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Prexasertib

Protein Kinase Inhibitors

Enzyme Inhibitors

Prexasertib (LY2606368) monotherapy treatment

105 mg/m\^2 intravenous (IV) once every 14 days of a 28 day cycle

LY2606368

Jung-Min Lee, M.D.

Background:

* All cells go through cycles which allow them to divide. In normal cells, checkpoint kinase 1 (Chk1) and checkpoint kinase 2 (Chk2) (CHEK 2 (Chk1/2) stop cell division at various points to allow any damage to deoxyribonucleic acid (DNA) to be repaired.
* When Chk1/2 are not present, cells stop dividing and eventually die. Chk1/2 Inhibitor (Prexasertib (LY2606368) blocks the Chk1/2 proteins.
* Researchers hope that by blocking Chk1/2, it will cause tumor cells to die, thereby shrinking tumors.

Objective:

- To see if LY2606368 helps shrink tumors in patients with certain breast, ovarian or prostate cancers.

Eligibility:

- Participants at least 18 years old with breast or ovarian cancer. They must have a mutation in BRCA1 BReast CAncer gene 1 and BRCA2 BReast CAncer gene 2 (BRCA1/2) genes for group 1, high grade serious ovarian cancer without BRCA1/2 mutation for group 2, or triple negative breast cancer without BRCA1/2 mutation for group 3, or prostate cancer with or without BRCA1/2 mutation for group 4.

Design:

* Participants will be screened with a medical history and physical exam. They will have blood tests, an electrocardiogram (ECG) heart test, scans, and X-rays. They will have a piece of their tumor removed at entry (computed tomography (CT)-assisted biopsy).
* Study Day 1: Participants will have a physical exam and blood drawn. They may have a CT scan of the chest, abdomen, and pelvis.
* Day 1 and Day 15 of each 28-day cycle: Participants will receive the study drug through an intravenous (IV).
* Vital signs will be checked before and after. An ECG will be done within 1 hour after.
* Day 15 and Day 28: Participants will have a physical exam, blood drawn, and a 12 lead ECG.
* Cycle 1: Participants will have weekly phone calls and blood draws. Participants may have another CT-assisted biopsy at the end of cycle 1.
* Cycle 2 and beyond, blood will be drawn every other week for routine blood tests.
* Participants will have an after-study visit with a physical exam and blood tests. Participants may have another biopsy when they progressed on treatment. They will have scans of the chest, pelvis, and abdomen and a 12 lead ECG.

Background:

* Checkpoint kinases 1 and 2 (Chk1/2) are major regulators of the cell cycle and are intimately associated with the cellular response to deoxyribonucleic acid (DNA) damage and repair. Chk1/2 also function as the primary mediators of cell cycle arrest in tumors with tumor protein P53 (p53) dysfunction, such as high-grade serous ovarian cancer (HGSOC), and triple negative breast cancer (TNBC).
* Participants with germline BRCA1 BReast CAncer gene 1 and BRCA2 BReast CAncer gene 2 (BRCA1/2) mutation have inherent defects in DNA damage repair pathways.
* Chk1/2 inhibition alone yielded DNA damage and mitotic catastrophe preclinically, even in the absence of DNA damage by external agents in tumors with underlying DNA repair dysfunction.
* The second-generation Chk1/2 inhibitor (Prexasertib (LY2606368) yielded safety and preliminary single agent activity in advanced cancer participants.
* We hypothesize that LY2606368 will result in clinical benefit in participants with Germline BRCA-Mutated (gBRCAm)-associated breast or ovarian cancers, and HGSOC and TNBC with low genetic risk.

Objectives:

* To determine the objective response rate (Complete Response (CR)+Partial Response (PR) of single agent LY2606368 in patients with gBRCAm-associated breast or ovarian cancer, HGSOC and TNBC with low genetic risk.
* To determine the safety and toxicity, and progression-free interval (PFI) of LY2606368 in pretreated participants.
* To determine biochemical changes in the DNA damage repair and cell cycle check point pathways in tumor and blood samples in response to treatment.
* To determine potential resistance mechanisms to LY2606368 treatment in HGSOC.

Eligibility:

* Participants with recurrent/refractory BReast CAncer gene (BRCA) mutant breast or ovarian cancer, HGSOC, and TNBC, for whom there remains no standard curative measures.
* A documented deleterious germline or somatic BRCA mutation for breast or ovarian cancer participants enrolling in Cohort 1.
* Negative BRCA mutation testing or negative family history of hereditary breast and ovarian cancer syndrome for HGSOC (Cohort 2).
* Negative BRCA mutation testing or negative family history of hereditary breast and ovarian cancer syndrome for TNBC (Cohort 3).
* Effective with amendment I (version date 4/24/2017), Metastatic Castration-Resistant Prostate Cancer (mCRPC), Cohort 4 was closed.
* Negative BRCA mutation testing or negative family history of hereditary breast and ovarian cancer syndrome for recurrent platinum-resistant HGSOC with measurable and biopsiable disease (Cohort 5).
* Negative BRCA mutation testing or negative family history of hereditary breast and ovarian cancer syndrome for recurrent platinum-resistant HGSOC with measurable but without biopsiable disease (Cohort 6).
* Participants must be off prior chemotherapy, radiation therapy, hormonal therapy, or biological therapy for at least 4 weeks.
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2 and adequate organ and marrow function.

Design:

* This is an open label, single arm phase II trial to examine activity of LY2606368 in participants in the 6 independent cohorts (Cohorts 1-6).
* LY2606368 will be dosed at the recommended phase 2 dose (RP2D) of 105 mg/m\^2 intravenous (IV) once every 14 days of a 28 day-cycle.
* Research samples including whole blood, circulating tumor cells (CTCs), and tumor biopsies will be obtained for pharmacodynamics (PD) endpoints at baseline, Cycle 1 Day 15 (6-24hour (hr) post-2nd dose), and/or at progression in all participants. Tumor biopsies will not be performed in Cohort 6.
* Participants (Cohorts 1-3, 5 and 6) will be evaluated every two cycles for response using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and every cycle for safety using Common Terminology Criteria for Adverse Events (CTCAE) v4.0.

A Phase II Single Arm Pilot Study of the Chk1/2 Inhibitor (LY2606368) in BRCA1/2 Mutation Associated Breast or Ovarian Cancer, Triple Negative Breast Cancer, High Grade Serous Ovarian Cancer, and Metastatic Castrate-Resistant Prostate Cancer

A Phase II Single Arm Pilot Study of the Chk1/2 Inhibitor (LY2606368) In BRCA1/2 Mutation Associated Breast or Ovarian Cancer, Triple Negative Breast Cancer, and High Grade Serous Ovarian Cancer

For All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request.

In addition, all large-scale genomic sequencing data will be shared with subscribers to database of Genotypes and Phenotypes (dbGaP).

Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Objective response (CR+PR) of single agent Prexasertib (LY2606368) in participants with germline BReast CAncer gene -Mutated (gBRCAm)-associated breast and ovarian cancers, high grade serous ovarian cancer (HGSOC) and triple-negative breast cancer (TNBC) at low genetic risk. Response was measured using the Response Evaluation Criteria in Solid Tumors (RECIST)v1.1. Complete Response is disappearance of all target lesions. Partial Response is at least a 30% decrease in the sum of diameters of target lesions.

National Cancer Institute (NCI)

Principal Investigator

Cohorts 5 \& 6 are combined because they are for platinum resistant BRCA wild type high grade serous ovarian cancer (HGSOC) participants, literally the same population. Only difference between the two cohorts is cohort 5 is a research biopsy cohort \&cohort 6 had no safely biopsiable disease. Given that Eli Lilly prematurely terminated the study we could not enroll enough number of participants for both cohorts. Thus, it is appropriate and scientifically relevant to report the data in one group.

All participants received Prexasertib (LY2606368) 105 mg/m\^2 on dose level 1.

Cohort 1 Breast/Ovarian Breast Cancer (BRCA) Mutation Positive

All participants received Prexasertib (LY2606368) 105 mg/m\^2 on dose level 1, except six participants who received Prexasertib 105 mg/m\^2 on dose level 1 followed by 80 mg/m\^2 on dose level -1. And one participant did not receive drug.

Cohort 2 Breast/Ovarian Breast Cancer (BRCA) Wild-Type (wt) Cohort

All participants received Prexasertib (LY2606368) 105 mg/m\^2 on dose level 1, except two participants who received Prexasertib 105 mg/m\^2 on dose level 1 followed by 80 mg/m\^2 on dose level -1.

Cohort 3 Breast Cancer (BRCA) Wild-Type (wt) Triple Negative Breast Cancer

One participant received Prexasertib (LY2606368) 105 mg/m\^2 on dose level -1 followed by Prexasertib 80 mg/m\^2 on dose level -1. And one participant received Prexasertib 105 mg/m\^2 on dose level 1.

Cohort 4 Castration-resistant Metastatic Prostate

All participants received Prexasertib (LY2606368) 105 mg/m\^2 on dose level 1, except six participants in cohort 5 received Prexasertib 105 mg/m\^2 on dose level 1 followed by 80 mg/m\^2 on dose level -1. And three participants on cohort 6 received Prexasertib 105 mg/m\^2 on dose level 1 followed by 80 mg/m\^2 on dose level -1.

Cohorts 5 and 6 Ovarian Breast Cancer (BRCA) Wild-Type (wt) Platinum-resistant

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Cohorts 5 \& 6 are combined because they are for platinum resistant BRCA wild type high grade serous ovarian cancer (HGSOC) participants, literally the same population. Only difference between the two cohorts is cohort 5 is a research biopsy cohort \& cohort 6 had no safely biopsiable disease. Given that Eli Lilly prematurely terminated the study we could not enroll enough number of participants for both cohorts. Thus, it is appropriate and scientifically relevant to report the data in one group.

Dr. Jung-min Lee

Complete Response

Partial Response

Cohorts 5 and 6 are combined because they are for platinum resistant BRCA wild type high grade serous ovarian cancer (HGSOC) participants, literally the same population. Only difference between the two cohorts is cohort 5 is a research biopsy cohort and cohort 6 had no safely biopsiable disease. Given that Eli Lilly prematurely terminated the study we could not enroll enough number of participants for both cohorts.

All participants received Prexasertib (LY2606368) 105 mg/m\^2 on dose level 1, except six participants in cohort 5 received Prexasertib 105 mg/m\^2 on dose level 1 followed by 80 mg/m\^2 on dose level -1. And three participants on cohort 6 received Prexasertib 105 mg/m\^2 on dose level 1 followed by 80 mg/m\^2 on dose level -1.

Overall, 17 participants were not evaluable for this outcome measure. Overall participants analyzed adjusted to include only evaluable subjects as defined by the protocol (i.e., only those participants who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated; Response Evaluation Criteria in Solid Tumors (RECIST) Evaluable).

Objective Response (Complete Response (CR) + Partial Response (PR)

All participants received Prexasertib (LY2606368) 105 mg/m\^2 on dose level 1, except four participants in cohort 5 received Prexasertib 105 mg/m\^2 on dose level 1 followed by 80 mg/m\^2 on dose level -1. And one participant on cohort 6 received Prexasertib 105 mg/m\^2 on dose level 1 followed by 80 mg/m\^2 on dose level -1.

Cohorts 5 and 6 Breast Cancer (BRCA) Wild-Type (wt) Platinum Resistant Cohort

Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0).

Overall Study

Antineoplastic Agents

Cisplatin

Vinblastine

Tubulin Modulators

Antimitotic Agents

Part I: Patients will receive up to 3 doses of INT230-6 injected weekly prior to breast surgery

Part II: Patients will receive up to 2 intratumoral doses of INT230-6 (over a 15-day period) prior to breast surgery

Part I: No intervention while awaiting surgery

Part II: Placebo saline injection

INT230-6 is a formulation of two well known chemotherapeutic agents, cisplatin (0.5mg/mL) and vinblastine sulfate (0.1mg/mL), combined with 2-hydroxybenzoylaminooctanoate (also known as SHAO-FA or SHAO as a sodium salt at 10mg/mL).

INT230-6

Saline injection

Angel Arnaout, MD

Arif Awan, MD

This is a phase II, randomized, multi-center, parallel design, window of opportunity trial evaluating intratumoral INT230-6 in up to 90 patients with early stage breast cancer. In a 2:1 randomization, patients on the treatment arm will receive intratumoral INT230-6 injections prior to breast surgery.

The study comprises 2 consecutive parts. The first part will be to test safety and feasibility of the dosing procedures. Results from Part I of the study will standardise the optimal dose and frequency of INT230-6 for participants in Part II.

Part I: Open-label 2:1 randomized study of up to 30 patients. Treatment arm patients will be given up to 3 doses of INT230-6 injected weekly prior to breast surgery, at a dose based on longest diameter. The control arm patients receive no treatment.

Part II: Double-blind, 2:1 randomized study of up to an additional 60 patients. The placebo arm includes a saline injection of similar dose and frequency as the treatment arm (up to 2 doses of INT230-6/saline injected weekly prior to breast surgery).

INVINCIBLE TRIAL: Intratumoral INT230-6 in Breast Cancer

A Phase II Randomized Window of Opportunity Trial Evaluating Clinical and Biological Effects of Intratumoral INT230-6 in Early Stage Breast Cancer: The INVINCIBLE Trial

Tumor's viable plus necrotic tissue, at the post-treatment specimen.

Assessed by the local pathologist at the time of definitive surgery in subjects with breast cancer

Comparison of pre (diagnostic biopsy) and post treatment (surgical resection) samples

overall safety of INT230-6 injected prior to surgery

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Phase II Single Arm Pilot Study of the Chk1/2 Inhibitor (LY2606368) in BRCA1/2 Mutation Associated Breast or Ovarian Cancer, Triple Negative Breast Cancer, High Grade Serous Ovarian Cancer, and Metastatic Castrate-Resistant Prostate Cancer	NCT02203513	Ovarian Cancer Breast Cancer Prostate Cancer	LY2606368	18 Years -	National Institutes of Health Clinical Center (CC)
A Phase II Single Arm Pilot Study of the Chk1/2 Inhibitor (LY2606368) in BRCA1/2 Mutation Associated Breast or Ovarian Cancer, Triple Negative Breast Cancer, High Grade Serous Ovarian Cancer, and Metastatic Castrate-Resistant Prostate Cancer	NCT02203513	Ovarian Cancer Breast Cancer Prostate Cancer	LY2606368	18 Years -	National Institutes of Health Clinical Center (CC)
INVINCIBLE TRIAL: Intratumoral INT230-6 in Breast Cancer	NCT04781725	Breast Cancer	INT230-6 Saline injectio...	-	Ottawa Hospital Research Institute

Spots Global Cancer Trial Database for cell cycle arrest