Clinical Trials /

A Basket Trial of an ERK1/2 Inhibitor (LY3214996) in Combination With Abemaciclib.

NCT04534283

Description:

The purpose of CTO-IUSCC-0730 study is to assess the clinical efficacy of LY3214996 in combination with abemaciclib at the recommended phase 2 dose of LY3214996 200 mg orally daily and abemaciclib 150 mg orally twice daily. Patients will be treated until evidence of disease progression, non-compliance with study protocol, unacceptable major toxicity, at subject's own request for withdrawal, or if the study closes for any reason.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Basket Trial of an ERK1/2 Inhibitor (LY3214996) in Combination With Abemaciclib.
  • Official Title: A Phase 2 Basket Trial of an ERK1/2 Inhibitor (LY3214996) in Combination With Abemaciclib for Patients Whose Tumors Harbor Pathogenic Alterations in BRAF, RAF1, MEK1/2, ERK1/2, and NF1.

Clinical Trial IDs

  • ORG STUDY ID: CTO-IUSCC-0730
  • NCT ID: NCT04534283

Conditions

  • Cancer
  • Cancer Metastatic
  • BRAF V600E
  • MEK1 Gene Mutation
  • MEK2 Gene Mutation
  • ERK Mutation
  • RAF1 Gene Mutation

Interventions

DrugSynonymsArms
AbemaciclibLY2835219Abemaciclib + LY3214996
LY3214996Abemaciclib + LY3214996

Purpose

The purpose of CTO-IUSCC-0730 study is to assess the clinical efficacy of LY3214996 in combination with abemaciclib at the recommended phase 2 dose of LY3214996 200 mg orally daily and abemaciclib 150 mg orally twice daily. Patients will be treated until evidence of disease progression, non-compliance with study protocol, unacceptable major toxicity, at subject's own request for withdrawal, or if the study closes for any reason.

Trial Arms

NameTypeDescriptionInterventions
Abemaciclib + LY3214996ExperimentalSubjects will receive Abemaciclib 150 mg orally twice daily with LY3214996 200 mg orally daily until disease progression, unacceptable toxicity, or patient preference to withdraw from study.
  • Abemaciclib
  • LY3214996

Eligibility Criteria

        Inclusion Criteria:

        Have a histological or cytological diagnosis of advanced unresectable or metastatic cancer
        (American Joint Committee on Cancer Staging Criteria) (Edge et al. 2009).

        2. The patient must be, in the judgement of the investigator, an appropriate candidate for
        experimental therapy, either after available standard therapies (per available local
        guidelines) have failed to provide clinical benefit for their disease or after the patient
        has refused standard treatments.

        3. Have one of the following alterations as defined below using a CLIA-certified
        next-generation sequencing test:

        a. Point mutation in BRAF, RAF1, MEK1/2, or ERK1/2 that have been previously characterized
        to be gain-of-function mutations. These mutations have to be specified as gain-of-function
        as listed in the OncoKB and/or JAX-CKB databases. i. Patients with NSCLC that harbor BRAF
        V600E treated with prior RAF and/or MEK inhibition therapy will be excluded.

        ii. Patients with tumor types other than NSCLC that harbor BRAF V600E mutations who have
        been treated and progressed on prior BRAF and/or MEK inhibition will be included.

          1. Amplification of RAF1 defined as >6 copies of the respective gene.

          2. Gene fusion in which BRAF, RAF1, MEK1/2, or ERK1/2, is a fusion partner; in which the
             fusion is determined to be in-frame; and the kinase domain of BRAF, RAF1, MEK1/2, or
             ERK1/2 is retained.

          3. Point mutations, frameshift insertions/deletions, splice site mutations, or stop gain
             mutations that results in loss-of-function of NF1.

             4. Have measurable disease amenable to biopsy. If biopsy is deemed unsafe at time of
             procedure, patients will remain eligible for study.

             5. Must be able to provide written informed consent and HIPAA authorization for
             release of personal health information.

             6. Have a performance status (PS) of 0 or 1 on the Eastern Cooperative Oncology (Group
             (ECOG) scale (Oken et al. 1982) within 21 (+/-7) days prior to registration for
             protocol therapy.

             7. Have discontinued previous systemic treatments > 3 weeks for cancer prior to first
             dose of investigational therapy. Patient must have resolution, except for alopecia, of
             all clinically significant toxic effects of prior chemotherapy, surgery, or
             radiotherapy to Grade ≤1 by National Cancer Institute (NCI) Common Terminology
             Criteria for Adverse Events (CTCAE), Version 5.0.

             8. Have adequate organ function, as defined below: Laboratory Value (Abbreviations:
             ALT = alanine aminotransferase; AST = aspartate aminotransferase; ANC = absolute
             neutrophil count; ULN = upper limit of normal.) Hematologic ANC ≥1.5 × 109/L Platelets
             ≥100 × 109/L Hemoglobin ≥9.0 g/dL Transfusions to increase the patient's hemoglobin
             level to 9 g/dL are not permitted within 1 week prior to the baseline hematology
             profile Hepatic Total bilirubin ≤1.5 × ULN OR <2.0 mg/dL in patients with Gilbert's
             disease ALT and AST ≤2.5 × ULN OR ≤5 × ULN if the liver has tumor involvement Renal
             Serum creatinine OR Calculated creatinine clearance (see Appendix 3) ≤1.5 × ULN OR ≥50
             mL/min

             9. Are at least 18 years old at the time of screening. 10. Are male patients who are
             sterile (including vasectomy confirmed by post vasectomy semen analysis), or agree to
             use an effective method of contraception and not to donate sperm, or who practice
             total abstinence from heterosexual activity, starting with the first dose of study
             treatment, during the study, and for at least 6 months following the last dose of
             study treatment.

             11. Are female patients of non-childbearing potential (surgically sterile after having
             a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy or
             postmenopausal), or are female patients of child-bearing potential who are not
             pregnant, as confirmed by a serum pregnancy test within 14 (+/-7) days prior to
             receiving first dose of study treatment and who agree to use 2 methods of birth
             control (hormonal or intrauterine plus a barrier method) or practice total abstinence
             from heterosexual activity during the study for at least 6 months following the last
             dose of the study treatment.

             12. Are able to swallow capsules or tablets 13. Have an estimated life expectancy of
             ≥12 weeks, in the judgment of the investigator.

             Exclusion Criteria:

             - 1. Have a serious concomitant systemic disorder (for example, active infection or a
             gastrointestinal disorder causing clinically significant symptoms such as nausea,
             vomiting or diarrhea, or profound immune suppression) that, in the opinion of the
             investigator, would compromise the patient's ability to adhere to the protocol.

             2. Have or known activated/reactivated hepatitis A, B, or C (screening is not
             required).

             3. Uncontrolled human immunodeficiency virus (HIV) infection are considered
             ineligible. HIV- infected patients on effective anti-retroviral therapy with
             undetectable viral load within 6 months are eligible for this trial.

             Known HIV positive patients who meet the following criteria will be considered
             eligible:

        a. CD4 count ≥ 350 cells/mm3 b. Undetectable viral load c. Maintained on modern therapeutic
        regimens utilizing non-CYP interactive agents (i.e. excluding ritonavir) d. No history of
        AIDS-defining opportunistic infections 4. Have symptomatic and untreated central nervous
        system (CNS) malignancy or metastasis (screening is not required).

        a. Patients with treated CNS metastases are eligible for this study if they are not
        currently receiving corticosteroids for their CNS metastasis and/or anticonvulsants.
        Patient must be > 4 weeks from therapy completion (including radiation and/or surgery) and
        clinically stable at time of study entry. Brain MRI or head CT is required at screening for
        patients with known brain metastases.

        5. Have current hematologic malignancies, acute or chronic leukemia 6. Have a second
        primary malignancy that in the judgment of the principle investigator may affect the
        interpretation of results 7. Have prior malignancies within the last 3 years prior to study
        enrollment. Patients with carcinoma in situ of any origin and patients with prior
        malignancies who completed curative intent-treatment and whose likelihood of recurrence is
        very low, as judged by the principal investigator, will remain eligible for this study. The
        principal investigator will approve enrollment of patients with prior malignancies in
        remission before these patients are enrolled. 8. Are currently enrolled in a clinical trial
        involving an investigational product or any other type of medical research judged not to be
        scientifically or medically compatible with this study 9. Have participated, within the
        last 28 days in a clinical trial involving an investigational product.

        10. Have previously completed or withdrawn from this study or any other study investigating
        an ERK1/2 inhibitor.

        11. Had prior therapy with an ERK1/2 inhibitor. 12. Had prior chemotherapy within 3 weeks
        of study registration. 13. Had prior non-CNS radiation within 2 weeks of study
        registration. Please refer to exclusion criteria #4 for patients who have required
        radiation for CNS disease.

        14. If female, is pregnant, breastfeeding, or planning to become pregnant. 15. Currently
        using concomitant medications that are strong inhibitors or inducers of CYP3A4.

        16. Have serious and/or uncontrolled preexisting medical condition(s) that, in the judgment
        of the investigator, would preclude participation in this study.

          1. This includes cardiogenic syncope, ventricular arrhythmias, history of sudden cardiac
             arrest, or severe dyspnea at rest or requiring oxygen therapy.

          2. This includes patients with any evidence of interstitial lung disease (ILD) (not just
             serious and/or uncontrolled ILD) and any history of severe ILD.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate
Time Frame:from cycle 1 day 1 until safety follow up visit (up to 1 year)
Safety Issue:
Description:the number of patients who achieve a best overall response of complete response (CR) or partial response (PR) divided by the total number of patients treated (safety population)

Secondary Outcome Measures

Measure:Incidence of Adverse Events
Time Frame:baseline until safety follow up visit (up to 1 year)
Safety Issue:
Description:CTCAE Version 5.0 will be used to summarize adverse events in the assessment of safety for incorporating LY3214996 in combination with abemaciclib. Summaries of treatment related adverse events in the population will be tabulated. All adverse events (AEs) will be presented in incidence tables coded by CTC term.
Measure:Duration of Overall Response Rate
Time Frame:up to 1 year
Safety Issue:
Description:measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented
Measure:Duration of Progression free survival
Time Frame:up to 1 year
Safety Issue:
Description:the time from the date of start of treatment to the first date of the observed clinical or radiologically documented PD or death due to any cause, whichever occurs first. For patients who are not known to have died or progressed as of the data-inclusion cut-off date, PFS time will be censored at the date of the last objective progression-free disease assessment prior to the date of any subsequent systematic anticancer therapy.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Anita Turk

Trial Keywords

  • Point Mutation
  • Metastatic Cancer
  • Advanced Cancer

Last Updated

September 21, 2020