CDK 4/6 Dual Inhibitor

LY2835219

CDK 4/6 Dual Inhibitor Derived from Shapiro GI1; Ibrahim N and Haluska FG.2

Target

Many human tumors acquire alterations, which can lead to the activation of cyclin-dependent kinases (CDKs)—CDK4 and CDK6. These alterations include mutations that directly activate CDK4/6, gene amplifications, which increase expression of various protein activators such as cyclin D, as well as genetic losses, which reduce expression of protein inhibitors such as p16.3,4 These various mechanisms as well as loss of retinoblastoma (Rb) can lead to an enhanced proliferative potential by decreasing dependency on external growth factors and mitogenic signaling pathways, which are required to stimulate growth under normal conditions.3,4

Molecule

LY2835219 has been shown in vitro to be a selective ATP-competitive inhibitor of CDK4/6 kinase activity that prevents the phosphorylation and subsequent inactivation of the Rb tumor suppressor protein, thereby inducing G1 cell cycle arrest and inhibition of cell proliferation.5,6

Clinical Development

LY2835219 is being investigated in a phase I clinical trial and in clinical trials in patients with mantle cell lymphoma, NSCLC, and breast cancer.

CDK 4/6 Dual Inhibitor

Phase 2 Study of a CDK 4/6 Inhibitor for Patients With Relapsed or Refractory Mantle Cell Lymphoma (MCL)

Key Inclusion Criteria

  • Has a diagnosis of MCL that has relapsed after, or been refractory to, available standard treatments
  • Has disease that is assessable according to the Response Criteria for Non-Hodgkin's Lymphomas
  • ECOG performance status of ≤2
  • Has adequate organ function including:
    -
    Hematologic: Absolute neutrophil count (ANC) ≥1.5 x 109/L, platelets ≥75 x 109/L, and hemoglobin ≥8 g/dL
    -
    Hepatic: Bilirubin ≤1.5 times upper limit of normal (ULN) and ALT ≤3.0 times ULN
    -
    Renal: Estimated creatinine clearance ≥50 mL/min
  • Has discontinued all previous therapies for cancer for at least 21 days for myelosuppressive agents or 14 days for nonmyelosuppressive agents prior to receiving study drug and recovered from the acute effects of therapy

Key Exclusion Criteria

  • Has serious preexisting medical conditions that, in the judgment of the investigator, would preclude participation in this study
  • Has symptomatic metastasis to the central nervous system (CNS)
  • Has received an autologous or allogeneic stem-cell transplant within 75 days of the initial dose of study drug
  • Has a baseline electrocardiogram (ECG) with any of the following findings: ventricular tachycardia, ventricular fibrillation, abnormal QTcB (defined as ≥450 ms for males and ≥470 ms for females), or evidence of acute myocardial ischemia

Please visit www.clinicaltrials.gov for more information on this clinical trial [NCT01739309].

CDK 4/6 Dual Inhibitor

A Phase 1b Study of LY2835219 in Combination With Endocrine Therapies for Patients With Hormone-Receptor-Positive (HR+), HER2-Negative, Metastatic Breast Cancer (mBC)

Key Inclusion Criteria

  • Diagnosis of HR+, HER2-negative breast cancer that expresses, by immunohistochemistry, at least one of the hormone receptors (estrogen receptor [ER] or progesterone receptor [PR])
  • For parts A and B, the patient must not have received prior systemic endocrine therapy for metastatic disease except for ongoing therapy with letrozole (part A) or anastrozole (part B)
  • For part C, the patient may have received prior systemic endocrine therapy for metastatic disease and may be receiving ongoing therapy with tamoxifen
  • For parts D and E, the patient must have received prior systemic endocrine therapy with at least one nonsteroidal aromatase inhibitor (anastrozole or letrozole) for metastatic disease and may be receiving ongoing therapy with exemestane (part D) or exemestane + everolimus (part E)
  • Female ≥18 years of age who must have either post-menopausal status or pre-menopausal status if continuing or beginning ovarian suppression with a luteinizing hormone-releasing hormone (LHRH) agonist
  • ECOG performance status of ≤1
  • Has discontinued all previous therapies for breast cancer, except for ongoing endocrine therapy, for at least 21 days for myelosuppressive agents or 14 days for nonmyelosuppressive agents prior to receiving study drug(s) and recovered from the acute effects of therapy
  • Has either measurable or nonmeasurable disease but evaluable bone disease as defined by RECIST 1.1
  • Has adequate organ function

Key Exclusion Criteria

  • Has mBC with visceral crisis, lymphangitic spread, or leptomeningeal carcinomatosis
  • Has received prior systemic chemotherapy for metastatic disease
  • Intolerant of the standard endocrine therapy drug(s) administered in a specific part of the study
  • Has initiated bisphosphonates or approved RANK ligand (RANK-L) targeted agents (for example, denosumab) ≤28 days prior to day 1 of cycle 1
  • Has central nervous system (CNS) metastasis without prior radiotherapy or either radiotherapy or development of neurological changes ≤14 days prior to receiving study treatment

Please visit www.clinicaltrials.gov for more information on this clinical trial.

CDK 4/6 Dual Inhibitor

A Phase 1 Study of a CDK 4/6 Dual Inhibitor in Participants With Advanced Cancer

Key Inclusion Criteria

  • The participant must be, in the judgment of the investigator, an appropriate candidate for experimental therapy either after available standard therapies have ceased to provide clinical benefit (parts A-F) or in combination with fulvestrant (part G only)
  • For part A, the participant must have histological or cytological evidence of cancer, either a solid tumor or a lymphoma, which is advanced and/or metastatic
  • For parts B-G, the participant must have histological or cytological evidence of one of the following cancers:
    • Part B: Non-small cell lung cancer (NSCLC) of any subtype that is advanced and/or metastatic
    • Part C: Glioblastoma multiforme that has progressed or recurred after radiotherapy and/or chemotherapy
    • Part D: Breast cancer that is advanced and/or metastatic
    • Part E: Melanoma that is advanced and/or metastatic
    • Part F: Colorectal cancer
    • Part G: Breast cancer that is not only advanced and/or metastatic but also hormone-receptor-positive (HR+)
  • As defined by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) or the Revised Response Criteria for Malignant Lymphoma
    • Parts A and G: Has measurable or nonmeasurable disease
    • Parts B-F: Has measurable disease
  • ECOG performance status of ≤1 (part A); ECOG performance status of ≤2 (parts B-G)
  • Has discontinued all previous therapies for cancer (including chemotherapy, radiotherapy, immunotherapy, and investigational therapy) with the exception of fulvestrant (for part G only) for at least 21 days for myelosuppressive agents or 14 days for nonmyelosuppressive agents prior to receiving study drug and recovered from the acute effects of therapy (treatment-related toxicity resolved to baseline) except for residual alopecia

Key Exclusion Criteria

  • For part A, the patient may not have CNS malignancy or metastasis
  • For parts B, D, E, F, and G, the patient may not have CNS disease that is radiographically or clinically unstable less than 14 days prior to receiving study drug
  • For part C, the patient may not have glioblastoma multiforme that is radiographically or clinically unstable less than 14 days prior to receiving study drug, regardless of whether they are receiving corticosteroids

Please visit www.clinicaltrials.gov for more information on this clinical trial [NCT01394016].

Lung Cancer    A Phase 1b Study of LY2835219 in Combination With Multiple Therapies for Patients With Stage IV NSCLC

Lilly defines the start of phase II as the first dose in a clinical trial for the purpose of evaluating efficacy, whether that occurs in a phase I cohort or a separate phase II trial. This asset is considered by Lilly to be in phase II, although this website and www.clinicaltrials.gov list it as phase I based on a phase I trial.