6482/Arm 2
Time Frame:Defined as the time from trial treatment start to the earlier of progression or death due to any cause up to 21 months
Safety Issue:
Description:Response and progression will be evaluated in this study using the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1)
Measure:Overall survival (OS) Abemaciclib and MK-6482/Arm 2
Time Frame:Defined as the time from trial treatment start to death due to any cause, or censored at date last known alive up to 21 months
Safety Issue:
Description:Estimated using the method of Kaplan-Meier, for each treatment arm. Median and event-free

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Dana-Farber Cancer Institute

Trial Keywords

  • Clear Cell Renal Cell Carcinoma

Last Updated

November 13, 2020