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

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

Status

Completed

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03092934

Enrollment

Registered

2017-03-28

Start date

2017-05-29

Completion date

2020-04-20

Last updated

2021-07-02

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

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

Brief summary

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.

Interventions

DRUGLY3295668

Oral capsules

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Masking description

Open-Label

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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)

Design outcomes

Primary

Measure	Time frame	Description
Phase 1: Maximum Tolerated Dose	Cycle 1 (21 days)	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.
Phase 2: Percentage of Participants Who Achieved Partial Response (PR) or Complete Response (CR) [Objective Response Rate (ORR)]	Baseline to Objective Disease Progression (Up to 11 months)	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.

Secondary

Measure	Time frame	Description
Phase 1: Number of Participants With One or More Treatment-Emergent Adverse Events	Cycle 1 Day 1 through 30 Days After Treatment End Date (Up to 29 Months)	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.
Phase 2: Number of Participants With One or More Treatment-Emergent Adverse Events	Cycle 1 Day 1 through 30 Days After Treatment End Date (Up to 29 Months)	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.
Phase 2: Pharmacokinetic (PK): Area Under the Plasma Concentration-time Curve From Time Zero to 12 Hours Post-dose (AUC[0-12]) (Phase 2)	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	Area under the plasma concentration-time curve for LY3295668 from time zero to 12 hours.
Phase 2: PK: Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours Post-dose (AUC[0-24])	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	Area under the plasma concentration-time curve for LY3295668 from time zero to 24 hours.
Phase 2: PK: Maximum Observed Plasma Concentration (Cmax)	Cycle 1: Day 1 and Day 15: Predose, 1, 2, 4, 6, and 8 hours post-dose	Maximum observed plasma concentration for LY3295668.
Phase 2: PK: Time of Maximum Observed Plasma Concentration (Tmax)	Cycle 1: Day 1 and Day 15: Predose, 1, 2, 4, 6, and 8 hours post-dose	Time of maximum observed plasma concentration of LY3295668.
Phase 2: PK: Apparent Terminal Elimination Half-life (t1/2)	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	Apparent terminal elimination half-life of LY3295668.
Phase 2: PK: Apparent Total Plasma Clearance (CL/F)	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	Apparent total plasma clearance of LY3295668.
Phase 2: PK: Apparent Volume of Distribution (Vz/F)	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	Apparent volume of distribution of LY3295668.
Phase 1: Number of Participants With Worst Post-Baseline Grade >=3 White Blood Cell Count (WBC)	Cycle 1 Day 1 through 30 Days After Treatment End Date (Up to 29 Months)	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.
Phase 1: Number of Participants With Worst Post-Baseline Grade >=3 Neutrophils (Segmented and Blended)	Cycle 1 Day 1 through 30 Days After Treatment End Date (Up to 29 Months)	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.
Phase 1: Number of Participants With Worst Post-Baseline Grade >=3 Lymphocytes	Cycle 1 Day 1 through 30 Days After Treatment End Date (Up to 29 Months)	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.

Countries

Canada

Participant flow

Pre-assignment details

Phase I participants are said to have completed the study if they completed Dose Limiting Toxicity (DLT) period or have had a DLT. Phase II participants who died or are alive and on study at conclusion but off treatment are defined as completed.

Participants by arm

Arm	Count
25 Milligrams (mg) LY3295668 (Phase 1) 25 mg LY3295668 twice daily (BID) administered orally in 21-day cycles.	8
50 mg LY3295668 (Phase 1) 50 milligrams (mg) LY3295668 BID administered orally in 21-day cycles. LY3295668: Oral capsules	2
75 mg LY3295668 (Phase 1) 75 mg LY3295668 BID administered orally in 21-day cycles. LY3295668: Oral capsules	2
25 mg LY3295668 (Phase 2) 25 mg LY3295668 BID administered orally in 21-day cycles. LY3295668: Oral capsules	1
Total	13

Baseline characteristics

Characteristic	25 Milligrams (mg) LY3295668 (Phase 1)	50 mg LY3295668 (Phase 1)	75 mg LY3295668 (Phase 1)	25 mg LY3295668 (Phase 2)	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	1 Participants	2 Participants	2 Participants	1 Participants	6 Participants
Age, Categorical Between 18 and 65 years	7 Participants	0 Participants	0 Participants	0 Participants	7 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	8 Participants	2 Participants	2 Participants	1 Participants	13 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	1 Participants	0 Participants	0 Participants	0 Participants	1 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants	0 Participants	0 Participants	0 Participants	2 Participants
Race (NIH/OMB) White	5 Participants	2 Participants	2 Participants	1 Participants	10 Participants
Region of Enrollment Canada	8 Participants	2 Participants	2 Participants	1 Participants	13 Participants
Sex: Female, Male Female	4 Participants	1 Participants	2 Participants	1 Participants	8 Participants
Sex: Female, Male Male	4 Participants	1 Participants	0 Participants	0 Participants	5 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	1 / 9	0 / 2	0 / 2
other Total, other adverse events	9 / 9	2 / 2	2 / 2
serious Total, serious adverse events	4 / 9	1 / 2	2 / 2

Outcome results

Primary

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.

Time frame: Cycle 1 (21 days)

Population: All participants who received at least one dose of study drug and experienced a DLT; or received ≥ 38 doses of study drug in Cycle 1 and were not discontinued from the study before completing Cycle 1.

Arm	Measure	Value (NUMBER)
LY3295668 Phase 1	Phase 1: Maximum Tolerated Dose	25 milligram (mg)

Primary

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.

Time frame: Baseline to Objective Disease Progression (Up to 11 months)

Population: All patients who received at least 1 dose of AK-01, whether or not they completed all protocol requirements.

Arm	Measure	Value (NUMBER)
LY3295668 Phase 1	Phase 2: Percentage of Participants Who Achieved Partial Response (PR) or Complete Response (CR) [Objective Response Rate (ORR)]	0 percentage of participants

Secondary

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.