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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 CDK 4/6, 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. 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

Abemaciclib (LY2853219) has been shown in vitro to be a selective ATP-competitive inhibitor of CDK 4/6 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

Abemaciclib is being investigated in phase I clinical trials and in clinical trials in patients with breast cancer, mantle cell lymphoma, and non-small cell lung cancer.

NCT02107703 Schema

MONARCH 2: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Fulvestrant With or Without Abemaciclib, a CDK 4/6 Inhibitor, for Women With Hormone-Receptor-Positive (HR+), HER2-Negative Locally Advanced or Metastatic Breast Cancer

Key Inclusion Criteria

  • Presence of either locally advanced disease not amenable to curative treatment by surgery or metastatic disease
  • Postmenopausal status due to either surgical/natural menopause or ovarian suppression with a gonadotropin-releasing hormone agonist (initiated ≥28 days prior to randomization)
  • Measurable disease or nonmeasurable bone only disease (according to Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1)
  • Adequate organ function
  • ECOG performance status of ≤1
  • Discontinuation of prior cancer therapies for at least 21 or 14 days for myelosuppressive or nonmyelosuppressive agents, respectively, and recovered from acute effects of therapy

Key Exclusion Criteria

  • Visceral crisis, lymphangitic spread, or leptomeningeal carcinomatosis
  • Central nervous system metastases
  • Prior treatment with chemotherapy (except for neoadjuvant/adjuvant chemotherapy), fulvestrant, everolimus, or any CDK 4/6 inhibitor

Please visit www.clinicaltrials.gov for more information on this clinical trial [NCT02107703].

NCT02152631 Schema

JUNIPER: A Randomized Phase 3 Study of Abemaciclib Plus Best Supportive Care vs Erlotinib Plus Best Supportive Care in Patients With Stage IV Non-small Cell Lung Cancer (NSCLC) With a Detectable KRAS Mutation Who Have Progressed After Platinum-Based Chemotherapy

Key Inclusion Criteria

  • Confirmed diagnosis of stage IV NSCLC
  • Determined to have detectable mutations in codons 12 or 13 of the KRAS oncogene by an investigational assay at the central study laboratory
  • The participant must have progressed after platinum-based chemotherapy (with or without maintenance therapy) and have received one additional chemotherapy for advanced and/or metastatic disease or is judged by the physician as ineligible for further standard second-line chemotherapy
  • Has measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
  • ECOG performance status of 0 to 1
  • Has discontinued all previous therapies for cancer (including chemotherapy, radiotherapy, immunotherapy, and investigational therapy) for at least 21 or 14 days for myelosuppressive or nonmyelosuppressive agents, respectively, prior to receiving study drug

Key Exclusion Criteria

  • Has received treatment with a drug that has not received regulatory approval for any indication within 14 or 21 days of the initial dose of study drug for a nonmyelosuppressive or myelosuppressive agent, respectively
  • Has a personal history of any of the following conditions: presyncope or syncope of either unexplained or cardiovascular etiology, ventricular arrhythmia (including but not limited to ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest
  • Has the presence of unstable central nervous system (CNS) metastasis. Histories of CNS metastasis or stable CNS metastases are allowed (no longer requiring active therapy such as steroid medications). Participants with a history of CNS metastases must have a brain scan (for example, magnetic resonance imaging) within 28 days of randomization to document stability, even if there have been no changes in symptoms

Please visit www.clinicaltrials.gov for more information on this clinical trial [NCT02152631].

NCT02246621 Schema

A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Nonsteroidal Aromatase Inhibitors (Anastrozole or Letrozole) Plus LY2835219, a CDK 4/6 Inhibitor, or Placebo in Postmenopausal Women With Hormone-Receptor-Positive (HR+), HER2-Negative Locoregionally Recurrent or Metastatic Breast Cancer With No Prior Systemic Therapy in This Disease Setting (Monarch 3)

Key Inclusion Criteria

  • Has a diagnosis of HR+, HER2-negative breast cancer
  • Has locoregionally recurrent disease not amenable to resection or radiation therapy with curative intent or metastatic disease
  • Has postmenopausal status
  • Has measurable disease or nonmeasurable bone only disease (according to Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1)
  • ECOG performance status of ≥1
  • Has discontinued previous localized radiotherapy for palliative purposes or for lytic lesions at risk of fracture at least 2 weeks prior to randomization and recovered from the acute effects of therapy (until the toxicity resolves to either baseline or at least grade 1) except for residual alopecia or peripheral neuropathy

Key Exclusion Criteria

  • Has visceral crisis, lymphangitic spread, or leptomeningeal carcinomatosis
  • Has clinical evidence or a history of central nervous system metastasis
  • Currently receiving or has previously received chemotherapy or endocrine therapy for locoregionally recurrent or metastatic breast cancer
  • Has received prior (neo)adjuvant endocrine therapy (eg, anti-estrogens or aromatase inhibitors) with a disease-free interval ≤12 months from completion of treatment
  • Prior treatment with everolimus or any CDK 4/6 inhibitor

Please visit www.clinicaltrials.gov for more information on this clinical trial [NCT02246621].

NCT02308020 Schema

A Phase 2 Study of Abemaciclib in Patients With Brain Metastases Secondary to Hormone-Receptor-Positive (HR+) Breast Cancer

Key Inclusion Criteria

  • Women with brain metastases secondary to HR+ breast cancer
  • Has either HER2-positive disease (part A) or HER2-negative disease (part B)
  • Has either HER2-positive or HER2-negative disease, and must have brain lesions clinically indicated for surgical resection as well as provide consent to provide tissue for drug concentration determination after 5 to 14 days of study drug dosing (part C)
  • Parts A and B: ≥1 new or not previously irradiated measurable brain lesion (≥10 mm) or a progressive previously irradiated brain lesion
  • Part C: 1 to 3 brain lesions for which surgical resection is clinically indicated
  • Receiving stable or decreasing dose of corticosteroids for ≥7 days prior to baseline magnetic resonance imaging
  • Karnofsky performance status of ≥70
  • Life expectancy of ≥12 weeks

Key Exclusion Criteria

  • Requires immediate local therapy for brain metastases
  • Receiving enzyme-inducing antiepileptic drugs
  • Has evidence of significant intracranial hemorrhage
  • Has evidence of leptomeningeal disease
  • Has experienced >2 seizures within 4 weeks prior to study entry

Please visit www.clinicaltrials.gov for more information on this clinical trial [NCT02308020].

neoMONARCH Schema

neoMONARCH: A Phase 2 Neoadjuvant Trial Comparing the Biological Effects of 2 Weeks of Abemaciclib (LY2835219) in Combination With Anastrozole to Those of Abemaciclib Monotherapy and Anastrozole Monotherapy and Evaluating the Clinical Activity and Safety of a Subsequent 14 Weeks of Therapy With Abemaciclib in Combination With Anastrozole in Postmenopausal Women With Hormone-Receptor-Positive (HR+), HER2-Negative Breast Cancer

Key Inclusion Criteria

  • Postmenopausal status
  • Histologically or cytologically proven HR+, HER2-negative adenocarcinoma of the breast
  • Has clinical stage I breast tumor ≥1 cm in diameter, stage II, or stage IIIA or IIIB breast cancer. Multifocal disease is allowed if confined to 1 breast, and if each tumor is HR+, HER2-negative and at least 1 tumor is ≥1 cm
  • At least 1 measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria
  • Neoadjuvant endocrine monotherapy is deemed to be a suitable therapy
  • Primary breast cancer that is suitable for baseline core biopsy
  • ECOG performance status of ≤1
  • Adequate organ function

Key Exclusion Criteria

  • Currently enrolled in a clinical trial involving an investigational product or nonapproved use of a drug or device (other than the study drugs used in this study) or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study
  • Bilateral invasive breast cancer
  • Metastatic breast cancer (local spread to axillary lymph nodes is permitted)
  • Inflammatory breast cancer, defined as the presence of erythema or induration involving one third or more of the breast
  • Concurrent therapy with any other nonprotocol anticancer therapy
  • History of any other malignancy within the past 5 years, with the exception of nonmelanoma skin cancer or carcinoma in situ of the cervix
  • Prior systemic therapy or radiotherapy for invasive or noninvasive breast cancer in the same breast as currently being treated
  • Prior antiestrogen therapy with raloxifene, tamoxifen, aromatase inhibitor, or other selective estrogen receptor modulator, either for osteoporosis or for the prevention of breast cancer. Prior hormone-replacement therapy is permitted

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

CDK Trial Schema

A Randomized Phase 2 Study of Abemaciclib (LY2835219) vs Docetaxel in Patients With Stage IV Squamous Non-small Cell Lung Cancer (NSCLC) Previously Treated With Platinum-Based Chemotherapy

Key Inclusion Criteria

  • Confirmed diagnosis of stage IV NSCLC
  • Has progressed during or after platinum-based chemotherapy for advanced disease
  • Has not received prior treatment with docetaxel
  • Has availability of adequate formalin-fixed, paraffin-embedded tumor-derived material
  • Has adequate organ function, including hematologic, renal, and hepatic
  • ECOG performance status of 0 to 1
  • Has the presence of measurable disease as defined by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1
  • Agrees to use a reliable medically approved method of birth control

Key Exclusion Criteria

  • Has received prior treatment with any CDK 4/6 inhibitor or participated in a clinical trial with a CDK 4/6 inhibitor and the treatment administered is not known
  • Currently receiving treatment in a clinical trial involving an investigational product or nonapproved use of a drug or device
  • Has the presence of unstable central nervous system metastasis
  • Has had major surgery (excluding biopsy) <28 days from the initial dose of study drug

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

NCT02057133 Schema

A Phase 1b Study of Abemaciclib in Combination with Therapies for Patients With Metastatic Breast Cancer (mBC)

Key Inclusion Criteria

  • For parts A through E, diagnosis of hormone-receptor-positive, HER2-negative mBC
  • For part F, HER2-positive mBC
  • 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)
  • For part F, the patient must have received at least one thermotherapy regimen for metastatic disease and may be receiving ongoing therapy with trastuzumab
  • Female ≥18 years of age. For parts A through E, patients must have either postmenopausal status or premenopausal 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 corresponding combination therapy, for at least 21 or 14 days for myelosuppressive or nonmyelosuppressive agents, respectively, 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 Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
  • Has adequate organ function

Key Exclusion Criteria

  • Has mBC with visceral crisis, lymphangitic spread, or leptomeningeal carcinomatosis
  • For parts A through E, 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 central nervous system 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 [NCT02057133].

NCT02079636 Schema

A Phase 1b Study of Abemaciclib in Combination With Multiple Single-Agent Options for Patients With Stage IV Non-small Cell Lung Cancer (NSCLC)

Key Inclusion Criteria

  • For all study parts: The patient must have stage IV NSCLC. All patients with nonsquamous NSCLC with EGFR-activating mutations or anaplastic lymphoma kinase alterations should have received appropriate tyrosine kinase inhibitor therapy prior to enrollment
    -
    Part A: Nonsquamous subtypes only. The patient must have received 1-3 prior therapies, including 1 platinum-based chemotherapy for advanced/metastatic NSCLC. Patients who have received pemetrexed as first-line or maintenance therapy must be ≥3 months after treatment for determining eligibility
    -
    Part B: Any subtype. The patient must have received 1-3 prior therapies for advanced/metastatic NSCLC
    -
    Part C: Any subtype. The patient must have received 2-3 prior therapies for advanced/metastatic NSCLC
    -
    Part D (US only): Any subtype. The patient must have received 2-3 prior therapies for advanced/metastatic NSCLC. The patient must not have received prior treatment with any PI3K or mTOR inhibitor
  • Has the presence of either measurable or nonmeasurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
  • ECOG performance status of ≤1
  • Has discontinued all previous therapies for cancer (including chemotherapy, radiotherapy, immunotherapy, and investigational therapy) for at least 21 or 14 days for myelosuppressive or nonmyelosuppressive agents, respectively, prior to receiving study drug and recovered from the acute effects of therapy (treatment-related toxicity resolved to baseline) except for residual alopecia
  • Males and females with reproductive potential must agree to use medically approved contraceptive precautions during the trial and for 3 months following the last dose of study drug. Females with childbearing potential must have a negative serum pregnancy test within 7 days of the first dose of study drug

Key Exclusion Criteria

  • All study parts: Has a history of syncope of unexplained or cardiovascular etiology, or cardiac arrest. Subjects with controlled atrial fibrillation for >30 days prior to study treatment are eligible
  • Parts A, B, and D only: Has central nervous system (CNS) metastasis with development of associated neurological changes 14 days prior to receiving study drug. Patients may be receiving a stable dose of corticosteroids. Screening of asymptomatic patients without history of CNS metastasis is not required. Patients with untreated CNS metastases are ineligible
  • Part C:
    -
    History of cardiac disease, coronary artery disease, heart failure, or syncope. History or evidence of CNS metastases. Radiographic screening of all patients without history of CNS metastasis is required
    -
    Radiologically documented evidence of major blood vessel invasion or encasement by cancer or radiographic evidence of intratumor cavitation, regardless of tumor histology
    -
    Patients with uncontrolled thromboembolic or hemorrhagic disorders
    -
    Patients receiving chronic daily treatment with aspirin ≥325 mg/day or other known inhibitors of platelet function
    -
    Patients with a history of gross hemoptysis (defined as bright red blood of ≥1/2 teaspoon) within 2 months of study entry
    -
    Patients with nonhealing wounds, ulcers, or bone fractures, or undergone a major surgery within 28 days prior to study entry
  • Part D:
    -
    Has insulin-dependent diabetes mellitus or a history of gestational diabetes mellitus
    -
    History of acute coronary syndromes (including myocardial infarction and angina), coronary angioplasty, or stenting within 6 months prior to enrollment

Please visit www.clinicaltrials.gov for more information on this clinical trial [NCT02079636].

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