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

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.