A Study of AK-01 (LY3295668) in Solid Tumors

Study Overview
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Brief Summary
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This two-part study consists of a phase 1 dose escalation study in participants with locally advanced or metastatic solid tumors, and a phase 2 portion in up to 3 groups with either small cell lung cancer, breast cancer and/or one other solid tumor type.

Official Title
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A Phase I/II Open-Label Multicenter Study to Evaluate the Safety and Efficacy of AK-01 as Monotherapy in Patients With Locally Advanced or Metastatic Solid Tumors

Conditions
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Neoplasms, Neoplasm Metastasis, Triple Negative Breast Neoplasms, Head and Neck Neoplasms, Breast Neoplasms, Solid Tumor, Adult, Small Cell Lung Carcinoma

Intervention / Treatment
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* Drug: LY3295668


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have received at least 1 but no more than 4 prior systemic therapies Have adequate organ function Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale Have estimated life expectancy greater than or equal to (≥)12 weeks Have fully recovered from radiation therapy or surgery, and are recovering from any acute adverse effects of other cancer therapies Have discontinued all chemotherapy, investigational therapy, molecularly-targeted therapy, and cancer-related hormonal therapy at least 14 days prior, biologic or immunotherapeutic therapy at least 21 days prior, or mitomycin-C or nitrosoureas at least 6 weeks prior Female participants with reproductive potential agree to use 2 forms of highly effective contraception during the study and for the following 3 months Male participants must use a barrier method of contraception during the study and for the following 3 months Phase 1 Have evidence of a solid tumor that is locally advanced and/or metastatic (excluding primary brain tumor) Phase 2 Have disease measurable by Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 Have evidence of a solid tumor that is locally advanced and/or metastatic, and in: Small Cell Lung Cancer (SCLC), must have failed platinum-containing therapy Breast Cancer, be Estrogen Receptor positive and/or Progesterone Receptor positive, but Human Epidermal Growth Factor Receptor 2 (HER2) negative, and must have failed a hormone therapy and a Cyclin-dependent kinase 4/6 (CDK4/6) inhibitor Triple negative breast cancer (TNBC) and failed standard therapy Squamous cell cancers of the head neck associated with the human papilloma virus (HPV), and have failed standard therapy Other solid tumor type that has been approved by the sponsor Exclusion Criteria: Have symptomatic central nervous system (CNS) metastasis (unless asymptomatic and not current receiving corticosteroids) or a primary tumor of the CNS Have a medical condition that precludes participation (swallowing disorder, organ transplant, pregnant or nursing, HIV, active Hepatitis B or C, cardiac disease, history of major surgery in upper gastrointestinal (GI) tract or GI disease, hypokalemia, hypomagnesaemia or hypocalcaemia that cannot be controlled)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 25 milligrams (mg) LY3295668 (Phase 1)<br>25 milligrams (mg) LY3295668 twice daily (BID) administered orally in 21-day cycles. | Drug: LY3295668<br>* Oral capsules<br>* Other names: Erbumine;|
| Experimental: 50 mg LY3295668 (Phase 1)<br>50 mg LY3295668 BID administered orally in 21-day cycles. | Drug: LY3295668<br>* Oral capsules<br>* Other names: Erbumine;|
| Experimental: 75 mg LY3295668 (Phase 1)<br>75 mg LY3295668 BID administered orally in 21-day cycles. | Drug: LY3295668<br>* Oral capsules<br>* Other names: Erbumine;|
| Experimental: 25 mg LY3295668 (Phase 2)<br>25 mg LY3295668 BID administered orally in 21-day cycles. | Drug: LY3295668<br>* Oral capsules<br>* Other names: Erbumine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Maximum Tolerated Dose | Maximum Tolerated Dose (MTD) was defined as the dose immediately below the dose at which ≥2/3, ≥2/6, or ≥3/9 participants in a cohort experienced a dose limiting toxicity (DLT) during the first 21 days of treatment (Cycle 1) in Phase 1. | Cycle 1 (21 days) | 
| Phase 2: Percentage of Participants Who Achieved Partial Response (PR) or Complete Response (CR) [Objective Response Rate (ORR)] | Objective response rate (ORR) was defined as a percentage of responders who achieved complete response or partial response (CR+PR) as assessed by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v 1.1). Complete response (CR) is defined as disappearance of all target (and non-target) lesions, and no appearance of new lesion. Partial response (PR) was defined as at least a 30% decrease in the sum of longest diameters (LD) of target lesions, taking as reference the baseline sum of LD, no progression of non-target lesions, and no appearance of new lesions. | Baseline to Objective Disease Progression (Up to 11 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Number of Participants With One or More Treatment-Emergent Adverse Events | A treatment-emergent adverse event (AE) is an AE that started or worsened (increased in severity) from the treatment start date to 30 days after the treatment end date. A summary of other non-serious Adverse Events (AEs), and all Serious Adverse Events (SAE's), regardless of causality, is located in the Reported Adverse Events section. | Cycle 1 Day 1 through 30 Days After Treatment End Date (Up to 29 Months) | 
| Phase 2: Number of Participants With One or More Treatment-Emergent Adverse Events | A treatment-emergent adverse event (AE) is an AE that started or worsened (increased in severity) from the treatment start date to 30 days after the treatment end date. A summary of other non-serious Adverse Events (AEs), and all Serious Adverse Events (SAE's), regardless of causality, is located in the Reported Adverse Events section. | Cycle 1 Day 1 through 30 Days After Treatment End Date (Up to 29 Months) | 
| Phase 2: Pharmacokinetic (PK): Area Under the Plasma Concentration-time Curve From Time Zero to 12 Hours Post-dose (AUC[0-12]) (Phase 2) | Area under the plasma concentration-time curve for LY3295668 from time zero to 12 hours. | Cycle 1: Day 1 and Day 15: Predose, 1, 2, 4, 6, and 8 - 12 hours postdose; Cycle 1: Day 2 and Day 8 predose | 
| Phase 2: PK: Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours Post-dose (AUC[0-24]) | Area under the plasma concentration-time curve for LY3295668 from time zero to 24 hours. | Cycle 1: Day 1 and Day 15: Predose, 1, 2, 4, 6, and 8-12 hours post-dose; Cycle 1: Day 2 and Day 8 Predose | 
| Phase 2: PK: Maximum Observed Plasma Concentration (Cmax) | Maximum observed plasma concentration for LY3295668. | Cycle 1: Day 1 and Day 15: Predose, 1, 2, 4, 6, and 8 hours post-dose | 
| Phase 2: PK: Time of Maximum Observed Plasma Concentration (Tmax) | Time of maximum observed plasma concentration of LY3295668. | Cycle 1: Day 1 and Day 15: Predose, 1, 2, 4, 6, and 8 hours post-dose | 
| Phase 2: PK: Apparent Terminal Elimination Half-life (t1/2) | Apparent terminal elimination half-life of LY3295668. | Cycle 1: Day 1 and Day 15: Predose, 1, 2, 4, 6, and 8-12 hours post-dose; Cycle 1: Day 2 and Day 8 Predose | 
| Phase 2: PK: Apparent Total Plasma Clearance (CL/F) | Apparent total plasma clearance of LY3295668. | Cycle 1: Day 1 and Day 15: Predose, 1, 2, 4, 6, and 8 -12 hours post-dose; Cycle 1: Day 2 and Day 8 Predose | 
| Phase 2: PK: Apparent Volume of Distribution (Vz/F) | Apparent volume of distribution of LY3295668. | Cycle 1: Day 1 and Day 15: Predose, 1, 2, 4, 6, and 8 -12 hours post-dose; Cycle 1: Day 2 and Day 8 Predose | 
| Phase 1: Number of Participants With Worst Post-Baseline Grade >=3 White Blood Cell Count (WBC) | Presented are participants with the worst post-baseline WBC Grade >= 3 using the National Cancer Institute (NCI) Common Terminology Criteria For Adverse Events version 4.03 (CTCAE v4.03). where Grade 1: < Lower Limit Normal (LLN) - 3000/mm3; <LLN - 3.0 x10e9/L, Grade 2: <3000 - 2000/mm3; <3.0 - 2.0 x10e9/L, Grade 3: <2000 - 1000/mm3; <2.0 1.0 x10e9/L, Grade 4: <1000/mm3; <1.0 x10e9/L. | Cycle 1 Day 1 through 30 Days After Treatment End Date (Up to 29 Months) | 
| Phase 1: Number of Participants With Worst Post-Baseline Grade >=3 Neutrophils (Segmented and Blended) | Presented are participants with the worst post-baseline neutrophils Grade >=3 using the NCI-CTCAE v4.03 where Grade 1: < LLN - 1500/mm3; <LLN - 1.5 x10e9/L, Grade 2: <1500 - 1000/mm3; <1.5 - 1.0 x10e9/L, Grade 3: <1000 - 500/mm3; <1.0 - 0.5 x10e9/L, Grade 4: <500/mm3; <0.5 x 10e9/L. | Cycle 1 Day 1 through 30 Days After Treatment End Date (Up to 29 Months) | 
| Phase 1: Number of Participants With Worst Post-Baseline Grade >=3 Lymphocytes | Presented are participants with the worst post-baseline lymphocytes Grade >=3 using the NCI-CTCAE version 4.03 where Grade 1: <LLN - <800/mm3, <LLN - 0.8 x 10e9/L, Grade 2: <800 - 500/mm3; <0.8 - 0.5 x 10e9/L, Grade 3: <500 - 200/mm3; <0.5 - 0.2 x 10e9/L, <200mm3; <0.2 x 10e9/L. | Cycle 1 Day 1 through 30 Days After Treatment End Date (Up to 29 Months) |