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Prexasertib

Protein Kinase Inhibitors

Enzyme Inhibitors

Participants received 105 milligram per square meter (mg/m²) prexasertib as an approximately 60 (+10) minute IV infusion on Day 1 and 15 of a 28-day cycle. Participants were with platinum-resistant disease, breast cancer susceptibility gene (BRCA) negative and have received ≥3 lines of prior therapy.

Participants received 105 mg/m² prexasertib as an approximately 60 (+10) minute IV infusion on Day 1 and 15 of a 28-day cycle. Participants were with platinum-resistant disease, BRCA negative and have received \<3 lines of prior therapy.

Participants received 105 mg/m² prexasertib as an approximately 60 (+10) minute IV infusion on Day 1 and 15 of a 28-day cycle. Participants were with platinum-resistant disease, BRCA positive and received a prior poly ADP ribose polymerase (PARP) inhibitor.

Participants received 105 mg/m² prexasertib as an approximately 60 (+10) minute IV infusion on Day 1 and 15 of a 28-day cycle. Participants were with platinum refractory disease, BRCA positive or negative, no restriction on number of lines of prior therapy.

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The purpose of this study is to evaluate the efficacy and safety of prexasertib in women with platinum-resistant or refractory recurrent ovarian cancer.

A Study of Prexasertib (LY2606368) in Platinum-Resistant or Refractory Recurrent Ovarian Cancer

A Phase 2 Study of Prexasertib in Platinum-Resistant or Refractory Recurrent Ovarian Cancer

Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.

Overall response rate is the best response of complete response (CR) or partial response (PR) as classified by the independent central review according to the Response Evaluation Criteria In Solid Tumors (RECIST v1.1). CR is a disappearance of all target and non-target lesions and normalization of tumor marker level. PR is an at least 30% decrease in the sum of the diameters of target lesions (taking as reference the baseline sum diameter) without progression of non-target lesions or appearance of new lesions. Overall response rate is calculated as a total number of participants with CR or PR divided by the total number of participants per cohort with at least 1 measurable lesion, multiplied by 100.

Pharmacokinetics(PK): Maximum Plasma Concentration of Prexasertib. The same dose was administered to Cohort 1, 2, 3 and 4 and were combined for analysis.

DCR is defined as the number of participants who achieve a best overall response of CR, PR or SD for ≥4 months as determined by per RECIST version 1.1. CR is the disappearance of all target and non-target lesions; PR is a ≥30% decrease in sum of longest diameter of target lesions without new lesion and progression of non-target lesion; SD is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease. Disease control rate is calculated as a total number of participants with CR or PR or SD divided by the total number of participants treated, then multiplied by 100.

Duration of response is defined as the time from the date measurement criteria for CR or PR (whichever is first recorded) are first met until the first date that disease is recurrent or objective progression is observed, per RECIST 1.1, or the date of death from any cause in the absence of objectively determined disease progression or recurrence. Participants known to be alive and without disease progression will be censored at the time of the last adequate tumor assessment.

CA-125 response is defined as ≥50% reduction in CA-125 levels from a pretreatment sample. The response must be confirmed and maintained for ≥28 days according to GCIG criteria. Participants must have a pretreatment sample that is ≥2 times the upper limit of the reference range and obtained within 2 weeks before starting the treatment.

Progression-Free Survival (PFS) is defined as the time from the date of enrollment until the first occurrence of documented disease progression per RECIST 1.1, or death from any cause in the absence of progressive disease (PD). Participants known to be alive and without disease progression will be censored at the time of the last adequate tumor assessment.

Overall survival (OS) is defined as the time from the date of enrollment until death from any cause. If the participant is alive, lost to follow-up or withdrawn from study at the time of data analysis, OS data will be censored on the last date the participant is known to be alive.

Eli Lilly and Company

All randomized participants who received at least one dose.

Prexasertib Cohort 1

Prexasertib Cohort 2

Prexasertib Cohort 3

Prexasertib Cohort 4

Participants received 105 mg/m² prexasertib as an approximately 60 (+10) minute IV infusion on Day 1 and 15 of a 28-day cycle. Participants were with platinum-resistant disease, breast cancer susceptibility gene (BRCA) negative and have received ≥3 lines of prior therapy.

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

South Korea

Belgium

United States

United Kingdom

Italy

Israel

Australia

Spain

Region of Enrollment

All randomized participants who received at least one dose of study drug.

Chief Medical Officer

Percentage of Participants Who Achieve Complete Response (CR) or Partial Response (PR): Overall Response Rate (ORR)

Cycle 1

Cycle 2

Cycle 4

Cycle 6

Participants received 105 mg/m² prexasertib as an approximately 60 (+10) minute IV infusion on Day 1 and 15 of a 28-day cycle. (Participants combined from all the Cohorts 1 to 4)

All randomized participants who received at least one dose of study drug and had evaluable PK data. Cohort 1, 2, 3 and 4 received the same dose and were combined per protocol.

Pharmacokinetics (PK): Maximum Plasma Concentration (Cmax) of Prexasertib

Disease Control Rate (DCR): Percentage of Participants With a Best Overall Response of CR, PR, or Stable Disease (SD) for at Least 4 Months

All randomized participants who received at least one dose of study drug and had CR or PR responses. Number of participants censored Cohort 1 = 0, Cohort 2 = 1, Cohort 3 = 0 and Cohort 4 = 0.

Duration of Response

Percentage of Participants With at Least a 50% Reduction in CA-125 Levels From Baseline

All randomized participants who received at least one dose of study drug. Number of participants censored Cohort 1 = 6, Cohort 2 = 4, Cohort 3 = 4 and Cohort 4 = 4.

Progression-Free Survival

All randomized participants who received at least one dose of study drug and had overall survival data. Number of participants censored Cohort 1 = 18, Cohort 2 = 12, Cohort 3 = 12 and Cohort 4 = 4.

Overall Survival

Overall Study

Respiratory Tract (Lung and Bronchial) Diseases

Blood and Lymph Conditions

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SRA737 will be administered orally on each day of a 28-day cycle. Subjects will receive a single dose of SRA737 between 4 to 7 days prior to starting the first cycle for PK profiling. Subjects can continue taking SRA737 if they are receiving clinical benefit and able to safely take the drug and follow the requirements of the study.

SRA737

The purpose of this clinical study is to establish the safety profile, determine the maximum tolerated dose (MTD) and recommend a Phase 2 dose and schedule of SRA737; and to evaluate the efficacy of SRA737 in prospectively-selected subjects with genetically-defined tumors that harbor genomic alterations linked to increased replication stress and that are hypothesized to be more sensitive to checkpoint kinase 1 (Chk1) inhibition via synthetic lethality. Specific cancer indications that frequently harbor these genetic mutations will be studied.

SRA737 is a potent, highly selective, orally bioavailable small molecule inhibitor of Chk1, a key regulator of cell cycle progression and the DNA Damage Response (DDR) replication stress response. In cancer cells, intrinsic replication stress (RS) is induced by factors such as oncogenes (e.g., CCNE1 or MYC), genetic mutations in DNA repair machinery (e.g. BRCA1 or FANCA), genetic mutations leading to a dysregulated cell cycle (e.g., TP53 or RAD50) or other genomic alterations. This replication stress results in persistent DNA damage and genomic instability, leading to an increased dependency on Chk1 for survival. Targeted inhibition of Chk1 by SRA737 may therefore be synthetically lethal to cancer cells with elevated intrinsic RS.

This study has been designed to: establish the safety profile; determine the pharmacokinetic profile; identify the optimal dose, schedule, and MTD; obtain preliminary evidence of activity; and evaluate SRA737's efficacy in prospectively-selected subjects with tumors that harbor genomic alterations linked to increased replication stress and that are hypothesized to be more sensitive to Chk1 inhibition via synthetic lethality.

This clinical study consists of two phases, a Dose Escalation Phase 1 portion and a Cohort Expansion Phase 2 portion.

In the Dose Escalation Phase 1 portion, cohorts consisting initially of a single subject will receive escalating doses of SRA737, administered orally on a continuous daily dosing schedule in 28-day cycles. Once an SRA737-related Grade 2 toxicity is observed in a dose escalation cohort during Cycle 1, that cohort will be expanded to 3 to 6 subjects, and subsequent dose level cohorts will follow a rolling 6 design until the MTD has been identified.

In the Cohort Expansion Phase 2 portion, subjects with genetically-defined tumors that harbor genomic alterations linked to increased replication stress and that are hypothesized to be more sensitive to Chk1 inhibition will be prospectively enrolled into six indication-specific cohorts to explore the preliminary efficacy of SRA737. Subjects must have advanced or metastatic disease of one of the following types:

* castration-resistant prostate cancer (mCRPC);
* high grade serous ovarian cancer (HGSOC) without CCNE1 gene amplification;
* HGSOC with CCNE1 gene amplification (or alternative genetic alteration with similar functional effect);
* non-small cell lung cancer (NSCLC);
* head and neck squamous cell carcinoma (HNSCC) or squamous cell carcinoma of the anus (SCCA); and
* colorectal cancer (mCRC).

To qualify for enrolment in the Cohort Expansion Phase 2 portion, the subject's tumor must have a confirmed combination of mutations which are expected to confer sensitivity to Chk1 inhibition, determined by the Sponsor's review of genetic abnormalities detected in the following categories:

* Oncogenic drivers such as CCNE1 or MYC, etc.
* Genes involved in the DNA repair process including BRCA1, BRCA2, FANC genes, mismatch repair (MMR) genetic alterations and/or high microsatellite instability.
* Key tumor suppressor genes regulating G1 cell cycle progression/arrest such as TP53, RAD50, etc. For patients with HNSCC or SCCA, positive human papilloma virus (HPV) status is also considered for eligibility.
* Genetic indicators of replicative stress such as gain of function/amplification of CHEK1, ATR or other related genes.

Tumor genetics will be prospectively determined using Next-Generation Sequencing.

A Phase 1/2 Trial of SRA737 in Subjects With Advanced Cancer

A Phase 1/2 Trial of SRA737 (a Chk1 Inhibitor) Administered Orally in Subjects With Advanced Cancer

Treatment-emergent adverse events (TEAEs) were reported until the safety Follow up (SFU) visit, 30 days after the last dose of SRA737 or prior to the initiation of a new anticancer treatment, whichever came first.

The highest dose at which ≤ 33% of subjects have a dose limiting toxicity (DLT) in a cohort of up to 6 subjects.

The RP2D and schedule were defined by the Cohort Review Committee at the end of the study and took all clinically relevant toxicity, PK and PDn data into account. The RP2D was to be a dose equal to or less than the MTD for the selected schedule.

The disease control rate (DCR) was defined as the number of subjects achieving complete response (CR) + partial response (PR) + stable disease (SD) per RECIST 1.1 criteria. Since no subjects achieved CR or PR in this study, the DCR represents the proportion of subjects in each group who achieved SD.

Time to progression (TTP) was defined as the time from Cycle 1 Day 1 to the earliest date of radiographic disease progression per RECIST 1.1, or if the subject did not experience disease progression, to the last imaging assessment. TTP was analyzed using the K-M method.

Progression free survival (PFS) was defined as time from Cycle 1 Day 1 to the earliest date of radiographic disease progression per RECIST 1.1 or death, whichever happened first. Censoring rules are defined in the SAP. PFS was analyzed using the K-M method.

Overall survival (OS) was defined as time from Cycle 1 Day 1 to the date of death (or date last known to be alive). OS was analyzed using the K-M method.

Sierra Oncology LLC - a GSK company

An AE was defined as any untoward, undesired, or unplanned medical occurrence in a subject administered SRA737. All AEs and SAEs were assessed for seriousness, causality, and expectedness.

As specified in the Statistical Analysis Plan, the frequency of each AE was evaluated in the overall Safety Evaluable Population (all enrolled subjects who receive at least 1 dose of SRA737) of patients with advanced solid tumors, irrespective of tumor type. All AEs collected are included in the summary.

Due to the small numbers of patients in some tumor type subgroups and with the intention of displaying the overall safety profile of SRA737 in advanced solid tumors, the frequency of each AE was evaluated in the overall Safety Evaluable Population rather than by tumor type subgroups. The Safety Evaluable Population includes all enrolled subjects who receive at least 1 dose of SRA737.

Safety Evaluable Population

Metastatic colorectal cancer (CRC) defined as histologically and/or cytologically confirmed CRC, and must have received at least 1 prior regimen for advanced/metastatic disease.

Colorectal Cancer

High grade serous ovarian cancer (HGSOC) defined as histologically confirmed high grade serous ovarian, fallopian tube or primary peritoneal cancer who were recurrent platinum intolerant, or with platinum resistant disease defined as radiological evidence of disease progression within 6 months of the last receipt of platinum based chemotherapy.

High Grade Serous Ovarian Cancer

Advanced non small cell lung cancer (NSCLC) defined as locally advanced and recurrent or metastatic, histologically confirmed NSCLC, and must have received at least 1 prior regimen for advanced/metastatic disease.

Non Small Cell Lung Cancer

Metastatic castration resistant prostate cancer (mCRPC) defined as histologically or cytologically confirmed adenocarcinoma of the prostate that has progressed after androgen deprivation therapy.

Metastatic Other Tumor Type Castration Resistant Prostate Cancer

Histologically confirmed HNSCC from any primary site; locally advanced disease (ie, persistent or progressive disease following curative intent radiation, and not a candidate for surgical salvage due to incurability or morbidity), or metastatic disease.

Head and Neck Squamous Cell Carcinoma

Any locally advanced or metastatic, histologically or cytologically proven solid tumor or NHL, that had relapsed after or progressing despite conventional treatment for which no conventional therapy was considered appropriate by the investigator or had been declined by the subject.

Other Tumor Type

American Indian or Alaska Native

Asian

Black or African American

Native Hawaiian or Other Pacific Islander

White

Other

Not Reported

Race/Ethnicity, Customized

The Safety Evaluable Population includes all enrolled subjects who receive at least 1 dose of SRA737.

GSK Response Center

As specified in the Statistical Analysis Plan, the frequency of each AE was evaluated in the overall Safety Evaluable Population rather than by tumor type subgroups with the intention of displaying the overall safety profile of SRA737 in advanced solid tumors. The Safety Evaluable Population includes all enrolled subjects who receive at least 1 dose of SRA737.

Number of Subjects With Adverse Events as Assessed by CTCAE 4.03

The Dose Escalation Phase included a total of 18 subjects in 9 different dosage cohorts: 20 mg QD, 40 mg QD, 80 mg QD, 160 mg QD, 300 mg QD, 600 mg QD, 1000 mg QD, 500 mg BID, and 1300 mg QD.

Dose Escalation Phase

In order to determine the MTD, a total of 18 subjects were enrolled in the dose escalation phase of the study in 9 dosage cohorts. All subjects receiving at least 75% of planned doses of SRA737 within Cycle 1 and those subjects receiving less than these planned doses of SRA737 due to DLT were considered evaluable for dose review decisions.

Maximum Tolerated Dose of SRA737

All 107 subjects treated in the study were included in the review of toxicity, PK and PDn, data in order to determine the RP2D. All clinically relevant toxicity, PK and PDn data up to 30 days after last dose of SRA737 were taken into account.

Recommended Phase 2 Dose of SRA737

The Response Evaluable Population (REP) included all enrolled subjects who satisfy all of the following conditions:

1. Measurable disease and assessment at baseline
2. Received at least 75% of 1 cycle of study medication, based on dosing information
3. At least one post baseline disease assessment OR discontinued treatment due to AE or disease progression or death

Disease Control Rate (DCR) of SRA737

Time to Progression (TTP)

Progression Free Survival (PFS)

Metastatic Castration Resistant Prostate Cancer

All subjects included in the Response Evaluable Population

Overall

The Response Evaluable Population (REP) included all subjects who satisfy the following conditions:

1. Measurable disease and assessment at baseline
2. Received at least 75% of 1 cycle of study medication, based on dosing information
3. At least 1 post baseline disease assessment OR discontinued treatment due to AE or disease progression or death Note: The median OS was not estimated in the mCRPC, HNSCC, or "Other" tumor type subgroups due to insufficient number of participants with events.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study of Prexasertib (LY2606368) in Platinum-Resistant or Refractory Recurrent Ovarian Cancer	NCT03414047	Ovarian Cancer	Prexasertib	18 Years -	Eli Lilly and Company
A Phase 1/2 Trial of SRA737 in Subjects With Advanced Cancer	NCT02797964	Advanced Solid ...	SRA737	18 Years -	Sierra Oncology LLC - a GSK company
A Phase 1/2 Trial of SRA737 in Subjects With Advanced Cancer	NCT02797964	Advanced Solid ...	SRA737	18 Years -	Sierra Oncology LLC - a GSK company

Spots Global Cancer Trial Database for replication stress