042773 elonmr q3 fc lo8 - lilly oncology pipeline · chk1 inhibitor prexasertib, ... • locally...

CHK1 InhibitorPrexasertib, LY2606368 MsOH H2O

Drug Discovery Platform: Cancer Cell Signaling

Derived from Garrett MD and Collins I1; Thompson R and Eastman A.2

The safety and efficacy of the agents under investigation have not been established. There is no guarantee that the agents will receive regulatory approval and become commercially available for the uses being investigated.

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A Phase 2 Study of LY2606368 in Patients With Extensive-Stage Disease Small Cell Lung Cancer*

Key Inclusion Criteria• Extensive-stage disease small cell lung cancer (ED-SCLC) and received a prior platinum-based regimen

- Cohort 1: Must have had an objective response to prior platinum-based therapy with subsequent progression ≥90 days after the last dose of platinum

- Cohort 2: Must have either not had an objective response to prior platinum-based therapy or had progression <90 days after the last dose of platinum

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

• At least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

Key Exclusion Criteria• Received more than two prior therapies for ED-SCLC (including

immunotherapy, targeted therapies, or chemotherapy)

• Symptomatic central nervous system malignancy or metastasis

• Serious cardiac condition

Please visit www.clinicaltrials.gov for more information on this clinical trial [NCT02735980].* This clinical trial is being conducted globally.

Patients with ED-SCLC who have either platinum-sensitive or platinum-resistant/

refractory disease

Primary endpoint: Objective response rate in patients with platinum-sensitive

ED-SCLC

Primary endpoint: Objective response rate in patients with platinum-resistant/refractory ED-SCLC

Patients with platinum-sensitive disease

Patients with platinum-resistant/refractory disease

CHK1 Inhibitor Prexasertib, LY2606368 MsOH H2O


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A Phase 1b Trial of LY2606368 in Combination With Chemotherapy or Targeted Agents in Advanced and/or Metastatic Tumors*

Key Inclusion Criteria• For all parts except part B dose expansion: A diagnosis of cancer that is advanced or metastatic

• For part B dose expansion: Confirmed KRAS wild-type colorectal cancer (CRC) that is metastatic or recurrent and has failed oxaliplatin- and irinotecan-based chemotherapy or must be intolerant of irinotecan or oxaliplatin

• Must be, in the judgment of the investigator, an appropriate candidate for experimental therapy after available standard therapies have failed

• Adequate organ function

• Discontinuation of all previous systemic treatments for cancer and recovery from the acute effects of therapy. Participants must have discontinued mitomycin C or nitrosourea therapy at least 42 days, and have discontinued any cytotoxic therapies at least 28 days, prior to study enrollment. Radiation therapy and surgery must be completed at least 4 weeks before study enrollment

• 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 or urine pregnancy test within 14 days of the first dose of study drug and must not be breast-feeding

Primary endpoint:Safe and tolerable phase 2 dose of prexasertib in combination

with cisplatin, cetuximab, pemetrexed, 5-FU, or LY3023414

Part A: Dose escalation of cisplatin + prexasertib with or without prophylactic G-CSF followed by dose expansion of recommended part A dose and schedule in participants

with advanced and/or metastatic disease

Part B: Dose escalation of cetuximab + prexasertib with or without prophylactic G-CSF followed by dose expansion of recommended part B dose in participants with CRC

Part C: Dose escalation of pemetrexed + prexasertib followed by dose expansion of recommended part C dose in participants with advanced and/or metastatic disease

Part D: Dose escalation of 5-FU + prexasertib followed by dose expansion of recommended part D dose in participants with advanced and/or metastatic disease

Part E: Dose escalation of prexasertib + LY3023414 followed by dose expansion of recommended part E dose in participants with advanced and/or metastatic disease

Key Exclusion Criteria• Taken an unapproved drug as treatment for any indication

within the last 28 days prior to starting study treatment

• Active symptomatic fungal, bacterial, or viral infection, including HIV or hepatitis A, B, or C

• Serious heart condition, such as congestive heart failure, unstable angina pectoris, or heart attack within the last 3 months

• Family history of long QTc syndrome

• Serotonin-secreting carcinoid tumor or a prior history of drug-induced serotonin syndrome

• Acute leukemia

Please visit www.clinicaltrials.gov for more information on this clinical trial [NCT02124148].* This clinical trial is being conducted in the United States.



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A Phase 1b Trial of LY2606368 in Combination With Chemoradiation in Patients With Locally Advanced Head and Neck Squamous Cell Cancer*

Key Inclusion Criteria• Locally advanced head and neck squamous cell carcinoma of the oropharynx (tonsil, base of tongue,

soft palate, or oropharyngeal walls), hypopharynx, or larynx

• Must be able to comply with the treatment plan and follow-up schedule

• Adequate organ function

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

• Participants of reproductive potential must agree to use medically approved contraceptive precautions during the study, and for 3 months following the last dose of study drug, and must not be breast-feeding

Key Exclusion Criteria• Taken an unapproved drug as treatment for any indication within the

last 28 days prior to starting study treatment

• Any of the following prior therapies or treatments: Systemic therapy for the study cancer, radiation therapy to the head and neck region that overlaps with a prior radiation therapy field, or surgery with curative intent in the head and neck region for locally advanced disease

• Evidence of a distant metastatic disease

• Active symptomatic fungal, bacterial, or viral infection, including HIV or hepatitis A, B, or C

• Serious heart condition, such as congestive heart failure, unstable angina pectoris, or heart attack within the last 3 months

• Family history of long QTc interval syndrome

• Known allergic reaction against any of the components of the study treatment


Primary endpoint:Recommended phase 2 dose for parts A and B

Part A:Prexasertib + cisplatin + radiation

Part B:Prexasertib + cetuximab + radiation



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A Phase 1 Dose-Escalation Study of LY2606368 in Combination With Ralimetinib in Patients With Advanced or Metastatic Cancer*

Key Inclusion Criteria• Advanced or metastatic cancer

• Part B: Colorectal cancer (CRC) or non-small cell lung cancer (NSCLC) with known KRAS and/or BRAF mutations

• Discontinuation of all previous treatments for cancer and recovered from the acute effects from the therapy

Key Exclusion Criteria• Evidence or history of central nervous system metastasis

• Serious heart condition

• Disease that requires immunosuppressive medication

• Major small bowel resection that will interfere significantly with the absorption, distribution, metabolism, or excretion of oral therapy or inflammatory bowel disease

• Prior participation in a clinical trial with prexasertib or ralimetinib



Primary endpoint: Determine recommended phase 2 dose of prexasertib in combination

with ralimetinib

Part B1: Dose confirmation of

prexasertib + ralimetinib in patients with known

mutations in KRAS and/or BRAF (CRC)

Part B2: Dose confirmation of

prexasertib + ralimetinib in patients with known

mutations in KRAS and/or BRAF (NSCLC)

Part A: Dose escalation of prexasertib + ralimetinib in patients

with solid tumors


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TargetCheckpoint kinase 1 (CHK1) is a global regulator of the mammalian cell cycle. In addition to regulating DNA damage checkpoints, CHK1 plays a central role in normal DNA replication, resolving replication stress, progression to mitosis, and cytokinesis. Inhibition of CHK1 in the absence of DNA damage can cause impaired DNA replication, loss of DNA damage checkpoints, premature entry into mitosis with highly fragmented DNA, and cell death via replication catastrophe.3

MoleculePrexasertib (LY2606368 monomesylate monohydrate) is a small molecule that in vitro preferentially binds to and inhibits CHK1 and, to a lesser extent, inhibits CHK2, thus inducing DNA double-strand breaks, a loss in checkpoint function, increased replication stress, and cell death.3

Clinical DevelopmentPrexasertib is being investigated in phase I clinical trials and in clinical trials in patients with head and neck cancer and small cell lung cancer.

References: 1. Garrett MD, Collins I. Trends Pharmacol Sci. 2011;32(5):308-316. 2. Thompson R, Eastman A. Br J Clin Pharmacol. 2013;76(3):358-369. 3. King C, et al. Mol Cancer Ther. 2015;14(9):2004-2013.

Study Schemas Not Available[NCT02514603] Early Development A Study of Prexasertib (LY2606368) in Japanese Participants With Advanced Cancers

ON98968 07/2016 PRINTED IN USA © Lilly USA, LLC 2016. All rights reserved.



042773 elonmr q3 fc lo8 - lilly oncology pipeline · chk1 inhibitor prexasertib, ... • locally...

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