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.
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
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
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
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.
- 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
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
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.