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

• ClinicalTrials.gov Identifier: NCT04534283
• Recruitment Status: Recruiting
• First Posted: September 1, 2020
• Last Update Posted: January 17, 2023
• Sponsor: Anita Turk
• Collaborator: Eli Lilly and Company
• Information provided by (Responsible Party): Anita Turk, Indiana University

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Cancer; Cancer Metastatic; BRAF V600E; MEK1 Gene Mutation; MEK2 Gene Mutation; ERK Mutation; RAF1 Gene Mutation	Drug: Abemaciclib; Drug: LY3214996	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 35 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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.
• Actual Study Start Date: October 5, 2020
• Estimated Primary Completion Date: June 1, 2024
• Estimated Study Completion Date: July 1, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Abemaciclib + LY3214996; Subjects 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.	Drug: Abemaciclib; Subjects will receive Abemaciclib 150 mg orally twice daily until disease progression, unacceptable toxicity, or patient preference to withdraw from study.; Other Name: LY2835219; Drug: LY3214996; Subjects will recieve LY3214996 200 mg orally daily until disease progression, unacceptable toxicity, or patient preference to withdraw from study.

Outcome Measures

Primary Outcome Measures :

1. Overall response rate [ Time Frame: from cycle 1 day 1 until safety follow up visit (up to 1 year) ]
   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 :

1. Incidence of Adverse Events [ Time Frame: baseline until safety follow up visit (up to 1 year) ]
   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.
2. Duration of Overall Response Rate [ Time Frame: up to 1 year ]
   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
3. Duration of Progression free survival [ Time Frame: up to 1 year, 1 month ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

iii. Patients with NSCLC that harbor BRAF V600E will only be enrolled if they are not a candidate for FDA approved therapy

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:

   1. CD4 count ≥ 350 cells/mm3
   2. Undetectable viral load
   3. Maintained on modern therapeutic regimens utilizing non-CYP interactive agents (i.e. excluding ritonavir)
   4. 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.

Contacts and Locations

Contacts

Contact: Anne Younger, RN; 317-274-0951; anefoste@iupui.edu

Locations

United States, Indiana

Indiana University Hospital / IU Simon Cancer Center; Recruiting

Indianapolis, Indiana, United States, 46202

Contact: Anne Younger, RN 317-274-0951 anefoste@iupui.edu

Sub-Investigator: Bryan Schneider, MD

Sub-Investigator: Kathy Miller, MD

Sub-Investigator: Paul Helft, MD

Sponsors and Collaborators

Anita Turk

Eli Lilly and Company

Investigators

• Principal Investigator: Anita Turk, MD; Indiana University

More Information

• Responsible Party: Anita Turk, Assistant Professor of Clinical Medicine, Indiana University
• ClinicalTrials.gov Identifier: NCT04534283
• Other Study ID Numbers: CTO-IUSCC-0730
• First Posted: September 1, 2020
• Last Update Posted: January 17, 2023
• Last Verified: January 2023

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Anita Turk, Indiana University:

Point Mutation; Metastatic Cancer; Advanced Cancer